Comparative effectiveness of heterologous third dose vaccine schedules against severe covid-19 during omicron predominance in Nordic countries: population based cohort analyses.

OBJECTIVE: To investigate the comparative vaccine effectiveness of heterologous booster schedules (ie, three vaccine doses) compared with primary schedules (two vaccine doses) and with homologous mRNA vaccine booster schedules (three vaccine doses) during a period of omicron predominance. DESIGN: Population based cohort analyses. SETTING: Denmark, Finland, Norway, and Sweden, 27 December 2020 to 31 December 2022. PARTICIPANTS: All adults aged ≥18 years who had received at least a primary vaccination schedule of AZD1222 (Oxford-AstraZeneca) or monovalent SARS-CoV-2 wild type (ancestral) strain based mRNA vaccines BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna), in any combination. MAIN OUTCOME MEASURES: The main outcome measure was country combined risks of covid-19 related hospital admission and death with covid-19 and additional outcomes of covid-19 related admission to an intensive care unit and SARS-CoV-2 infection. During a period of omicron predominance, these outcomes were compared in those who received a heterologous booster versus primary schedule (matched analyses) and versus those who received a homologous mRNA vaccine booster (weighted analyses). Follow-up was for 75 days from day 14 after the booster dose; comparative vaccine effectiveness was calculated as 1-risk ratio. RESULTS: Across the four Nordic countries, 1 086 418 participants had received a heterologous booster schedule of AZD1222+BNT162b2 or mRNA-1273 and 2 505 093 had received a heterologous booster schedule of BNT162b2+mRNA-1273. Compared with the primary schedule only (two doses), the vaccine effectiveness of heterologous booster schedules comprising AZD1222+BNT162b2 or mRNA-1273 and BNT162b2+mRNA-1273 was 82.7% (95% confidence interval 77.1% to 88.2%) and 81.5% (78.9% to 84.2%) for covid-19 related hospital admission and 95.9% (91.6% to 100.0%) and 87.5% (82.5% to 92.6%) for death with covid-19, respectively. Homologous mRNA booster schedules were similarly associated with increased protection against covid-19 related hospital admission (≥76.5%) and death with covid-19 (≥84.1%) compared with previous primary course vaccination only. When a heterologous booster schedule was compared with the homologous booster schedule, vaccine effectiveness was 27.2% (3.7% to 50.6%) for AZD1222+BNT162b2 or mRNA-1273 and 23.3% (15.8% to 30.8%) for BNT162b2+mRNA-1273 schedules against covid-19 related hospital admission and 21.7% (-8.3% to 51.7%) and 18.4% (-15.7% to 52.5%) against death with covid-19, respectively. CONCLUSION: Heterologous booster schedules are associated with increased protection against severe, omicron related covid-19 outcomes compared with primary course schedules and homologous booster schedules.

Enabling technologies driving drug research and development.

One of the strategic goals of the European Medicines Agency (EMA) and the European Medicines Regulatory Network is to support the research and uptake of innovative methods and technologies in the development of medicines. To promote this goal, EMA drew up a list of enabling technologies (ETs), which are novel and fast-growing technologies that have the potential to enable innovation and therefore exert considerable impact on drug development. In this work, enabling technologies identified by the EMA are analysed to measure their impact on drug development by following their journey from publications through early regulatory interactions to clinical trials between 2019 and 2022. This work also reviews the current list of EMA-identified ETs by scrutinising previously unseen innovative technologies identified in EMA submissions data. The analysis shows large variations in the appearance of the various innovative technologies in the different studied data sources, which provided valuable insights into the "Journey of Innovation" that innovative technologies undergo. Several emerging technologies were identified and endorsed for inclusion in the enabling technologies list, whereas some others already on the list were proposed to be excluded due to their low appearance in regulatory interactions as well as clinical trials and publications. Overall, this analysis highlights the relevance and value of continuously scanning and monitoring enabling technologies, supporting Europe's goal to remain a leader in research and development of innovative technologies, methods, and methodologies relevant to drug development.

A feasibility study of the transdiagnostic self-injury interview.

OBJECTIVES: The Transdiagnostic Self-injury Interview (TSI) is a new measure that assesses the onset, frequency, methods, and severity of non-suicidal self-injury. The aims were to demonstrate the feasibility of a TSI validation study, and to investigate TSI's criterion validity, clinical correlates, and interrater reliability. MATERIALS AND METHODS: Recruiting sites were psychiatric in- and outpatient units. Feasibility targets included number of participants completing the study, TSI completion time, total participation time, participants experiencing exacerbation of symptoms, along with other targets. Criterion validity was evaluated using the Deliberate Self-Harm Inventory (DSHI). Clinical correlates were examined with the Columbia-Suicide Severity Rating Scale (C-SSRS), the Personal and Social Performance Scale, the Affective Lability Scale-18, and the Brief Trauma Questionnaire. Interrater reliability was evaluated with video recordings and written material. RESULTS: Fifty participants were included. The majority were women (76%) and had a mean age of 31.3 years (SD: 10.4). Schizophrenia (44%) and schizoaffective disorder (18%) were the most prevalent diagnoses. TSI took an average 9.3 min to complete and the total participation time was on average less than one hour. One participant experienced an exacerbation of self-injury ideation (without the need of intervention). A significant correlation was found between TSI and DSHI (r: 0.94, p-value: < 0.001). TSI was correlated to C-SSRS ideation intensity and ideation frequency but not suicidal attempts. TSI was not significantly correlated to other measures. Interrater reliabilities were statistically significant. CONCLUSIONS: The results support the feasibility of a TSI validation study, which is needed to validate TSI in different settings and across diagnoses.

Safety of heterologous primary and booster schedules with ChAdOx1-S and BNT162b2 or mRNA-1273 vaccines: nationwide cohort study.

OBJECTIVE: To assess the risk of adverse events associated with heterologous primary (two dose) and booster (three dose) vaccine schedules for covid-19 with Oxford-AstraZeneca's ChAdOx1-S priming followed by mRNA vaccines (Pfizer-BioNTech's BNT162b2 or Moderna's mRNA-1273) as compared with homologous mRNA vaccine schedules for covid-19. DESIGN: Nationwide cohort study. SETTING: Denmark, 1 January 2021 to 26 March 2022. PARTICIPANTS: Adults aged 18-65 years who received a heterologous vaccine schedule of priming with ChAdOx1-S and one or two mRNA booster doses (with either the BNT162b2 or mRNA-1273 vaccine) were compared with adults who received a homologous BNT162b2 or mRNA-1273 vaccine schedule (ie, two dose v two dose, and three dose v three dose schedule). MAIN OUTCOME MEASURES: The incidence of hospital contacts for a range of adverse cardiovascular and haemostatic events within 28 days after the second or third vaccine dose, comparing heterologous versus homologous vaccine schedules. Secondary outcomes included additional prioritised adverse events of special interest. Poisson regression was used to estimate incidence rate ratios with adjustment for selected covariates. RESULTS: Individuals who had had a heterologous primary vaccine (n=137 495) or a homologous vaccine (n=2 688 142) were identified, in addition to those who had had a heterologous booster (n=129 770) or a homologous booster (n=2 197 213). Adjusted incidence rate ratios of adverse cardiovascular and haemostatic events within 28 days for the heterologous primary and booster vaccine schedules in comparison with the homologous mRNA vaccine schedules were 1.22 (95% confidence interval 0.79 to 1.91) and 1.00 (0.58 to 1.72) for ischaemic cardiac events, 0.74 (0.40 to 1.34) and 0.72 (0.37 to 1.42) for cerebrovascular events, 1.12 (0.13 to 9.58) and 4.74 (0.94 to 24.01) for arterial thromboembolisms, 0.79 (0.45 to 1.38) and 1.09 (0.60 to 1.98) for venous thromboembolisms, 0.84 (0.18 to 3.96) and 1.04 (0.60 to 4.55) for myocarditis or pericarditis, 0.97 (0.45 to 2.10) and 0.89 (0.21 to 3.77) for thrombocytopenia and coagulative disorders, and 1.39 (1.01 to 1.91) and 1.02 (0.70 to 1.47) for other bleeding events, respectively. No associations with any of the outcomes were found when restricting to serious adverse events defined as stay in hospital for more than 24 h. CONCLUSION: Heterologous primary and booster covid-19 vaccine schedules of ChAdOx1-S priming and mRNA booster doses as both second and third doses were not associated with increased risk of serious adverse events compared with homologous mRNA vaccine schedules. These results are reassuring but given the rarity of some of the adverse events, associations cannot be excluded.

Wellbeing, psychiatric morbidity and psychological distress amongst medical students in Denmark.

BACKGROUND: Medical students in Denmark undertake a demanding 6-year course which is generally during a critical age for the development of psychiatric disorder and harmful substance or alcohol use behaviours. Previous literature has highlighted significant rates of distress in Danish students. AIMS: We surveyed medical students in Denmark to better understand wellbeing, psychiatric morbidity, sources of stress, substance and alcohol use, psychological distress and burnout. METHODS: Medical students were invited to participate in a single survey via email and social media which was completed through an online form, available for a 6-month period. The survey used a mixture of pre-defined answer options alongside free-text responses. Embedded within the survey were standardised and reliable specific instruments related to alcohol use (the CAGE questionnaire), overall psychological wellbeing and burnout. RESULTS: There were 647 respondents, with a quite even year-group distribution, representing just over 16% of total number of students attending medical school in Denmark. Prior to medical school 35% had visited a professional regarding their mental health. While at medical school 16% reported a diagnosis of a mental health condition. 83% reported significant stress from study. Around 7 in 10 met case criteria using instruments designed to test for minor psychiatric morbidity and burnout. 13% tested CAGE positive, whilst 4% reported concerns from themselves or others about their substance use. CONCLUSIONS: Our study demonstrates high levels of psychiatric morbidity and worrying levels of burnout in this population. The striking 13% CAGE positive rate suggests this demographic is at risk of harm from alcohol. Our results suggest a high level of need to support this population - with further study required to demonstrate which interventions would be of most benefit for this population in light of our findings.

Technology Considerations for Enabling eSource in Clinical Research: Industry Perspective.

BACKGROUND: The technological complexities and broad operational scope of eSource impede coordinated, inter-organizational action on advancing at-scale solutions. METHODS: We introduce an architectural framework for articulating technological considerations across organizations. The architecture neither implies nor endorses solution implementations; rather, it proposes solution functionality based upon principles and good clinical practices. RESULTS: Key technology considerations include patterns of anticipated use, implications to the current state of clinical trial operations, and the need for new technologies (i.e., IoT, Big Data, Predictive Analytics). CONCLUSION: Technology considerations drive implications beyond technology-influencing regulatory, process, and ethical realms of clinical research.

Existing Data Sources in Clinical Epidemiology: The Danish COVID-19 Cohort.

BACKGROUND: To facilitate research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a prospective cohort of all Danish residents tested for SARS-CoV-2 in Denmark is established. DATA STRUCTURE: All Danish residents tested by reverse transcriptase polymerase chain reactions (RT-PCR) for SARS-CoV-2 in Denmark are included. The cohort is identified using the Danish Microbiology Database. Individual-level record linkage between administrative and health-care registries is facilitated by the Danish Civil Registration System. Information on outcomes related to SARS-CoV-2 infection includes hospital admission, intensive care unit admission, mechanical ventilation, and death and is retrieved from the five administrative Danish regions, the Danish National Patient Registry, and the Danish Register of Causes of Death. The Patient Registry further provides a complete hospital contact history of somatic and psychiatric conditions and procedures. Data on all prescriptions filled at community pharmacies are available from the Danish National Prescription Registry. Health-care authorization status is obtained from the Danish Register of Healthcare Professionals. Finally, selected laboratory values are obtained from the Register of Laboratory Results for Research. The cohort is governed by a steering committee with representatives from the Danish Medicines Agency, Statens Serum Institut, the Danish Health Authority, the Danish Health Data Authority, Danish Patients, the Faculties of Health Sciences at the Danish universities, and Danish regions. The steering committee welcomes suggestions for research studies and collaborations. Research proposals will be prioritized based on timeliness and potential clinical and public health implications. All research protocols assessing specific hypotheses for medicines will be made publicly available using the European Union electronic Register of Post-Authorisation Studies. CONCLUSION: The Danish COVID-19 cohort includes all Danish residents with an RT-PCR test for SARS-CoV-2. Through individual-level linkage with existing Danish health and administrative registries, this is a valuable data source for epidemiological research on SARS-CoV-2.

Accelerating the Adoption of eSource in Clinical Research: A Transcelerate Point of View.

For almost a decade, regulators and pharmaceutical industry groups have been interested in electronic source (eSource) in clinical trials (Nordo et al. in Learn Health Syst 3:e10076, 2019). eSource may provide efficiencies and value; however, eSource adoption is fragmented and slow. Acceleration of eSource adoption is a critical step in modernizing the conduct of clinical trials. The desired future state is one in which all source data, acquired through any context (e.g., healthcare delivery, chronic disease management) and actor (e.g., healthcare professional, patient, caregiver), are completely electronic, adequate in quality, and fully acceptable in clinical trial submissions by regulators worldwide. Achieving this desired future state requires transformative change management to foster adoption and minimize the burden of implementing eSource. Realizing this vision requires collaborative and dedicated efforts from multiple stakeholders, including patients, clinical trial participants, sites, technology vendors, standards organizations, regulators, payers, and sponsors. Stakeholders should align upon guidance to promote data integrity, data privacy, data security, and interoperability. The eSource revolution requires open dialogue, inclusive of shared learnings among stakeholders, to collectively and rapidly advance adoption. Adoption of eSource will optimize clinical research by enabling faster access to research data and more rapid decision-making, increasing clinical trial efficiency. Furthermore, adoption of eSource will improve data integrity by allowing direct data flow from the source to the sponsor's system, with minimal or no human intervention. This paper provides the TransCelerate point of view (POV) and recommendations to achieve the future state vision of complete utilization of eSource data in clinical trials and builds on previous TransCelerate eSource publications.

Evaluation of an electronic, patient-focused management system aimed at preventing cytomegalovirus disease following solid organ transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection is common among solid organ transplant (SOT) recipients and may cause CMV disease. To optimize the implementation of existing prevention strategies, the Management of Post-transplant Infections in Collaborating Hospitals (MATCH) program was developed. Two key performances of MATCH (diagnosing CMV infection at low viral load (VL) and before the onset of CMV disease) were assessed prior to, during and after the implementation of MATCH. METHODS: The MATCH program included a personalized surveillance plan, prophylaxis and preemptive therapy determined by the recipient's risk of CMV infection. The plan was composed through predefined algorithms and implemented through harvesting of real-time data from medical records. Risk of CMV disease was compared for recipients transplanted during and after vs prior to the implementation of MATCH. Lung and non-lung transplants were analyzed separately. RESULTS: A total of 593, 349, 520, and 360 SOT recipients were transplanted before (2007-2010), during (2011-2012), early after (2013-2015), and late after (2016-2017) implementation of MATCH with an observed reduction of diagnostic VL (P < .001) over time. Risk of CMV disease was reduced among non-lung transplant recipients transplanted during (adjusted hazard ratios [95% CI] 0.15 [0.04-0.54], P = .003), early after (aHR 0.27 [0.11-0.63], P = .003), and late after (aHR 0.17 [0.06-0.52], P = .002) compared with prior to MATCH. No significant change was observed among lung transplants. CONCLUSION: Implementation of CMV preventive strategies through MATCH was associated with a reduced risk of CMV disease among non-lung transplant recipients. Furthermore, the limitations of VL as a sole indicator for CMV disease in lung transplants were emphasized.

All-Cause Mortality of Hospital-Treated Borderline Personality Disorder: A Nationwide Cohort Study.

Patients with borderline personality disorder (BPD) are known to present frequently in emergency rooms, and they have a high rate of suicide. The mortality rate of patients with BPD is still unclear. The Danish Psychiatric Central Research Register and The Danish Register for Causes of Death were used to identify patients with a first-ever diagnosis of BPD (ICD-10: F60.31) from 1995 through 2011 together with time and cause of death. A total of 10,545 patients with a BPD diagnosis were followed for a mean time of 7.98 years. A total of 547 deaths were registered. The standardized mortality ratio of patients with BPD compared to the general population was 8.3 (95% CI [7.6, 9.1]). More than three inpatient admissions per year or a comorbid diagnosis of substance use disorder correlated with a higher mortality rate. The increased mortality rate in patients with BPD treated in secondary care emphasizes that it is a severe mental disorder.

The association of time since spousal loss and depression in widowhood: a systematic review and meta-analysis.

PURPOSE: To conduct a systematic review and meta-analysis examining the association of the prevalence of depression and time since spousal loss in widowed people. METHODS: The databases MEDLINE, Embase and PsycInfo were searched (May 2017) for papers reporting on time since spousal loss in widowed people and the prevalence of common mental disorders. A systematic review was conducted according to MOOSE guidelines. Random effects meta-analyses of the prevalence of depression were conducted by intervals of time since spousal loss. RESULTS: The literature search identified 12,982 studies of which 22 were eligible for inclusion in the systematic review. Of these, 14 were furthermore eligible for inclusion in the meta-analysis. The summary estimates found in the meta-analysis for the prevalence of depression in the intervals of time since spousal loss were: ≤ 1 month: 38.2% (21.9-55.8%); > 1 month to 3 months: 25.0% (17.3-33.5%); > 3 months to 6 months: 23.1% (18.0-28.7%); > 6 months to 12 months: 19.4% (15.2-24.0%); > 12 months to 18 months: 11.1% (5.3-18.7%); > 18 months to 24 months: 15.2% (12.3-18.2%); > 24 months to 60 months: 10.5% (4.3-18.5%). CONCLUSION: Widowhood is associated with a high prevalence of depression and the study identifies a population group needing special attention in daily clinical practice. The prevalence is highest in the first month of widowhood, however, continues to be high at least 5 years into widowhood.

Prevalence of common mental disorders in widowhood: A systematic review and meta-analysis.

BACKGROUND: Widowed people have a high risk of common mental disorders, however no summary estimates of the prevalences exist. The aim of this study was to conduct a systematic review and meta-analysis of the prevalence of common mental disorders in widowed people in the community. METHODS: MEDLINE, Embase and PsycInfo were searched for papers reporting on prevalence of common mental disorders and widowhood. Eligible studies were included in random effects meta-analyses of the prevalence of depression and anxiety disorders. Subgroup analyses were performed on method of assessment of depression and age and sex. RESULTS: The literature search identified 13,781 titles of which 42 were eligible for meta-analysis. The pooled prevalence of depression in studies using a screening scale was 40.6% (33.6%-47.6%) (n = 30). For studies using full diagnostic criteria the pooled prevalence of depression was 19.2% (13.4%-25.0%) (n = 12). Subgroup analyses of age (≥ or < 65) and sex did not show any differences regarding depression. Five studies reported the prevalence of anxiety disorders. The pooled prevalence estimate was 26.9% (8.1%-45.7%). LIMITATIONS: The prevalence estimates in this study are summary estimates of prevalences from existing literature. Although the reporting bias assessment showed no evidence, there could be some reporting bias, as studies might only present results if there is a high prevalence. CONCLUSIONS: Widowed people have a high prevalence of depression and anxiety disorders. The high prevalence of depression was independent of age and sex. The study identifies a population group at high risk needing special attention in clinical practice.

Mechanical restraint and characteristics of patient, staff and shifts in a psychiatric ward.

BACKGROUND: The use of coercion is a balance between depriving the patients' autonomy and dignity and preventing endangerment of the body or health of self or others. It is of importance to obtain more knowledge about mechanisms leading to mechanical restraint in the attempt of reducing it. OBJECTIVE: To analyse for associations between incidence of mechanical restraint (MR) and staffing level, staff demographics, patient characteristics, type of shift (day/evening/night) and change of shifts. METHOD: A naturalistic descriptive method was used to study cases of MR in a psychiatric ward. Data for each case of MR was obtained from an electronic reporting system. Care workers from each shift were identified using duty rosters. Analyses included binary logistic regression analyses. RESULTS: In 82% of the 114 cases of MR, the patient was diagnosed with personality disorders. In the multiple regression analysis, a significant association was found between the use of MR and the presence of male care workers on the ward (OR:1.44, 95% CI: 1.01-2.05; p = .04). Moreover, MR was associated with evening shifts, compared with day and night shifts (OR =1,29, 95% CI: 1.14-2.57, p = .01). Besides, months from January to December was associated with a decrease in MRs (OR: 0.88, 95% CI: 0.83-0.94; p = 7.3 E-6). No significant associations were found between MR and staffing level or experience. CONCLUSIONS: MR was associated with evening shifts, higher number of male care workers on duty and a decrease from January to December.

A multi-disciplinary perspective on emergent and future innovations in peer review.

Peer review of research articles is a core part of our scholarly communication system. In spite of its importance, the status and purpose of peer review is often contested. What is its role in our modern digital research and communications infrastructure? Does it perform to the high standards with which it is generally regarded? Studies of peer review have shown that it is prone to bias and abuse in numerous dimensions, frequently unreliable, and can fail to detect even fraudulent research. With the advent of web technologies, we are now witnessing a phase of innovation and experimentation in our approaches to peer review. These developments prompted us to examine emerging models of peer review from a range of disciplines and venues, and to ask how they might address some of the issues with our current systems of peer review. We examine the functionality of a range of social Web platforms, and compare these with the traits underlying a viable peer review system: quality control, quantified performance metrics as engagement incentives, and certification and reputation. Ideally, any new systems will demonstrate that they out-perform and reduce the biases of existing models as much as possible. We conclude that there is considerable scope for new peer review initiatives to be developed, each with their own potential issues and advantages. We also propose a novel hybrid platform model that could, at least partially, resolve many of the socio-technical issues associated with peer review, and potentially disrupt the entire scholarly communication system. Success for any such development relies on reaching a critical threshold of research community engagement with both the process and the platform, and therefore cannot be achieved without a significant change of incentives in research environments.

The clinical trajectory of patients with borderline personality disorder.

OBJECTIVE: The epidemiological data on the diagnostic course of patients with borderline personality disorder (BPD) is limited. We used a nationwide register to investigate the diagnostic stability and changes over time. METHOD: The Danish nationwide registers were used to follow all patients with a diagnosis of BPD and investigate their first-ever psychiatric diagnosis and their latest diagnosis in the time period of 1995-2012. From this, we found the diagnostic stability and described the diagnostic changes. RESULTS: A total of 10 786 patients diagnosed with BPD were identified. The prospective diagnostic stabilities were 37% for females and 25% for males, and retrospective stabilities were 20% for females and 22% for males. More than 60% of patients received other diagnoses than BPD as their first-ever diagnosis. Stress-related (17%) and depressive disorders (14%) were most frequent as first-ever diagnosis. The latest diagnosis remained BPD in nearly half of females and one third of males, followed by schizophrenia, notably for those with longer follow-up and males. CONCLUSION: This study gives a detailed display of complicated clinical trajectories. The low diagnostic stabilities demonstrate a heterogenous patient group diagnosed with many other psychiatric diagnoses over time. Copyright © 2016 John Wiley & Sons, Ltd.

Mild induced hypothermia: effects on sepsis-related coagulopathy--results from a randomized controlled trial.

INTRODUCTION: Coagulopathy associates with poor outcome in sepsis. Mild induced hypothermia has been proposed as treatment in sepsis but it is not known whether this intervention worsens functional coagulopathy. MATERIALS AND METHODS: Interim analysis data from an ongoing randomized controlled trial; The Cooling And Surviving Septic shock (CASS) study. Patients suffering severe sepsis/septic shock are allocated to either mild induced hypothermia (cooling to 32-34°C for 24hours) or control (uncontrolled temperature). TRIAL REGISTRATION: NCT01455116. Thrombelastography (TEG) is performed three times during the first day after study enrollment in all patients. Reaction time (R), maximum amplitude (MA) and patients' characteristics are here reported. RESULTS: One hundred patients (control n=50 and intervention n=50; male n=59; median age 68years) with complete TEG during follow-up were included. At enrollment, 3%, 38%, and 59% had a hypocoagulable, normocoagulable, and hypercoagulable TEG clot strength (MA), respectively. In the hypothermia group, functional coagulopathy improved during the hypothermia phase, measured by R and MA, in patients with hypercoagulation as well as in patients with hypocoagulation (correlation between ΔR and initial R: rho=-0.60, p<0.0001 and correlation between ΔMA and initial MA: rho=-0.50, p=0.0002). Similar results were not observed in the control group neither for R (rho=-0.03, p=0.8247) nor MA (rho=-0.15, p=0.3115). CONCLUSION: Mild induced hypothermia did seem to improve functional coagulopathy in septic patients. This improvement of functional coagulopathy parameters during the hypothermia intervention persisted after rewarming. Randomized trials are warranted to determine whether the positive effect on sepsis-related coagulopathy can be transformed to improved survival.

Risk factors and outcomes for late presentation for HIV-positive persons in Europe: results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE).

BACKGROUND: Few studies have monitored late presentation (LP) of HIV infection over the European continent, including Eastern Europe. Study objectives were to explore the impact of LP on AIDS and mortality. METHODS AND FINDINGS: LP was defined in Collaboration of Observational HIV Epidemiological Research Europe (COHERE) as HIV diagnosis with a CD4 count <350/mm(3) or an AIDS diagnosis within 6 months of HIV diagnosis among persons presenting for care between 1 January 2000 and 30 June 2011. Logistic regression was used to identify factors associated with LP and Poisson regression to explore the impact on AIDS/death. 84,524 individuals from 23 cohorts in 35 countries contributed data; 45,488 were LP (53.8%). LP was highest in heterosexual males (66.1%), Southern European countries (57.0%), and persons originating from Africa (65.1%). LP decreased from 57.3% in 2000 to 51.7% in 2010/2011 (adjusted odds ratio [aOR] 0.96; 95% CI 0.95-0.97). LP decreased over time in both Central and Northern Europe among homosexual men, and male and female heterosexuals, but increased over time for female heterosexuals and male intravenous drug users (IDUs) from Southern Europe and in male and female IDUs from Eastern Europe. 8,187 AIDS/deaths occurred during 327,003 person-years of follow-up. In the first year after HIV diagnosis, LP was associated with over a 13-fold increased incidence of AIDS/death in Southern Europe (adjusted incidence rate ratio [aIRR] 13.02; 95% CI 8.19-20.70) and over a 6-fold increased rate in Eastern Europe (aIRR 6.64; 95% CI 3.55-12.43). CONCLUSIONS: LP has decreased over time across Europe, but remains a significant issue in the region in all HIV exposure groups. LP increased in male IDUs and female heterosexuals from Southern Europe and IDUs in Eastern Europe. LP was associated with an increased rate of AIDS/deaths, particularly in the first year after HIV diagnosis, with significant variation across Europe. Earlier and more widespread testing, timely referrals after testing positive, and improved retention in care strategies are required to further reduce the incidence of LP.