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Abstract Background Periods of droughts can lead to decreased food security, and altered behaviours, potentially affecting outcomes on antiretroviral therapy (ART) among persons with HIV (PWH). We investigated whether decreased rainfall is associated with adverse outcomes among PWH on ART in Southern Africa. Methods Data were combined from 11 clinical cohorts of PWH in Lesotho, Malawi, Mozambique, South Africa, Zambia, and Zimbabwe, participating in the International epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA-SA) collaboration. Adult PWH who had started ART prior to 01/06/2016 and were in follow-up in the year prior to 01/06/2016 were included. Two-year rainfall from June 2014 to May 2016 at the location of each HIV centre was summed and ranked against historical 2-year rainfall amounts (1981–2016) to give an empirical relative percentile rainfall estimate. The IeDEA-SA and rainfall data were combined using each HIV centre’s latitude/longitude. In individual-level analyses, multivariable Cox or generalized estimating equation regression models (GEEs) assessed associations between decreased rainfall versus historical levels and four separate outcomes (mortality, CD4 counts 400 copies/mL, and > 12-month gaps in follow-up) in the two years following the rainfall period. GEEs were used to investigate the association between relative rainfall and monthly numbers of unique visitors per HIV centre. Results Among 270,708 PWH across 386 HIV centres (67% female, median age 39 [IQR: 32–46]), lower rainfall than usual was associated with higher mortality (adjusted Hazard Ratio: 1.18 [95%CI: 1.07–1.32] per 10 percentile rainfall rank decrease) and unsuppressed viral loads (adjusted Odds Ratio: 1.05 [1.01–1.09]). Levels of rainfall were not strongly associated with CD4 counts 12-month gaps in care. HIV centres in areas with less rainfall than usual had lower numbers of PWH visiting them (adjusted Rate Ratio: 0.80 [0.66–0.98] per 10 percentile rainfall rank decrease). Conclusions Decreased rainfall could negatively impact on HIV treatment behaviours and outcomes. Further research is needed to explore the reasons for these effects. Interventions to mitigate the health impact of severe weather events are required.

BackgroundSepsis, a life-threatening condition caused by the dysregulated host response to infection, is a major global health concern. Understanding the impact of viral or bacterial pathogens in sepsis is crucial for improving patient outcomes. This study aimed to investigate the human cytomegalovirus (HCMV) seropositivity as a risk factor for development of sepsis in patients with COVID-19.MethodsA multicenter observational study enrolled 95 intensive care patients with COVID-19-induced sepsis and 80 post-surgery individuals as controls. HCMV serostatus was determined using an ELISA test. Comprehensive clinical data, including demographics, comorbidities, and 30-day mortality, were collected. Statistical analyses evaluated the association between HCMV seropositivity and COVID-19 induced sepsis.ResultsThe prevalence of HCMV seropositivity did not significantly differ between COVID-19-induced sepsis patients (78%) and controls (71%, p = 0.382) in the entire cohort. However, among patients aged ≤60 years, HCMV seropositivity was significantly higher in COVID-19 sepsis patients compared to controls (86% vs 61%, respectively; p = 0.030). Nevertheless, HCMV serostatus did not affect 30-day survival.DiscussionThese findings confirm the association between HCMV seropositivity and COVID-19 sepsis in non-geriatric patients. However, the lack of an independent effect on 30-day survival can be explained by the cross-reactivity of HCMV specific CD8+ T-cells towards SARS-CoV-2 peptides, which might confer some protection to HCMV seropositive patients. The inclusion of a post-surgery control group strengthens the generalizability of the findings. Further research is needed to elucidate the underlying mechanisms of this association, explore different patient populations, and identify interventions for optimizing patient management.ConclusionThis study validates the association between HCMV seropositivity and severe COVID-19-induced sepsis in non-geriatric patients, contributing to the growing body of evidence on viral pathogens in sepsis. Although HCMV serostatus did not independently influence 30-day survival, future investigations should focus on unraveling the intricate interplay between HCMV, immune responses, and COVID-19. These insights will aid in risk stratification and the development of targeted interventions for viral sepsis.

Abstract Introduction Recent evidence suggests an association of plasma Proenkephalin A 119–159 (penKid) with early and successful liberation from continuous renal replacement therapy (CRRT) in critically ill patients with acute kidney injury. However, these exploratory results are derived from a monocentric trial and therefore require external validation in a multicenter cohort. Methods Data and plasma samples from the “Effect of Regional Citrate Anticoagulation versus Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury—A Randomized Clinical Trial” (RICH Trial) were used for this validation study. PenKid was measured in all plasma samples available at CRRT initiation and at day 3 of CRRT. Patients were categorized into low and high penKid groups with a cutoff at 100 pmol/l. Competing-risk time-to-event analyses were performed. Competing risk endpoints were successful and unsuccessful liberation from CRRT, the latter meaning death or initiation of a new RRT within one week of discontinuation of primary CRRT. Then penKid was compared to urinary output. Results Low pre-CRRT penKid levels at CRRT initiation were not associated with early and successful liberation from CRRT compared to patients with high pre-CRRT penKid levels [subdistribution hazard ratio (sHR) 1.01, 95% CI 0.73–1.40, p = 0.945]. However, the landmark analysis on day 3 of ongoing CRRT demonstrated an association between low penKid levels and successful liberation from CRRT (sHR 2.35, 95% CI 1.45–3.81, p 436 ml/d) was even stronger associated with successful liberation (sHR 2.91, 95% CI 1.80–4.73, p

Introduction: Acute kidney injury (AKI) is a common complication in cardiac surgery patients and prevention is needed to improve clinical outcomes. Alpha-1-microglobulin (A1M) is a physiological antioxidant with strong tissue-protective and cell-protective properties that has demonstrated renoprotective effects. RMC-035, a recombinant variant of endogenous human A1M, is being developed for the prevention of AKI in cardiac surgery patients. Methods: In this phase 1b, randomized, double-blind, and parallel group clinical study, 12 cardiac surgery patients undergoing elective, open-chest, on-pump coronary artery bypass graft and/or valve surgery with additional predisposing AKI risk factors were enrolled to receive in total 5 intravenous doses of either RMC-035 or placebo. The primary objective was to evaluate the safety and tolerability of RMC-035. The secondary objective was to evaluate its pharmacokinetic properties. Results: RMC-035 was well tolerated. The nature and frequency of adverse events (AEs) were consistent with the expected background rates in the underlying patient population with no AEs reported as related to study drug. No clinically relevant changes were observed for vital signs or laboratory parameters except for renal biomarkers. Several established AKI urine biomarkers were reduced at 4 hours after first dose administration in the treatment group, indicating a reduced perioperative tubular cell injury following RMC-035 treatment. Conclusion: Multiple intravenous doses of RMC-035 were well tolerated in patients undergoing cardiac surgery. Observed RMC-035 plasma exposures were safe and in the range of expected pharmacological activity. Furthermore, urine biomarkers suggest reduced perioperative kidney cell injury, warranting further investigation of RMC-035 as a potential renoprotective treatment.

Patients undergoing extracorporeal membrane oxygenation (ECMO) often require therapy with anti-infective drugs. The pharmacokinetics of these drugs may be altered during ECMO treatment due to pathophysiological changes in the drug metabolism of the critically ill and/or the ECMO therapy itself. This study investigates the latter aspect for commonly used anti-infective drugs in an ex vivo setting. A fully functional ECMO device circulated an albumin–electrolyte solution through the ECMO tubes and oxygenator. The antibiotic agents cefazolin, cefuroxim, cefepime, cefiderocol, linezolid and daptomycin and the antifungal agent anidulafungin were added. Blood samples were taken over a period of four hours and drug concentrations were measured via high-pressure liquid chromatography (HPLC) with UV detection. Subsequently, the study analyzed the time course of anti-infective concentrations. The results showed no significant changes in the concentration of any tested anti-infectives throughout the study period. This ex vivo study demonstrates that the ECMO device itself has no impact on the concentration of commonly used anti-infectives. These findings suggest that ECMO therapy does not contribute to alterations in the concentrations of anti-infective medications in severely ill patients.

Abstract Background Renal replacement therapy (RRT) remains the key rescue therapy for critically ill patients with severe acute kidney injury (AKI). However, there are currently no tools available to predict successful liberation from RRT. Biomarkers may allow for risk stratification and individualization of treatment strategies. Proenkephalin A 119–159 (penKid) has been suggested as a promising marker of kidney function in the context of AKI, but has not yet been evaluated for RRT liberation in critically ill patients with AKI. Methods This post hoc analysis included 210 patients from the randomized clinical ELAIN trial and penKid levels were measured in the blood of these patients. Competing risk time-to-event analyses were performed for pre-RRT penKid at initiation of RRT and in a landmark analysis at day 3 after initiation of RRT. Competing risk endpoints were successful liberation from RRT or death without prior liberation from RRT. Results Low pre-RRT penKid levels (penKid ≤ 89 pmol/l) at RRT initiation were associated with early and successful liberation from RRT compared to patients with high pre-RRT penKid levels (subdistribution hazard ratio (sHR) 1.83, 95%CI 1.26–2.67, p = 0.002, estimated 28d-cumulative incidence function (28d-CIF) of successful liberation from RRT 61% vs. 45%, p = 0.022). This association persisted in the landmark analysis on day 3 of RRT (sHR 1.78, 95%CI 1.17–2.71, p = 0.007, 28d-CIF of successful liberation from RRT 67% vs. 47%, p = 0.018). For both time points, no difference in the competing event of death was detected. Conclusions In critically ill patients with RRT-dependent AKI, plasma penKid appears to be a useful biomarker for the prediction of shorter duration and successful liberation from RRT and may allow an individualized approach to guide strategies of RRT liberation in critically ill patients with RRT-dependent AKI. Trial registration: The ELAIN trial was prospectively registered at the German Clinical Trial Registry (Identifier: DRKS00004367) on 28th of May 2013. Graphical Abstract

Introduction"Treat All" - the treatment of all people with HIV, irrespective of disease stage or CD4 cell count - represents a paradigm shift in HIV care that has the potential to end AIDS as a public health threat. With accelerating implementation of Treat All in sub-Saharan Africa (SSA), there is a need for a focused agenda and research to identify and inform strategies for promoting timely uptake of HIV treatment, retention in care, and sustained viral suppression and addressing bottlenecks impeding implementation.MethodsThe Delphi approach was used to develop consensus around research priorities for Treat All implementation in SSA. Through an iterative process (June 2017 to March 2018), a set of research priorities was collectively formulated and refined by a technical working group and shared for review, deliberation and prioritization by more than 200 researchers, implementation experts, policy/decision-makers, and HIV community representatives in East, Central, Southern and West Africa.Results and discussionThe process resulted in a list of nine research priorities for generating evidence to guide Treat All policies, implementation strategies and monitoring efforts. These priorities highlight the need for increased focus on adolescents, men, and those with mental health and substance use disorders - groups that remain underserved in SSA and for whom more effective testing, linkage and care strategies need to be identified. The priorities also reflect consensus on the need to: (1) generate accurate national and sub-national estimates of the size of key populations and describe those who remain underserved along the HIV-care continuum; (2) characterize the timeliness of HIV care and short- and long-term HIV care continuum outcomes, as well as factors influencing timely achievement of these outcomes; (3) estimate the incidence and prevalence of HIV-drug resistance and regimen switching; and (4) identify cost-effective and affordable service delivery models and strategies to optimize uptake and minimize gaps, disparities, and losses along the HIV-care continuum, particularly among underserved populations.ConclusionsReflecting consensus among a broad group of experts, researchers, policy- and decision-makers, PLWH, and other stakeholders, the resulting research priorities highlight important evidence gaps that are relevant for ministries of health, funders, normative bodies and research networks.

Introduction Acute kidney injury (AKI) is a common complication after cardiac surgery (CS) and is associated with adverse short-term and long-term outcomes. Alpha-1-microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme binding and mitochondrial-protective mechanisms. RMC-035 is a modified, more soluble, variant of A1M and has been proposed as a novel targeted therapeutic protein to prevent CS-associated AKI (CS-AKI). RMC-035 was considered safe and generally well tolerated when evaluated in four clinical phase 1 studies.Methods and analysis This is a phase 2, randomised, double-blind, adaptive design, parallel group clinical study that evaluates RMC-035 compared with placebo in approximately 268 cardiac surgical patients at high risk for CS-AKI. RMC-035 is administered as an intravenous infusion. In total, five doses will be given. Dosing is based on presurgery estimated glomerular filtration rate (eGFR), and will be either 1.3 or 0.65 mg/kg.The primary study objective is to evaluate whether RMC-035 reduces the incidence of postoperative AKI, and key secondary objectives are to evaluate whether RMC-035 improves postoperative renal function compared with placebo. A blinded interim analysis with potential sample size reassessment is planned once 134 randomised subjects have completed dosing. An independent data monitoring committee will evaluate safety and efficacy data at prespecified intervals throughout the trial. The study is a global multicentre study at approximately 30 sites.Ethics and dissemination The trial was approved by the joint ethics committee of the physician chamber Westfalen-Lippe and the University of Münster (code ‘2021-778 f-A’) and subsequently approved by the responsible ethics committees/relevant institutional review boards for the participating sites. The study is conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and other applicable regulations. Results of this study will be published in a peer-reviewed scientific journal.Trial registration number NCT05126303.

Introduction Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation.Methods and analysis The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage.Ethics and dissemination The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research.Trial registration number NCT04647396.

Patients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to a weight-banded nominal dose of 11, 14, 17, or 20 mg/kg/day levofloxacin (minimum, 750 mg) in combination with other second-line agents. A total of 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median areas under the concentration-time curve from 0 to 24 h (AUC0-24) were 109.49, 97.86, 145.33, and 207.04 μg · h/ml. Median maximum plasma concentration (Cmax) were 11.90, 12.02, 14.86, and 19.17 μg/ml, respectively. Higher levofloxacin doses, up to 1,500 mg daily, resulted in higher exposures. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.).

Abstract The evidence-based medicine (EBM) movement is stepping up its efforts to assess medical artificial intelligence (AI) and data science studies. Since 2017, there has been a marked increase in the number of published systematic reviews that assess medical AI studies. Increasingly, data from observational studies are used in systematic reviews of medical AI studies. Assessment of risk of bias is especially important in medical AI studies to detect possible “AI bias”.

BackgroundCurrent guidelines for treatment of multidrug-resistant tuberculosis (MDR-TB) are largely based on expert opinion and observational data. Fluoroquinolones remain an essential part of MDR-TB treatment, but the optimal dose of fluoroquinolones as part of the regimen has not been defined.Methods/designWe designed a randomized, blinded, phase II trial in MDR-TB patients comparing across levofloxacin doses of 11, 14, 17 and 20 mg/kg/day, all within an optimized background regimen. We assess pharmacokinetics, efficacy, safety and tolerability of regimens containing each of these doses. The primary efficacy outcome is time to culture conversion over the first 6 months of treatment. The study aims to determine the area under the curve (AUC) of the levofloxacin serum concentration in the 24 hours after dosing divided by the minimal inhibitory concentration of the patient's Mycobacterium tuberculosis isolate that inhibits > 90% of organisms (AUC/MIC) that maximizes efficacy and the AUC that maximizes safety and tolerability in the context of an MDR-TB treatment regimen.DiscussionFluoroquinolones are an integral part of recommended MDR-TB regimens. Little is known about how to optimize dosing for efficacy while maintaining acceptable toxicity. This study will provide evidence to support revised dosing guidelines for the use of levofloxacin as part of combination regimens for treatment of MDR-TB. The novel methodology can be adapted to elucidate the effect of other single agents in multidrug antibiotic treatment regimens.Trial registrationClinicalTrials.gov, NCT01918397 . Registered on 5 August 2013.

Clonal hematopoiesis of indeterminate potential (CHIP) leads to higher mortality, carries a cardiovascular risk and alters inflammation. All three aspects harbor overlaps with the clinical manifestation of COVID-19. This study aimed to identify the impact of CHIP on COVID-19 pathophysiology. 90 hospitalized patients were analyzed for CHIP. In addition, their disease course and outcome were evaluated. With a prevalence of 37.8%, the frequency of a CHIP-driver mutation was significantly higher than the prevalence expected based on median age (17%). CHIP increases the risk of hospitalization in the course of the disease but has no age-independent impact on the outcome within the group of hospitalized patients. Especially in younger patients (45 – 65 years), CHIP was associated with persistent lymphopenia. In older patients (> 65 years), on the other hand, CHIP-positive patients developed neutrophilia in the long run. To what extent increased values of cardiac biomarkers are caused by CHIP independent of age could not be elaborated solely based on this study. In conclusion, our results indicate an increased susceptibility to a severe course of COVID-19 requiring hospitalization associated with CHIP. Secondly, they link it to a differentially regulated cellular immune response under the pressure of SARS-CoV-2 infection. Hence, a patient’s CHIP-status bears the potential to serve as biomarker for risk stratification and to early guide treatment of COVID-19 patients.

Abstract Background Navigating the rapidly growing body of scientific literature on the SARS-CoV-2 pandemic is challenging, and ongoing critical appraisal of this output is essential. We aimed to summarize and critically appraise systematic reviews of coronavirus disease (COVID-19) in humans that were available at the beginning of the pandemic. Methods Nine databases (Medline, EMBASE, Cochrane Library, CINAHL, Web of Sciences, PDQ-Evidence, WHO’s Global Research, LILACS, and Epistemonikos) were searched from December 1, 2019, to March 24, 2020. Systematic reviews analyzing primary studies of COVID-19 were included. Two authors independently undertook screening, selection, extraction (data on clinical symptoms, prevalence, pharmacological and non-pharmacological interventions, diagnostic test assessment, laboratory, and radiological findings), and quality assessment (AMSTAR 2). A meta-analysis was performed of the prevalence of clinical outcomes. Results Eighteen systematic reviews were included; one was empty (did not identify any relevant study). Using AMSTAR 2, confidence in the results of all 18 reviews was rated as “critically low”. Identified symptoms of COVID-19 were (range values of point estimates): fever (82–95%), cough with or without sputum (58–72%), dyspnea (26–59%), myalgia or muscle fatigue (29–51%), sore throat (10–13%), headache (8–12%) and gastrointestinal complaints (5–9%). Severe symptoms were more common in men. Elevated C-reactive protein and lactate dehydrogenase, and slightly elevated aspartate and alanine aminotransferase, were commonly described. Thrombocytopenia and elevated levels of procalcitonin and cardiac troponin I were associated with severe disease. A frequent finding on chest imaging was uni- or bilateral multilobar ground-glass opacity. A single review investigated the impact of medication (chloroquine) but found no verifiable clinical data. All-cause mortality ranged from 0.3 to 13.9%. Conclusions In this overview of systematic reviews, we analyzed evidence from the first 18 systematic reviews that were published after the emergence of COVID-19. However, confidence in the results of all reviews was “critically low”. Thus, systematic reviews that were published early on in the pandemic were of questionable usefulness. Even during public health emergencies, studies and systematic reviews should adhere to established methodological standards.

Objectives To examine the proportion of people living with HIV who screen positive for common mental disorders (CMD) and the associations between CMD and self-reported adherence to antiretroviral therapy (ART).Setting Sixteen government-funded health facilities in the rural Bikita district of Zimbabwe.Design Cross-sectional study.Participants HIV-positive non-pregnant adults, aged 18 years or older, who lived in Bikita district and had received ART for at least 6 months.Outcome measures The primary outcome was the proportion of participants screening positive for CMD defined as a Shona Symptoms Questionnaire score of 9 or greater. Secondary outcomes were the proportion of participants reporting suicidal ideation, perceptual symptoms and suboptimal ART adherence and adjusted prevalence ratios (aPR) for factors associated with CMD, suicidal ideation, perceptual symptoms and suboptimal ART adherence.Results Out of 3480 adults, 18.8% (95% CI 14.8% to 23.7%) screened positive for CMD, 2.7% (95% CI 1.5% to 4.7%) reported suicidal ideations, and 1.5% (95% CI 0.9% to 2.6%) reported perceptual symptoms. Positive CMD screens were more common in women (aPR 1.67, 95% CI 1.19 to 2.35) than in men and were more common in adults aged 40–49 years (aPR 1.47, 95% CI 1.16 to 1.85) or aged 50–59 years (aPR 1.51, 95% CI 1.05 to 2.17) than in those 60 years or older. Positive CMD screen was associated with suboptimal adherence (aPR 1.53; 95% CI 1.37 to 1.70).Conclusions A substantial proportion of people living with HIV in rural Zimbabwe are affected by CMD. There is a need to integrate mental health services and HIV programmes in rural Zimbabwe.Trial registration number NCT03704805.

HIV-1 increases susceptibility to pulmonary infection and disease, suggesting pathogenesis in the lung. However, the lung immune environment during HIV infection remains poorly characterized. This study examined T cell activation and the cytokine milieu in paired bronchoalveolar lavage (BAL) and blood from 36 HIV-uninfected and 32 HIV-infected participants. Concentrations of 27 cytokines were measured by Luminex, and T cells were phenotyped by flow cytometry. Blood and BAL had distinct cytokine profiles (p=0.001). In plasma, concentrations of inflammatory cytokines like IFN-γ (p=0.004) and TNF-α (p=0.004) were elevated during HIV infection, as expected. Conversely, BAL cytokine concentrations were similar in HIV-infected and uninfected individuals, despite high BAL viral loads (VL; median 48,000 copies/ml epithelial lining fluid). HIV-infected individuals had greater numbers of T cells in BAL compared to uninfected individuals (p=0.007); and BAL VL positively associated with CD4+ and CD8+ T cell numbers (p=0.006 and p=0.0002, respectively) and CXCL10 concentrations (p=0.02). BAL T cells were highly activated in HIV-infected individuals, with nearly 2-3 fold greater frequencies of CD4+CD38+ (1.8-fold; p=0.007), CD4+CD38+HLA-DR+ (1.9-fold; p=0.0006), CD8+CD38+ (2.8-fold; p=0.0006), CD8+HLA-DR+ (2-fold; p=0.022) and CD8+CD38+HLA-DR+ (3.6-fold; p

Purpose The objectives of the International epidemiology databases to evaluate AIDS (IeDEA) are to (i) evaluate the delivery of combination antiretroviral therapy (ART) in children, adolescents and adults in sub-Saharan Africa, (ii) to describe ART regimen effectiveness, durability and tolerability, (iii) to examine HIV-related comorbidities and coinfections and (iv) to examine the pregnancy-related and HIV-related outcomes of women on ART and their infants exposed to HIV or ART in utero or via breast milk.Participants IeDEA is organised in four regions (Central, East, Southern and West Africa), with 240 treatment and care sites, six data centres at African, European and US universities, and almost 1.4 million children, adolescents and adult people living with HIV (PLWHIV) enrolled.Findings to date The data include socio-demographic characteristics, clinical outcomes, opportunistic events, treatment regimens, clinic visits and laboratory measurements. They have been used to analyse outcomes in PLWHIV-1 or PLWHIV-2 who initiate ART, including determinants of mortality, of switching to second-line and third-line ART, drug resistance, loss to follow-up and the immunological and virological response to different ART regimens. Programme-level estimates of mortality have been corrected for loss to follow-up. We examined the impact of coinfection with hepatitis B and C, and the epidemiology of different cancers and of (multidrug resistant) tuberculosis, renal disease and of mental illness. The adoption of ‘Treat All’, making ART available to all PLWHIV regardless of CD4+ cell count or clinical stage was another important research topic.Future plans IeDEA has formulated several research priorities for the ‘Treat All’ era in sub-Saharan Africa. It recently obtained funding to set up sentinel sites where additional data are prospectively collected on cardiometabolic risks factors as well as mental health and liver diseases, and is planning to create a drug resistance database.

New evidence on the COVID-19 pandemic is being published daily. Ongoing high-quality assessment of this literature is therefore needed to enable clinical practice to be evidence-based. This review builds on a previous scoping review and aimed to identify associations between disease severity and various clinical, laboratory and radiological characteristics. We searched MEDLINE, CENTRAL, EMBASE, Scopus and LILACS for studies published between January 1, 2019 and March 22, 2020. Clinical studies including ≥10 patients with confirmed COVID-19 of any study design were eligible. Two investigators independently extracted data and assessed risk of bias. A quality effects model was used for the meta-analyses. Subgroup analysis and meta-regression identified sources of heterogeneity. For hospitalized patients, studies were ordered by overall disease severity of each population and this order was used as the modifier variable in meta-regression. Overall, 86 studies (n = 91,621) contributed data to the meta-analyses. Severe disease was strongly associated with fever, cough, dyspnea, pneumonia, any computed tomography findings, any ground glass opacity, lymphocytopenia, elevated C-reactive protein, elevated alanine aminotransferase, elevated aspartate aminotransferase, older age and male sex. These variables typically increased in prevalence by 30-73% from mild/early disease through to moderate/severe disease. Among hospitalized patients, 30-78% of heterogeneity was explained by severity of disease. Elevated white blood cell count was strongly associated with more severe disease among moderate/severe hospitalized patients. Elevated lymphocytes, low platelets, interleukin-6, erythrocyte sedimentation rate and D-dimers showed potential associations, while fatigue, gastrointestinal symptoms, consolidation and septal thickening showed non-linear association patterns. Headache and sore throat were associated with the presence of disease, but not with more severe disease. In COVID-19, more severe disease is strongly associated with several clinical, laboratory and radiological characteristics. Symptoms and other variables in early/mild disease appear non-specific and highly heterogeneous. Clinical Trial Registration: PROSPERO CRD42020170623.

Abstract Background Rehabilitation is crucial for the realization of the right to health and a proper concern of global health. Yet, reliable information to guide rehabilitation service planning is unavailable in many countries in part due to the lack of appropriate indicators. To ensure universal health coverage and meet the central imperative of “leaving no one behind” countries must be able to assess key aspects of rehabilitation policy and provision and monitor how they have discharged their human rights responsibilities towards those most disadvantaged, including people with disability. This article describes the process of developing an expert guided indicator framework to assess governments’ efforts and progress in strengthening rehabilitation in line with the Convention on the Rights of Persons with Disabilities. Methods A systems methodology - concept mapping - was used to capture, aggregate and confirm the knowledge of diverse stakeholders on measures thought to be useful for monitoring the implementation of the Convention with respect to health related rehabilitation. Fifty-six individuals generated a list of 107 indicators through online brainstorming which were subsequently sorted by 37 experts from the original panel into non overlapping categories. Forty-one participants rated the indicators for importance and feasibility. Multivariate statistical techniques where used to explore patterns and themes in the data and create the indicators’ organizing framework which was verified and interpreted by a select number of participants. Results A concept map of 11 clusters of indicators emerged from the analysis grouped into three broader themes: Governance and Leadership (3 clusters); Service Delivery, Financing and Oversight (6 clusters); and Human Resources (2 clusters). The indicator framework was comprehensive and well aligned with the Convention. On average, there was a moderately positive correlation between importance and feasibility of the indicators (r = .58) with experts prioritizing the indicators contained in the clusters of the Governance and Leadership domain. Two of the most important indicators arose from the Service Delivery, Financing and Oversight domain and reflect the need to monitor unmet needs and barriers in access to rehabilitation. In total, 59 indicators achieved above average score for importance and comprised the two–tiered priority set of indicators. Conclusion Concept mapping was successful in generating a shared model that enables a system’s view of the most critical legal, policy and programmatic factors that must be addressed when assessing country efforts to reform, upscale and improve rehabilitation services. The Rehabilitation Systems Diagnosis and Dialogue framework provides a data driven basis for the development of standardized data collection tools to facilitate comparative analysis of rehabilitation systems. Despite agreement on the importance and feasibility of 59 indicators, further research is needed to appraise the applicability and utility of the indicators and secure a realistic assessment of rehabilitation systems.

Abstract Background Current guidelines for treatment of multidrug-resistant tuberculosis (MDR-TB) are largely based on expert opinion and observational data. Fluoroquinolones remain an essential part of MDR-TB treatment, but the optimal dose of fluoroquinolones as part of the regimen has not been defined. Methods/design We designed a randomized, blinded, phase II trial in MDR-TB patients comparing across levofloxacin doses of 11, 14, 17 and 20 mg/kg/day, all within an optimized background regimen. We assess pharmacokinetics, efficacy, safety and tolerability of regimens containing each of these doses. The primary efficacy outcome is time to culture conversion over the first 6 months of treatment. The study aims to determine the area under the curve (AUC) of the levofloxacin serum concentration in the 24 hours after dosing divided by the minimal inhibitory concentration of the patient’s Mycobacterium tuberculosis isolate that inhibits > 90% of organisms (AUC/MIC) that maximizes efficacy and the AUC that maximizes safety and tolerability in the context of an MDR-TB treatment regimen. Discussion Fluoroquinolones are an integral part of recommended MDR-TB regimens. Little is known about how to optimize dosing for efficacy while maintaining acceptable toxicity. This study will provide evidence to support revised dosing guidelines for the use of levofloxacin as part of combination regimens for treatment of MDR-TB. The novel methodology can be adapted to elucidate the effect of other single agents in multidrug antibiotic treatment regimens. Trial registration ClinicalTrials.gov, NCT01918397 . Registered on 5 August 2013.

Prior to the introduction of chemotherapy, tuberculosis management relied upon aerotherapy, heliotherapy and good nutrition. This “treatment”, exemplified by the regimen applied in Swiss and other European mountain resorts, is described by Thomas Mann in the book “The Magic Mountain”. Tuberculosis chemotherapy began in 1944 with the introduction of streptomycin and para-amino-salicylic acid, later augmented by isoniazid. Early experience taught physicians that treatment must be given with multiple drugs to prevent emergence of resistance and that prolonged treatment adherence for 18–24 months was needed for a permanent cure of tuberculosis. Between 1970 and 1980 rifampicin was introduced and with pyrazinamide it made “short-course” treatment possible. For 30 years, a 6-month directly observed treatment short-course (DOTS) based on the three compounds isoniazid, rifampicin and pyrazinamide was the foundation of tuberculosis control strategies world-wide, and in recent years this was supplemented with ethambutol in view of increasing rates of isoniazid resistance. However, even 6 months of treatment is too long to easily ensure the compliance necessary to permanently cure tuberculosis. The recent spread of the HIV/AIDS epidemic has placed tuberculosis programmes under severe pressure and is accompanied by an increase in drug-resistance making tuberculosis virtually untreatable in some instances. In 2004 the first of a new generation of anti-tuberculosis drugs entered clinical evaluation. A series of clinical trials, often conducted at sites in Cape Town, South Africa, has shown them to be efficacious and hold promise of being able to shorten tuberculosis treatment and treat drug-resistant tuberculosis. Development and assessment of these drugs is ongoing but there is renewed hope that these new drugs and regimens will assist in finally conquering tuberculosis, preventing a return to Magic Mountain where sunshine and fresh air was all that could be offered to patients.

Therapeutic bronchoscopy has come a long way from removal of foreign bodies to minimally invasive techniques in management of diseases like lung cancer, chronic obstructive pulmonary disease and asthma. This article discusses the exciting new techniques of therapeutic bronchoscopy namely; bronchoscopic lung volume reduction, bronchial thermoplasty, radiofrequency ablation, and use of fiducial markers in external beam irradiation.

Secession of the Abkhazia and South Ossetia regions of Georgia in the early 1990s displaced over a quarter of a million Georgians, many of whom remain in collective shelters. As Georgia embraces democracy, what can be done to resolve the country’s protracted IDP crisis?

Summary Background Delamanid is one of two recently approved drugs for the treatment of multidrug-resistant tuberculosis. We aimed to evaluate the safety and efficacy of delamanid in the first 6 months of treatment. Methods This randomised, double-blind, placebo-controlled, phase 3 trial was done at 17 sites in seven countries (Estonia, Latvia, Lithuania, Moldova, Peru, the Philippines, and South Africa). We enrolled eligible adults (>18 years) with pulmonary multidrug-resistant tuberculosis to receive, in combination with an optimised background regimen developed according to WHO and national guidelines, either oral delamanid (100 mg twice daily) for 2 months followed by 200 mg once daily for 4 months or placebo (same regimen). Patients were centrally randomised (2:1) and stratified by risk category for delayed sputum culture conversion. Primary outcomes were the time to sputum culture conversion over 6 months and the difference in the distribution of time to sputum culture conversion over 6 months between the two groups, as assessed in the modified intention-to-treat population. The trial is registered at ClinicalTrials.gov , number NCT01424670. Findings Between Sept 2, 2011, and Nov 27, 2013, we screened 714 patients, of whom 511 were randomly assigned (341 to delamanid plus optimised background regimen [delamanid group] and 170 to placebo plus optimised background regimen [placebo group]) and formed the safety analysis population. 327 patients were culture-positive for multidrug-resistant tuberculosis at baseline and comprised the efficacy analysis population (226 in the delamanid group and 101 in the placebo group). Median time to sputum culture conversion did not differ between the two groups (p=0·0562; modified Peto-Peto), with 51 days (IQR 29–98) in the delamanid group and 57 days (43–85) in the placebo group; the hazard ratio was 1·17 (95% CI 0·91–1·51, p=0·2157). 501 (98·0%) of 511 patients had at least one treatment-emergent adverse event. 136 (26·6%) of 511 patients had at least one serious treatment-emergent adverse event; the incidence was similar between treatment groups (89 [26·1%] of 341 patients for delamanid and 47 [27·6%] of 170 for placebo). Deaths related to treatment-emergent adverse events were similar between groups (15 [4·4%] of 341 for delamanid and six [3·5%] of 170 for placebo). No deaths were considered to be related to delamanid. Interpretation The reduction in median time to sputum culture conversion over 6 months was not significant in the primary analysis. Delamanid was well tolerated with a highly characterised safety profile. Further evaluation of delamanid is needed to determine its role in a rapidly evolving standard of care. Funding Otsuka Pharmaceutical. [ABSTRACT FROM AUTHOR]

Summary: Time to liquid culture positivity (TTP) is a technically accessible and widely available measure of viable mycobacterial load in sputum samples. We describe the ability of TTP to predict colony forming unit counts of Mycobacterium tuberculosis from sputum samples collected before or during the first 14 days of antituberculosis therapy. [Copyright &y& Elsevier]