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Social Campaigns for Protecting Natural Resources: The Case of Poland

The quality of business model disclosure in integrated reporting: evidence from poland, evaluation of selected methods for the construction of sustainable energy development index: application for european union member states, convection and radiation as important metropolitan functions in a penitential system, health literacy and its role in relational communication with patients: the study of literature and concepts, impact of personal branding on the development of professional careers of managers, the negotiated settlement of the crisis and the cash flows of large unlisted italian companies, social attitudes towards the phenomenon of corruption in poland, the homogenization of carbon management practices: how organizations response to isomorphic pressures to reduce ghg emissions, the logistics 4.0 implementation supported by the balanced scorecard method, export citation format, share document.

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Co-creating smart cities – design thinking for 21st century urban planning.

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- European Research Studies Journal - Year 2022

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• Volume 31, Issue 3
• Safe handling of cytostatic drugs: recommendations from independent science
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• http://orcid.org/0000-0002-4929-2388 Mirjam Crul 1 ,
• oscar Breukels 2
• 1 Clinical Pharmacology and Pharmacy , Amsterdam UMC Locatie VUmc , Amsterdam , The Netherlands
• 2 Hospital Pharmacy , Meander Medisch Centrum , Amersfoort , The Netherlands
• Correspondence to Dr Mirjam Crul, Clinical Pharmacology and Pharmacy, Amsterdam UMC Locatie VUmc, Amsterdam, Noord-Holland, Netherlands; m.crul{at}vumc.nl

Objectives Due to their mechanism of action, most classical cytostatic drugs have carcinogenic, mutagenic and/or reprotoxic properties. Therefore, occupational exposure of healthcare staff to these drugs should be prevented. Our objective was to lay out European legislation on this topic and reflect on the process of revising the European CM-directive. We summarise independent European and Dutch studies, and give a concise set of basic recommendations for safe working with cytotoxic drugs in healthcare facilities.

Methods We were directly involved in the process of revising the CM-directive: first, through an EU commissioned workshop in the Netherlands, and after that by contributing to the pan-European stakeholder symposium. For this aim, we had to gather the relevant study data from the Netherlands and from Europe. We analysed all relevant industry-independent studies and collated a set of basic recommendations.

Results Independent studies show that the development of measures in recent years can lead to a safe work environment. Standardising the cleaning process leads to a significant improvement in environmental contamination in the majority of hospitals. In the Netherlands, exposure of workers was shown to be well beneath the limit value of 0.74 µg cyclophosphamide per week, therefore showing that the measures taken in recent years are adequate.

Conclusions The safety of healthcare workers is of the utmost importance. Current practice in the Netherlands show that measures taken in recent years are adequate. European legislation should be based on independent scientific research and practice. The first goal should be to bring countries with less safe working levels to a higher level instead of introducing measures that only increase healthcare budgets but not healthcare safety.

• antineoplastic agents
• occupational medicine
• practice guideline
• international health regulations

Data availability statement

Data are available upon reasonable request. Data are available based on the data use agreement policies of Amsterdam UMC hospital. Data from this study are available on reasonable request by sending an email message to the corresponding author.

https://doi.org/10.1136/ejhpharm-2022-003469

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Prevention of exposure of healthcare workers to cytostatic drugs is pivotal in providing a safe working environment. How to achieve this is not regulated centrally in Europe.

WHAT THIS STUDY ADDS

With the upcoming revision of the European legislation, data from independent science should be used to provide centralised guidance on safe handling practices. We report on the scientifically proven measures that can be taken to improve worker safety.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

Decision-making on a European level can be influenced by lobbying of companies that have financial gain as their primary aim. Data from independent science presented in this paper show which mitigating strategies to improve worker safety should be taken.

Introduction

Classical cytostatic drugs are inherently toxic, due to their mechanism of action. Accordingly, almost all of these drugs are ‘CMR substances’, which means that they have carcinogenic, mutagenic, and/or reprotoxic properties. For a number of substances, the European Chemical Agency has set an occupational exposure limit (OEL), previously known as maximum allowable concentration in air at the workplace (MAC). 1 However, exposure can occur via several different routes: via ingestion, via the eye, via inhalation, and via the skin. 2 3 OEL values only indicate limits for possible inhalation. In fact, cytostatic drugs in nursing wards are not usually administered as dry powders but as solutions in an infusion or injection, so there is only a small risk of inhalation in this setting. 4 Pharmacy technicians, on the other hand, do handle dry powders. Hence, they should be protected from inhaling these substances by technical measures and personal protective equipment. In general, in hospital practice there is only a negligible risk of exposure via ingestion or via the eye, so exposure via the skin is considered to be the greatest risk. 2 4 The at-risk staff in this regard are nurses, doctors, pharmacists, pharmacy technicians, and transport and cleaning staff.

The Netherlands has a long history of setting up guidance on safe handling of cytotoxic drugs. We want to share the knowledge gained and experience on this topic with a broader public, laying out practices that can be implemented elsewhere to enhance worker safety.

In this paper, we will lay-out the European legislation on this topic, summarise recent independent European and Dutch studies, and give a concise set of recommendations for safe working with cytotoxic drugs in healthcare facilities.

The European directives comprise the highest form of legislation within the European Union (EU). Member states still have national laws, but these always have to adhere to the general rules set out in the European directives. Member states are allowed to be stricter, but not less strict, than the legal framework of the centralised European directives. European directives are revised and updated periodically. With regards to the current foreseen update of the directive regarding carcinogens and mutagens, we have followed the preparations of that process closely, and have striven for improved guidance on the safety of workers that handle cytotoxic drugs. Additionally, we have learnt that currently the variance of measures in place to protect workers between member states is large. 5–7 To aid decision-making on a European level, we presented the data from independent peer reviewed literature to participants at two workshops commissioned by the EU in 2021. The first one was held in the Netherlands, and was one of five national workshops the European Parliament had ushered. For this workshop, we were asked to give an overview of the Dutch guidelines and the Dutch studies that were done by academia or independent research organisations. Hence, we performed a PubMed and Scopus search using the keywords: ‘cytotoxic’ OR ‘cytostatic’ OR ‘antineoplastic’; ‘contamination’ OR ‘exposure’ OR ‘wipe sample’; ‘Dutch’ OR ‘Netherlands’. Next, we performed the same search for the pan-European workshop without ‘Dutch’ OR ‘Netherlands’. We included only industry-independent studies, that included either an active intervention with before and after measurements, or that compared contamination levels in different hospitals that use different working procedures from Europe.

In this paper, we present the data from the literature we found, after giving an outline of the legislative framework.

European legislative framework

In daily healthcare practice, ‘CMR’ is used as a handle to define the hazards of specified drugs. 8 European legislation, however, is different. In that context, cytotoxic substances fall under the directive on the protection of workers from the risks related to exposure to carcinogens or mutagens at work, 9 but reprotoxic substances do not. On further enquiry with the Directorate of Employment of the EU, the difference appears to derive from the assumption that reprotoxicity has a limit value beneath which exposure is safe. However, this may not be the case for carcinogenic and mutagenic substances. In the case of healthcare staff though, with a large number of young individuals, reprotoxicity is at least as important to prevent as carcinogenicity or mutagenicity. 10 The directive on the protection of workers from the risks related to exposure to carcinogens or mutagens at work 9 was drawn up 16 years ago and is now in need of revision. The directive on safety for pregnant workers and workers who have recently given birth or are breastfeeding 11 is even older. The guidelines in these directives do not specifically describe handling of drug products. They are based on two key principles of occupational hygiene though, that are applicable in any situation where a potential hazard is present: (1) the occupational hygiene strategy, which starts by tackling the source (if possible), followed by collective measures (eg, technical measures such as the use of special safety cabinets and the use of infusion systems fitted only with needleless connectors, centralising the preparation of cytostatic drugs in the pharmacy, and using clear hazard pictograms and labels), followed by individual measures (eg, rotation of tasks), and finally personal protective equipment such as gloves and aprons; (2) the precautionary principle—if a substance is suspected of being harmful, based only on a limited amount of scientific evidence, measures should nevertheless be taken without delay and, for safety reasons, efforts must be made to minimise any exposure.

European studies

Many related European studies were published during the period from 2000 to 2010, in particular. The literature search yielded 112 results, from which 12 met the criteria (being industry-independent, from Europe, and including an intervention to reduce contamination or exposure or comparing different settings). These studies mainly focused on environmental contamination. For example, a study group from Munich published results of 24 German hospitals participating in a wipe sampling study. They found that, overall, 60.9% of all wipes (n=375) were positive for one or more cytotoxics. When looking into work practices in the participating hospitals, a significant positive effect of the use of multi-way infusion systems was found on the amount of contamination. 12 Another German study also showed widespread surface contamination in a clinical oncology ward (116 wipe samples were tested), but found no evidence of internal exposure in urine from workers, when gloves were regularly worn. 13 In a study from the Czech Republic (Czechia), a combination of measures aimed at standardising and improving cleaning procedures, both in the pharmacy and on the wards, resulted in effectively lowering surface contamination levels. 14 Cleaning optimisation comprised three changes to the earlier routine: establishing a cleaning order from the cleanest to the dirtiest spots, cleaning the outside of incoming vials and cleaning work tables every 2 hours with 50% l-isopropanol in water. 14

These were all single-centre or single-country studies though, and many studies that were published, in addition to the ones mentioned above, were excluded because they were sponsored by the manufacturers of medical devices.

As yet, it has not been possible to translate contamination of the environment and of surfaces directly into actual cancer risks for staff. 15 One reason for this is that different substances have different physico-chemical properties (a substance’s ability to detach from a surface depends both on the substance itself and on the surface; furthermore some cytostatic drugs are more readily absorbed via the skin than others). Another reason is that very large-scale epidemiological studies are needed to quantify late health risks.

To conduct an independent comparative study, the European Society of Oncology Pharmacy (ESOP) has launched the MASHA (Research about Environmental Contamination by Cytotoxics and Management of Safe Handling Procedures) project. The first MASHA study spanned 15 hospitals in 11 European countries ( figure 1 ). It involved an extensive questionnaire on the (cleaning) procedures and tools used in each hospital, in combination with standardised surface wipe sampling, and an intervention. For the purposes of this study, three series of 10 surface wipe samplings were performed per hospital (five in the pharmacy and five in a nursing ward). The first series was a baseline measurement. This was followed by a training course on risks and risk management for staff from the participating hospitals. In addition, a standardised cleaning protocol was universally implemented, consisting of daily cleaning of exposed surfaces with 70% isopropanol or ethanol and a weekly extra cleaning with an alkaline solution of 0.05 mol/L sodium hydroxide. The second series was performed immediately after this intervention, and the third series followed a year later. Environmental contamination was found in all of the participating hospitals. The level of contamination for the samples that were used in the baseline measurement was found to be 20%. This figure dropped to 14% after the intervention ( figure 2 ), at which point 70% of the hospitals showed a statistically significant improvement in the number of positive samples as well as in the degree of contamination. The most contaminated locations were the areas of floor directly beneath infusion poles in the nursing wards. An extensive analysis of hospital variables was performed to see if there were any associations between the number of contaminated samples/degree of contamination and specific hospital characteristics and working practices. This showed that the number of chemotherapy treatments that were prepared and administered annually was not a factor. Furthermore, the use of closed-system drug-transfer devices (CSTDs) showed no statistical benefit over the use of spikes (small plastic devices that prevent aerosol formation via a built-in filter and also prevent needle prick injuries). In fact, the hospitals with the highest contamination levels were hospitals where CSTDs were used. The only variable that showed a statistically significant correlation was the use of special chemotherapy infusion sets, with needleless connectors and infusion bags that have a side line filled with a neutral solution attached. 7 These infusion sets are mandatory in the Netherlands, where they are used by every hospital in the country. The results of the second MASHA study are currently being processed. That study, which focuses on environmental contamination in oncology nursing wards, is being carried out in cooperation with the European Society of Medical Oncology (ESMO).

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Hospitals participating in the MASHA (Research about Environmental Contamination by Cytotoxics and Management of Safe Handling Procedures) project. Reprinted with permission from Korczowska et al. 7

Contamination results in the MASHA (Research about Environmental Contamination by Cytotoxics and Management of Safe Handling Procedures) project. BSC, Biological Safety Cabinet reprinted with permission from Korczowska et al 7 .

Examples from the Netherlands

The literature search yielded 24 results, of which eight met the criteria (industry-independent and multicentric). We used these eight in the national workshop in the Netherlands.

The Netherlands was one of the first countries in Europe to start drawing up guidelines to protect health workers against exposure to cytostatic drugs. The first guideline was written in 1992 by the Netherlands Comprehensive Cancer Organisation, 16 and has been periodically revised on the basis of new knowledge. The results of a study into reprotoxic effects among oncology nurses in the Netherlands were published in 1999. 17 This study found that oncology nurses had a longer time to conception than nurses working in other specialisms (ie, surgery). The former were also found to have an increased rate of premature deliveries and an increased rate of newborns with a low birth weight. These findings accelerated the development and implementation of effective precautionary measures to prevent exposure by the hospitals as well as by the authorities in the years after these results were published. In 2001, the Ministry of Employment issued a Working Conditions Policy Rule under the Dutch working conditions act 18 that included binding regulations for any staff who could come into contact with cytostatic drugs in hospitals. This Working Conditions Policy Rule was replaced in 2004 by a Working Conditions Covenant (a sector-wide agreement). In 2009, that covenant was replaced by the current Occupational Health and Safety Catalogues. 19 20 Finally, in 2018, the Occupational Health and Safety Catalogues’ guidelines were translated into specific working instructions by a multidisciplinary working group. Details of these working instructions can be found at the website containing all Dutch medical guidelines called ‘richtlijnendatabase’. 21 Based on the above mentioned 1999 study of fertility effects among nurses, a limit value has been derived for the occurrence of reprotoxicity. This value has been calculated for cyclophosphamide, a cytostatic drug in relatively common use that is known to persist in the environment for a relatively long period of time. This makes it an effective worst-case marker substance. This tentative limit value is 0.74 µg cyclophosphamide skin contamination per week. 22

Since 2000, several studies have been conducted in the Netherlands into the safe handling of cytostatic drugs. In 2009, at the request of the Dutch Association of Hospital Pharmacists (NVZA), the Netherlands Organisation for Applied Scientific Research (TNO) conducted a study into the risks associated with handling cytostatic drugs in Dutch hospital pharmacies. 23 This study showed that these drugs can be handled safely without the need for a negative air pressure cleanroom (which had previously been mandatory). However, it did report a potential risk of cytostatic drug carry-over from one room to another. This risk was subsequently investigated by analysing a database containing the results of surface wipe sampling over a 10-year period (2001–2011) at nine different hospitals. During this period, the set of safety guidelines was amended in 2004. After 2004, compounding with spikes, in a dedicated cleanroom with safety cabinets or isolators by trained staff, was mandatory. The study showed that the incidence of contamination in areas outside the preparation areas amounted to a total of 6%, and that these no longer occurred after 2008. 24 This shows that it is likely that the full effect of issuing guidelines only becomes visible after time for implementation is allowed, but that these guidelines were able to reduce contamination. The risk of carry-over from inside the compounding rooms to adjacent areas in the Netherlands is extremely small. Another study, performed in 2017, focused on the risk of contaminating the exterior surfaces of prepared cytostatic drug infusions. In this perspective, a study carried out in eight hospitals examined the exterior surfaces of a total of 146 5-fluorouracil infusions by means of surface wipe sampling. None of the infusion bags were found to have contamination on their external surfaces. 25

The largest Dutch study was carried out in six different hospitals by the Dutch Occupational Hygiene Society, in cooperation with the Dutch Association of Hospital Pharmacists in 2014. In this study, actual skin exposure to cytostatic drugs was measured in nurses, pharmacy technicians, and cleaning staff by taking hand-wash samples after these individuals had completed their routine activities. The hand-wash samples were tested for the presence of eight different cytostatic drugs. Weekly exposure to the marker substance (cyclophosphamide) was calculated. The average weekly exposure was 0.12 µg for nurses, 0.05 µg for pharmacy technicians, and 0.03 µg for cleaning staff. All of these are well below the limit value of 0.74 µg. The values -per task were also compared with those from previous studies, carried out from 2001 to 2003 ( table 1 ). It was found that the average exposure had decreased by a factor of 10.

Average exposure is important, but so is the risk of peak exposures. Accordingly, Monte Carlo simulations were used to calculate the risk of exceeding the limit value. Here, a risk of ≤5% serves as a statistically acceptable cut-off limit. The risks of nurses and cleaning staff exceeding the limit values were 3.6% and 3.1%, respectively. However, pharmacy technicians had a risk of 9.7%, which was much higher. 26 A follow-up study was carried out in 2017, to investigate the cause of this discrepancy. In addition to taking a larger number of hand-wash samples from pharmacy technicians, this study involved a further analysis of potential contamination in relation to the tasks these individuals performed. The study found that the preparation process itself resulted in low-level contamination and a low risk of exceeding the limit values. However, the preparatory tasks (collecting vials and materials in the preparation area) led to an excessively high level of contamination if gloves were not worn when performing such tasks. 27 In the literature, one commonly cited fact is that contaminants are present on the external surfaces of cytostatic drug vials when these products leave the factory. 28 Yet, the Dutch Occupational Health and Safety Catalogues do not include an obligation to wear gloves when performing preparatory tasks. These preparatory tasks involve removing cytostatic drug vials from the outer packaging. Accordingly, it is very likely that the higher value found in the hand-wash study was due to contamination of the vials’ external surface with cytostatic drugs. This exposure route can easily be eliminated by consistently wearing gloves when handling vials.

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Cyclophosphamide contamination on the hands (µg/task). Reprinted with permission from van Rooij and Hilhorst 26

The CM-directive (Directive 2004/37/EC of the European Parliament and of the Council on the Protection of Workers from the Risks Related to Exposure to Carcinogens or Mutagens at Work) is up for revision in 2023 or 2024. In the run-up to that process, the producers of CSTDs are lobbying strongly to get their devices included in the guidelines, 29 despite the lack of independent scientific evidence to support their added value compared with the method of using spikes, 30 the higher costs for healthcare systems when implementing CSTDs, 31 and the emerging evidence that, in some cases, CSTDs can compromise the quality of drug products through particle formation. 32 33 Following persistent pressure from professional associations such as the European Oncology Nursing Society (EONS), European Cancer Organisation (ECO) and ESOP, the Directorate-General of Employment, Social Affairs and Inclusion of the EU launched an investigation to study the current situation in its member states. This involved a comparison of the national guidelines used by all of the member states and visits to five of these countries (Netherlands, Spain, Portugal, Poland and Romania). Unfortunately, here too, there might be more evidence of this lobby’s power to influence events in Europe. This is because the report 34 makes no mention of what was discussed at the closing conference: good safety measures such as training and education, or using flushing lines, or standardising cleaning protocols, which are measures that can be installed without high costs. Furthermore, when the report was published, it transpired that the individuals it had referred to as experts had not, in fact, been consulted on its text. Finally, disclosures of the reports’ authors on financial ties with industries that have potential interests in the topic were not provided.

There is substantial variation between individual European countries, with a prominent east-west divide. In at least five eastern European countries, cytostatic drugs are prepared by nurses, in nursing wards (data on file, ESOP). Sometimes, even no use is made of protective measures, such as safety cabinets. Furthermore, these drugs are administered without adequate gloves or needleless systems. Here, there appears to be a great need for the EU to harmonise measures. Rather than tightening measures in richer countries still further, it should help less prosperous European regions to launch procedures that are already routinely used in the west, and which lead to safe working conditions. Hopefully, the recently published tender from the EU, calling for applicants who wish to be engaged in writing guidance on the safe handling of hazardous medicinal products, 35 will result in equal safe working conditions for all healthcare staff in all European countries.

In conclusion, recommendations based on independent scientific studies are available and have been implemented in the Dutch Safety Catalogues. 19 20 These are summarised in box 1 and most are also described in the Quapos guidelines from the European Society of Oncology Pharmacy. 36 With regard to further safety improvements, the use of hand protection during preparatory procedures that include handling of cytostatic drug vials merits special attention. Independent research from the Netherlands shows that compliance with the set of measures given in box 1 is sufficient to enable cytostatic drugs to be handled safely. 26 , 27 Therefore, the EU’s goal should be to bring countries with less safe working environments to the same level.

Recommendations on safe handling of cytotoxic drugs 19 20 36

Training and education

Provide training for each staff member that can come into contact with cytotoxic drugs on risks, risk management and safe handling practices

Provide training for each staff member that can come into contact with cytotoxic drugs on how to act in case of accidents and spills

Provide each area where cytotoxics are handled with a spill kit and written instructions on how to act in case of accidents and spills at hand

Receipt, transport and storage

Label all cytotoxic drugs with an adequate warning sign (the yellow hand)

Never touch primary packaging without wearing protective gloves

Transport cytotoxic drugs in a sealed secondary packaging

Compounding

Compound in a separate, dedicated room with entry through a lock

Compound in a safety cabinet or isolator with negative pressure

Do not recirculate air from the safety cabinet or isolator into the room or hospital ventilation system (0% recirculation principle)

Compound using spikes

Wear adequate gloves and gowns with full length sleeves and cuffs that have been tested and proven to protect against cytotoxic substances

Dispense compounded cytotoxic drugs with a barrier that prevents exposure of the administrating staff: a side-line or multi-way connector set filled with a neutral fluid

Administration

Use dedicated area’s for administration of cytotoxic drugs

Use multi-way infusions sets with needle-free luer lock connections

After administration: rinse and dismount the infusion set as a whole

Never crush oral cytotoxic drugs in an open mortar. Let oral cytotoxics dissolve in a closed compartment such as a syringe for patients who are tube-fed or have difficulty swallowing

Care for patients treated with cytotoxics

Use dedicated areas for care of patients who are treated with cytotoxic drugs

Assign dedicated toilets and sanitary areas to patients who are treated with cytotoxic drugs

Take the period in which excreta are contaminated into account:

Wear gloves and gowns when handling excreta of patients who are still in the contaminated period

Do not decant urine of patients who are in the contaminated period

Use gloves and gowns when washing patients who are in the contaminated period

Cleaning and disposal

Use a written cleaning protocol that includes:

The use of dedicated cleaning sets for all areas where cytotoxic drugs are handled

Cleaning from the cleanest to the dirtiest spot

Check the efficacy of the cleaning protocol by taking periodic wipe samples

Use adequate personal protective equipment when cleaning: always gloves and gowns in case of wet cleaning

Dispose of any material that might be contaminated with cytotoxic drugs or residues via dedicated cytotoxic waste bins.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

Acknowledgments.

We thank Falko Schüllner and Joan Peppard for critically reading the manuscript and providing us with relevant feedback.

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EAHP Statement 3: Production and Compounding.

Contributors Acquisition of the data: OB and MC. Writing of the manuscript: OB and MC. Guarantor MC

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Map disclaimer The depiction of boundaries on the map shown in figure 1 does not imply the expression of any opinion whatsoever on the part of BMJ (or any member of its group) concerning the legal status of any country, territory, jurisdiction or area or of its authorities. This map is provided without any warranty of any kind, either express or implied.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

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Volume 14, issue 1, December 2022

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A scoping review of academic and grey literature on migrant health research conducted in Scotland

• G. Petrie 1 ,
• K. Angus 2 &
• R. O’Donnell 2  

BMC Public Health volume  24 , Article number:  1156 ( 2024 ) Cite this article

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Migration to Scotland has increased since 2002 with an increase in European residents and participation in the Asylum dispersal scheme. Scotland has become more ethnically diverse, and 10% of the current population were born abroad. Migration and ethnicity are determinants of health, and information on the health status of migrants to Scotland and their access to and barriers to care facilitates the planning and delivery of equitable health services. This study aimed to scope existing peer-reviewed research and grey literature to identify gaps in evidence regarding the health of migrants in Scotland.

A scoping review on the health of migrants in Scotland was carried out for dates January 2002 to March 2023, inclusive of peer-reviewed journals and grey literature. CINAHL/ Web of Science/SocIndex and Medline databases were systematically searched along with government and third-sector websites. The searches identified 2166 journal articles and 170 grey literature documents for screening. Included articles were categorised according to the World Health Organisation’s 2016 Strategy and Action Plan for Refugee and Migrant Health in the European region. This approach builds on a previously published literature review on Migrant Health in the Republic of Ireland.

Seventy-one peer reviewed journal articles and 29 grey literature documents were included in the review. 66% were carried out from 2013 onwards and the majority focused on asylum seekers or unspecified migrant groups. Most research identified was on the World Health Organisation’s strategic areas of right to health of refugees, social determinants of health and public health planning and strengthening health systems. There were fewer studies on the strategic areas of frameworks for collaborative action, preventing communicable disease, preventing non-communicable disease, health screening and assessment and improving health information and communication.

While research on migrant health in Scotland has increased in recent years significant gaps remain. Future priorities should include studies of undocumented migrants, migrant workers, and additional research is required on the issue of improving health information and communication.

Peer Review reports

The term migrant is defined by the International Organisation for Migration as “ a person who moves away from his or her place of usual residence, whether within a country or across an international border, temporarily or permanently, and for a variety of reasons. The term includes several well-defined legal categories of people, including migrant workers; persons whose particular types of movements are legally-defined, such as smuggled migrants; as well as those whose status are not specifically defined under international law, such as international students.” [ 1 ] Internationally there are an estimated 281 million migrants – 3.6% of the world population, including 26.4 million refugees and 4.1 million asylum seekers – the highest number ever recorded [ 2 ]. The UN Refugee Society defines the term refugee as “ someone who has been forced to flee his or her country because of persecution, war or violence…most likely, they cannot return home or are afraid to do so .” The term asylum-seeker is defined as “someone whose request for sanctuary has yet to be processed.” [ 3 ].

Net-migration to Europe was negative in the 19th century due to higher levels of emigration, however in the mid-20th century immigration began to rise, because of an increase in migrant workers and following conflicts in the Middle East and North Africa [ 4 ]. Current migration drivers include conflicts alongside world-wide economic instability, exacerbated by the Covid-19 pandemic [ 5 ]. Environmental damage due to climate change is expected to inflate the number of asylum seekers entering Europe in future [ 6 ]. The increase in migration to Europe is not a short-term influx but a long-term phenomenon, and European nations must adapt and find solutions to resulting financial, safeguarding and health challenges [ 7 ].

Data on healthcare use by migrants in Europe is variable, which means cross-country comparisons are inadequate [ 8 ]. Many countries do not record migration information within health records and all use disparate criteria to classify migrant status. The lack of comparative data hinders public health surveillance and effective interventions [ 9 ]. Even where information is available, results can be contradictory due to the multifarious migrant population. Migrants have a wide range of origin countries, socio-economic position, age and journeys undertaken which can affect health status [ 10 ].

Migrants initially may have better health than the general population, known as the ‘Healthy Migrant effect’ [ 11 ]. However, health declines with increasing length of residence [ 12 ] and over time to levels comparable with the general population [ 13 ]. Second generation immigrants may have higher mortality than average [ 14 ]. The process of acculturation to the host country, with adoption of unhealthy lifestyle and behaviours, increases the risk for chronic disease [ 15 ]. In addition, inequalities in health of migrants compared to host populations has been confirmed by wide-ranging research [ 16 ].

Host countries may limit healthcare access, with undocumented migrants sometimes only entitled to emergency care [ 17 ]. Even when access is granted, inequitable services can affect quality of care due to language barriers and cultural factors [ 18 ]. Poor working/living conditions and discrimination can exacerbate health inequalities [ 12 ]. Processing facilities for asylum seekers are frequently overpopulated, stressful environments [ 19 ] and threat of deportation, lack of citizenship rights and integration can negatively affect health and access to care [ 20 ]. Undocumented workers are unprotected by health and safety legislation leading to dangerous working conditions and injuries [ 15 ].

A systematic review of migrant health in the European Union (EU) found migrants have worse self-perceived health than the general population [ 21 ]. Research evidence indicates increased prevalence of cardiovascular disease, diabetes, mental health disorders and adverse pregnancy outcomes. Exposure to conflict, harsh travel conditions and suboptimal vaccine programmes can mean higher risk of communicable disease [ 22 ]. Scoping reviews have also been conducted to describe trends within migration health research in the United Kingdom (UK) [ 23 ] and identify gaps for future research agendas in the UK [ 23 ] and in the Republic of Ireland [ 24 ].

Almost three-quarters (73%) of published migration health research in the UK has been conducted in England, focusing primarily on infectious diseases and mental health. There is limited evidence on the social determinants of health, access to and use of healthcare and structural and behavioural factors behaviours that influence migrant health in the UK [ 23 ]. By contrast, a large amount of the migration research conducted in the Republic of Ireland has focused on the social determinants of health, and on health system adaptations, with a paucity of research focusing on improving health information systems [ 24 ].

Migration and Health in Scotland

Immigration to Scotland began to rise in 2003 with the expansion of the EU [ 25 ]. The population in Scotland increased from 5.11 million to 5.47 million between 2005 and 2020 and is predicted to continue rising until 2028 [ 26 ] despite low birth rates, with the increased population resulting from inward migration [ 27 ]. Scotland’s population is becoming more ethnically diverse [ 28 ] and susceptibility to different health conditions varies by ethnic group, which has implications for the planning and provision of health services [ 29 ]. 7% of the current Scottish population are non-UK nationals and 10% were born outside Britain. The commonest countries of origin were Poland, Ireland, Italy, Nigeria and India [ 30 ].

Within Scotland, linking health data to ethnicity is standard in order to monitor and improve health of minority groups [ 31 ]. Ethnic background can differ from country of birth which means migration status cannot be assumed [ 32 ], although health inequalities experienced by migrants often extend to affect all ethnic minority groups [ 33 ]. The Scottish Health and Ethnicity Linkage Study (SHELS) linked census data to health records of 91% of the population which has provided information on mortality and morbidity by ethnic group and country of birth [ 34 ]. SHELS research indicates that the white-Scottish population have a higher mortality rate than other ethnic groups. This may be consequent to the comparatively poor health of the Scottish population relative to other European nations: high mortality rates in the general population may cause a perception that the health of minorities is more advantageous than in reality [ 35 ].

Cezard et al’s [ 13 ] analysis of self-perceived health among people in Scotland found that being born abroad had a positive impact on health status. Health declined with increased length of residence, which may be explained by cultural convergence with the majority population. Allik et al. [ 36 ] compared health inequalities by ethnic background and found that with increasing age, health differences reduced thus people aged over 75 of all ethnicities had similar or worse health status than White-Scottish people. While working-age migrants appear to be healthier than the White Scottish population, it cannot be assumed that in future this would extend to older age groups.

Research has shown deprivation as a cause of heath inequalities among ethnic minority and migrant groups [ 37 ]. The socio-economic status of minority ethnic groups in Scotland is unusual, as most are of similar or higher status than the white-Scottish population [ 38 ]. Therefore, public health interventions targeting deprivation may not address risk-factors for ethnic minorities and migrants [ 36 ]. Further research on determinants of health in migrants can help with planning and design of inclusive policies.

The 2011 census indicated that 50% of immigrants lived in the cities of Edinburgh, Glasgow, and Aberdeen. Glasgow had a greater percentage of non-European immigrants due to participation in the Asylum dispersal programme [ 39 ]. 10% of UK asylum seekers are placed in Glasgow, but records are not kept following approval of asylum claims, therefore the size of the refugee population is unknown [ 40 ]. While immigration is controlled by the British government, in policy areas devolved to the Scottish government, refugees and asylum seekers have more rights than elsewhere in UK, including access to primary healthcare for undocumented migrants [ 40 ]. Despite the mitigating effect of Scottish policies, asylum seekers’ health is worsened by the asylum process and associated poverty, marginalisation, and discrimination [ 40 ]. Health deteriorates with increasing length of time in the asylum system [ 40 ] and asylum seekers and refugees have additional health needs and require enhanced support [ 41 ]. Research on the health needs of asylum seekers in Scotland is required to ensure adequate healthcare.

Aim and objectives

While scoping reviews on migrant health have been carried out in Europe [ 12 ], Ireland [ 24 ] and the UK [ 23 ] none are currently specific to the Scottish context. Given the devolved government of Scotland and demographics described above, a targeted review would help to clarify research priorities, with the aim of improving health and health care within the migrant community in Scotland. This work therefore builds on the published scoping review of migrant health in the Republic of Ireland [ 24 ]. The authors recommend replication of the study in other countries to facilitate cross-country comparison. Our aim was to scope peer-reviewed research and grey literature on migrant health conducted in Scotland and identify any gaps in the evidence. Our objectives were to: [1] understand the extent of the available research by topic area [2] summarise the types of research already conducted, populations studied, topics covered and approaches taken [3], map the existing research conducted in Scotland and [4] identify areas for future research based on any gaps in the evidence identified.

A scoping review was conducted as they can aid detection of evidence gaps [ 42 ] and allow incorporation of grey literature in topics with insufficient published research [ 43 ]. Arksey and O’Malley’s [ 44 ] five stage scoping review framework was used.

Stage 1: identifying the research question

Arskey and O’Malley [ 44 ] suggest maintaining a broad approach to identifying the research question, in order to generate breadth of coverage. On this basis, and in line with the research question identified in the Villarroel et al. [ 24 ] scoping review, our research question was framed as follows: What is the scope, main topics and gaps in evidence in the existing literature on health of international migrants living in Scotland? Arksey and O’Malley [ 44 ] highlight the importance of defining terminology at the outset of scoping reviews. For consistency, we used the broad definition of ‘migrant’ as per Villaroel et al. [ 24 ], from the International Organisation for Migration (IOM) [ 1 ]. References to refugees or asylum seekers followed the United Nations Refugee Agency definitions [ 3 ].

Stage 2: identifying relevant studies

Electronic database searches identified reports alongside a grey literature search, in line with Arskey and O’Malley’s [ 44 ] guidance to search for evidence via different sources. CINAHL, Web of Science, SocIndex and Medline academic databases were selected with input from co-authors. Search terms for the review were based upon those used by Villaroel et al. [ 24 ] with additional relevant terms from Hannigan et al. [ 9 ] The strategy combined three sets of terms for: Migrants (e.g., refugee, migrant, immigrant or newcomer), Scotland and Health. Both free text terms and index terms were used and adapted to the 4 academic databases and searches were run on 10th March 2023 (see Additional File 1 for database search strategies). Thirteen Government, University, and third-sector websites in Scotland were scoped for selection then hand-searched for grey literature (listed in Additional File 1 ).

Stage 3: study selection

Net-migration to Scotland increased in the 2000s [ 27 ] hence a date range of January 2002-March 2023 was used to identify evidence. The search was limited to English only. Inclusion/exclusion criteria for the studies were based on those used by Villaroel et al. [ 24 ] and expanded upon following discussion with co-authors (see Table  1 ). Reports were included if based on primary or secondary research on the health of international migrants in Scotland and used qualitative, quantitative or mixed methods research design. International or UK based reports were only included if Scottish results were documented separately. Reports on the health of ethnic minority groups in Scotland was included if place of birth was recorded. Research on internal (non-international) migrants within Scotland, either moving from one Scottish area to another or from another part of the United Kingdom to Scotland, were excluded.

Stage 4: data charting

All records were saved to RefWorks for screening. Records were first screened at title/abstract stage with 10% independently checked by the co-authors. The remaining reports were single screened using full text by the first author. Data from the included records was extracted and organised in tabular form under the following headings, which were agreed by team members: article type (peer-reviewed article or grey literature), publication date, geographical setting, study/intervention’s target population, funding, primary research focus on migrant health (y/n), study objective, data collection method, study design (qualitative/quantitative/mixed) and main finding. Reports were not critically appraised in this scoping review.

Stage 5: collating, summarising and reporting results

A report (either a peer-reviewed journal article or grey literature report) is used as our unit of analysis. In order to present the range of research identified, reports were grouped by the different headings in our data charting table and the outcomes considered for relevance to our scoping review’s aim. Our Results summarise the recency, focus, study designs and funding sources of the identified research, followed by the geographical settings and whether Scotland was included in international research reports. Reports were grouped by their study population and further sub-divided by publication type and geographical area for summarising. Finally, the WHO’s European strategy and action plan (SAAP) for refugee and migrant health [ 7 ] is a policy framework designed to help governments and other stakeholders monitor and improve migrant health in Europe. There are nine strategic areas in the WHO’s SAAP, which prioritise the most salient issues. In line with Villaroel et al’s [ 24 ] approach and in order to compare scoping review outcomes, these areas were used to categorise the findings of this review. Each report was matched to the most appropriate SAAP:

Establishing a Framework for Collaborative Action.

Advocating for the right to health of refugees.

Addressing the social determinants of health.

Achieving public health preparedness and ensuring an effective response.

Strengthening health systems and their resilience.

Preventing communicable disease.

Preventing and reducing the risks caused by non-communicable disease.

Ensuring ethical and effective health screening and assessment.

Improving health information and communication.

The primary focus (aims and objectives) of each report was used to identify the relevant SAAP area/areas. To improve reliability, results were compared using coding criteria used in Villaroel et al’s study (MacFarlane 2023, personal communication, 31st May). 10% of the reports were checked by one co-author to ensure consistent coding to SAAP categories. Any instances of uncertainty in mapping reports to the relevant SAAP area/areas were discussed and resolved by team members.

This scoping review of the literature on migrant health in Scotland identified 2166 records from academic literature databases, following duplicate removal, and 170 records from website searches (see Fig.  1 ). Following screening, a total of 71 peer-reviewed journal articles and 29 grey literature studies (totalling 100 reports) were included for analysis (Results table and reference list are presented in Additional File 2 ).

Flow chart illustrating the identification of sources of evidence included in the scoping review

Overall findings

The majority of reports were published between 2013 and 2022. Fifty-eight reports (58%) focused exclusively on migrant health [ 18 , 39 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ]. 23 centred on health but included other populations in addition to migrants – for example research on ethnic minorities or other vulnerable groups [ 13 , 31 , 35 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 ]. Seventeen reports were included where the sample population were migrants, but the primary topic was not health – for example destitution, integration, and service needs [ 27 , 73 , 74 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 ]. Health data was reported as part of the wider subject matter. One report [ 136 ] looked at the social determinants of breastfeeding including migrant status and one [ 137 ] compared attitudes to aging and family support between countries.

Funding sources were not declared for 35 (35%) of reports. The Scottish Government funded 20 reports (20%) [ 13 , 27 , 32 , 39 , 45 , 46 , 47 , 66 , 77 , 88 , 99 , 100 , 101 , 102 , 113 , 116 , 119 , 121 , 129 , 134 ]. Other common sources of funding included Government funded public bodies ( n  = 13) [ 45 , 48 , 49 , 50 , 51 , 52 , 53 , 104 , 107 , 113 , 116 , 131 , 136 ], the Scottish Health Service ( n  = 18) (either the National Health Service (NHS) [ 13 , 54 , 56 , 57 , 58 , 59 , 102 , 113 , 116 ], local NHS trusts [ 45 , 60 , 61 , 77 , 102 , 103 , 112 ] or by Public Health Scotland [ 13 , 113 ]) Eleven reports (11%) were funded by Universities. The charity sector financed 15 (15%) reports [ 53 , 63 , 66 , 69 , 70 , 71 , 72 , 73 , 74 , 103 , 111 , 123 , 125 , 132 , 138 ] and the EU and Scottish local authorities funded four reports each [ 45 , 62 , 75 , 76 , 77 , 102 , 125 , 135 ]. Professional bodies financed one report [ 126 ] as did the Japanese government [ 64 ]. No reports received funding from the business sector. The biggest sources of funding for grey literature were Refugee charities (40%) and the Scottish government (30%) (see Fig. 2 ).

Sources of funding for migrant health research in Scotland

Research methods and data collection

52% of reports used qualitative research methods. Forty-five reports (86%) collected data using 1–1 interviews and 24 (46%) used focus groups. Other methods of data collection included questionnaires (six studies (11%)), workshops (two studies (3.85%)) and observation (two studies (3.85%)). Oral/written evidence, guided play sessions, family case studies and participatory activity sessions were used in one report each.

28% of reports used quantitative research methods, most commonly cross section design (ten studies (36%)) and cohort design (18 studies (64%)). Information was obtained from databases including medical records, Census data and national records in 21 reports (75%). Questionnaires were used in six reports (21%). Other methods including body measurements, food diaries, blood samples, interviews and case reviews were used in 1 report each.

20% of reports used mixed methods. The most common method of data collection was questionnaires in 14 reports (70%), interviews in ten reports (50%), focus groups in seven reports (35%), workshops in three reports (13.6%), and databases in three reports (13.6%). Other methods included literature review in two reports (10%), case note reviews in two reports (10%) and one reports each used mapping and school records.

Geographical areas of study

Ninety-one reports were situated in Scotland, of which 35 (38.5%) covered the whole country and 56 (61.5%) specified a city or area where research was undertaken. Some UK and international reports also specified the area of Scotland. The largest share of research within Scotland overall was in Glasgow with 36 reports, followed by Edinburgh with 16 reports, Lothian with six reports, Aberdeen with five reports and Grampian with three reports. The Northeast, Stirling, Highlands, Inverness, Lanarkshire, Motherwell and Selkirk had one report in each area.

There were seven international reports, three on mortality by country of birth [ 75 , 76 , 78 ], one on cross cultural communication [ 79 ], one on maternity care in Poland and Scotland [ 99 ], one comparing attitudes to aging in China and Scotland [ 137 ] and one on the link between birthweights and integration of migrants [ 64 ]. The remaining two reports were UK based, one on immunisation of Roma and traveller communities [ 117 ] and one on the link between ethnic diversity and mortality [ 104 ]. All the included international and UK reports documented the Scottish data separately within results.

Migrant population

Thirty-one reports included all migrants in the study population. The remaining reports included 30 studies on asylum seekers/refugees, 11 on Polish migrants, ten on Africans, six each on South Asians/Chinese/European, three on Arabs, and two on Roma populations (see Fig.  3 ). Most reports did not specify the country of origin for Asylum seekers and refugees - where country of birth was specified, reports were also included in the appropriate category.

Migrant populations studied in health research in Scotland

Grey literature and peer-reviewed reports differed in population focus. The most common populations of interest in grey literature were asylum seekers/refugees consisting of 18 reports (62%) [ 27 , 47 , 54 , 55 , 59 , 63 , 70 , 71 , 72 , 73 , 74 , 123 , 125 , 127 , 128 , 132 , 134 , 138 ] while for peer-reviewed journals 24 reports (34%) focused on all migrants [ 13 , 35 , 45 , 48 , 64 , 76 , 78 , 79 , 80 , 81 , 104 , 105 , 108 , 109 , 113 , 114 , 115 , 116 , 118 , 120 , 121 , 122 , 136 ].

Migrant study population also differed by local area; Glasgow city, where the majority of research occurred, had 18 reports of 36 (50%) on Asylum seekers/refugees [ 47 , 48 , 52 , 53 , 54 , 55 , 58 , 63 , 70 , 71 , 72 , 82 , 83 , 127 , 128 , 130 , 138 , 139 ] eight reports (22%) on Africans [ 52 , 53 , 84 , 85 , 86 , 87 , 106 , 107 ], seven reports (19%) on all migrants [ 45 , 48 , 80 , 102 , 104 , 105 , 121 ] and two reports (5.5%) on Roma migrants [ 103 , 117 ]. Other populations had one reports each. In Edinburgh five reports of 16 (31%) were on the Polish population [ 56 , 67 , 68 , 89 , 90 ], and two reports (12.5%) on Asylum seekers/refugees [ 60 , 133 ], Chinese [ 62 , 137 ], South Asian [ 46 , 119 ], all migrants [ 105 , 121 ] and Africans [ 87 , 107 ]. The remaining migrant groups had one report each. Other areas of Scotland show no clear pattern with studies in disparate migrant population groups.

Number of reports per Strategic and Action Plan (SAAP) Area

SAAP Area mapping

1. establishing a framework for collaborative action.

Nine reports had a primary focus on collaborative action and were categorised under SAAP area 1 (see Fig.  4 ) [ 66 , 70 , 72 , 73 , 103 , 125 , 129 , 132 , 134 ]. Four reports (33%) used a mixed methods study design, the remaining five reports (67%) used a qualitative design. One report [ 66 ] focused on the epidemiology of female genital mutilation and a proposed intervention strategy. One report [ 66 ] focused on the epidemiology of female genital mutilation and a proposed intervention strategy. One report [ 103 ] evaluated service provision to the Roma community in Glasgow. The remaining reports focused on refugees and asylum seekers: four [ 73 , 125 , 132 , 134 ] evaluations of refugee integration projects, one [ 70 ] on services available to pregnant women, and one [ 72 ] an assessment of a peer-education service. One report [ 129 ] was a review of service provisions for migrants during the Covid-19 pandemic. All reports in SAAP area 1 were grey literature and three (37.5%) had a primary focus on migrant health while four (50%) focused on integration, one (11%) included data on ethnic minorities and one (11%) on services during the covid-19 pandemic. The majority (seven reports (78%)) were also categorised to another SAAP area most commonly area 2 (five studies (55%)) or area 5 (four studies (44%)).

2. Advocating for the right to health of refugees

Nineteen reports focused on SAAP area 2, advocating for the right to health of refugees (see Fig.  4 ) [ 47 , 52 , 53 , 54 , 55 , 63 , 70 , 71 , 83 , 103 , 123 , 124 , 125 , 127 , 128 , 129 , 134 , 138 , 140 ]. Sixteen reports (84%) had a qualitative study design and the remaining three (16%) reports used mixed methods. Nine reports (47%) focused on the health impact of the asylum system [ 52 , 55 , 71 , 74 , 123 , 127 , 128 , 129 , 138 ], five (26%) on health and access to care [ 47 , 54 , 83 , 103 , 124 ], two (10.5%) on maternity care [ 63 , 70 ], two (10.5%) on integration services [ 125 , 134 ] and one report on mental health in HIV positive migrants [ 53 ]. Nine reports (47%) had a primary focus on migrant health while the remaining 10 (53%) also involved wider social issues. The majority (15 (79%)) of reports were grey literature. All the articles in this group overlapped with another SAAP area. Area 3 is the most common joint category with ten reports (53%) followed by area 5 with seven reports (37%), area 1 shares five reports (26%), while areas 4 and 8 share one report each (5%).

3. Addressing the social determinants of health

Twenty-nine reports were categorised to SAAP area 3 – addressing the social determinants of health (see Fig.  4 ) [ 13 , 27 , 45 , 50 , 52 , 55 , 60 , 62 , 63 , 65 , 68 , 71 , 74 , 80 , 81 , 82 , 91 , 92 , 93 , 102 , 112 , 123 , 124 , 127 , 128 , 136 , 137 , 138 ]. The majority (14 (48%)) used a qualitative study method, eight (28%) used quantitative methodology and the remaining seven reports (24%) used mixed methods. Nineteen reports (65.5%) were peer-reviewed journals [ 13 , 45 , 50 , 52 , 60 , 62 , 63 , 65 , 68 , 80 , 81 , 82 , 91 , 92 , 93 , 104 , 112 , 124 , 136 , 137 ] and ten (34.5%) were grey literature [ 27 , 55 , 63 , 71 , 74 , 102 , 123 , 127 , 128 , 138 ]. Ten reports (34.5%) discussed the effects of the asylum system on health [ 27 , 52 , 63 , 71 , 74 , 123 , 124 , 127 , 128 , 137 ] and one (3.5%) migration and health [ 50 ]. Six reports (21%) focused on culture and ethnicity [ 82 , 92 , 102 , 104 , 112 , 137 ], five reports (17%) discussed economic and environmental determinants of health [ 13 , 45 , 67 , 81 , 93 ] and five reports (17%) the health impact of social activities [ 55 , 60 , 62 , 80 , 91 ]. Of the remaining reports, one [ 65 ] discussed Brexit and mental health of European migrants and one discussed the effect of coping strategies on wellbeing in Polish migrants [ 68 ]. Most reports, 18 (62%) had a primary focus on migrant health [ 45 , 50 , 52 , 55 , 60 , 62 , 63 , 65 , 67 , 68 , 71 , 80 , 81 , 82 , 91 , 92 , 93 , 102 ], six reports (21%) discussed wider social factors in addition to health [ 74 , 123 , 124 , 127 , 128 , 138 ]. Of the remaining reports three (10%) looked at ethnic background and country of birth [ 13 , 112 , 136 ], one [ 27 ] included other vulnerable groups and one [ 137 ] included people living in China and Chinese migrants to Scotland. Thirteen reports were also categorised to one or more additional SAAP area - ten (34%) were also applicable to area 2 [ 52 , 55 , 63 , 71 , 74 , 123 , 124 , 127 , 128 , 138 ], three (10%) to area 5 [ 63 , 82 , 92 ] and one (7%) to area 4 [ 27 ].

4. Achieving public health preparedness and ensuring an effective response

Twenty-one reports were assigned to SAAP area 4 (see Fig.  4 ) [ 27 , 31 , 35 , 39 , 47 , 57 , 64 , 75 , 76 , 77 , 78 , 94 , 104 , 108 , 109 , 111 , 113 , 114 , 116 , 120 , 135 ] of which fourteen (67%) used quantitative research methods, four (19%) mixed methods and three (14%) qualitative methods. Thirteen (62%) reports were peer-reviewed journals [ 35 , 59 , 64 , 75 , 78 , 104 , 108 , 109 , 111 , 113 , 114 , 116 , 120 ] and eight (38%) grey literature [ 27 , 31 , 39 , 47 , 57 , 77 , 94 , 135 ]. Most reports (12 (57%)) focused on morbidity and mortality in migrant populations [ 31 , 35 , 64 , 75 , 76 , 78 , 104 , 108 , 109 , 113 , 114 , 116 ]. Six (29%) investigated health status and healthcare needs in migrant groups in Scotland [ 39 , 47 , 57 , 77 , 94 , 135 ]. Two reports (9.5%) analysed the epidemiology of HIV infections [ 111 , 120 ] and the remaining report focused on the health needs of young people during the covid-19 pandemic [ 27 ]. Nine reports (43%) had a primary focus on migrant health [ 39 , 47 , 55 , 64 , 75 , 76 , 77 , 78 , 94 ] while eight (38%) also analysed data by ethnicity [ 31 , 35 , 104 , 108 , 109 , 113 , 114 , 116 ]. Of the remaining reports, three (14%) included other populations within Scotland [ 27 , 111 , 120 ] and one (5%) included other characteristics in addition to health information [ 135 ]. Ten reports (48%) were also categorised to another SAAP area; one to area 2 [ 47 ], one to area 3 [ 27 ], four to area 5 [ 47 , 57 , 77 , 135 ], two to area 6 [ 111 , 120 ] and two to area 9 [ 31 , 108 ].

5. Strengthening health systems and their resilience

Twenty-nine reports were assigned to SAAP area 5 (see Fig.  4 ) [ 18 , 47 , 48 , 49 , 54 , 57 , 63 , 69 , 70 , 72 , 77 , 79 , 82 , 83 , 92 , 95 , 96 , 97 , 99 , 101 , 103 , 118 , 119 , 126 , 129 , 131 , 133 , 135 , 141 ] of which 23 (79%) used qualitative research methods. Three reports used quantitative methods (10.3%) and the remaining three used mixed methods (10.3%). Twelve reports (41%) examined migrants needs and experiences of health care [ 47 , 49 , 54 , 57 , 58 , 77 , 83 , 95 , 103 , 119 , 129 , 135 ], eight (24%) focused on pregnancy and childcare [ 63 , 70 , 92 , 96 , 97 , 99 , 101 , 118 ] and two (7%) on barriers to healthcare access [ 48 , 131 ]. Two reports (7%) evaluated healthcare programmes [ 72 , 133 ] and two focused on communication in primary care [ 79 ] and maternity services [ 69 ]. The remaining three reports (10%) covered sexual health [ 82 ], health information needs of Syrian refugees [ 126 ] and general practitioner training [ 18 ]. Nineteen (65.5%) were peer reviewed journals [ 18 , 48 , 49 , 58 , 69 , 79 , 82 , 83 , 92 , 95 , 96 , 97 , 99 , 101 , 118 , 119 , 125 , 131 , 133 ] and ten (34.5%) were grey literature [ 47 , 54 , 57 , 63 , 70 , 72 , 77 , 103 , 129 , 135 ]. Twenty-one (72%) had a primary focus on migrant health [ 18 , 47 , 48 , 49 , 54 , 57 , 58 , 63 , 69 , 70 , 72 , 77 , 79 , 82 , 83 , 92 , 95 , 96 , 97 , 99 , 101 ]. Six reports (21%) included research on other characteristics or services [ 103 , 126 , 129 , 131 , 133 , 135 ]. The remaining two reports (7%) included ethnic groups as well as migrants in the data [ 118 , 119 ]. Nineteen reports (65.5%) were also assigned to one or more other category areas: five reports (17%) to area 1 [ 47 , 70 , 72 , 103 , 129 ], five reports (17%) to area 2 [ 54 , 63 , 83 , 103 , 129 ], three reports (10%) to area 3 [ 63 , 82 , 92 ], four reports (14%) to area 4 [ 47 , 57 , 77 , 135 ], one (3.5%) to area 7 [ 119 ] and one (3.5%) to area 9 [ 48 ].

6. Preventing communicable diseases

Fourteen reports were assigned to SAAP area 6 (see Fig.  4 ) [ 56 , 61 , 87 , 88 , 89 , 90 , 105 , 106 , 107 , 111 , 115 , 117 , 120 , 122 ] of which four (31%) used quantitative methods, five (38%) used qualitative methods and five (38%) used mixed methods. Five reports (38.5%) examined immunisation behaviour [ 56 , 61 , 89 , 90 , 117 ], five (38%) on epidemiology and treatment of HIV [ 106 , 107 , 111 , 120 , 122 ]. The remaining four reports (31%) focused on tuberculosis in healthcare workers [ 115 ], malaria [ 105 ] and sexual health services [ 87 , 88 ]. Only one reports was grey literature [ 88 ], the remainder were peer-reviewed journals. Six reports (46%) had a primary focus on migrant health [ 56 , 61 , 87 , 88 , 89 , 90 ] while seven reports (54%) also included other at-risk groups in the analysis. Four reports (31%) were also assigned to another SAAP category, two (15%) to area 4 [ 111 , 120 ] and two (15%) to area 8 [ 88 , 115 ].

7. Preventing and reducing the risks posed by non-communicable diseases

Eight reports were categorised to SAAP area 7 (see Fig.  4 ) [ 46 , 51 , 59 , 84 , 85 , 86 , 98 , 119 ] of which six (75%) used qualitative research methods, one (12.5%) used quantitative methods and one (12.5%) used mixed methods. Only one report (12.5%) was grey literature [ 59 ] the remaining seven reports (87.5%) were peer-reviewed journals [ 48 , 87 , 92 , 126 , 127 , 128 , 140 ]. Three reports (37.5%) focused on health behaviours [ 51 , 85 , 98 ], two (25%) on mental health, two (25%) on diabetes and one (12.5%) on chronic disease. Seven reports(87.5%) had a primary focus on migrant health [ 46 , 51 , 59 , 84 , 85 , 86 , 98 ], with the remaining report (12.5%) including ethnic minority groups [ 119 ]. One report (12.5%) was also assigned to SAAP area number 5 [ 119 ].

8. Ensuring ethical and effective health screening and assessment

There were six reports assigned to category 8 (see Fig.  4 ) [ 53 , 88 , 100 , 110 , 115 , 121 ] of which two (33%) used a quantitative research method, three (50%) used a qualitative method and one used mixed methods. One report (14%) was grey literature [ 88 ] the remaining five reports (83%) were peer reviewed journals [ 53 , 100 , 110 , 115 , 121 ]. Three reports (50%) focused on cancer screening in migrant women [ 21 , 100 , 110 ], one (17%) analysed access to HIV testing among African migrants [ 53 ], one (17%) on T.B in healthcare workers [ 72 ] and one (17%) on sexual health [ 36 ]. Three reports (50%) had a primary focus on migrant health [ 53 , 88 , 100 ] while the remaining three reports (50%) included other at-risk groups in the analysis [ 110 , 115 , 121 ]. There were three reports which overlapped with other SAAP areas: one [ 53 ] (17%) was categorised to area 2 while two [ 88 , 115 ] (33%) were categorised to area 6.

9. Improving health information and communication

Three reports were assigned to SAAP area 9 (see Fig.  4 ) [ 31 , 108 , 130 ]. One of these (33%) used a qualitative approach, one (33%) used a quantitative approach and one (33%) used mixed methods. Two [ 108 , 130 ] (66%) were peer-reviewed journal articles and one [ 31 ] (33%) was grey literature. Two reports (66%) focused on improving migrant demographics and health information using databases [ 31 , 108 ] while one (33%) described an information-needs matrix for refugees and asylum seekers [ 130 ]. Two [ 31 , 108 ] included ethnicities in the data while one [ 130 ] had a primary focus on migrant health. Two reports [ 31 , 108 ] (66%) also applied to SAAP area 4 while one report [ 130 ] (33%) was in SAAP area 9 only.

To our knowledge this is the first scoping review conducted on migrant health in Scotland. A previous rapid literature review [ 94 ] found most research focused on health behaviours, mental health, communicable disease and use of and access to healthcare; however, the review limited migrant definition to those who had immigrated within five years and asylum seekers were not included.

In our review, the majority of reports were published from 2013 onwards, aligning with the expansion in migrant research internationally [ 142 ]. 52% used qualitative research methods, 28% used quantitative methods and 20% used mixed methods. 58% focused on migrant health: the remaining papers included other populations or health as part of a wider remit. Research funding was mostly provided by the Scottish Government, NHS, refugee charities and Universities. No studies received funding from the private sector, although this sector has the potential resource and capacity to play a key role in funding future research to improve migrant health in Scotland. Geographically, most studies took place in Glasgow (36%), nationwide (38.5%) or Edinburgh (16%) – other areas were under-represented including Aberdeen (5%), despite being the city with the largest migrant population [ 30 ]. There was a lack of studies in rural localities. These findings concur with a UK migrant health review by Burns et al. [ 23 ] where research was concentrated in larger cities and data was sparse in rural areas relative to the migrant population.

Half of the research identified that was conducted in Glasgow focused on asylum seekers/refugees. Glasgow was previously the only Scottish city to host asylum seekers [ 143 ] and currently supports the most asylum seekers of any local authority in the UK [ 29 ]. In April 2022, the UK government widened the Asylum dispersal scheme to all local authorities [ 144 ]. Around 70% of Scotland’s refugee support services are based in Glasgow and the South-west [ 145 ]. As reduced access to services may impact the health of asylum seekers, research in Glasgow may not be generalizable to other regions of Scotland.

Almost one-third (30%) of all reports focused on asylum seekers and refugees – an overrepresentation given that only 18% of migrants to the UK are asylum seekers [ 146 ] and as low as 2% of all migrants in Scotland [ 147 ]. Asylum seekers and refugees are at risk of poor health due to trauma, difficult journeys, overcrowded camps, poor nutrition and lack of access to healthcare [ 148 ]. They have worse maternity outcomes and increased rates of mental illness [ 149 ]. Increased research on health of asylum seekers and refugees is necessary due to their additional vulnerabilities [ 142 ]. However, asylum seeker’s country of origin was generally not specified. Asylum seekers have heterogenic backgrounds [ 150 ] and nationality and trauma experience affect health status [ 151 ]. Further research focused on specific nationalities of asylum seekers would enhance understanding of the health needs in this population.

Almost one-third (31%) of studies did not specify a migrant group. This concurs with a Norwegian migrant health study by Laue et al. [ 152 ] where 36% of research did not identify country of birth. Where nationality was identified, Polish, African and South Asian were most prevalent. Poles are the largest migrant group in Scotland, however for the other most common immigrant groups of Irish, Italian and Nigerian [ 30 ] there was an absence of research. No studies took place on Nigerian migrants – nine studies indicated African populations, but country of birth was not specified. Since March 2022, 23,000 Ukrainians have migrated to Scotland [ 153 ], however no studies on Ukrainians were identified currently. Research may be underway which is yet to be published.

Only one study explored the impact of Brexit on European migrants’ health despite 56% of migrants to Scotland being EU nationals [ 30 ]. Again, research may be taking place currently, which is yet to be published. No studies involved undocumented migrants despite this populations’ high rates of poor physical/mental health exacerbated by poor housing and working conditions [ 154 ]. An estimated 7.2–9.5% of the workforce in the UK are migrant workers who have higher risks of poor working conditions and injury [ 155 ]. Scotland depends on a migrant workforce for some industries such as agriculture [ 156 ] but only two research papers specified migrant workers.

Most research papers related to the right to health of refugees (SAAP 2), social determinants of health (SAAP 3), public health planning (SAAP 4) and strengthening health systems (SAAP 5). Areas with less research were frameworks for collaborative action (SAAP 1), preventing communicable disease (SAAP 6), preventing non-communicable disease (SAAP 7) and health screening and assessment (SAAP 8). Only three studies related to improving health information and communication (SAAP 9). Lebano et al. [ 12 ] conducted a literature review of migrant health in Europe and found data collection unreliable and disorganised. There is a lack of data on the numbers and types of migrants entering Scotland and research tends not to differentiate between ethnic minorities and migrants [ 94 ]. As poor-quality information hinders surveillance and planning of services SAAP area 9 is an important consideration for increased research.

Villarroel et al. [ 24 ] also found more research in SAAP areas 3 to 5 and less in areas 6 to 9. However, their study returned no results in category 1, collaborative action, or 2, the right to health of refugees, while this study assigned 9% of articles to category 1 and 19% to category 2. Most articles in our study relating to categories 1 and 2 were grey literature, which was excluded from the original Irish scoping review. This highlights a potential difference in the focus of peer-reviewed articles compared to government/refugee charity commissioned reports. Collaborative action and the right to health of refugees and asylum seekers are entwined in Scotland due to the complex policy environment; the social determinants of health such as housing, education, welfare rights and social integration are influenced by a variety of UK and Scottish statutory bodies as well as third sector organisations [ 157 ]. Despite this complexity, organisations work well together [ 158 ]. Further academic research in this area would enhance joint working practices and networks.

A scoping review in the UK [ 23 ] found similar quantities of research corresponding to SAAP areas 3, 2 and 9. However in Scotland areas 1, 5 and 8 were a combined 44% of included papers compared with 27.8% of results on health systems and structures in Burns et al’s [ 23 ] study. Almost half of the articles in SAAP areas 1,5 and 8 were grey literature, which was not included in Burns et al’s [ 23 ] review. Conversely, Burns et al. [ 23 ] found 81.9% of research in the UK related to epidemiology, equivalent to SAAP categories 4,6 and 7. In a Norwegian scoping review of migrant health [ 152 ] 65% of research was related to epidemiological data on health and disease. Only 42% of the research in this current study related to epidemiological data; the quantity of evidence was reduced by excluding combined research from the UK. As Scotland has higher mortality and morbidity than elsewhere in the UK [ 29 ] it is important to undertake further epidemiological research limited to Scotland.

Strengths and weaknesses

Strengths of this review include the use of the WHO’s SAAP categories [ 7 ] to classify data, in accordance with the Villarroel et al’s [ 24 ] study: this means results are linked to policy on migrant health and facilitates comparability to the Irish study results. Additionally results include data on migrant groups, locality, and funding of included papers; these highlight potential omissions for future research consideration. Results include diverse research methods and published and grey literature giving a wide overview of available evidence, reported using the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) checklist (see Additional File 3 ) [ 159 ].

Limitations included the lack of an open-access protocol and search limitations of English language and selected databases. This means some relevant reports may be omitted. Due to time and resource limitations no quality appraisal was planned for included reports. Whilst we did not synthesise the findings for each topic area and migrant group, future systematic reviews could be undertaken to address this limitation and build on this work.

Conclusions

Immigration and ethnic diversity in Scotland have increased since 2002 which is reflected in the expansion of migrant health research. This review highlights evidence gaps including a lack of research in rural areas, undocumented migrants and migrant workers. There is a tendency to cluster asylum seekers together rather than differentiate between national groups. Within the SAAP areas there is less evidence relating to collaborative action, preventing communicable disease, preventing non-communicable disease and health screening and assessment. Further research is required on improving health information and communication for migrant populations in Scotland – a significant omission given the importance of accurate information for health service planning.

Availability of data and materials

All data analysed during this review comes from the papers listed in Additional file 2 .

Abbreviations

European Union

Human Immunodeficiency Virus

National Health Service

Strategy and Action Plan

The Scottish Health and Ethnicity Linkage Study

United Kingdom

World Health Organisation

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Acknowledgements

Thank-you to Professor Anne MacFarlane and PHD student Anne Cronin, of the University of Limerick, Ireland for sharing the coding guidelines currently used in an update to Villarroel et. al’s 2019 study on Migrant Health in the Republic of Ireland.

No funding was received for this work, which was undertaken as G. Petrie’s Master of Public Health dissertation module at the University of Stirling.

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Petrie, G., Angus, K. & O’Donnell, R. A scoping review of academic and grey literature on migrant health research conducted in Scotland. BMC Public Health 24 , 1156 (2024). https://doi.org/10.1186/s12889-024-18628-1

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Reversal and resumption of anticoagulants in patients with anticoagulant-associated intracerebral hemorrhage

• Jingfei Yang 1 ,
• Jie Jing 1 ,
• Shiling Chen 1 ,
• Xia Liu 1 ,
• Jiahui Wang 1 ,
• Chao Pan 1 &
• Zhouping Tang   ORCID: orcid.org/0000-0002-4153-8590 1  

European Journal of Medical Research volume  29 , Article number:  252 ( 2024 ) Cite this article

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The use of anticoagulants has become more frequent due to the progressive aging population and increased thromboembolic events. Consequently, the proportion of anticoagulant-associated intracerebral hemorrhage (AAICH) in stroke patients is gradually increasing. Compared with intracerebral hemorrhage (ICH) patients without coagulopathy, patients with AAICH may have larger hematomas, worse prognoses, and higher mortality. Given the need for anticoagulant reversal and resumption, the management of AAICH differs from that of conventional medical or surgical treatments for ICH, and it is more specific. Understanding the pharmacology of anticoagulants and identifying agents that can reverse their effects in the early stages are crucial for treating life-threatening AAICH. When patients transition beyond the acute phase and their vital signs stabilize, it is important to consider resuming anticoagulants at the right time to prevent the occurrence of further thromboembolism. However, the timing and strategy for reversing and resuming anticoagulants are still in a dilemma. Herein, we summarize the important clinical studies, reviews, and related guidelines published in the past few years that focus on the reversal and resumption of anticoagulants in AAICH patients to help implement decisive diagnosis and treatment strategies in the clinical setting.

Introduction

Anticoagulants, which are effective for the prevention and treatment of venous thromboembolism (VTE) and the reduction of stroke risk in patients with atrial fibrillation (AF) [ 1 ], have increased in usage over the last decade [ 2 ]. Warfarin is the most commonly used Vitamin K antagonist (VKA) for preventing and treating arterial thromboembolism and VTE [ 3 ]. Direct oral anticoagulants (DOACs) include direct thrombin (factor IIa) inhibitors such as dabigatran and factor Xa inhibitors (FXa-Is) such as rivaroxaban, edoxaban, apixaban, and betrixaban [ 3 ,  4 ]. Moreover, heparin and its derivatives, including unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs, such as dalteparin and enoxaparin), and the synthetic pentasaccharide fondaparinux, can be used for anticoagulation.

With an increasing number of patients treated with anticoagulants, the use of anticoagulants is becoming a more common cause of intracerebral hemorrhage (ICH) [ 2 ,  5 ]. As the second most common and deadliest subtype of stroke, ICH is defined as a brain injury caused by acute blood infiltration into the brain parenchyma, with a high mortality rate and poor prognosis [ 6 ,  7 ]. Anticoagulant-associated ICH (AAICH) patients have increased hematoma volumes, higher risks of secondary hematoma expansion (HE), and increased morbidity and mortality compared to ICH patients without coagulopathy [ 7 , 8 , 9 , 10 , 11 ]. Although AAICH can be devastating, the rapid and early reversal of anticoagulants may limit HE and improve clinical prognosis [ 8 ,  12 ]. However, in patients with AAICH, thrombotic events caused by discontinuing and reversing anticoagulant therapy may increase morbidity and mortality [ 13 ,  14 ]. The risk of recurrent ICH due to resuming anticoagulants is also a significant clinical challenge [ 13 ,  14 ]. Clinicians should carefully select reversal agents of VKAs, DOACs, or heparins and resume anticoagulant therapy at the appropriate times following ICH. It is necessary to formulate individualized treatment strategies for patients with AAICH. In this article, we describe the characteristics of AAICH and review the reversal and resumption of anticoagulants for the management of thrombotic or bleeding events in patients with AAICH.

Characteristics of AAICH

The use of anticoagulants is linked to larger hematoma volumes, increased rates of HE, and contributes to an even higher mortality rate in patients with AAICH compared with general ICH patients [ 5 ,  8 , 9 , 10 ,  15 ]. The patients with ICH who are treated with anticoagulants have worse outcomes and higher prehospital blood pressure (BP) compared to those not taking anticoagulants [ 16 ]. In addition, patients with AAICH exhibit a higher incidence of intraventricular hemorrhage (IVH), AF, and prior stroke compared to those receiving non-antithrombotic therapy [ 12 ,  17 ]. Studies have shown that AAICH may preferentially involve the cerebellum [ 11 ] and form a fluid layer in the hematoma on magnetic resonance imaging (MRI), which represents hematocrit separation and is typical of hemorrhages associated with coagulopathy [ 18 ]. Furthermore, neuroimaging markers such as cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS) are associated with the increased risk of bleeding in VKA-related ICH and DOAC-related ICH [ 19 ]. A recent clinical study has shown that the cerebrovascular small vessel disease (SVD) burden including white matter lesions (WML), lacunes, and cerebral atrophy, is associated with DOAC–ICH [ 20 ].

In addition, there may be a difference between VKA-associated ICH and DOAC-associated ICH. Many clinical trials and meta-analyses have demonstrated that DOACs can significantly reduce the risk of ICH compared with VKAs. Because of the similar or better efficacy/safety and reduced risk of ICH compared to VKAs, DOACs have been the preferred treatment for VTE/AF, replacing VKAs as the most commonly used anticoagulants worldwide [ 21 , 22 , 23 ]. A network meta-analysis that included 23 randomized controlled trials (RCTs) in patients with AF confirmed that patients using either DOAC had a significantly lower risk of ICH than those using warfarin [ 24 ]. Another milestone meta-analysis, which included 28 high-quality real-world observational studies, also showed similar results and highlighted the validity of DOACs (dabigatran, rivaroxaban, and apixaban) [ 25 ]. Rivaroxaban at a daily dose of 20 mg [ 26 ], edoxaban at a daily dose of 60 mg [ 27 ], and apixaban at a dose of 5 mg twice daily [ 28 ] could significantly reduce the risk of ICH compared to warfarin. In addition, a meta-analysis suggested that DOACs were related to a lower risk of traumatic ICH compared with VKAs [ 29 ]. Furthermore, a recent meta-analysis involving 82,404 patients with AF confirmed that DOACs reduced the risk of ICH by almost half compared to VKAs, with dabigatran 110 mg likely being the safest option [ 30 ]. Another recent meta-analysis, which focused on 55 RCTs, is the first pairwise meta-analysis to compare the risk of ICH between DOACs and other antithrombotic drugs. The analysis found that the risk of ICH with DOACs was generally lower than that with warfarin and similar to aspirin. However, it suggested that rivaroxaban might increase the risk of ICH [ 31 ].

Moreover, a recent study included 5984 patients and found that DOACs were associated with a lower hazard than VKAs for the composite outcome of ICH in patients with AF and recent ischemic stroke (IS) aged 85 years or older [ 32 ]. DOACs were associated with a smaller baseline hematoma volume and less neurological deficit than VKAs. The J-ASPECT study reported that fewer severe outcomes and lower mortality rates might be related to milder hemorrhages and lower frequencies of HE in DOAC-ICH patients compared with VKA-ICH patients [ 33 ]. Similarly, a retrospective cohort study has shown comparable results [ 17 ]. However, several other studies found no significant difference in the rate of HE, 90-day mortality, and functional outcomes between DOAC-ICH patients and VKA-ICH patients [ 34 ,  35 ]. The reasons for the differences between these findings could be related to the different study types, heterogeneous conditions of the enrolled patients, and different post-admission treatments. More standardized clinical studies are expected to be published to explore the differences between patients with DOAC-associated ICH and those with VKA-associated ICH. These studies can provide guidance for future clinical decisions.

Reversal of anticoagulants in AAICH

Regardless of what kind of anticoagulants are used, earlier and complete reversal therapes are essential in patients with AAICH, as they potentially reduce the incidence of HE and improve clinical outcomes [ 12 ,  36 ]. The strategy of reversal therapy depends on the anticoagulants used, including specific or non-specific reversal (Table  1 ).

Reversal of VKAs

Warfarin depletes vitamin K reserves, thereby disrupting the production of clotting proteins such as factors II, VII, IX, and X, as well as proteins C and S (Fig.  1 ) [ 4 ]. A retrospective study revealed that lower rates of HE and reduced in-hospital mortality were associated with the normalization of international normalized ratio (INR) levels to < 1.3 and systolic BP reduction to < 160 mmHg within 4 h after admission [ 10 ]. Immediate reversal therapy and strengthening the management of BP are essential to reduce HE in VKA-related ICH [ 12 ]. Vitamin K combined with prothrombin complex concentrates (PCCs) has been the primary reversal therapy for VKAs. Several studies have also investigated the use of fresh frozen plasma (FFP) or recombinant activated factor VIIa (rFVIIa) for the reversal of VKAs recently [ 7 ,  37 ].

Coagulation cascade and targets of anticoagulants or potential reversal agents

Intravenous administration of 10 mg of vitamin K as the sole treatment for urgent partial reversal of warfarin for non-life-threatening bleeding may provide a sufficient hemostasis effect within 5 h [ 38 ]. However, intravenous vitamin K alone is insufficient for reversal in the case of acute ICH, because INR normalization with vitamin K takes up to a day, and most HE occurs within the first few hours of symptom onset [ 4 ,  39 ]. Therefore, vitamin K is usually administered in combination with FFP or PCCs to sustain a normal INR and reduce HE [ 40 ,  41 ]. FFP replenishes clotting factors by replacing plasma proteins and takes up to 30 h to reverse INR. However, the adverse reactions include fluid overload, which increases the risk of heart failure, transfusion-related acute lung injury, and infectious reactions [ 37 ,  40 ,  41 ].

It is recommended that PCCs be administered before FFP for urgent reversal of VKA in life-threatening major bleeding events [ 40 ,  42 ]. Due to the higher concentration of clotting factors in PCCs compared to FFP, data from randomized trials and large observational studies provide evidence that PCCs can rapidly reverse INR, improve hemostasis, reduce rates of HE, and lower mortality in patients with VKA-related ICH [ 7 ,  40 ,  43 , 44 , 45 , 46 ]. These studies supported that the use of PCCs was an effective, rapid, and appropriate treatment for the urgent reversal of VKA in patients with AAICH [ 7 ,  40 ,  43 , 44 , 45 , 46 ]. PCCs include 3-factor PCC (clotting factors II, IX, and X) and 4-factor PCC (clotting factors II, VII, IX, and X) [ 4 ]. The INCH trial suggested that 30 IU/kg intravenous 4-factor PCC might be superior to 20 mL/kg intravenous FFP in terms of normalizing the INR within 3 h in VKA-ICH patients. The average time for INR reversal in the PCC group was only 40 min, while in the FFP group, it was over 24 h [ 45 ]. 4-factor PCC is an effective substitute for plasma and is licensed for the rapid reversal of VKA. The dose is determined based on INR and body weight (25–50 IU/kg) [ 7 ,  44 ]. The latest guideline recommends using 4-factor PCC instead of FFP to achieve rapid correction of INR and limit HE in patients with VKA-related ICH and INR ≥ 2.0 [ 7 ]. However, a multicenter registry reported that PCC rapidly corrected the INR of most patients. Nevertheless, mortality and morbidity rates remained high, and discharge functional status was still poor [ 47 ]. Another study indicated that high doses of PCC (> 2000 and 3000 IU) were associated with VTE [ 48 ]. Although there is a lack of prospective RCTs to study the effectiveness and determine the optimal doses systematically, PCCs can still be recommended in VKA-associated ICH, and clinicians must carefully weigh the risks and benefits [ 7 ].

In addition, rFVIIa is a non-plasma-derived and rapid-acting potential agent for VKA-associated ICH [ 49 ]. rFVIIa at pharmacologic doses directly activates factor X on the surface of activated platelets, but it only partially replaces missing clotting factors and may not restore thrombin generation as FFP or PCC does [ 49 ,  50 ]. The randomized, double-blind, placebo-controlled FAST trial showed that rFVIIa significantly reduced the growth of the hematoma but failed to improve survival or functional outcome at 90 days [ 50 ]. Furthermore, later studies showed that rFVIIa increased the risk of arterial thromboembolic events and did not significantly improve radiographic or clinical outcomes in ICH patients [ 51 ,  52 ]. Therefore, the guideline published in 2015 recommended against using rFVIIa for the routine reversal of VKAs [ 37 ] and the latest guideline in 2022 did not mention the use of rFVIIa [ 7 ].

Reversal of DOACs

DOACs, which have rapid antithrombotic effects, block the coagulation process by inhibiting procoagulant enzymatic activity [ 53 ]. Dabigatran, converted from dabigatran etexilate, which is an orally absorbable prodrug, is a highly selective and reversible direct thrombin inhibitor. It inhibits both free and clot-bound thrombin and prevents thrombin-induced platelet aggregation [ 54 ,  55 ]. Apixaban, edoxaban, rivaroxaban, and betrixaban bind to and inhibit factor Xa which is responsible for converting prothrombin to thrombin [ 55 ]. Reversal agents for DOACs include specific and non-specific drugs. The specific reversal agents include idarucizumab, a specific antagonist of dabigatran; andexanet alfa, a specific antagonist of factor Xa inhibitors; and ciraparantag, which is purported to reverse DOACs and heparins [ 56 ]. The non-specific antidotes mainly refer to PCCs, including 3-factor PCC, 4-factor PCC, and aPCC (activated VII, II, IX, X, FEIBA) [ 12 ].

Idarucizumab for dabigatran-associated ICH

Idarucizumab is a humanized antibody fragment that binds to dabigatran with high affinity and forms a complex, resulting in the almost irreversible reversal of anticoagulation [ 57 ]. It has a short half-life, allowing the resumption of anticoagulation within a reasonable time frame, and does not increase the risk of hypercoagulability [ 57 ,  58 ]. Approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) in 2015, this medication is used to rapidly stop dabigatran-associated bleeding complications before emergency surgery or in cases of life-threatening bleeding [ 59 ].

The full cohort analysis of the RE-VERSE AD trial, a multicenter and prospective study of 503 patients, aimed to determine whether 5 g of intravenous idarucizumab could reverse the anticoagulant effect of dabigatran in patients with uncontrolled hemorrhage or in need of an urgent procedure. In the RE-VERSE AD trial, idarucizumab was shown to rapidly, durably, and safely reverse dabigatran within minutes without serious adverse safety signals [ 60 ]. Moreover, idarucizumab has no pharmacological prothrombotic effects [ 58 ], and the thrombotic events that occurred in the study are likely associated with the underlying prothrombotic state and the failure to resume anticoagulation promptly [ 60 ]. Later, a study collected retrospective data from 61 stroke centers in German, including 27 ICH patients. The study found that idarucizumab appeared to prevent HE, improve outcomes, and reduce mortality in dabigatran-associated ICH [ 61 ]. However, there are no more detailed clinical trials or evidence regarding the effects of idarucizumab on rates of HE or clinical endpoints. The lack of imaging data limits any conclusions about clinical efficacy in DOAC-associated ICH [ 7 ].

In addition, hemodialysis has been evaluated with good results and plays a role in accelerating the elimination of dabigatran, reducing the duration and/or severity of bleeding in patients with dabigatran-associated bleeding [ 62 , 63 , 64 ]. Dabigatran can be reduced by hemodialysis, particularly in cases of acute kidney injury or when idarucizumab is not available [ 3 ,  7 ].

Andexanet alfa for factor Xa inhibitor-associated ICH

Andexanet alfa, a specific antagonist of direct and indirect factor Xa inhibitors, is a modified recombinant protein analog of human factor Xa that binds and sequesters factor Xa inhibitors but does not induce prothrombotic activity, thereby rapidly reversing the anticoagulant effect [ 65 ]. It was approved by the FDA in 2018 for patients treated with apixaban or rivaroxaban who have life-threatening bleeding [ 65 ].

The ANNEXA-4 trial, a large, multicenter, prospective, single-group cohort study of 352 patients, assessed the efficacy and safety of andexanet alfa in patients with acute major bleeding occurring while taking either apixaban or rivaroxaban [ 65 ]. For patients who had received apixaban or rivaroxaban more than 7 h before bolus administration, the bolus dose was 400 mg over 15 min, and the infusion dose was 480 mg. For patients who had received factor Xa inhibitors within 7 h, the bolus dose was 800 mg over 30 min, and the infusion dose was 960 mg [ 65 ]. The results indicated that 82% of patients had excellent or good hemostatic efficacy 12 h after the end of infusion, and andexanet alfa markedly reduced anti-FXa activity [ 65 ]. A recent subgroup analysis of the ANNEXA-4 trial also showed that andexanet alfa effectively reduced anti-FXa activity with a high rate of hemostatic efficacy [ 66 ]. Moreover, in a rabbit hemorrhage model, andexanet alfa effectively reversed the effects of edoxaban, indicating its clinical value in treating edoxaban-related bleeding. Anti-FXa activity could serve as a biomarker for assessing the reversal [ 67 ]. However, it is still unknown whether andexanet alfa will have greater clinical efficacy for edoxaban reversal than ciraparantag [ 3 ]. In addition, ten percent of patients in the ANNEXA-4 trial experienced thrombotic events during the 30-day follow-up period, mostly in patients whose anticoagulation therapy was delayed or not restarted [ 65 ]. Another study analyzed 182 patients from the ANNEXA-4 trial and the RETRACE-II trial, suggesting that andexanet alfa was associated with a lower rate of HE compared with PCCs. However, it did not significantly improve clinical outcomes [ 68 ]. A retrospective study also found that higher rates of hemostatic efficacy and an increased incidence of thrombosis were observed in patients with AAICH who were treated with andexanet alfa compared to 4F-PCC for the reversal of rivaroxaban or apixaban [ 69 ]. Andexanet alfa has not been widely used due to its high cost [ 70 ]. There are not enough RCTs to evaluate the safety and effects of andexanet alfa in limiting HE and preventing thrombotic events.

Ciraparantag

Ciraparantag (PER977) is a new synthetic cationic molecule designed to bind to direct factor-Xa inhibitors, thrombin inhibitors, and heparinoids through noncovalent hydrogen bonding and charge-charge interactions [ 71 ], resulting in the reversal of anticoagulants [ 3 ,  12 ,  56 ]. Ansell et al. found that ciraparantag (100-300 mg) administered after edoxaban restored the whole blood clotting time to baseline levels within 10-30 min, which was sustained for 24 h. In addition, the mean fibrin-fiber diameter returned to normal within 30 min [ 72 ]. In animal models of bleeding (rat tail transection and liver laceration), ciraparantag significantly reduced bleeding and blood loss induced by heparin and various DOACs. It acted rapidly, exhibited broad-spectrum activity, and was easy to administer [ 71 ]. The latest randomized, placebo-controlled Phase 2 trials suggested that ciraparantag reversed the effects of apixaban or rivaroxaban in a dose-related manner in healthy elderly individuals and was well tolerated at all doses [ 73 ]. However, this study had limitations, including the small sample size and the inclusion of healthy volunteers who could not represent patients [ 70 ]. Ciraparantag is a new potential antidote in development, with advantages that include easy and rapid preparation for injection [ 71 ,  73 ]. Further studies are needed to clarify the benefits and potential side effects of this drug more comprehensively.

Several animal experiments, clinical studies, and meta-analyses have suggested that PCCs appear to enhance thrombin generation and nonspecifically reverse the effects of DOACs [ 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. Studies have shown that 50 IU/kg 4-factor or 3-factor PCCs could immediately reverse the effect of rivaroxaban, as measured by prothrombin time and thrombin generation [ 74 ,  78 ]. A retrospective cohort study demonstrated that PCCs were associated with a high hemostasis rate (81.8%) and a low incidence of thrombotic events (3.8%) in patients with apixaban- or rivaroxaban-related ICH [ 79 ]. The UPRATE study showed that the majority of patients treated with 4-factor PCCs achieved effective bleeding control, with a low risk of serious adverse events, such as thromboembolic events [ 81 ]. There seemed to be an acceptable balance between the efficacy and safety of PCCs in patients experiencing major bleeding events related to rivaroxaban or apixaban who were administered an initial 2000 IU of PCC [ 81 ].

In addition, a large and randomized study suggested that 4-factor PCCs dose-dependently reversed the effect of edoxaban, and a dose of 50 IU/kg might be suitable for the reversal [ 75 ]. A prospective cohort study found that patients with dabigatran-related bleeding, treated with aPCCs (50 U/kg), had better outcomes and no excessive thromboembolic events compared with the control subjects [ 82 ]. A cell-based model indicated that PCC could affect thrombin generation and promote hemostasis at therapeutic dabigatran levels, and PCC normalized hemostasis time in a mouse saphenous vein bleeding model [ 83 ]. In addition, a recent meta-analysis showed that the anticoagulation reversal, mortality, or thromboembolic events appeared similar between 4-factor PCCs and andexanet alfa in the absence of randomized clinical comparison trials [ 84 ]. These studies provide valuable insight that PCCs can be a viable alternative, and 4-factor PCCs may be more supported and widely used [ 7 ].

However, other studies have demonstrated that doses of 37.5 IU/kg and 25 IU/kg of PCCs were insufficient for an immediate complete reversal of peak therapeutic levels of rivaroxaban or apixaban [ 76 ,  80 ]. In a new retrospective study, there was no difference in the effects of aPCCs, low- and high-dose 4-factor PCCs on hematoma stability, mortality, and safety in ICH patients taking apixaban or rivaroxaban [ 85 ]. Moreover, some studies have shown that the reversal effect of PCCs may not be effective in dabigatran-treated patients [ 74 ,  86 ]. PCCs failed to restore changes in fibrin formation in healthy volunteers treated with rivaroxaban or dabigatran [ 87 ]. The RETRACE II study suggested that PCC was not associated with a reduced rate of HE, mortality, or improved functional outcomes in DOAC-related ICH, failing to show any benefits [ 88 ]. Thus, large, standardized RCTs evaluating the effect of PCCs in patients with DOAC-related ICH are urgently needed in the future.

Reversal of heparins

Heparins bind tightly to a specific antithrombin site and form a heparin-antithrombin complex, which inactivates thrombin factor (IIa) and factors Xa, IXa, XIa, and XIIa. Among these factors, thrombin and factor Xa are the most sensitive to inhibition by the complex [ 89 ]. Reversal drugs for heparins include protamine sulfate and others.

Protamine sulfate for reversal of UFH

Protamine sulfate is a positively charged alkaline protein extracted from fish sperm that forms a complex with negatively charged heparin by intravenous injection of 1 mg/100 U (maximum dose 50 mg), thus completely and rapidly reversing the effect of UFH [ 37 ,  77 ]. The activated partial thromboplastin time (APTT) can monitor the protamine-mediated reversal of UFH [ 77 ]. However, protamine sulfate may cause uncommon hypersensitivity reactions in patients with previous exposure to protamine sulfate-containing insulin, those with fish allergies, or those who have undergone vasectomy. These reactions can be pretreated with steroids and antihistamines [ 77 ,  90 ]. Protamine may also lead to severe adverse reactions such as hypotension, bronchoconstriction, thrombocytopenia, or bradycardia, which can be reduced by taking protamine slowly [ 7 ,  90 ,  91 ]. Therefore, the required doses of protamine sulfate need to be cautiously considered, and it is preferable to take smaller doses repeatedly [ 7 ,  92 ].

Reversal of LMWHs

LMWHs exert the anticoagulant effect mainly by inactivating factor Xa through antithrombin [ 77 ]. Protamine only partially affects the anti-Xa activity of LMWHs, and there is a need for more effective reversal agents to reverse the anticoagulant effect of LMWHs [ 77 ,  93 ]. Early studies found that rFVIIa could reverse the anticoagulant effects of enoxaparin and fondaparinux ex vivo, reduce LMWH-induced bleeding in rats, and was well tolerated in patients undergoing anticoagulant therapy [ 94 , 95 , 96 ]. However, another study suggested that rFVIIa was not an effective antidote to LMWH-related bleeding in a rabbit ear bleeding model [ 97 ]. There is currently insufficient clinical data demonstrating the reversal effect of rFVIIa in LMWH-related ICH, and the drug may be associated with undesirable clotting [ 98 ].

Reversal of fondaparinux

Fondaparinux does not have a specific reversal agent. Protamine has no neutralization activity against fondaparinux [ 37 ,  77 ]. In a randomized, placebo-controlled trial, rFVIIa (90 μg/kg) can normalize clotting times and thrombin generation and reverse the effect of fondaparinux (10 mg) when severe bleeding complications occur or urgent surgery is needed [ 99 ]. The addition of rFVIIa in vitro corrected the inhibited clot formation and partially reversed the acceleration of clot lysis induced by fondaparinux [ 100 ]. Furthermore, in a rabbit model, PCC normalized the increased clotting time and clotting formation time induced by fondaparinux and effectively reduced bleeding without increasing thrombosis [ 101 ]. In an in vitro study on the reversal of fondaparinux, low doses of aPCC at 20 U/kg can completely correct thrombin generating capacity, while rFVIIa partially corrected thrombin generation [ 102 ].

Other new agents

Studies have demonstrated that the universal heparin reversal agent (UHRA) can effectively bind to heparins with excellent biocompatibility, reducing heparin-induced bleeding and exceeding protamine in heparin neutralization [ 103 ]. A later study suggested that UHRA mainly formed the UHRA-heparin complex by directly and specifically binding to anionic heparin and disrupted heparin-activated antithrombin, neutralizing the activity of available heparin-based anticoagulants [ 104 ]. Moreover, a newly designed biocompatible antidote (GC4AOEG) with a strong binding affinity for UFH neutralized UFH in vitro and in vivo without adverse effects. This antidote may have important clinical potential for reversing UFH [ 105 ]. In addition, ciraparantag can weakly bind fondaparinux and bind UFH or enoxaparin with a near-micromolar affinity to reverse the anticoagulants [ 104 ]. Previously, a clinical study included 10 healthy volunteers who received incremental doses of ciraparantag (100 to 300 mg) or a placebo. The study found that ciraparantag specifically bound to enoxaparin and reversed the anticoagulant effect, as measured by the whole blood clotting time, in a dose-related manner [ 106 ]. To verify the efficacy and safety of these potential heparin reversal agents, more clinical trials, preferably RCTs, are needed in the future.

Resumption of anticoagulants in AAICH

Due to the limited evidence, the decision to resume anticoagulants after ICH is a common clinical dilemma. Theoretically, patients with AF and AAICH are at risk of thrombosis after the reversal of anticoagulants, so anticoagulants should be restarted promptly after the patient’s condition stablizes [ 56 ]. If the bleeding is caused by secondary or reversible factors, such as trauma or a tumor, anticoagulation can generally be resumed once the bleeding cause has been resolved [ 21 ,  107 ]. The decision to resume anticoagulants is a topic of intense debate, because inappropriate prescription of anticoagulants may increase the risk of rebleeding. There is no clear consensus on the decision and optimal timing of restarting anticoagulants in patients with AAICH in clinical practice [ 108 ].

Decision on anticoagulation resumption

In published clinical studies, the resumption of anticoagulant therapy in most patients with AAICH seems to provide net clinical benefits and is supported [ 21 ,  41 ]. Two nationwide Danish observational studies reported that the reintroduction of oral anticoagulants after ICH was associated with a significant reduction in thromboembolic events and all-cause mortality rates, without a significant increase in the risk of major bleeding [ 109 ,  110 ]. A retrospective cohort study including 5712 Asian patients with nonvalvular AF and prior ICH who subsequently initiated anticoagulant therapy and found that DOACs were associated with significantly reduced risks of ICH, ischemic stroke, and death compared with warfarin [ 111 ]. A cohort study published in JAMA, including 4540 patients with AF and prior ICH, also reached similar conclusions [ 112 ]. Moreover, a recent nationwide retrospective study showed that anticoagulants reduced the risk of ischemic stroke without an increase in the risk of subsequent ICH compared with no treatment. Users of DOACs also had significantly reduced all‐cause mortality compared with warfarin [ 113 ]. Several other observational and registry studies, as well as meta-analyses, also support the resumption of oral anticoagulants after ICH (Table  2 ) [ 10 ,  14 ,  114 , 115 , 116 , 117 , 118 , 119 , 120 ]. Thus, the resumption of anticoagulants is recommended in patients with AF with prior ICH, and DOACs may be a more effective and preferred treatment option for stroke prevention due to the lower risk of recurrent ICH and better functional recovery compared with VKAs [ 21 ,  121 , 122 , 123 , 124 ]. However, these studies were almost all retrospective, and there is still a lack of high-quality RCTs to guide the resumption of anticoagulants after ICH. The prospective, randomized SoSTART trial included 203 patients with ICH and AF with CHA2DS2-VASc scores of at least 2. Participants were randomly assigned to either start or avoid oral anticoagulation. The trial failed to demonstrate the benefits of resuming oral anticoagulation and showed that recurrent ICH was more frequent and fatal in the restart group compared with the avoid group [ 125 ]. In another randomized, phase 2 trial (APACHE-AF), both the apixaban group and the avoid group had high annual risks of non-fatal stroke or vascular death [ 126 ]. Overall, the high-quality evidence to guide the resumption of anticoagulants is limited, resulting in wide variation and uncertainty in clinical treatment strategies [ 108 ].

The decision to restore anticoagulants after ICH must balance the patient’s potential risk of thromboembolism and ICH recurrence, which can be measured by CHA2DS2–VASc (congestive heart failure, hypertension, age ≥ 75 years, type 2 diabetes, previous stroke/transient ischemic attack/thromboembolism, vascular disease, age 65 ~ 74 years, and sex category) and HAS–BLED scores (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly) [ 3 ]. Concerns for the recurrence of ICH are the main reason for not restarting anticoagulants [ 127 ]. The risk factors for recurrent ICH include age, BP, exposure to anticoagulants, concomitant antiplatelet agents, acute or worsening renal failure, the presence or number of multiple CMBs, the mechanism of bleeding (spontaneous versus traumatic), the severity of the bleeding, and the size and location of hematoma, all of which contribute to the individual patient’s risk–benefit assessment of resuming anticoagulants [ 37 ,  41 ,  113 ,  128 ]. The analysis of the MGH–ICH study and the ERICH study also suggested that the apolipoprotein E (APOE) ε2/ε4 variants, CMBs and cSS defined by MRI were independently related to ICH recurrence after AAICH [ 129 ]. The combination of APOE genotype and MRI markers (cSS and CMBs) helps predict the recurrence of ICH and make clinical decisions in patients with AAICH [ 129 ]. In addition, patients with cerebral amyloid angiopathy (CAA) are at higher risk of ICH, so ideally, all patients with CAA and AAICH should avoid anticoagulation, especially long-term anticoagulation therapy [ 130 ]. However, RCTs of anticoagulant therapy in patients with CAA have not yet been published. For patients with other risk factors for ICH, such as poorly controlled hypertension, lobar ICH location, and concurrent aspirin use, anticoagulant therapy should be delayed and restarted after achieving BP control or addressing potential risk factors for rebleeding [ 3 ,  121 ,  131 ]. In patients with non-lobar ICH, the resumption of anticoagulants should be considered depending on the characteristics of bleeding, changes in risk factors, and indications for anticoagulation [ 21 ,  37 ,  41 ]. While the resumption of anticoagulants should be performed with great caution in those patients with lobar ICH due to the extremely high risk of rebleeding [ 21 ,  41 ]. Once the risk of rebleeding is low enough to no longer exceed the risk of potential recurrent ischemic events, anticoagulation might be further resumed, but it should be noted that the optimal timing of anticoagulation resumption also has an important impact on the outcome of patients with AAICH [ 132 ].

Furthermore, when the risk of thromboembolism is extremely high (e.g., mechanical heart valve prosthesis, valvular AF, NVAF with CHA2DS2–VASc score ≥ 4, transient ischemic attack/ischemic stroke within 3 months, VTE within 3 months, or recurrent or cancer-related VTE), resuming anticoagulants may be beneficial to the patients even if the risk of ICH recurrence is high, and should be done as early as possible after hemostasis and stable clinical symptoms [ 21 ,  41 ]. Importantly, for patients at a high risk of thromboembolism and rebleeding who have relative or absolute contraindications to resume anticoagulants (e.g., severe and life-threatening bleeding without treatable causes), nonpharmacological therapy such as left atrial appendage closure/occlusion devices may be considered to alleviate the risk of thrombosis in AF [ 7 ,  21 ,  108 ,  121 ]. In addition, anticoagulants are not commonly recommended in patients with CHA2DS2‐VASc scores of 0 to 1 [ 113 ,  121 ]. Moreover, according to European guidelines, individualized treatment decisions are recommended based on the perceived risk of thromboembolism and ICH recurrence [ 124 ]. The latest guideline has a class IIB (very weak) recommendation that low-dose UFH or LMWH at 24–48 h from ICH onset may be reasonable and effectively reduce the risk of pulmonary embolism in nonambulatory patients with ICH [ 7 ]. Anyway, it is extremely prominent to measure the individual risk factors for thrombosis and bleeding in patients with AAICH.

Optimal timing of anticoagulation resumption

The clinical decision of when to reinitiate anticoagulants after reversal therapy in AAICH patients remains unclear. The balance between avoiding recurrent ICH and preventing VTE is challenging, especially in the first few days after the onset of ICH. The AHA/ASA guideline in 2015 recommended that anticoagulants should be discontinued for at least 4 weeks after ICH in patients without mechanical heart valves (MHVs) to reduce the risk of recurrent ICH [ 37 ]. For patients with a stable ICH and a high risk of cerebral ischemia (e.g., those with mechanical valve prosthesis or NVAF with CHA2DS2VASc score ≥ 4), anticoagulants can be resumed after 14 days [ 133 ,  134 ]. While it may be more appropriate to resume anticoagulants after 4–8 weeks in patients with a moderate or low risk of thromboembolic events [ 134 ].

Almost all studies on the evaluation of the optimal timing of anticoagulation resumption after ICH are observational [ 21 ]. An observational study identified 137 AAICH patients with MHVs from a nationwide multicenter cohort (RETRACE I and II), showing that the resumption of anticoagulants within less than 2 weeks after ICH in patients with MHV was related to increased hemorrhagic complications. The study weighed the incidence of hemorrhagic and thromboembolic complications and pointed out that the earliest resumption time was at day 6 for patients at high thromboembolic risk (e.g., MHV-patients with concomitant AF, mitral valve prostheses, cage–ball prostheses, etc.) [ 36 ]. A retrospective study, including patients with traumatic ICH and subsequently thrombotic complications, showed that therapeutic anticoagulation 1–2 weeks after the onset of ICH was safe when serial CT scans were used to monitor the stability of hematomas [ 135 ]. In addition, an observational study suggested that the optimal time was approximately 7–8 weeks after ICH. If anticoagulants were restarted in this interval, it would be beneficial for reducing the risk of thrombotic events, vascular death, and nonfatal stroke without an excess risk of major bleeding [ 116 ]. However, some researchers pointed out that this study only showed the safety of warfarin resumption at this time, and the various clinical characteristics, such as CAA or high-risk HE, might affect the timing of anticoagulant resumption [ 136 ]. Moreover, the timing for resumption of anticoagulants after ICH was 115 days in the SoSTART trial and 45 days in the APACHE-AF trial [ 125 ,  126 ]. A survey gathered the responses of 163 clinicians and found that 36.6% of clinicians restarted OAC > 30 day post-ICH onset for patients with AF, 24.2% restarted between days 15 and 30 post-event, and 16.3% restarted within the first 10-14 day post-ICH [ 127 ]. A recent meta-analysis included 13 studies and showed that the average timing of OAC resumption after ICH was about 30 days [ 137 ]. In addition, several RCTs, such as the TIMING trial [ 138 ], ELAN trial [ 139 ], and the ongoing OPTIMAS trial [ 140 ], aimed to explore the optimal timing of anticoagulation after acute ischemic stroke in AF patients. The TIMING trial found that early initiation (≤ 4 days) was not inferior to delayed onset (5-10 days) of DOAC after acute ischemic stroke and early initiation was safe due to the absence of symptomatic ICH [ 138 ]. The ELAN trial and a subsequent meta-analysis also suggested that it was safe to start DOAC therapy early compared with delayed initiation [ 139 ,  141 ]. A recent analysis of the PRODAST study included 3312 patients with acute IS or transient ischemic attack (TIA) who were treated with dabigatran or VKA and indicated that the early (≤ 7 days) initiation of dabigatran seemed to be safer and superior than VKA initiated at any time with regards to the risk of ICH [ 142 ]. Anyway, the timing of restarting anticoagulation varies greatly amongst centers and regions. There are currently insufficient well-designed randomized trials and sufficiently sized prospective observational studies to explore the optimal timing for the resumption of anticoagulants in patients with AAICH. The timing of anticoagulant resumption should be based on the specific conditions of individual patients [ 131 ].

Conclusions

AAICH is a fatal disease with a poor prognosis, and studies on AAICH are underway. On the one hand, a key point of its management is to stop the use of anticoagulants and reverse coagulopathy. Based on the current literature and guidelines, we have summarized the reversal of anticoagulants in AAICH, and the brief management of coagulopathy in patients with AAICH is presented in Fig.  2 . Although significant progress has been made on the reversal of anticoagulants, there is still a lack of strong evidence on the efficacy of new reversal agents, such as ciraparantag and rFVIIa, and on the use of nonspecific reversal agents, such as PCC, in heparin- or DOAC-related ICH. Large and high-quality clinical trials are needed to expand the indications of existing reversal agents and to determine the safety and efficacy of new reversal agents. On the other hand, resuming anticoagulants after AAICH is also an urgent problem affecting the prognosis of patients. In the context of insufficient data from RCTs, the credibility of the evidence for making recommendations is limited. It is necessary to improve the evaluation of coagulation function and weigh the risks of subsequent rebleeding and thromboembolic events in AAICH patients. In conclusion, there is an urgent need for more large-scale RCTs in the future to provide support for the clinical treatment decisions in patients with AAICH.

Process of reversal in anticoagulant-associated intracerebral hemorrhage. AAICH, anticoagulant-associated intracerebral hemorrhage; APTT, activated partial thromboplastin time; CMBs , cerebral microbleeds; cSS, cortical superficial siderosi; DOACs, direct oral anticoagulant; FFP , fresh frozen plasma; ICH, intracerebral hemorrhage; INR, international normalized ratio; LAAC, left atrial appendage closure; MHVs, mechanical heart valves; PCC, prothrombin complex concentrate; TIA, transient ischemic attack; TT, thrombin time; VKAs, vitamin K antagonists; VTE, venous thromboembolism.

Availability of data and materials

All data included in this article are available upon request by contact with the corresponding author.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (82071330 to Z.T., 92148206 to Z.T., 81901219 to C.P.) and the Science and Technology Department of Hubei Province (2021BCA109 to Z.T.).

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Yang, J., Jing, J., Chen, S. et al. Reversal and resumption of anticoagulants in patients with anticoagulant-associated intracerebral hemorrhage. Eur J Med Res 29 , 252 (2024). https://doi.org/10.1186/s40001-024-01816-5

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Articles from Emerging Infectious Diseases

Volume 30, Number 5—May 2024

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Research Letters

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Crimean-Congo hemorrhagic fever (CCHF), caused by CCHF virus, is a tickborne disease that can cause a range of illness outcomes, from asymptomatic infection to fatal viral hemorrhagic fever; the disease has been described in >30 countries. We conducted a literature review to provide an overview of the virology, pathogenesis, and pathology of CCHF for clinicians. The virus life cycle and molecular interactions are complex and not fully described. Although pathogenesis and immunobiology are not yet fully understood, it is clear that multiple processes contribute to viral entry, replication, and pathological damage. Limited autopsy reports describe multiorgan involvement with extravasation and hemorrhages. Advanced understanding of CCHF virus pathogenesis and immunology will improve patient care and accelerate the development of medical countermeasures for CCHF.

Crimean-Congo hemorrhagic fever (CCHF) is a tickborne infection that can range from asymptomatic to fatal and has been described in >30 countries. Early identification and isolation of patients with suspected or confirmed CCHF and the use of appropriate prevention and control measures are essential for preventing human-to-human transmission. Here, we provide an overview of the epidemiology, clinical features, and prevention and control of CCHF. CCHF poses a continued public health threat given its wide geographic distribution, potential to spread to new regions, propensity for genetic variability, and potential for severe and fatal illness, in addition to the limited medical countermeasures for prophylaxis and treatment. A high index of suspicion, comprehensive travel and epidemiologic history, and clinical evaluation are essential for prompt diagnosis. Infection control measures can be effective in reducing the risk for transmission but require correct and consistent application.

Crimean-Congo hemorrhagic fever virus (CCHFV) is the most geographically widespread tickborne viral infection worldwide and has a fatality rate of up to 62%. Despite its widespread range and high fatality rate, no vaccines or treatments are currently approved by regulatory agencies in the United States or Europe. Supportive treatment remains the standard of care, but the use of antiviral medications developed for other viral infections have been considered. We reviewed published literature to summarize the main aspects of CCHFV infection in humans. We provide an overview of diagnostic testing and management and medical countermeasures, including investigational vaccines and limited therapeutics. CCHFV continues to pose a public health threat because of its wide geographic distribution, potential to spread to new regions, propensity for genetic variability, potential for severe and fatal illness, and limited medical countermeasures for prophylaxis and treatment. Clinicians should become familiar with available diagnostic and management tools for CCHFV infections in humans.

Jamestown Canyon virus (JCV) is a mosquitoborne orthobunyavirus in the California serogroup that circulates throughout Canada and the United States. Most JCV exposures result in asymptomatic infection or a mild febrile illness, but JCV can also cause neurologic diseases, such as meningitis and encephalitis. We describe a case series of confirmed JCV-mediated neuroinvasive disease among persons from the provinces of British Columbia, Alberta, Quebec, and Nova Scotia, Canada, during 2011–2016. We highlight the case definitions, epidemiology, unique features and clinical manifestations, disease seasonality, and outcomes for those cases. Two of the patients (from Quebec and Nova Scotia) might have acquired JCV infections during travel to the northeastern region of the United States. This case series collectively demonstrates JCV’s wide distribution and indicates the need for increased awareness of JCV as the underlying cause of meningitis/meningoencephalitis during mosquito season.

We analyzed hospital discharge records of patients with coccidioidomycosis-related codes from the International Classification of Diseases, 10th revision, Clinical Modification, to estimate the prevalence of hospital visits associated with the disease in Texas, USA. Using Texas Health Care Information Collection data for 2016–2021, we investigated the demographic characteristics and geographic distribution of the affected population, assessed prevalence of hospital visits for coccidioidomycosis, and examined how prevalence varied by demographic and geographic factors. In Texas, 709 coccidioidomycosis-related inpatient and outpatient hospital visits occurred in 2021; prevalence was 3.17 cases per 100,000 total hospital visits in 2020. Geographic location, patient sex, and race/ethnicity were associated with increases in coccidioidomycosis-related hospital visits; male, non-Hispanic Black, and Hispanic patients had the highest prevalence of coccidioidomycosis compared with other groups. Increased surveillance and healthcare provider education and outreach are needed to ensure timely and accurate diagnosis and treatment of coccidioidomycosis in Texas and elsewhere.

High incidences of congenital syphilis have been reported in areas along the Pacific coast of Colombia. In this retrospective study, conducted during 2018–2022 at a public hospital in Buenaventura, Colombia, we analyzed data from 3,378 pregnant women. The opportunity to prevent congenital syphilis was missed in 53.1% of mothers because of the lack of syphilis screening. Characteristics of higher maternal social vulnerability and late access to prenatal care decreased the probability of having > 1 syphilis screening test, thereby increasing the probability of having newborns with congenital syphilis. In addition, the opportunity to prevent congenital syphilis was missed in 41.5% of patients with syphilis because of the lack of treatment, which also increased the probability of having newborns with congenital syphilis. We demonstrate the urgent need to improve screening and treatment capabilities for maternal syphilis, particularly among pregnant women who are more socially vulnerable.

Understanding SARS-CoV-2 infection in populations at increased risk for poor health is critical to reducing disease. We describe the epidemiology of SARS-CoV-2 infection in Kakuma Refugee Camp Complex, Kenya. We performed descriptive analyses of SARS-CoV-2 infection in the camp and surrounding community during March 16, 2020‒December 31, 2021. We identified cases in accordance with national guidelines.We estimated fatality ratios and attack rates over time using locally weighted scatterplot smoothing for refugees, host community members, and national population. Of the 18,864 SARS-CoV-2 tests performed, 1,024 were positive, collected from 664 refugees and 360 host community members. Attack rates were 325.0/100,000 population (CFR 2.9%) for refugees,150.2/100,000 population (CFR 1.11%) for community, and 628.8/100,000 population (CFR 1.83%) nationwide. During 2020–2021, refugees experienced a lower attack rate but higher CFR than the national population, underscoring the need to prioritize SARS-CoV-2 mitigation measures, including vaccination.

Considering patient room shortages and prevalence of other communicable diseases, reassessing the isolation of patients with Clostridioides difficile infection (CDI) is imperative. We conducted a retrospective study to investigate the secondary CDI transmission rate in a hospital in South Korea, where patients with CDI were not isolated. Using data from a real-time locating system and electronic medical records, we investigated patients who had both direct and indirect contact with CDI index patients. The primary outcome was secondary CDI transmission, identified by whole-genome sequencing. Among 909 direct and 2,711 indirect contact cases, 2 instances of secondary transmission were observed (2 [0.05%] of 3,620 cases), 1 transmission via direct contact and 1 via environmental sources. A low level of direct contact (113 minutes) was required for secondary CDI transmission. Our findings support the adoption of exhaustive standard preventive measures, including environmental decontamination, rather than contact isolation of CDI patients in nonoutbreak settings.

During the 2022 multicountry mpox outbreak, the United Kingdom identified cases beginning in May. UK cases increased in June, peaked in July, then rapidly declined after September 2022. Public health responses included community-supported messaging and targeted mpox vaccination among eligible gay, bisexual, and other men who have sex with men (GBMSM). Using data from an online survey of GBMSM during November–December 2022, we examined self-reported mpox diagnoses, behavioral risk modification, and mpox vaccination offer and uptake. Among 1,333 participants, only 35 (2.6%) ever tested mpox-positive, but 707 (53%) reported behavior modification to avoid mpox. Among vaccine-eligible GBMSM, uptake was 69% (95% CI 65%–72%; 601/875) and was 92% (95% CI 89%–94%; 601/655) among those offered vaccine. GBMSM self-identifying as bisexual, reporting lower educational qualifications, or identifying as unemployed were less likely to be vaccinated. Equitable offer and provision of mpox vaccine are needed to minimize the risk for future outbreaks and mpox-related health inequalities.

We investigated clinically suspected measles cases that had discrepant real-time reverse transcription PCR (rRT-PCR) and measles-specific IgM test results to determine diagnoses. We performed rRT-PCR and measles-specific IgM testing on samples from 541 suspected measles cases. Of the 24 IgM-positive and rRT-PCR­–negative cases, 20 were among children who received a measles-containing vaccine within the previous 6 months; most had low IgG relative avidity indexes (RAIs). The other 4 cases were among adults who had an unknown previous measles history, unknown vaccination status, and high RAIs. We detected viral nucleic acid for viruses other than measles in 15 (62.5%) of the 24 cases with discrepant rRT-PCR and IgM test results. Measles vaccination, measles history, and contact history should be considered in suspected measles cases with discrepant rRT-PCR and IgM test results. If in doubt, measles IgG avidity and PCR testing for other febrile exanthematous viruses can help confirm or refute the diagnosis.

To determine the kinetics of hepatitis E virus (HEV) in asymptomatic persons and to evaluate viral load doubling time and half-life, we retrospectively tested samples retained from 32 HEV RNA-positive asymptomatic blood donors in Germany. Close-meshed monitoring of viral load and seroconversion in intervals of ≈4 days provided more information about the kinetics of asymptomatic HEV infections. We determined that a typical median infection began with PCR-detectable viremia at 36 days and a maximum viral load of 2.0 × 10 4 IU/mL. Viremia doubled in 2.4 days and had a half-life of 1.6 days. HEV IgM started to rise on about day 33 and peaked on day 36; IgG started to rise on about day 32 and peaked on day 53 . Although HEV IgG titers remained stable, IgM titers became undetectable in 40% of donors. Knowledge of the dynamics of HEV viremia is useful for assessing the risk for transfusion-transmitted hepatitis E.

We evaluated Q fever prevalence in blood donors and assessed the epidemiologic features of the disease in Israel in 2021. We tested serum samples for Coxeilla burnetii phase I and II IgG using immunofluorescent assay, defining a result of > 200 as seropositive. We compared geographic and demographic data. We included 1,473 participants; 188 (12.7%) were seropositive. The calculated sex- and age-adjusted national seroprevalence was 13.9% (95% CI 12.2%–15.7%). Male sex and age were independently associated with seropositivity (odds ratio [OR] 1.6, 95% CI 1.1–2.2; p = 0.005 for male sex; OR 1.2, 95% CI 1.01–1.03; p<0.001 for age). Residence in the coastal plain was independently associated with seropositivity for Q fever (OR 1.6, 95% CI 1.2–2.3; p<0.001); residence in rural and farming regions was not. Q fever is highly prevalent in Israel. The unexpected spatial distribution in the nonrural coastal plain suggests an unrecognized mode of transmission.

During December 11, 2020–March 29, 2022, the US government delivered ≈700 million doses of COVID-19 vaccine to vaccination sites, resulting in vaccination of ≈75% of US adults during that period. We evaluated accessibility of vaccination sites. Sites were accessible by walking within 15 minutes by 46.6% of persons, 30 minutes by 74.8%, 45 minutes by 82.8%, and 60 minutes by 86.7%. When limited to populations in counties with high social vulnerability, accessibility by walking was 55.3%, 81.1%, 86.7%, and 89.4%, respectively. By driving, lowest accessibility was 96.5% at 15 minutes. For urban/rural categories, the 15-minute walking accessibility between noncore and large central metropolitan areas ranged from 27.2% to 65.1%; driving accessibility was 79.9% to 99.5%. By 30 minutes driving accessibility for all urban/rural categories was >95.9%. Walking time variations across jurisdictions and between urban/rural areas indicate that potential gains could have been made by improving walkability or making transportation more readily available.

We estimated COVID-19 transmission potential and case burden by variant type in Alberta, British Columbia, and Ontario, Canada, during January 23, 2020–January 27, 2022; we also estimated the effectiveness of public health interventions to reduce transmission. We estimated time-varying reproduction number (R t ) over 7-day sliding windows and nonoverlapping time-windows determined by timing of policy changes. We calculated incidence rate ratios (IRRs) for each variant and compared rates to determine differences in burden among provinces. R t corresponding with emergence of the Delta variant increased in all 3 provinces; British Columbia had the largest increase, 43.85% (95% credible interval [CrI] 40.71%–46.84%). Across the study period, IRR was highest for Omicron (8.74 [95% CrI 8.71–8.77]) and burden highest in Alberta (IRR 1.80 [95% CrI 1.79–1.81]). Initiating public health interventions was associated with lower R t and relaxing restrictions and emergence of new variants associated with increases in R t .

We conducted a large surveillance study among members of an integrated healthcare delivery system in Pacific Northwest of the United States to estimate medical costs attributable to medically attended acute gastroenteritis (MAAGE) on the day care was sought and during 30-day follow-up. We used multivariable regression to compare costs of MAAGE and non-MAAGE cases matched on age, gender, and index time. Differences accounted for confounders, including race, ethnicity, and history of chronic underlying conditions. Analyses included 73,140 MAAGE episodes from adults and 18,617 from children who were Kaiser Permanente Northwest members during 2014–2016. Total costs were higher for MAAGE cases relative to non-MAAGE comparators as were costs on the day care was sought and costs during follow-up. Costs of MAAGE are substantial relative to the cost of usual-care medical services, and much of the burden accrues during short-term follow-up.

We investigated links between antimicrobial resistance in community-onset bacteremia and 1-year bacteremia recurrence by using the clinical data warehouse of Europe’s largest university hospital group in France. We included adult patients hospitalized with an incident community-onset Staphylococcus aureus , Escherichia coli , or Klebsiella spp. bacteremia during 2017–2019. We assessed risk factors of 1-year recurrence using Fine–Gray regression models. Of the 3,617 patients included, 291 (8.0%) had > 1 recurrence episode. Third-generation cephalosporin (3GC)-resistance was significantly associated with increased recurrence risk after incident Klebsiella spp. (hazard ratio 3.91 [95% CI 2.32–6.59]) or E. coli (hazard ratio 2.35 [95% CI 1.50–3.68]) bacteremia. Methicillin resistance in S. aureus bacteremia had no effect on recurrence risk. Although several underlying conditions and infection sources increased recurrence risk, 3GC-resistant Klebsiella spp. was associated with the greatest increase. These results demonstrate a new facet to illness induced by 3GC-resistant Klebsiella spp. and E. coli in the community setting.

We conducted a cross-sectional study in wild boar and extensively managed Iberian pig populations in a hotspot area of Crimean-Congo hemorrhagic fever virus (CCHFV) in Spain. We tested for antibodies against CCHFV by using 2 ELISAs in parallel. We assessed the presence of CCHFV RNA by means of reverse transcription quantitative PCR protocol, which detects all genotypes. A total of 113 (21.8%) of 518 suids sampled showed antibodies against CCHFV by ELISA. By species, 106 (39.7%) of 267 wild boars and 7 (2.8%) of 251 Iberian pigs analyzed were seropositive. Of the 231 Iberian pigs and 231 wild boars analyzed, none tested positive for CCHFV RNA. These findings indicate high CCHFV exposure in wild boar populations in endemic areas and confirm the susceptibility of extensively reared pigs to CCHFV, even though they may only play a limited role in the enzootic cycle.

African swine fever virus (ASFV) genotype II is endemic to Vietnam. We detected recombinant ASFV genotypes I and II (rASFV I/II) strains in domestic pigs from 6 northern provinces in Vietnam. The introduction of rASFV I/II strains could complicate ongoing ASFV control measures in the region.

In a representative sample of female children and adolescents in Germany, Toxoplasma gondii seroprevalence was 6.3% (95% CI 4.7%–8.0%). With each year of life, the chance of being seropositive increased by 1.2, indicating a strong force of infection. Social status and municipality size were found to be associated with seropositivity.

We describe the detection of Paranannizziopsis sp. fungus in a wild population of vipers in Europe. Fungal infections were severe, and 1 animal likely died from infection. Surveillance efforts are needed to better understand the threat of this pathogen to snake conservation.

We evaluated the in vitro effects of lyophilization for 2 vesicular stomatitis virus–based vaccines by using 3 stabilizing formulations and demonstrated protective immunity of lyophilized/reconstituted vaccine in guinea pigs. Lyophilization increased stability of the vaccines, but specific vesicular stomatitis virus–based vaccines will each require extensive analysis to optimize stabilizing formulations.

We report a cluster of serogroup B invasive meningococcal disease identified via genomic surveillance in older adults in England and describe the public health responses. Genomic surveillance is critical for supporting public health investigations and detecting the growing threat of serogroup B Neisseria meningitidis infections in older adults.

We detected Mayaro virus (MAYV) in 3.4% (28/822) of febrile patients tested during 2018–2021 from Roraima State, Brazil. We also isolated MAYV strains and confirmed that these cases were caused by genotype D. Improved surveillance is needed to better determine the burden of MAYV in the Amazon Region.

Across 133 confirmed mpox zoonotic index cases reported during 1970–2021 in Africa, cases occurred year-round near the equator, where climate is consistent. However, in tropical regions of the northern hemisphere under a dry/wet season cycle, cases occurred seasonally. Our findings further support the seasonality of mpox zoonotic transmission risk.

We investigated molecular evolution and spatiotemporal dynamics of atypical Legionella pneumophila serogroup 1 sequence type 1905 and determined its long-term persistence and linkage to human disease in dispersed locations, far beyond the large 2014 outbreak epicenter in Portugal. Our finding highlights the need for public health interventions to prevent further disease spread.

Norovirus is a major cause of acute gastroenteritis; GII.4 is the predominant strain in humans. Recently, 2 new GII.4 variants, Hong Kong 2019 and San Francisco 2017, were reported. Characterization using GII.4 monoclonal antibodies and serum demonstrated different antigenic profiles for the new variants compared with historical variants.

Cruise ships carrying COVID-19–vaccinated populations applied near-identical nonpharmaceutical measures during July–November 2021; passenger masking was not applied on 2 ships. Infection risk for masked passengers was 14.58 times lower than for unmasked passengers and 19.61 times lower than in the community. Unmasked passengers’ risk was slightly lower than community risk.

During a 2023 outbreak of Mycoplasma pneumoniae –associated community-acquired pneumonia among children in northern Vietnam, we analyzed M. pneumoniae isolated from nasopharyngeal samples. In almost half (6 of 13) of samples tested, we found known A2063G mutations (macrolide resistance) and a novel C2353T variant on the 23S rRNA gene.

We report the detection of Crimean-Congo hemorrhagic fever virus (CCHFV) in Corsica, France. We identified CCHFV African genotype I in ticks collected from cattle at 2 different sites in southeastern and central-western Corsica, indicating an established CCHFV circulation. Healthcare professionals and at-risk groups should be alerted to CCHFV circulation in Corsica.

In Latin America, rabies virus has persisted in a cycle between Desmodus rotundus vampire bats and cattle, potentially enhanced by deforestation. We modeled bovine rabies virus outbreaks in Costa Rica relative to land-use indicators and found spatial-temporal relationships among rabies virus outbreaks with deforestation as a predictor.

With the use of metagenomic next-generation sequencing, patients diagnosed with Whipple pneumonia are being increasingly correctly diagnosed. We report a series of 3 cases in China that showed a novel pattern of movable infiltrates and upper lung micronodules. After treatment, the 3 patients recovered, and lung infiltrates resolved.

Dogs are known to be susceptible to influenza A viruses, although information on influenza D virus (IDV) is limited. We investigated the seroprevalence of IDV in 426 dogs in the Apulia region of Italy during 2016 and 2023. A total of 14 samples were positive for IDV antibodies, suggesting exposure to IDV in dogs.

We report the detection of OXA-181 carbapenemase in an azithromycin-resistant Shigella spp. bacteria in an immunocompromised patient. The emergence of OXA-181 in Shigella spp. bacteria raises concerns about the global dissemination of carbapenem resistance in Enterobacterales and its implications for the treatment of infections caused by Shigella bacteria.

Although a vaccine against SARS-CoV-2 Omicron-XBB.1.5 variant is available worldwide and recent infection is protective, the lack of recorded infection data highlights the need to assess variant-specific antibody neutralization levels. We analyzed IgG levels against receptor-binding domain–specific SARS-CoV-2 ancestral strain as a correlate for high neutralizing titers against XBB variants.

We describe a feline sporotrichosis cluster and zoonotic transmission between one of the affected cats and a technician at a veterinary clinic in Kansas, USA. Increased awareness of sporotrichosis and the potential for zoonotic transmission could help veterinary professionals manage feline cases and take precautions to prevent human acquisition.

We report a clinical isolate of Burkholderia thailandensis 2022DZh obtained from a patient with an infected wound in southwest China. Genomic analysis indicates that this isolate clusters with B. thailandensis BPM, a human isolate from Chongqing, China. We recommend enhancing monitoring and surveillance for B. thailandensis infection in both humans and livestock.

To determine changes in Bordetella pertussis and B. parapertussis detection rates, we analyzed 1.43 million respiratory multiplex PCR test results from US facilities from 2019 through mid-2023. From mid-2022 through mid-2023, Bordetella spp. detection increased 8.5-fold; 95% of detections were B. parapertussis. While B. parapertussis rates increased, B. pertussis rates decreased.

We report a case of Sphingobium yanoikuyae bacteremia in an 89-year-old patient in Japan. No standard antimicrobial regimen has been established for S. yanoikuyae infections. However, ceftriaxone and ceftazidime treatments were effective in this case. Increased antimicrobial susceptibility data are needed to establish appropriate treatments for S. yanoikuyae .

Disclaimer: Early release articles are not considered as final versions. Any changes will be reflected in the online version in the month the article is officially released.

Volume 30, Number 6—June 2024

Perspective.

• Decolonization and Pathogen Reduction to Prevent Antimicrobial Resistance and Healthcare-Associated Infections M. R. Mangalea et al.
• Deciphering Unexpected Vascular Locations of Scedosporium spp. and Lomentospora prolificans Fungal Infections, France C. Vignals et al.
• An Electronic Health Record–Based Algorithm for Respiratory Virus–like Illness N. M. Cocoros et al.
• Severe Human Parainfluenza Virus Community- and Healthcare-Acquired Pneumonia in Adults at Tertiary Hospital in Seoul, South Korea, 2010–2019 J. H. Park et al.
• SARS-CoV-2 Disease Severity in Children during Pre-Delta, Delta, and Omicron Periods, Colorado L. Bankers et al.
• Effectiveness of 23-Valent Pneumococcal Polysaccharide Vaccine Against Invasive Pneumococcal Disease in Follow-Up Study, Denmark K. Nielsen et al.
• Chest Radiograph Screening for Detection of Subclinical Tuberculosis in Asymptomatic Household Contacts, Peru Q. Tan et al.
• Outbreak of Highly Pathogenic Avian Influenza Virus H5N1 in Seals in the St. Lawrence Estuary, Quebec, Canada S. Lair et al.
• Carbapenem-Resistant and Extended-Spectrum β-Lactamase–Producing Enterobacterales Cases among Children, United States, 2016–2020 H. N. Grome et al.
• Antibodies to H5N1 Influenza A Virus in Retrieving Hunting Dogs, Washington State, USA J. D. Brown et al.

We characterized the evolution and molecular characteristics of avian influenza A(H7N9) viruses isolated in China during 2021–2023. We systematically analyzed the 10-year evolution of the hemagglutinin gene to determine the evolutionary branch. Our results showed recent antigenic drift, providing crucial clues for updating the H7N9 vaccine and disease prevention and control.

• Burkholderia semiarida as Cause of Recurrent Pulmonary Infection in Immunocompetent Patient, China D. Kuang et al.
• SARS-CoV-2 in Captive Nonhuman Primates, Spain, 2020–2023 D. Cano-Terriza et al.
• Infection- and Vaccine-Induced SARS-CoV-2 Seroprevalence in Persons 0–101 Years of Age, Japan, 2023 R. Kinoshita et al.
• Zoonotic Ancylostoma ceylanicum Infection in Coyotes from the Guanacaste Conservation Area, Costa Rica, 2021 P. A. Zendejas-Heredia et al.
• Detection of Encephalitozoon cuniculi in Cerebrospinal Fluid from Immunocompetent Patients, Czech Republic B. Sak et al.
• Emergence of Group B Streptococcus Disease in Pigs and Porcupines, Italy C. Garbarino et al.
• Molecular Identification of Fonsecaea monophora , Novel Agent of Fungal Brain Abscess S. Gourav et al.

During May–July 2023, a cluster of 7 patients at local hospitals in Florida, USA, received a diagnosis of Plasmodium vivax malaria. Whole-genome sequencing of the organism from 4 patients and phylogenetic analysis with worldwide representative P. vivax genomes indicated probable single parasite introduction from Central/South America.

Because novel SARS-CoV-2 variants continue to emerge, immunogenicity of XBB.1.5 monovalent vaccines against live clinical isolates needs to be evaluated. We report boosting of IgG (2.1×), IgA (1.5×), and total IgG/A/M (1.7×) targeting the spike receptor-binding domain and neutralizing titers against WA1 (2.2×), XBB.1.5 (7.4×), EG.5.1 (10.5×), and JN.1 (4.7×) variants.

Using the GISAID EpiCoV database, we identified 256 COVID-19 patients in Japan during March 31–December 31, 2023, who had mutations in the SARS-CoV-2 nonstructural protein 5 conferring ensitrelvir resistance. Ongoing genomic surveillance is required to monitor emergence of SARS-CoV-2 mutations that are resistant to anticoronaviral drugs.

• Novel Avian Influenza A(H5N6) in Wild Birds, South Korea, 2023 A. Cho et al.

Volume 30, Number 7—July 2024

• Borrelia miyamotoi -associated Acute Meningoencephalitis, Minnesota, United States J. M. Kubiak et al.

Research Letter

• Pasteurella bettyae Infections in Men Who Have Sex With Men, France A. Li et al.

Medscape, LLC is pleased to provide online continuing medical education (CME) for selected journal articles, allowing clinicians the opportunity to earn CME credit. In support of improving patient care, these activities have been planned and implemented by Medscape, LLC and Emerging Infectious Diseases. Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. CME credit is available for one year after publication.

Active CME Articles

During October 2021–June 2023, a total of 392 cases of acute hepatitis of unknown etiology in children in the United States were reported to Centers for Disease Control and Prevention as part of national surveillance. We describe demographic and clinical characteristics, including potential involvement of adenovirus in development of acute hepatitis, of 8 fatally ill children who met reporting criteria. The children had diverse courses of illness. Two children were immunocompromised when initially brought for care. Four children tested positive for adenovirus in multiple specimen types, including 2 for whom typing was completed. One adenovirus-positive child had no known underlying conditions, supporting a potential relationship between adenovirus and acute hepatitis in previously healthy children. Our findings emphasize the importance of continued investigation to determine the mechanism of liver injury and appropriate treatment. Testing for adenovirus in similar cases could elucidate the role of the virus.

In 2022, concurrent outbreaks of hepatitis A, invasive meningococcal disease (IMD), and mpox were identified in Florida, USA, primarily among men who have sex with men. The hepatitis A outbreak (153 cases) was associated with hepatitis A virus genotype IA. The IMD outbreak (44 cases) was associated with Neisseria meningitidis serogroup C, sequence type 11, clonal complex 11. The mpox outbreak in Florida (2,845 cases) was part of a global epidemic. The hepatitis A and IMD outbreaks were concentrated in Central Florida and peaked during March–­June, whereas mpox cases were more heavily concentrated in South Florida and had peak incidence in August. HIV infection was more common (52%) among mpox cases than among hepatitis A (21%) or IMD (34%) cases. Where feasible, vaccination against hepatitis A, meningococcal disease, and mpox should be encouraged among at-risk groups and offered along with program services that target those groups.

Disseminated leishmaniasis (DL) is an emergent severe disease manifesting with multiple lesions. To determine the relationship between immune response and clinical and therapeutic outcomes, we studied 101 DL and 101 cutaneous leishmaniasis (CL) cases and determined cytokines and chemokines in supernatants of mononuclear cells stimulated with leishmania antigen. Patients were treated with meglumine antimoniate (20 mg/kg) for 20 days (CL) or 30 days (DL); 19 DL patients were instead treated with amphotericin B, miltefosine, or miltefosine and meglumine antimoniate. High levels of chemokine ligand 9 were associated with more severe DL. The cure rate for meglumine antimoniate was low for both DL (44%) and CL (60%), but healing time was longer in DL (p = 0.003). The lowest cure rate (22%) was found in DL patients with >100 lesions. However, meglumine antimoniate/miltefosine treatment cured all DL patients who received it; therefore, that combination should be considered as first choice therapy.

Streptococcus suis , a zoonotic bacterial pathogen circulated through swine, can cause severe infections in humans. Because human S. suis infections are not notifiable in most countries, incidence is underestimated. We aimed to increase insight into the molecular epidemiology of human S. suis infections in Europe. To procure data, we surveyed 7 reference laboratories and performed a systematic review of the scientific literature. We identified 236 cases of human S. suis infection from those sources and an additional 87 by scanning gray literature. We performed whole-genome sequencing to type 46 zoonotic S. suis isolates and combined them with 28 publicly available genomes in a core-genome phylogeny. Clonal complex (CC) 1 isolates accounted for 87% of typed human infections; CC20, CC25, CC87, and CC94 also caused infections. Emergence of diverse zoonotic clades and notable severity of illness in humans support classifying S. suis infection as a notifiable condition.

During January–August 2021, the Community Prevalence of SARS-CoV-2 Study used time/location sampling to recruit a cross-sectional, population-based cohort to estimate SARS-CoV-2 seroprevalence and nasal swab sample PCR positivity across 15 US communities. Survey-weighted estimates of SARS-CoV-2 infection and vaccine willingness among participants at each site were compared within demographic groups by using linear regression models with inverse variance weighting. Among 22,284 persons > 2 months of age and older, median prevalence of infection (prior, active, or both) was 12.9% across sites and similar across age groups. Within each site, average prevalence of infection was 3 percentage points higher for Black than White persons and average vaccine willingness was 10 percentage points lower for Black than White persons and 7 percentage points lower for Black persons than for persons in other racial groups. The higher prevalence of SARS-CoV-2 infection among groups with lower vaccine willingness highlights the disparate effect of COVID-19 and its complications.

Invasive fusariosis can be life-threatening, especially in immunocompromised patients who require intensive care unit (ICU) admission. We conducted a multicenter retrospective study to describe clinical and biologic characteristics, patient outcomes, and factors associated with death and response to antifungal therapy. We identified 55 patients with invasive fusariosis from 16 ICUs in France during 2002­–­­2020. The mortality rate was high (56%). Fusariosis-related pneumonia occurred in 76% of patients, often leading to acute respiratory failure. Factors associated with death included elevated sequential organ failure assessment score at ICU admission or history of allogeneic hematopoietic stem cell transplantation or hematologic malignancies. Neither voriconazole treatment nor disseminated fusariosis were strongly associated with response to therapy. Invasive fusariosis can lead to multiorgan failure and is associated with high mortality rates in ICUs. Clinicians should closely monitor ICU patients with a history of hematologic malignancies or stem cell transplantation because of higher risk for death.

Using whole-genome sequencing, we characterized Escherichia coli strains causing early-onset sepsis (EOS) in 32 neonatal cases from a 2019–2021 prospective multicenter study in France and compared them to E. coli strains collected from vaginal swab specimens from women in third-trimester gestation. We observed no major differences in phylogenetic groups or virulence profiles between the 2 collections. However, sequence type (ST) analysis showed the presence of 6/32 (19%) ST1193 strains causing EOS, the same frequency as in the highly virulent clonal group ST95. Three ST1193 strains caused meningitis, and 3 harbored extended-spectrum β-lactamase. No ST1193 strains were isolated from vaginal swab specimens. Emerging ST1193 appears to be highly prevalent, virulent, and antimicrobial resistant in neonates. However, the physiopathology of EOS caused by ST1193 has not yet been elucidated. Clinicians should be aware of the possible presence of E. coli ST1193 in prenatal and neonatal contexts and provide appropriate monitoring and treatment.

We describe detection of the previously rarely reported gram-positive bacterium Auritidibacter ignavus in 3 cases of chronic ear infections in Germany. In all 3 cases, the patients had refractory otorrhea. Although their additional symptoms varied, all patients had an ear canal stenosis and A. ignavus detected in microbiologic swab specimens. A correct identification of A. ignavus in the clinical microbiology laboratory is hampered by the inability to identify it by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Also, the bacterium might easily be overlooked because of its morphologic similarity to bacterial species of the resident skin flora. We conclude that a high index of suspicion is warranted to identify A. ignavus and that it should be particularly considered in patients with chronic external otitis who do not respond clinically to quinolone ear drop therapy.

We reviewed invasive Nocardia infections in 3 noncontiguous geographic areas in the United States during 2011–2018. Among 268 patients with invasive nocardiosis, 48.2% were from Minnesota, 32.4% from Arizona, and 19.4% from Florida. Predominant species were N. nova complex in Minnesota (33.4%), N. cyriacigeorgica in Arizona (41.4%), and N. brasiliensis in Florida (17.3%). Transplant recipients accounted for 82/268 (30.6%) patients overall: 14 (10.9%) in Minnesota, 35 (40.2%) in Arizona, and 33 (63.5%) in Florida. Manifestations included isolated pulmonary nocardiosis among 73.2% of transplant and 84.4% of non–transplant patients and central nervous system involvement among 12.2% of transplant and 3.2% of non–transplant patients. N. farcinica (20.7%) and N. cyriacigeorgica (19.5%) were the most common isolates among transplant recipients and N. cyriacigeorgica (38.0%), N. nova complex (23.7%), and N. farcinica (16.1%) among non–transplant patients. Overall antimicrobial susceptibilities were similar across the 3 study sites.

We collected stool from school-age children from 352 households living in the Black Belt region of Alabama, USA, where sanitation infrastructure is lacking. We used quantitative reverse transcription PCR to measure key pathogens in stool that may be associated with water and sanitation, as an indicator of exposure. We detected genes associated with > 1 targets in 26% of specimens, most frequently Clostridioides difficile (6.6%), atypical enteropathogenic Escherichia coli (6.1%), and enteroaggregative E. coli (3.9%). We used generalized estimating equations to assess reported risk factors for detecting > 1 pathogen in stool. We found no association between lack of sanitation and pathogen detection (adjusted risk ratio 0.95 [95% CI 0.55–1.7]) compared with specimens from children served by sewerage. However, we did observe an increased risk for pathogen detection among children living in homes with well water (adjusted risk ratio 1.7 [95% CI 1.1–2.5]) over those reporting water utility service.

Campylobacter fetus accounts for 1% of Campylobacter spp. infections, but prevalence of bacteremia and risk for death are high. To determine clinical features of C. fetus infections and risks for death, we conducted a retrospective observational study of all adult inpatients with a confirmed C. fetus infection in Nord Franche-Comté Hospital, Trevenans, France, during January 2000–December 2021. Among 991 patients with isolated Campylobacter spp. strains, we identified 39 (4%) with culture-positive C. fetus infections, of which 33 had complete records and underwent further analysis; 21 had documented bacteremia and 12 did not. Secondary localizations were reported for 7 (33%) patients with C. fetus bacteremia, of which 5 exhibited a predilection for vascular infections (including 3 with mycotic aneurysm). Another 7 (33%) patients with C. fetus bacteremia died within 30 days. Significant risk factors associated with death within 30 days were dyspnea, quick sequential organ failure assessment score > 2 at admission, and septic shock.

Group A Streptococcus (GAS) primary peritonitis is a rare cause of pediatric acute abdomen (sudden onset of severe abdominal pain); only 26 pediatric cases have been reported in the English language literature since 1980. We discuss 20 additional cases of pediatric primary peritonitis caused by GAS among patients at Starship Children’s Hospital, Auckland, New Zealand, during 2010–2022. We compare identified cases of GAS primary peritonitis to cases described in the existing pediatric literature. As rates of rates of invasive GAS increase globally, clinicians should be aware of this cause of unexplained pediatric acute abdomen.

In Mississippi, USA, infant hospitalization with congenital syphilis (CS) spiked by 1,000%, from 10 in 2016 to 110 in 2022. To determine the causes of this alarming development, we analyzed Mississippi hospital discharge data to evaluate trends, demographics, outcomes, and risk factors for infants diagnosed with CS hospitalized during 2016–2022. Of the 367 infants hospitalized with a CS diagnosis, 97.6% were newborn, 92.6% were covered by Medicaid, 71.1% were African American, and 58.0% were nonurban residents. Newborns with CS had higher odds of being affected by maternal illicit drug use, being born prematurely (<37 weeks), and having very low birthweight (<1,500 g) than those without CS. Mean length of hospital stay (14.5 days vs. 3.8 days) and mean charges ($56,802 vs. $13,945) were also higher for infants with CS than for those without. To address escalation of CS, Mississippi should invest in comprehensive prenatal care and early treatment of vulnerable populations.

Ongoing surveillance after pneumococcal conjugate vaccination (PCV) deployment is essential to inform policy decisions and monitor serotype replacement. We report serotype and disease severity trends in 3,719 adults hospitalized for pneumococcal disease in Bristol and Bath, United Kingdom, during 2006–2022. Of those cases, 1,686 were invasive pneumococcal disease (IPD); 1,501 (89.0%) had a known serotype. IPD decreased during the early COVID-19 pandemic but during 2022 gradually returned to prepandemic levels. Disease severity changed throughout this period: CURB65 severity scores and inpatient deaths decreased and ICU admissions increased. PCV7 and PCV13 serotype IPD decreased from 2006–2009 to 2021–2022. However, residual PCV13 serotype IPD remained, representing 21.7% of 2021–2022 cases, indicating that major adult PCV serotype disease still occurs despite 17 years of pediatric PCV use. Percentages of serotype 3 and 8 IPD increased, and 19F and 19A reemerged. In 2020–2022, a total of 68.2% IPD cases were potentially covered by PCV20.

Borrelia miyamotoi , transmitted by Ixodes spp. ticks, was recognized as an agent of hard tick relapsing fever in the United States in 2013. Nine state health departments in the Northeast and Midwest have conducted public health surveillance for this emerging condition by using a shared, working surveillance case definition. During 2013–2019, a total of 300 cases were identified through surveillance; 166 (55%) were classified as confirmed and 134 (45%) as possible. Median age of case-patients was 52 years (range 1–86 years); 52% were male. Most cases (70%) occurred during June–September, with a peak in August. Fever and headache were common symptoms; 28% of case-patients reported recurring fevers, 55% had arthralgia, and 16% had a rash. Thirteen percent of patients were hospitalized, and no deaths were reported. Ongoing surveillance will improve understanding of the incidence and clinical severity of this emerging disease.

During 2006–2021, Canada had 55 laboratory-confirmed outbreaks of foodborne botulism, involving 67 cases. The mean annual incidence was 0.01 case/100,000 population. Foodborne botulism in Indigenous communities accounted for 46% of all cases, which is down from 85% of all cases during 1990–2005. Among all cases, 52% were caused by botulinum neurotoxin type E, but types A (24%), B (16%), F (3%), and AB (1%) also occurred; 3% were caused by undetermined serotypes. Four outbreaks resulted from commercial products, including a 2006 international outbreak caused by carrot juice. Hospital data indicated that 78% of patients were transferred to special care units and 70% required mechanical ventilation; 7 deaths were reported. Botulinum neurotoxin type A was associated with much longer hospital stays and more time spent in special care than types B or E. Foodborne botulism often is misdiagnosed. Increased clinician awareness can improve diagnosis, which can aid epidemiologic investigations and patient treatment.

Corynebacterium ulcerans is a closely related bacterium to the diphtheria bacterium C. diphtheriae , and some C. ulcerans strains produce toxins that are similar to diphtheria toxin. C. ulcerans is widely distributed in the environment and is considered one of the most harmful pathogens to livestock and wildlife. Infection with C. ulcerans can cause respiratory or nonrespiratory symptoms in patients. Recently, the microorganism has been increasingly recognized as an emerging zoonotic agent of diphtheria-like illness in Japan. To clarify the overall clinical characteristics, treatment-related factors, and outcomes of C. ulcerans infection, we analyzed 34 cases of C. ulcerans that occurred in Japan during 2001–2020. During 2010–2020, the incidence rate of C. ulcerans infection increased markedly, and the overall mortality rate was 5.9%. It is recommended that adults be vaccinated with diphtheria toxoid vaccine to prevent the spread of this infection.

Mycolicibacterium neoaurum is a rapidly growing mycobacterium and an emerging cause of human infections. M. neoaurum infections are uncommon but likely underreported, and our understanding of the disease spectrum and optimum management is incomplete. We summarize demographic and clinical characteristics of a case of catheter-related M. neoaurum bacteremia in a child with leukemia and those of 36 previously reported episodes of M. neoaurum infection. Most infections occurred in young to middle-aged adults with serious underlying medical conditions and commonly involved medical devices. Overall, infections were not associated with severe illness or death. In contrast to other mycobacteria species, M. neoaurum was generally susceptible to multiple antimicrobial drugs and responded promptly to treatment, and infections were associated with good outcomes after relatively short therapy duration and device removal. Delays in identification and susceptibility testing were common. We recommend using combination antimicrobial drug therapy and removal of infected devices to eradicate infection.

We retrospectively reviewed consecutive cases of mucormycosis reported from a tertiary-care center in India to determine the clinical and mycologic characteristics of emerging Rhizopus homothallicus fungus. The objectives were ascertaining the proportion of R. homothallicus infection and the 30-day mortality rate in rhino-orbital mucormycosis attributable to R. homothallicus compared with R. arrhizus. R. homothallicus accounted for 43 (6.8%) of the 631 cases of mucormycosis. R. homothallicus infection was independently associated with better survival (odds ratio [OR] 0.08 [95% CI 0.02–0.36]; p = 0.001) than for R. arrhizus infection (4/41 [9.8%] vs. 104/266 [39.1%]) after adjusting for age, intracranial involvement, and surgery. We also performed antifungal-susceptibility testing, which indicated a low range of MICs for R. homothallicus against the commonly used antifungals (amphotericin B [0.03–16], itraconazole [0.03–16], posaconazole [0.03–8], and isavuconazole [0.03–16]). 18S gene sequencing and amplified length polymorphism analysis revealed distinct clustering of R. homothallicus .

Zoonotic outbreaks of sporotrichosis are increasing in Brazil. We examined and described the emergence of cat-transmitted sporotrichosis (CTS) caused by the fungal pathogen Sporothrix brasiliensis . We calculated incidence and mapped geographic distribution of cases in Curitiba, Brazil, by reviewing medical records from 216 sporotrichosis cases diagnosed during 2011–May 2022. Proven sporotrichosis was established in 84 (39%) patients and probable sporotrichosis in 132 (61%). Incidence increased from 0.3 cases/100,000 outpatient visit-years in 2011 to 21.4 cases/100,000 outpatient visit-years in 2021; of the 216 cases, 58% (n = 126) were diagnosed during 2019–2021. The main clinical form of sporotrichosis was lymphocutaneous (63%), followed by localized cutaneous (24%), ocular (10%), multisite infections (3%), and cutaneous disseminated (<0.5%). Since the first report of CTS in Curitiba in 2011, sporotrichosis has increased substantially, indicating continuous disease transmission. Clinician and public awareness of CTS and efforts to prevent transmission are needed.

Babesiosis is a globally distributed parasitic infection caused by intraerythrocytic protozoa. The full spectrum of neurologic symptoms, the underlying neuropathophysiology, and neurologic risk factors are poorly understood. Our study sought to describe the type and frequency of neurologic complications of babesiosis in a group of hospitalized patients and assess risk factors that might predispose patients to neurologic complications. We reviewed medical records of adult patients who were admitted to Yale-New Haven Hospital, New Haven, Connecticut, USA, during January 2011–October 2021 with laboratory-confirmed babesiosis. More than half of the 163 patients experienced > 1 neurologic symptoms during their hospital admissions. The most frequent symptoms were headache, confusion/delirium, and impaired consciousness. Neurologic symptoms were associated with high-grade parasitemia, renal failure, and history of diabetes mellitus. Clinicians working in endemic areas should recognize the range of symptoms associated with babesiosis, including neurologic.

Tularemia is a zoonotic infection caused by Francisella tularensis . Its most typical manifestations in humans are ulceroglandular and glandular; infections in prosthetic joints are rare. We report 3 cases of F. tularensis subspecies holarctica –related prosthetic joint infection that occurred in France during 2016–2019. We also reviewed relevant literature and found only 5 other cases of Francisella -related prosthetic joint infections worldwide, which we summarized. Among those 8 patients, clinical symptoms appeared 7 days to 19 years after the joint placement and were nonspecific to tularemia. Although positive cultures are typically obtained in only 10% of tularemia cases, strains grew in all 8 of the patients. F. tularensis was initially identified in 2 patients by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; molecular methods were used for 6 patients. Surgical treatment in conjunction with long-term antimicrobial treatment resulted in favorable outcomes; no relapses were seen after 6 months of follow-up.

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EUROPEAN RESEARCH STUDIES JOURNAL ISSN: 1108-2976

Volume xxiv, issue 2b, 2021, dynamic capabilities affecting the functioning of e-administration in polish public admistration entities liliana hawrysz european research studies journal , volume xxiv, issue 2b, 3-22, 2021 view article download article, e-consumers and their agile qualities as creators of eco-innovations: a case study agnieszka rzepka, magdalena maciaszczyk, anna maria wisniewska, maria kocot european research studies journal , volume xxiv, issue 2b, 23-38, 2021 view article download article, changes in the journalist’s profession caused by the covid-19 pandemic in the context of relations with representatives of the public relations industry dariusz tworzydlo, slawomir gawronski, ewelina nycz european research studies journal , volume xxiv, issue 2b, 39-51, 2021 view article download article, managing support for entrepreneurs during a pandemic: the problem of proper selection of those in need arkadiusz gorski european research studies journal , volume xxiv, issue 2b, 52-61, 2021 view article download article, influence of economic and political variables on the mortality rate per covid-19 javier cifuentes-faura european research studies journal , volume xxiv, issue 2b, 62-67, 2021 view article download article, safe business in a pandemic risk environment agnieszka parkitna european research studies journal , volume xxiv, issue 2b, 68-77, 2021 view article download article, supply chain performance measurement system of logistics service providers vs. supply chain performance: a conceptual framework rafal haffer european research studies journal , volume xxiv, issue 2b, 78-97, 2021 view article download article, changes in the global shipbuilding industry on the examples of selected states worldwide in the 21st century malgorzata kamola-cieslik european research studies journal , volume xxiv, issue 2b, 98-112, 2021 view article download article, liabilities of local government units in poland: identification and analysis of diversification factors alinska agnieszka, kosztowniak aneta, wajda marcin european research studies journal , volume xxiv, issue 2b, 113-134, 2021 view article download article, electromobility and its development prospects in the context of industry 4.0: a comparative study of poland and the european union wojciech lewicki, wojciech drozdz european research studies journal , volume xxiv, issue 2b, 135-144, 2021 view article download article, principles of entrepreneurship auditing: a framework for understanding audit efficacy zbyslaw dobrowolski european research studies journal , volume xxiv, issue 2b, 145-157, 2021 view article download article, the tourism sector under uncertainty due to covid-19 pandemic and the assumptions of new institutional economics* barbara marciszewska european research studies journal , volume xxiv, issue 2b, 158-169, 2021 view article download article, the influence of the ethnic diversity on the regional development as exemplified by the silesian autochthonous population in poland katarzyna lukaniszyn-domaszewska, romuald jonczy european research studies journal , volume xxiv, issue 2b, 170-188, 2021 view article download article, a model on the decision to conduct independent verification of csr data: the case of poland jolanta wisniewska, joanna gorka european research studies journal , volume xxiv, issue 2b, 189-212, 2021 view article download article, sustainable remote work market – diagnosis of digital it, information and functional competences in the aspect of equal opportunities artur kwasek, magdalena maciaszczyk, maria kocot, adam depta european research studies journal , volume xxiv, issue 2b, 213-226, 2021 view article download article, the organizational conditions impacting on employees’ perception of counter-ecological behaviors anna szeliga-duchnowska european research studies journal , volume xxiv, issue 2b, 227-239, 2021 view article download article, cybersecurity as the main challenge to the effective use of digital technology platforms in e-commerce krzysztof bartczak european research studies journal , volume xxiv, issue 2b, 240-256, 2021 view article download article, technological innovation at pc sector during covid-crisis adam swida, yasmin ziaeian european research studies journal , volume xxiv, issue 2b, 257-265, 2021 view article download article, continuity of care as a customer service quality indicator in health sector iga rudawska european research studies journal , volume xxiv, issue 2b, 266-275, 2021 view article download article, road transport in poland - status and development prospects bartosz zakrzewski, katarzyna szopik-depczynska european research studies journal , volume xxiv, issue 2b, 276-289, 2021 view article download article, investment funds of emerging markets as alternative forms of capital investment in the conditions of low interest rates rubaj piotr, wazna elzbieta european research studies journal , volume xxiv, issue 2b, 290-307, 2021 view article download article, nautical tourism in croatia and the covid-19 pandemic aleksandra lapko, ewa hacia, lovorko lucic european research studies journal , volume xxiv, issue 2b, 308-319, 2021 view article download article, impact of eu funds on the level of regional socio-economic development: the case of poland elzbieta ociepa-kicinska, rafal czyzycki, piotr szklarz , rafal kloska european research studies journal , volume xxiv, issue 2b, 328-362, 2021 view article download article, the choice between publicly and privately financed health care systems in the context of access to health care services in rural areas of west pomerania voivodship dorota rdzanek, marek bulsa european research studies journal , volume xxiv, issue 2b, 363-370, 2021 view article download article, business μodels of βanks for the financial markets in the eu* igor kravchuk, viktoriia stoika european research studies journal , volume xxiv, issue 2b, 371-382, 2021 view article download article, lessons from covid‑19: toward the conceptual model of university management during pandemic jagoda mrzyglocka-chojnacka, radoslaw rynca european research studies journal , volume xxiv, issue 2b, 383-393, 2021 view article download article, identification of areas of corporate social responsibility based on the example of polish and german seaports in the baltic sea region marianna maruszczak, natalia drop, piotr durajczyk european research studies journal , volume xxiv, issue 2b, 394-409, 2021 view article download article, the intellectual capital and its impact on the sustainable development of the sml-sized enterprises in poland elwira gross-golacka, marta kusterka-jefmanska, radoslaw miskiewicz, bartlomiej jefmanski, agnieszka rzepka, teresa kupczyk european research studies journal , volume xxiv, issue 2b, 410-429, 2021 view article download article, the level of economic development and the savings rate of households malgorzata grzywinska-rapca, aleksandra a. olejarz european research studies journal , volume xxiv, issue 2b, 430-442, 2021 view article download article, motivational impact of environmental management on the environmental awareness in a workplace boleslaw goranczewski, anna szeliga-duchnowska european research studies journal , volume xxiv, issue 2b, 443-455, 2021 view article download article, language audit in the management of language and cultural competences: research on the european program children's university ‘little polyglot’ elzbieta szaruga, agnieszka szlachta, nina pielacinska european research studies journal , volume xxiv, issue 2b, 456-468, 2021 view article download article, events and festivals in times of uncertainty dariusz kloskowski, grzegorz kwiatkowski european research studies journal , volume xxiv, issue 2b, 469-487, 2021 view article download article, use of the port community system in sustainable ship-generated waste management agnieszka deja, magdalena kaup, marek grobarczyk, wojciech slaczka european research studies journal , volume xxiv, issue 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consumer neuroscience – the application of selected neurobiological methods in consumer research barbara wasikowska european research studies journal , volume xxiv, issue 2b, 1153-1162, 2021 view article download article, quality of life of young consumers: evidence from poland agnieszka bretyn european research studies journal , volume xxiv, issue 2b, 1163-1173, 2021 view article download article, implementation of the directive 2006/7/ec in selected eu member states in the 2017-2019 period apoloniusz kurylczyk, tomasz czapiewski, malgorzata zakrzewska european research studies journal , volume xxiv, issue 2b, 1174-1184, 2021 view article download article.

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Highly Pathogenic Bird Flu Detected For The First Time In Common Bottlenose Dolphin

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The bottlenose dolphin died in Florida in March 2022.

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The brain tissues of the bottlenose dolphin showed similar characteristics to other infected species.

Image Credit: Wonderful Nature/Shutterstock.com

Unfortunately, bird flu shows no signs of slowing down. As well as infecting scores of bird life  and even showing up in milk , the virus has been known to spread to mammalian species, including bears , and seals. Now, new research reports the first case of highly pathogenic avian influenza (HPAI) virus in a common bottlenose dolphin ( Tursiops truncatus ) observed in Florida. 

The clade of 2.3.4.4b A(H5N1) viruses has been seen in common dolphins ( Delphinus delphis ), harbor porpoises ( Phocoena phocoena ), and an Atlantic white-sided dolphin ( Lagenorhynchus acutus ) in places such as Peru, the United Kingdom, Sweden, and Canada, highlighting how widespread this virus can be found in cetaceans . 

Some of the mammal species are suspected to have caught the virus through consuming infected birds. Examination of these carcasses and other species with the disease have shown meningoencephalitis, a condition involving swelling and inflammation of the area around the brain and spinal cord. This can cause unusual behaviors in the species that exhibit these symptoms prior to passing away. 

On March 29, 2022 , a dolphin was reported to be in distress and trapped between a seawall and a dock piling near West Horseshoe Beach in Dixie County, Florida. The team arrived to find the dolphin had died despite attempts to free the dolphin from the channel. 

“We still don’t know where the dolphin got the virus and more research needs to be done,” said Dr Richard Webby, who directs the World Health Organization Collaborating Center for Studies on the Ecology of Influenza in Animals and Birds at St. Jude’s, in a  statement ,

A postmortem revealed that the male dolphin was in a thin body condition, with an empty gastrointestinal tract and numerous lacerations to the body. On closer examination, the team discovered inflammation in the brain, in a similar manner to those previously seen in other mammal species. 

The presence of A(H5N1) was subsequently tested for and found in the brain tissue samples of the dolphin. Interestingly there was a low detection of HPAI in the lungs of the dolphin and the highest viral load was found in the brain tissues. This is similar to the harbor porpoise from Sweden, which also had meningoencephalitis. 

While this is worrying news, the presence of the virus in this species means officials and researchers can be better prepared for more cases. 

“Now, everybody’s going to be on guard for this,” Dr Michael Walsh, a veterinarian at the University of Florida College of Veterinary Medicine and study co-author, told the New York Times . “And that’ll help tell us how serious this really is for cetaceans on the coastlines.”

The paper is published in the journal Communications Biology .

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The trains and stations of the Moscow Metro

2 Comments · Posted by Alex Smirnov in Cities , Travel , Video

The Moscow Metro is the third most intensive subway system in the world after Tokyo and Seoul subways. The first line was opened on May 15, 1935. Since 1955, the metro has the name of V.I. Lenin.

The system consists of 12 lines with a total length of 305.7 km. Forty four stations are recognized cultural heritage. The largest passenger traffic is in rush hours from 8:00 to 9:00 and from 18:00 to 19:00.

Cellular communication is available on most of the stations of the Moscow Metro. In March 2012, a free Wi-Fi appeared in the Circle Line train. The Moscow Metro is open to passengers from 5:20 to 01:00. The average interval between trains is 2.5 minutes.

The fare is paid by using contactless tickets and contactless smart cards, the passes to the stations are controlled by automatic turnstiles. Ticket offices and ticket vending machines can be found in station vestibules.

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The bridge over Zolotoy Rog Bay in Vladivostok

The views of St. Petersburg from the TV tower >>

Tomás · August 27, 2012 at 11:34 pm

The Moscow metro stations are the best That I know, cars do not.

Alberto Calvo · September 25, 2016 at 8:57 pm

Great videos! Moscow Metro is just spectacular. I actually visited Moscow myself quite recently and wrote a post about my top 7 stations, please check it out and let me know what you think! :)

http://www.arwtravels.com/blog/moscow-metro-top-7-stations-you-cant-miss

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Cecilia Bobrovskaya Twenty Years in Underground Russia: Memoirs of a Rank-and-File Bolshevik

VIII. Moscow

FROM Baku I went to recuperate a little at the estate in Zhiroslavka near Kostroma which I have already mentioned, whose mistress, Elizaveta Kolodeznikova, considered it her mission in life to provide a haven for all tired and homeless Party workers. About midsummer 1905, after I had had a short rest, I left for Moscow. According to the decision of the Moscow Committee I was to start work as district organizer. I was to take up my new duties after the city conference, at which I hoped to gain a better knowledge of Moscow Party work. The conference was to be held on a Sunday in the woods near Obiralovka on the Nizhnenovgorod line.

When our group of comrades alighted at the suburban terminus of Obiralovka, the station was crowded with gendarmes, detectives, spies, and other police department officials. The "splendour" of the scene petrified us for a moment. Then we began to pretend that we were all strangers to each other. But the police only laughed at us. One of the delegates to our conference had betrayed us, so that the police knew everything to a detail. Notwithstanding all the information they had, however, they arrested only fifteen comrades. The others, who had come by an earlier train, managed to escape the trap laid for us at the station. I was arrested with several workers employed at the Guzhon Works in Moscow. I particularly recollect one dark-haired young worker with squinting eyes, who kept us merry all the way from Obiralovka to Moscow whither the police were taking us. At every stop the holiday crowd tried to get into our car. The police zealously attempted to drive the crowd away, while the dark-haired Guzhon worker cried to the newcomers:

"Ladies and gentlemen, it is strictly forbidden to come into this carriage. The ambassadors from Portsmouth are here!" (This happened at the time of the peace negotiations with Japan.)

At the police headquarters we were closely crossexamined. But I could not say anything for myself. I had just recently arrived in Moscow and had had no time to obtain a passport. I lived without being registered, at the home of my husband's mother, Sophia Bobrovskaya, and avoided the janitor. This apartment was very convenient for secret work because the house had two exits, one of which was particularly useful because it led into a yard in which there was a postoffice. If anything happened one could always pretend to be going to the postoffice. These features were taken into consideration when Sophia and her younger daughter, Nina, rented the apartment. It often happened that mother and daughter, not having had time to consult each other, both offered the apartment for meeting purposes on the same day. Once, for example, a secret meeting of soldiers--representatives of the army--was held in one room, which Sophia had lent for the purpose, while in another room the girl cashiers of the Chichkin dairies met to discuss the forthcoming strike of the employees of that firm. Nina had consented to let them have the room without consulting her mother. The house was always used as a temporary hiding place for illegal literature and weapons. Furthermore, workers frequently made appointments at the house without telling the Bobrovskys beforehand because they knew that the latter would acquiesce.

Hence, when I was arrested I could not possibly give the Bobrovsky address. The only thing I could do was to refuse point blank to give any information about myself. I was immediately charged under Article 102 of the Criminal Code and sent to the Watch Tower in the Butirsky prison. Before me was the prospect of a quiet life (as a rest from my roving one) for a lengthy period, and I planned to take advantage of this to improve my theoretical knowledge. My deficiencies in this respect hindered me in my Party work. But this dream was not realized, owing to the breathless events that occurred on the other side of the prison bars. These events freed me from the Watch Tower--a freedom gained under strikingly happy circumstances. Each day the rumours which reached us in the Watch Tower as to the growing revolutionary spirit among the broad proletarian masses were more and more confirmed, particularly after we heard the singing of revolutionary songs in the main yard (the Watch Tower looked out into the hospital yard). They were sung by the arrested Philipov bakers. The crowds of workers in the neighbouring yard which we could see from our tower, and the snatches of speeches that were carried to us also helped confirm the fact. Besides these joyously disturbing signs, during the first days of October a group of Poles were imprisoned in the Watch Tower (because there was no room in the deportation prison) in the next flight above my cell. I learned from these comrades that they had been exiled from Warsaw to the Vyatka province and had been on their way there, but, owing to the strikes on the railroads, they had had to stop for an indefinite time in Moscow. Any day now, they predicted, Russia would be in the threes of a general strike; then we would not be in prison very much longer.

The Poles were in very high spirits and from the moment they arrived, our isolated yard in the Watch Tower changed as if by magic. For example, a few days before October 17 a very curious thing happened. It had snowed the previous night, and one of the Poles who was a sculptor made an excellent snow figure of Nicholas II. When the figure began to melt, another of the Poles approached my window and said audibly:

"Look, comrade, the autocracy is melting, let's give a cheer!"

The guard in the yard informed the governor of this. The assistant governor came, spoke briefly to the Poles and to me, then, apparently feeling the insecurity of the autocracy, limited himself to a mild lecture about our "disgraceful conduct" and returned to the office scratching his head. But not all the warders were so pessimistically inclined. The governor of the Butirsky prison still held aloft the banner of autocracy. My husband had been exiled to Siberia and I expected that he would stop at the Butirsky prison on his way there from the Caucasus. I asked the governor to permit me to see my husband if he came. The governor replied haughtily: "Prisoners are forbidden to talk to each other." A week later, after this haughty refusal, I met my husband in Moscow--both of us were free. He had been released on the road by the rebellious Rostov workers.

The last few days before October 17, the cream of the Moscow proletariat gathered about our Butirsky prison. There was not a workshop nor a trade that was not represented there. Prison life became unusually intense. The senior prison officials went about looking cross and gloomy. The middle ranks looked frightened and apologetic while the lower officials, warders and the rest went about gloatingly. They would forget to lock our cells (the corridors, of course, were locked), and we became so bold, that we not only carried on conversation with the Poles, but two of them even came to my cell for a few minutes. The prison officials visited us several times a day. Representatives of the public prosecutor often came to ask if we had "any complaints to make". At night our guardians had no rest. Lights flickered in the yard and in the corridors all night. It was apparent that they were profoundly disturbed. This filled us with fierce joy and, we were curious to know how it would all end. I was not very clear as to what was happening outside and things were still very vague to me even when a vast revolutionary Moscow crowd moved toward the Butirsky prison and demanded our release. The day before rumours had reached us that a royal manifesto would be issued granting us freedom. But we were indignant at the very suggestion of such a mark of the tsar's favour and would hear nothing of it.

On the morning of October 18 everything in the prison seemed as usual. Keys rattled in the corridor. The "hot water" was brought at the usual hour, but I could not think of drinking it--there was no time for such trifles. I made my morning survey from the window sill--endangering my ribs, because the sill was very high above the ground and there was nothing to grasp but the bars--and looked out into the yard; but I scarcely recognized it. It had changed into a military camp. Machine-guns, cannon and other death dealing instruments filled the yard. Gallant officers, ready for battle, shouted orders. They all looked as though they expected the enemy at any minute. It was not difficult to conjecture what enemy. Anyway, I was not kept guessing long, for very soon I saw a huge crowd moving down Dolgorukovskaya and Lesnaya streets towards our prison. But what agitated me most was the sea of red banners. A red banner meant a great deal to an underground professional. At that moment the sight of so many red banners seemed strange to me.

The exulting revolutionary crowd approached so near that I could actually see expressions on individual faces. In front of the crowd, threading his way toward my window, was my friend Makar. He was saying something to me that I could not quite understand. He was saying that he was afraid I might be kept in prison till the evening because no telegrams had yet been received from the Minister Witte, or something to that effect. His tone implied that it was the hardest thing in the world for me to have to stay in prison until the evening--I, who had been planning a bare week ago to stay in prison for more than a year!

The most inexplicable and surprising thing about Makar and all the others was their utter disregard for any consequences their conduct might entail--a disregard that was not the least shaken by my mentioning the cannon and machine-guns which awaited them on the other side of the prison. They simply laughed in reply, exclaiming, "They won't dare!"

When the crowd demanded the release of all political prisoners, the first to be freed were the Philipov strikers. These had been thrown into the prison in whole groups. A barrel was placed at the gates of the prison to serve as a platform for speakers. One of the released bakers mounted this barrel and delivered the following "speech": "Comrades, I am a Philipov baker! That is all I have to say!" This avowal was greeted with tremendous enthusiasm. After the baker, a few railroad workers spoke. No one tried to understand what they were saying. The speeches were not important in themselves--it was the circumstances in which they were delivered that were important.

I must admit that at that triumphant moment I was afraid of being released. I was afraid that I should have to make a speech from that barrel in my thin high-pitched voice. But the god of revolution preserved me--a voiceless underground worker--from this ordeal. I was released in the evening, when the crowd had dispersed, without being forced to deliver an agitational speech--a thing I never could, nor can do. I was permitted to leave the prison quietly. Although we had been freed by the revolutionary masses, we still had to pass through all the prison formalities at the prison office. That office had an unusual appearance. It was filled with tables at which officials sat who, apparently, had been hastily appointed. They rapidly checked us off the prisoners' list. The released comrades introduced themselves to each other, congratulated one another, laughed, and tied red ribbons on their arms. At the office I had a short but very characteristic talk with the prison officials. It seemed somewhat strange to go out of prison with a valise. The first thing I wanted to do in leaving the prison was to rush to a meeting, to be out in the street; a valise would only be a hindrance. So I asked permission to leave it in the office. The warder looked at me in surprise at my request and said: "Do you still have faith in us? To which I answered, "Of course, for most probably I will have to return to you very soon".

To tell the truth, I was not at all certain that this freedom would last very long. When I found myself at the University that evening, I became still more confused by the atmosphere. Going through the University corridors. I met many comrades, but none of them could explain to me what waS actually taking place. At last I saw Martin Lyadov (Mandelstamm), a member of the Moscow Committee. I showered questions upon him about the Moscow Committee and what I was to do with myself, but he merely answered:

"Tomorrow we are burying Bauman. You must come to the funeral; go to a meeting now and make a speech. All the comrades who were released today are doing that."

The news of our Comrade Bauman's death communicated to me in such a calm tone, was a great blow to me. I recalled his cheerful disposition in Geneva and was deeply distressed at the thought hat this brave, energetic revolutionary was no longer among the living. I met Zemlyachka, another member of the Moscow Committee, and began to question her. She also replied, "Tomorrow is Bauman's funeral," and then pushed me into a meeting saying, "You go and speak after that comrade. You're just out of prison, you know," whereupon she hurried off.

"That's a fine way for the Moscow Committee to get me to understand the situation," I thought, to myself. "To speak at a big meeting without the faintest gift of oratory and with my head still in a muddle." I pondered a while and decided not to become an "object of the celebrations," but instead to mingle with the crowd.

Next day, however, during Bauman's funeral, which was far more stirring and demonstrative than I had expected, I realized that Lyadov and Zemlyachka had been right. The organization of this funeral was a big Party task with which the Moscow Committee of our Party had coped admirably. I also understood that ones own individual sorrow at the loss of even such a dear comrade as Nikolai Bauman had to give precedence to the historical significance of the funeral.

I was unable to begin my work in the Moscow district for some time after the funeral. I was dreadfully unstrung by all that had happened and became ill and suffered from insomnia. In the moments of forgetfulness I still seemed to be walking from the Technical School to the Vagankovsky Cemetery with that solid mass of workers united by a single revolutionary aim. I could still see the coffin under its velvet pall sway on the shoulders of the men who carried it and the words of the funeral march still rang in my ears:

"Dying like soldiers, fighting for labour so did you fall ..."

My illness prevented me from working for three weeks--a very long time for that period.

On November 8, 1905, Lenin wrote in the paper Novaya Zhizn:

"The state that Russia is in at present is often expressed with the word 'anarchy'. This wrong and false term in reality expresses the fact that there is no established order in the country. The war of the new, free Russia against the old serf-autocratic Russia is being waged along the whole line; the autocracy is no longer capable of conquering the revolution, but the revolution is not yet capable of conquering tsarism. The old order is shattered, but it is not yet destroyed, and the new, free order is existing unrecognized, half hiding, often persecuted on all sides by the henchmen of the autocratic system."

Towards the end of November the scales definitely swung in favour of the revolution; deep in one's heart one felt that the great struggle between the working class and the tsarist autocracy would at any moment break out in open armed conflict on the Moscow streets.

In all save the most backward districts the atmosphere reached white heat. Proletarian Moscow was impregnated with the spirit of revolt.

Our Bolshevik organizations carried on feverish preparatory work, mustering the working masses, agitating the troops, and getting the workers' armed units which had been organizing since October into military shape.

The leading figure on the Moscow Committee at that time was Comrade Shantser, or "Marat," as we called him, but all the information I have is the meagre data found in the documents of the Moscow Secret Police obtained by Comrade Minitsky for a biographical dictionary of Moscow Committee members who had fallen in the revolution. From this data we learn that Comrade Shantser was born in 1867, that his father was a German and his mother a Frenchwoman, who had become Russian citizens and had settled in Odessa. He began doing cultural work among the workers while he was still a gymnasium student and, after finishing school, was arrested in 1887 for participating in the organization of a workers' library in Nikolayev. In 1895 he was arrested again, this time for conducting propaganda in workers' circles in Odessa and for making collections for political prisoners. Later, when he was a junior barrister, in Moscow, he maintained constant touch with workers who used to come to his home and among whom he distributed illegal literature. In September 1901 he was arrested at the home of Comrade Nikiforov, another old comrade now dead, for taking part in the preparations for a demonstration in Moscow; and he was exiled to Fast Siberia for three years where he was kept under the strict surveillance of the police. From there he returned to Moscow in November 1902 and worked with even greater energy in the Party, playing a leading role in the Moscow organization whose leader he was in the November-December days of 1905.

During the uprising he was arrested for the fourth and last time at his home where a meeting of the Federative Committee--a body organized to co-ordinate the activities of all the revolutionary organizations and on which Comrade Shantser represented the Bolsheviks--was to have been held. Since all evidence about this case was lost during the days of the rebellion, he got off with administrative exile to the Turukhansk region.

Here he suffered a nervous breakdown but, ill as he was, he nevertheless managed to escape abroad where the nervous disease developed into an incurable mental disorder. Due to his hopeless condition Shantsers wife, Natalia, managed to get permission to return to Russia with her sick husband in 1910. But the tsarist officials loved to spite their disarmed foes. When he returned to his native land, this hopelessly sick and emaciated comrade was not allowed to be placed in a private hospital, but was sent to the central police lunatic asylum. Comrade Shantser, whose memory should be preserved by the Moscow workers, died on January 29, 1911.

I personally worked as the organizer of the Lefortovo district where I met many comrades, some of whom, like myself, had been sent by the Moscow Committee, while others were local workers--representatives from the mills and factories.

The Moscow Committee regarded the Lefortovo district as one of the backward ones. And in truth, as the December days drew nearer, one could witness in Lefortovo more than in any other district the heartbreaking sight of individual workers, and even whole groups of them, with bundles on their backs--turning their faces towards the village--and their backs upon the revolution.

To make the Lefortovo workers fall into step with the more militant districts (Presnya, Zamoskvorechye) we had to carry on intensive agitational work. We organized meetings from morn till night at the Vedensky People's Palace to which the workers came in crowds. Before we could clear the hall of one group, another group would pour in, while crowds of workers would be waiting their turn on the Vedensky Square.

We organizers found it very difficult to provide agitators for all these meetings. In 1905 the Party in general, and the Moscow organization in particular, had an extremely limited number of agitators at their disposal. Not every underground Party worker who was accustomed to speaking at small workers' meetings held in the woods or on a boat, or in some out of way barn, could get up before a mass meeting of several thousand and speak from a high platform in a brilliantly lit hall.

We had to resort to all sorts of ruses to get an extra agitator from the centre. Thus, for example, early in the morning I would go to Fidler's house, the headquarters of the Central Board of Agitators of the Moscow Committee led by Comrade Stanislav. There I would catch one of the agitators and earnestly plead that today was the decisive day, that the Lefortovo district was not stable, that if we managed to carry off one or two successful meetings the Lefortovites would be roused, etc.

Having played upon the feelings of my agitator in this fashion, I would obtain his promise to come to Lefortovo, knowing all the while that he could only go where the centre sent him, and not where each district organizer wanted him to go. But such is the mentality of a district worker that it always seems to him that his district is more important than any other. These difficulties were eased somewhat in the days that followed, when, besides the official agitators, speakers appeared from among the masses themselves. At our meetings in the Vedensky People's Palace, workers would get up from the audience to address the meeting. I remember a worker from the Rontaller factory who once came over to me and said timidly that he would like to speak. He wound up his long and fairly able speech with the following words: "We button makers are a big power. If we choose we can leave all Moscow without a button."

A middle-aged working woman agitator in the audience spoke about the low wages paid to women, and to illustrate the point she said: "When I, a woman, am hungry and go to buy a cucumber, do I pay half a kopek, or do they charge me a kopek the same as they charge a man?" Her speech created a tremendous impression upon the audience. It was a rare thing for a woman worker, and an old one at that, to get up on a platform and speak before a big audience.

Our Party headquarters were located in the Vedensky People's Palace and we members of the District Committee were in the office day and night: from early morning till late at night we received delegations from factories and mills who came to us with all kinds of problems.

I vividly recall a group of workers from the Dufurmantel factory, five of them, led by a middle-aged, red-bearded worker. They were sent by the illiterate workers who had organized themselves and demanded that we immediately teach them to read and to write. "It's a crime not to be able to read at such times," they declared to us. This "illiterate" delegation made a deep impression upon us. We explained to them that we could not possibly teach them to read and write in so short a time as they desired, but that we would organize a school for this purpose without delay. And indeed we organized such a school for the workers in our district, using the nearest public school for this purpose and mobilizing teachers--our own people--to help. Despite the disturbed time, regardless of the fact that towards the end of November we had reached the verge of an armed uprising, our Party organization continued, as it had done in times of peace, to organize schools, lectures, clubs, in short, all sorts of cultural work. This work was carried on "under fire," so to speak, and was often intermingled with purely military work.

For example, during the barricade fighting in the Zamoskvorechye District, furniture which was being delivered to the club was seized and used for building barricades. The club organizers began to protest against the misuse of club property, but later, realizing the urgent necessity, they not only helped to pile up the furniture on the barricade but even removed the gate of the house where the club was situated and piled that on also.

Our Lefortovo unit of armed workers, with Comrade Rublevkin at its head, was a small, poorly equipped, but extremely militant group, which together with the District Committee members was very keen on getting the backward Lefortovo district to catch up with the other districts. Later, during the uprising, when fighting was taking place in the centre in the Presnya District, and in Zamoskvoretsky District, and when we Lefortovites were still holding meetings, our armed workers went off to help the other districts.

Towards the end of November the first Moscow Soviet of Workers' Deputies, uniting 134 industries with about 100,000 workers, was organized. On December 14 this Soviet passed a resolution to the effect that: "Moscow workers must hold themselves ready at any moment for a general political strike and for an armed uprising."

In accordance with the decision of the Soviet on the morning of the fifth, meetings were held in all the factories and mills where the question of the strike and the uprising were discussed and put to a vote; and in the evening of the same day the Lefortovites went to the Bolshevik Moscow City Conference where the question was to be decided.

At this time even the Lefortovo district had become aroused and the referendum we took in all the factories on the question of the strike and uprising gave positive results. But we all realized that when the forces were counted up at the Conference, the Lefortovo district would be found to be the weakest. This knowledge filled our hearts with bitterness.

Those who were present at the conference on the night of December 5, 1905, will remember what a militant spirit reigned there, with what eagerness the factory delegates were listened to, and how they all in one voice declared that the workers were ready to revolt. The deep conviction of the inevitability of the uprising was not shaken even when the military organizer, Comrade Andrey, in his report on the conditions of the Moscow garrison announced that though the soldiers would not go against us, he was not certain that they would go with us. A few comrades urged restraint on the grounds that the workers were almost unarmed, but all their arguments were unavailing, for everybody was convinced that the uprising was inevitable.

On December 7, the first issue of the Izvestia of the Moscow Soviet of Workers' Deputies was published containing a manifesto signed by all the revolutionary organizations in Moscow calling for "a general political strike on Thursday, December 7, at It o'clock noon" and for every effort to be made to "convert it into an armed uprising".

The Moscow Committee of our Party elected an Executive Committee which was entrusted with all authority; the rest of the committee members had to go back to work in their districts. From the very first days of the uprising reliable means of communication were established between the centre and the districts through the medium of comrades who were called couriers. At first the couriers were able to penetrate into the districts despite the difficulties, but later on they were unable to do so. Thus all communication between the centre and the districts was cut off and the latter were left to their own devices. At Presnya, fighting was going on under the leadership of Comrade Sedoy (Litvin), the Zamoskvoretsky District lived its own revolutionary life....

Our first Lefortovo courier was an old comrade, Alexander Blagonravov, who later worked in the Vladimir organization and died of typhus in 1919. I can clearly recall Blagonravov with his sad smile reporting about the affairs in other districts and delivering the instructions of the centre for the coming day. The proletariat must not forget its couriers who selflessly devoted their lives to maintaining communication between the various sections of the city during the memorable days of struggle.

But soon even Comrade Blagonravov was unable to reach us, and our district was completely isolated. We, however, continued to hold meetings and to organize demonstrations. Once we marched by the Spassky barracks from which some disarmed and imprisoned soldiers cheered us. Our armed workers' units had several clashes with the Black Hundreds who were numerous in Lefortovo, but the latter were not remarkable for their bravery even though they were armed as well as, if not better, than the police.

One morning, while the insurrection was still in progress, we were waiting for the workers to come to a meeting in the People's Palace. There were only about five or six of us District Committee members in the hall. Suddenly we saw a crowd of the Black Hundreds approaching and it looked as if we were going to be lynched. Fortunately, one of our comrades had a revolver. He fired one shot over the heads of the mob and this was enough to set the whole gang running.

We began to feel that we were really taking part in the insurrection only when barricades were put up in our district, but this was very belated, when the beginning of the end had set in the rest of the city.

That day, we commenced the usual round of meetings, but we all felt that there was nothing more to be said. I remember that I was particularly irritated by the "rational" appeals of the Menshevik Semyon who continued to shout, "comrades, build up the trade unions!" The answer to this trivial appeal came from someone in the audience. It was an appeal to us all to go out into the streets and build barricades. The whole audience responded to a man and the whole mass hurried out into the street. On the square it was joined by those who had been awaiting their turn to come into the hall, and all of us moved in close ranks to the Pokrovskaya Zastava where we overturned the tram cars that were standing as they had been left in the street when the general strike was declared. We erected a huge barricade--our own Lefortovo barricade. Our armed workers' units remained to guard it, although no one threatened to attack it that night, while the rest of the workers dispersed to their homes.

That evening, a comrade from the committee, who went by the name of Alexey, and I planned to make our way to the city without fail; it was a long time since our courier had visited us and we were completely cut off from the centre. We did not know what was happening there and had no means of keeping the centre informed of events in our district-we wanted to boast about our tardy barricade. Such a trip at night was risky, it being particularly dangerous to pass the posts of the so-called Committees of Residents set up by the Black Hundreds ostensibly for the purpose of protecting property, but in reality to catch, insult and beat up every passerby who had the least resemblance to a revolutionary.

We passed several streets in comparative safety, although we frequently got entangled in the telegraph wires which had been torn down and were scattered everywhere. Not far from Basmannaya we encountered a group of civilians who stopped us. They declared themselves members of the Residents' Committee, and demanded to know who we were and where we were going. I invented a story on the spur of the moment about my husband and myself trying to go from Cherkozovo into the city to Zhivoderka to visit our daughter-in-law who was seriously ill and needed immediate help. Because of the wires and the darkness we could not find our way to Krasnye Vorota. Alexey, "my husband," beside me also muttered something about a daughter-in-law and Zhivoderka. They believed us. It was our outward appearance that saved us. I was dressed like an old woman in a wide blouse and with a shawl over my head, while Alexey was also very poorly clad.

The Black Hundreds had so little suspicion of who we were that they even warned us not to fall into the hands of the workers' units who would be sure to shoot us at the first sight. We proceeded on our journey until we had almost reached Krasnye Vorota, where we saw a group of soldiers sitting around a bonfire and were obliged to turn aside and step into the Olkhov school where we were sure to find our own people.

The school resembled a dosshouse that night--on all the desks, tables, chairs and floors sprawled comrades who had been unable to get home and were obliged to remain at the school. We too decided that it would be wiser to stop at the school. I cannot refrain from mentioning a little incident in that night's adventure. One of the teachers, whom I had never seen before, called me into the kitchen, took a pot of broth from the stove, placed me on a stool, and, without even asking my name, declared: "You have eaten nothing all day; eat this broth!" And indeed, I had had absolutely no time for eating or drinking and was feeling very weak until the broth revived me.

Early next morning the bonfire at Krasnye Vorota burned out, the soldiers were withdrawn, probably for some strategic purposes, and we began cautiously to creep out one by one from our school dosshouse. I wanted to change my clothes and wash myself before going into the city. I went to my sister Rose who lived nearby on Kalanchovsky Street, but whose house I had been unable to reach the night before. She had rented a room among our own people, at the home of the worker Polumordvinov. When I reached her room I found her table, bed and bookshelves loaded with weapons. These had been taken from Torbek, the gunsmith, whose shop our unit had raided. A group of our men were lovingly handling these revolvers, parts of guns, sabres and cartridges and they were so merry that despite my weariness, I was cheered by the mere sight of them.

On the other hand, when at last I got to the Moscow committee, the mood prevailing was anything but cheerful. I learned that our affairs were in a very precarious condition, that St. Petersburg, exhausted by the November strike, was not in a position to support us. I also learned that the promises of the railroad union leaders had proved to be empty phrases, that the Nikolayev railway was in the hands of the government, that hostile troops from Tver and the Semyonovsky regiment from St. Petersburg had either already arrived or were on their way, I cannot recall which.

I hated to return to my district with such news--a district which had only just risen to the level of insurrection and whose active workers had been exulting over their "own" barricade the evening before. I decided to spend the night at my sister's as I needed a good night's rest; but I was not destined to get any sleep. When I returned to her apartment, the weapons were no longer there, the workers having cleared them away during the day. But the police had now got wind of the fact that the weapons seized at Torbek's had been taken to this apartment. So we were subjected to a raid which was carried off with great pomp--a squad of armed policemen with a police officer at their head broke into the room. The police were obviously afraid, thinking that we were armed to the teeth. They were extremely nervous and threatened to shoot us on the spot if we did not surrender our weapons. They bullied my sister and me because we were women, but they were unmistakably afraid of the worker, Glotov, who rented the corner of the room near the stove, especially when they stumbled over a pile of coal in his dark corner. With extreme caution the officer flashed his searchlight on Glotov's "dwelling place." To the officer's tremulous "What's there?" Comrade Glotov rolled out sonorously: "This is the study of his proletarian highness!"

Finding no weapons, the police left the place without arresting any of us, even though we were all in some way connected with the insurrection.

When on the morrow I reached our district headquarters--the People's Palace--I found Alexey had been there since the previous night. He had already communicated the bad news to the other comrades; but they were surprisingly little depressed by it. Indeed, it was difficult, after yesterday's enthusiasm, to take that sharp psychological jump and become immediately conscious of the fact that our struggle was weakening, that a temporary defeat was inevitable. But we, the backward Lefortovites, were not long comforted by our illusions. The defeat of the uprising approached, and when our last stronghold fell, when our heroic Presnya--the pride of the Moscow uprising of 1905--was wrecked and burned by the Semyonovsky regiment, the Soviet of Workers' Deputies had to declare an end to the strike and uprising, and temporarily haul down the scarlet banner which, after twelve more years of stubborn struggle, was again unfurled to blaze victoriously over Red Moscow in 1917.

When the revolt had been crushed, an orgy of the Black Hundred reaction broke loose, the Moscow prisons and police headquarters were overcrowded with arrested revolutionaries. Hideous rumours were abroad that the police headquarters had been turned into torture chambers by the brutalized victors and that our comrades were being subjected to unheard of torments; and along the Moscow suburban railroads the brutal gangs of the tsarist hangman, Riman, ran riot. The spirits of the workers in the district were extremely low, and it was under these unfavourable circumstances that the Moscow comrades who had survived the defeat were obliged to renew their Party work. Once more began the painful process of returning underground. At the first meeting of the Moscow Committee held in the early days of January 1906, it was decided to send the more "notorious" comrades to other cities, while the less prominent ones were to be transferred from one district to another. Thus it happened that I was sent from the Lefortovo District to the Zamoskvoretsky District where I had many comrades even before the uprising, both among the professionals and the factory workers.

During my first days in the Zamoskvoretsky District I set myself a very concrete though modest organizational task, namely, to re-establish at least in the larger factories our former illegal factory committees. But this proved to be an incredibly difficult task. I still remember the endless visits to individual workers' homes, the arrangement of a few small meetings with the representatives of the various factories, meetings which hardly ever took place, either because our meeting place was being watched, or because the landlady who had promised us the use of her room had funked it and refused to let us in when we arrived, or because only one or two of half a dozen who were expected, arrived. It is difficult to imagine anything more trying than the knowledge that the work was constantly slipping out of our hands, that the eyes of our comrades which had burned with such revolutionary courage, with such faith in the imminent victory of their cause not so very long ago, were now utterly weary and hopeless.

However, not all our efforts were in vain. The Moscow Bolshevik organization continued to work intensively, adapting itself to the new methods of struggle even though it often had to deal with extremely dejected and morbid moods among the district comrades. I recall several of the more poignant moments which I personally had to undergo, as characteristic of these moods.

I went to visit the family of a worker in the Danilov factory, with whom I had been formerly acquainted, hoping to renew connections with the Danilov factory through them. Both husband and wife greeted me joyously and promised to assist me, but as the attempts to resuscitate the organization grew more and more futile, the worker (I cannot remember his name) became gloomier and less frank with me. Once I arrived at dinner time when their little ten-year old daughter was bustling about prettily and setting the table for her parents who were due any minute. She placed four wooden spoons on the table--one for "auntie". When my hosts returned from the factory, both the mother and the daughter insisted that I stay for dinner.

We sat around the table eating cabbage soup out of a common bowl, fishing up bits of meat from the bottom of the dish with our spoons and conversing peacefully at first about the necessity of starting Party work in the district. But towards the end of the meal, the worker became agitated, suddenly banged on the table with his clenched fist and, raising his voice, exclaimed:

"Why in the world do you come here to disturb us? I am tired, do you understand--tired, and I can't do any more!"

The little girl became frightened and started to cry. Her mother begged me not to take offence, while I in the most unexpected and ignominious fashion burst into tears and left the place.

Some time later a similar incident occurred in the tiny room, or rather the cubicle, of a young worker who was employed in the Jako factory. He had displayed a splendid fighting spirit before the uprising, had participated in many battles during the barricade days and, did not appear to be particularly depressed after the defeat. I called on him towards the end of February, or in the early days of March, I don't quite remember which. It was about ten o'clock in the evening, I believe. The apartment was used as a sort of lodging house, the lodgers living in tiny cubicles. The stairs were indescribably filthy and from the rooms emerged a veritable Sodom of drunken voices, smoke and stench. But the cubicle to which I went was very neatly kept, almost pretentiously--the bed was covered with a pink cotton blanket, the walls were decorated with pictures and embroidered towels, and there was a canary in a cage suspended from the ceiling. Near the bed hung a guitar tied with a pink bow. I surprised my acquaintance while he sat on a bench holding a pocket mirror to his face; on the table before him stood a jar of cream for sunburn and freckles with which he was diligently smearing his face. He did not cease his occupation as I entered, but motioning me to a seat, continued to rub his cheeks with greater vigour than ever, casually remarking, "My respects, Olga Petrovna, what news have you? I bet you're here about what I have already long forgotten because I've lost all my faith in it". When I suggested that he stop playing the fool, wipe his face, and talk sensibly, the fellow answered: "You shouldn't talk that way about the cream because it's wonderful for getting rid of freckles. It is called 'metamorphosis' and costs a ruble and a half. I strongly recommend it to you, Olga Petrovna, for you, too, have a lot of freckles. Now's the time to think about yourself a little. You're still harping on old days that will never return; and if they do, we won't be there to see them." I wonder whether this comrade lived to see the great October Revolution and, if he did, whether he recalled the words he uttered in 1906?

The metamorphosis of this Jako worker, who so recently had been a brave comrade in our ranks, had a most depressing effect on me. I left his room at about eleven o'clock with such a crushed feeling that it mattered little to me where I went. There were moments when I felt that there was no place for me to go and I wandered aimlessly about the streets in the Zamoskvoretsky District.

These difficulties were not merely characteristic of Moscow. The disillusionment not only spread among the working masses, but was communicated to many of our individual active comrades, both workers and intellectuals.

As for the Mensheviks, who during the heroic October-December days of 1905 were forced to go against their Menshevism and temporarily join us, the defeat immediately restored them to their natural shape and gave them many opportunities to expiate their short-lived iniquity by bitter criticism of our revolutionary Bolshevik tactics.

At the beginning of 1906 the conditions in the Party organization were complicated. The split in the Russian Social-Democratic Labour Party, which took definite shape at the Third Bolshevik Congress in May 1905 and the Conference of the Mensheviks, that was held concurrentiy with the latter, did not hinder but helped the formation of a united proletarian front during the heroic last months of 1905. To co-ordinate activities, the Mensheviks were forced to join the Federative Committees.

What was happening in the districts was beginning to take place in the centre. Preparations for a Unity Congress of the Party were being made, but these preparations coincided with the defeat of the uprising and with the weariness of the proletariat who had been pressing for a united front before the uprising. Thus, a twofold process could be observed at the beginning of 1906--preparations for a Unity Congress were continued by inertia, while at the same time new disagreements with the Mensheviks on the cardinal questions of party tactics were constantly cropping up and becoming more sharply defined (estimation of the uprising, attitude towards the State Duma, etc).

In March we Muscovites were eagerly awaiting the arrival of Lenin who was to acquaint us with the resolutions he had drafted for the forthcoming Unity Congress of the Party, which was to be held in April.

Besides the natural interest in Lenin's report, the prospect of meeting Lenin in Moscow, on Russian soil, was particularly alluring. Imagine my distress when, a few days before his arrival, while walking about in the sleet and mud, I caught a severe cold, and was not in a condition to go to the meeting of the Moscow active workers at which Lenin was to speak. I was lying in bed grieving over my disappointment when a comrade burst into the room and told me for reasons of secrecy the meeting had to be transferred to other premises and that Lenin had expressed a desire to see me during the enforced intermission.

My joy knew no bounds when in half an hour Ilyich himself appeared, filling the room with his jests and laughter and with that comradely simplicity so characteristic of him when talking with the most insignificant Party workers if he felt that the latter were connected with the actual life of the Party.

The joy I felt that Lenin was sitting in my room prevented me from studying his mood, the more so that as I was ill he spoke to me only about pleasant trifles. But I clearly recall that he was very cheerful "as if nothing had happened," although what had happened was nothing more nor less than the defeat of the 1905 uprising!

Table of Contents: Twenty Years in Underground Russia