Mortality after stroke in patients with paroxysmal and chronic atrial fibrillation - The FibStroke study

Background: Recent studies have reported that patientswith paroxysmal atrial fibrillation (AF) have lower risk of thromboembolism and better prognosis than patients with chronic AF. We sought to address the differences in ischaemic events in patients with paroxysmal AF and chronic AF.Methods: The FibStroke study is a cross-sectional observational multicenter registry that included AF patients with an ischaemic stroke, TIA (transient ischaemic attack) or intracranial bleed during 2003-2012 identified from discharge registries of four Finnish hospitals. Altogether 1448 patients with paroxysmal and 1808 patients with chronic atrial fibrillation suffered a total of 707 TIA-episodes and 2549 ischaemic strokes.Results: Mortality within 30 days after the index event was significantly lower in patients with paroxysmal AF than with chronic AF (7.6% vs 16.9%, p < 0.01). At the onset of event, 62.8% of the patients with paroxysmal AF were in sinus rhythm, and these patients had better prognosis after the event compared to patients with other rhythmthan sinus rhythm(mortality 5.2% vs 15.7%, p < 0.01). In the propensity score matched analysismortality after stroke was significantly lower in patients with paroxysmal AF than in patients with chronic AF (11.6% vs 17.8%, p < 0.01), while mortality after TIA was also lower, but did not reach statistical significance (0.4% vs 1.7%, p = 0.31).Conclusions: Asignificant proportion of strokes in AF patients occur in patients with paroxysmal AF, but they have better prognosis than patients with chronic AF. The prognosis is also significantly better in patients who are in sinus rhythm at the onset of event.

Biochemical characterization of Acacia schweinfurthii serine proteinase inhibitor

One of the many control mechanisms of serine proteinases is their specific inhibition by protein proteinase inhibitors. An extract of Acacia schweinfurthii was screened for potential serine proteinase inhibition. It was successfully purified to homogeneity by precipitating with 80% (v/v) acetone and sequential chromatographic steps, including ion-exchange, affinity purifica- Q2 tion and RP-HPLC. Reducing SDS-PAGE conditions revealed an inhibitor (ASTI) consisting of two polypeptide chains A and B of approximate molecular weights of 16 and 10 kDa, respectively, and under non-reducing conditions, 26 kDa was observed. The inhibitor was shown to inhibit bovine trypsin (Ki of 3.45 nM) at an approximate molar ratio of inhibitor: trypsin (1:1). The A- and B-chains revealed complete sequences of 140 and 40 amino acid residues, respectively. Sequence similarity (70%) was reported between ASTI A-chain and ACTI A-chain (Acacia confusa) using the ClustalW. The B-chain produced a 76% sequence similarity between ASTI and Leucaena leucocephala trypsin inhibitor

Scaling Up Towards International Targets for AIDS, Tuberculosis, and Malaria: Contribution of Global Fund-Supported Programs in 2011–2015

OBJECTIVE: The paper projects the contribution to 2011-2015 international targets of three major pandemics by programs in 140 countries funded by the Global Fund to Fight AIDS, Tuberculosis and Malaria, the largest external financier of tuberculosis and malaria programs and a major external funder of HIV programs in low and middle income countries. DESIGN: Estimates, using past trends, for the period 2011-2015 of the number of persons receiving antiretroviral (ARV) treatment, tuberculosis case detection using the internationally approved DOTS strategy, and insecticide-treated nets (ITNs) to be delivered by programs in low and middle income countries supported by the Global Fund compared to international targets established by UNAIDS, Stop TB Partnership, Roll Back Malaria Partnership and the World Health Organisation. RESULTS: Global Fund-supported programs are projected to provide ARV treatment to 5.5-5.8 million people, providing 30%-31% of the 2015 international target. Investments in tuberculosis and malaria control will enable reaching in 2015 60%-63% of the international target for tuberculosis case detection and 30%-35% of the ITN distribution target in sub-Saharan Africa. CONCLUSION: Global Fund investments will substantially contribute to the achievement by 2015 of international targets for HIV, TB and malaria. However, additional large scale international and domestic financing is needed if these targets are to be reached by 2015

Prevalence and risk factors for HIV-1 infection in rural Kilimanjaro region of Tanzania: Implications for prevention and treatment

BACKGROUND: Variability in stages of the HIV-1 epidemic and hence HIV-1 prevalence exists in different areas in sub-Saharan Africa. The purpose of this study was to investigate the magnitude of HIV-1 infection and identify HIV-1 risk factors that may help to develop preventive strategies in rural Kilimanjaro, Tanzania. METHODS: A cross-sectional study was conducted between March and May of 2005 involving all individuals aged between 15–44 years having an address in Oria Village. All eligible individuals were registered and invited to participate. Participants were interviewed regarding their demographic characteristics, sexual behaviors, and medical history. Following a pre-test counseling, participants were offered an HIV test. RESULTS: Of the 2 093 eligible individuals, 1 528 (73.0%) participated. The overall age and sex adjusted HIV-1 prevalence was 5.6%. Women had 2.5 times higher prevalence (8.0% vs. 3.2%) as compared to men. The age group 25–44 years, marriage, separation and low education were associated with higher risk of HIV-1 infection for both sexes. HIV-1 infection was significantly associated with >2 sexual partners in the past 12 months (women: Adjusted odds ratio [AOR], 2.5 (95%CI: 1.3–4.7), and past 5 years, [(men: AOR, 2.2 (95%CI:1.2–5.6); women: AOR, 2.5 (95%CI: 1.4–4.0)], unprotected casual sex (men: AOR,1.8 95%CI: 1.2–5.8), bottled alcohol (Men: AOR, 5.9 (95%CI:1.7–20.1) and local brew (men: AOR, 3.7 (95%CI: 1.5–9.2). Other factors included treatment for genital ulcers and genital discharge in the past 1 month. Health-related complaints were more common among HIV-1 seropositive as compared to seronegative participants and predicted the presence of HIV-1 infection. CONCLUSION: HIV-1 infection was highly prevalent in this population. As compared to our previous findings, a shift of the epidemic from a younger to an older age group and from educated to uneducated individuals was observed. Women and married or separated individuals remained at higher risk of infection. To prevent further escalation of the HIV epidemic, efforts to scale up HIV prevention programmes addressing females, people with low education, lower age at marriage, alcohol consumption, condom use and multiple sexual partners for all age groups remains a top priority. Care and treatment are urgently needed for those infected in rural areas

Application of Phylodynamic Tools to Inform the Public Health Response to COVID-19: Qualitative Analysis of Expert Opinions

Background: In the wake of the SARS-CoV-2 pandemic, scientists have scrambled to collect and analyze SARS-CoV-2 genomic data to inform public health responses to COVID-19 in real time. Open source phylogenetic and data visualization platforms for monitoring SARS-CoV-2 genomic epidemiology have rapidly gained popularity for their ability to illuminate spatial-temporal transmission patterns worldwide. However, the utility of such tools to inform public health decision-making for COVID-19 in real time remains to be explored. Objective: The aim of this study is to convene experts in public health, infectious diseases, virology, and bioinformatics—many of whom were actively engaged in the COVID-19 response—to discuss and report on the application of phylodynamic tools to inform pandemic responses. Methods: In total, 4 focus groups (FGs) occurred between June 2020 and June 2021, covering both the pre- and postvariant strain emergence and vaccination eras of the ongoing COVID-19 crisis. Participants included national and international academic and government researchers, clinicians, public health practitioners, and other stakeholders recruited through purposive and convenience sampling by the study team. Open-ended questions were developed to prompt discussion. FGs I and II concentrated on phylodynamics for the public health practitioner, while FGs III and IV discussed the methodological nuances of phylodynamic inference. Two FGs per topic area to increase data saturation. An iterative, thematic qualitative framework was used for data analysis. Results: We invited 41 experts to the FGs, and 23 (56%) agreed to participate. Across all the FG sessions, 15 (65%) of the participants were female, 17 (74%) were White, and 5 (22%) were Black. Participants were described as molecular epidemiologists (MEs; n=9, 39%), clinician-researchers (n=3, 13%), infectious disease experts (IDs; n=4, 17%), and public health professionals at the local (PHs; n=4, 17%), state (n=2, 9%), and federal (n=1, 4%) levels. They represented multiple countries in Europe, the United States, and the Caribbean. Nine major themes arose from the discussions: (1) translational/implementation science, (2) precision public health, (3) fundamental unknowns, (4) proper scientific communication, (5) methods of epidemiological investigation, (6) sampling bias, (7) interoperability standards, (8) academic/public health partnerships, and (9) resources. Collectively, participants felt that successful uptake of phylodynamic tools to inform the public health response relies on the strength of academic and public health partnerships. They called for interoperability standards in sequence data sharing, urged careful reporting to prevent misinterpretations, imagined that public health responses could be tailored to specific variants, and cited resource issues that would need to be addressed by policy makers in future outbreaks. Conclusions: This study is the first to detail the viewpoints of public health practitioners and molecular epidemiology experts on the use of viral genomic data to inform the response to the COVID-19 pandemic. The data gathered during this study provide important information from experts to help streamline the functionality and use of phylodynamic tools for pandemic responses

The impact of HIV-1 on the malaria parasite biomass in adults in sub-Saharan Africa contributes to the emergence of antimalarial drug resistance

Background. HIV-related immune-suppression increases the risk of malaria (infection, disease and treatment failure) and probably the circulating parasite biomass, favoring the emergence of drug resistance parasites. Methods. The additional malaria parasite biomass related to HIV-1 co-infection in sub-Saharan Africa was estimated by a mathematical model. Parasite biomass was computed as the incidence rate of clinical malaria episodes multiplied by the number of parasites circulating in the peripheral blood of patients at the time symptoms appear. A mathematical model estimated the influence of HIV-1 infection on parasite density in clinical malaria by country and by age group, malaria transmission intensity and urban/rural area. In a multivariate sensitivity analysis, 95% confidence intervals (CIs) were calculated using the Monte Carlo simulation. Results. The model shows that in 2005 HIV-1 increased the overall malaria parasite biomass by 18.0% (95%CI: 11.6-26.9). The largest relative increase (134.9-243.9%) was found in southern Africa where HIV-1 prevalence is the highest and malaria transmission unstable. The largest absolute increase was found in Zambia, Malawi, the Central African Republic and Mozambique, where both malaria and HIV are highly endemic. A univariate sensitivity analysis shows that estimates are sensitive to the magnitude of the impact of HIV-1 infection on the malaria incidence rates and associated parasite densities. Conclusion. The HIV-1 epidemic by increasing the malaria parasite biomass in sub-Saharan Africa may also increase the emergence of antimalarial drug resistance, potentially affecting the health of the whole population in countries endemic for both HIV-1 and malaria

Lost opportunities in HIV prevention: programmes miss places where exposures are highest

Background: Efforts at HIV prevention that focus on high risk places might be more effective and less stigmatizing than those targeting high risk groups. The objective of the present study was to assess risk behaviour patterns, signs of current preventive interventions and apparent gaps in places where the risk of HIV transmission is high and in communities with high HIV prevalence. Methods: The PLACE method was used to collect data. Inhabitants of selected communities in Lusaka and Livingstone were interviewed about where people met new sexual partners. Signs of HIV preventive activities in these places were recorded. At selected venues, people were interviewed about their sexual behaviour. Peer educators and staff of NGOs were also interviewed. Results: The places identified were mostly bars, restaurants or sherbeens, and fewer than 20% reported any HIV preventive activity such as meetings, pamphlets or posters. In 43% of places in Livingstone and 26% in Lusaka, condoms were never available. There were few active peer educators. Among the 432 persons in Lusaka and 676 in Livingstone who were invited for interview about sexual behaviour, consistent condom use was relatively high in Lusaka (77%) but low in Livingstone (44% of men and 34% of women). Having no condom available was the most common reason for not using one. Condom use in Livingstone was higher among individuals socializing in places where condoms always were available. Conclusion: In the places studied we found a high prevalence of behaviours with a high potential for HIV transmission but few signs of HIV preventive interventions. Covering the gaps in prevention in these high exposure places should be given the highest priority

Higher dose corticosteroids in patients admitted to hospital with COVID-19 who are hypoxic but not requiring ventilatory support (RECOVERY): a randomised, controlled, open-label, platform trial

BACKGROUND: Low-dose corticosteroids have been shown to reduce mortality for patients with COVID-19 requiring oxygen or ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation). We evaluated the use of a higher dose of corticosteroids in this patient group. METHODS: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients with clinical evidence of hypoxia (ie, receiving oxygen or with oxygen saturation <92% on room air) were randomly allocated (1:1) to either usual care with higher dose corticosteroids (dexamethasone 20 mg once daily for 5 days followed by 10 mg dexamethasone once daily for 5 days or until discharge if sooner) or usual standard of care alone (which included dexamethasone 6 mg once daily for 10 days or until discharge if sooner). The primary outcome was 28-day mortality among all randomised participants. On May 11, 2022, the independent data monitoring committee recommended stopping recruitment of patients receiving no oxygen or simple oxygen only due to safety concerns. We report the results for these participants only. Recruitment of patients receiving ventilatory support is ongoing. The RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS: Between May 25, 2021, and May 13, 2022, 1272 patients with COVID-19 and hypoxia receiving no oxygen (eight [1%]) or simple oxygen only (1264 [99%]) were randomly allocated to receive usual care plus higher dose corticosteroids (659 patients) versus usual care alone (613 patients, of whom 87% received low-dose corticosteroids during the follow-up period). Of those randomly assigned, 745 (59%) were in Asia, 512 (40%) in the UK, and 15 (1%) in Africa. 248 (19%) had diabetes and 769 (60%) were male. Overall, 123 (19%) of 659 patients allocated to higher dose corticosteroids versus 75 (12%) of 613 patients allocated to usual care died within 28 days (rate ratio 1·59 [95% CI 1·20–2·10]; p=0·0012). There was also an excess of pneumonia reported to be due to non-COVID infection (64 cases [10%] vs 37 cases [6%]; absolute difference 3·7% [95% CI 0·7–6·6]) and an increase in hyperglycaemia requiring increased insulin dose (142 [22%] vs 87 [14%]; absolute difference 7·4% [95% CI 3·2–11·5]). INTERPRETATION: In patients hospitalised for COVID-19 with clinical hypoxia who required either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared with usual care, which included low-dose corticosteroids. The RECOVERY trial continues to assess the effects of higher dose corticosteroids in patients hospitalised with COVID-19 who require non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. FUNDING: UK Research and Innovation (Medical Research Council), National Institute of Health and Care Research, and Wellcome Trust

Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis

Background: We aimed to evaluate the use of baricitinib, a Janus kinase (JAK) 1–2 inhibitor, for the treatment of patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was done, which included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936) and is ongoing. Findings: Between Feb 2 and Dec 29, 2021, from 10 852 enrolled, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% were receiving tocilizumab (with planned use within the next 24 h recorded for a further 9%). Overall, 514 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0·87; 95% CI 0·77–0·99; p=0·028). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of eight previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths), in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0·57; 95% CI 0·45–0·72). Including the results from RECOVERY in an updated meta-analysis of all nine completed trials (involving 11 888 randomly assigned patients and 1485 deaths) allocation to baricitinib or another JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0·80; 95% CI 0·72–0·89; p<0·0001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no significant excess of thrombosis, or other safety outcomes. Interpretation: In patients hospitalised with COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Role of CCL3L1-CCR5 Genotypes in the Epidemic Spread of HIV-1 and Evaluation of Vaccine Efficacy

Polymorphisms in CCR5, the major coreceptor for HIV, and CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine, are determinants of HIV-AIDS susceptibility. Here, we mathematically modeled the potential impact of these genetic factors on the epidemic spread of HIV, as well as on its prevention.Ro, the basic reproductive number, is a fundamental concept in explaining the emergence and persistence of epidemics. By modeling sexual transmission among HIV+/HIV- partner pairs, we find that Ro estimates, and concordantly, the temporal and spatial patterns of HIV outgrowth are highly dependent on the infecting partners' CCL3L1-CCR5 genotype. Ro was least and highest when the infected partner possessed protective and detrimental CCL3L1-CCR5 genotypes, respectively. The modeling data indicate that in populations such as Pygmies with a high CCL3L1 gene dose and protective CCR5 genotypes, the spread of HIV might be minimal. Additionally, Pc, the critical vaccination proportion, an estimate of the fraction of the population that must be vaccinated successfully to eradicate an epidemic was <1 only when the infected partner had a protective CCL3L1-CCR5 genotype. Since in practice Pc cannot be >1, to prevent epidemic spread, population groups defined by specific CCL3L1-CCR5 genotypes might require repeated vaccination, or as our models suggest, a vaccine with an efficacy of >70%. Further, failure to account for CCL3L1-CCR5-based genetic risk might confound estimates of vaccine efficacy. For example, in a modeled trial of 500 subjects, misallocation of CCL3L1-CCR5 genotype of only 25 (5%) subjects between placebo and vaccine arms results in a relative error of approximately 12% from the true vaccine efficacy.CCL3L1-CCR5 genotypes may impact on the dynamics of the HIV epidemic and, consequently, the observed heterogeneous global distribution of HIV infection. As Ro is lowest when the infecting partner has beneficial CCL3L1-CCR5 genotypes, we infer that therapeutic vaccines directed towards reducing the infectivity of the host may play a role in halting epidemic spread. Further, CCL3L1-CCR5 genotype may provide critical guidance for optimizing the design and evaluation of HIV-1 vaccine trials and prevention programs