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In Staphylococcus aureus bacteremia, mortality rates in randomized controlled trials (RCTs) are consistently lower than observational studies. Stringent eligibility criteria and omission of early deaths in RCTs contribute to this mortality gap. Clinicians should acknowledge the possibility of a lower treatment effect when applying RCT results to bedside care. [ABSTRACT FROM AUTHOR]

Background Deaths following Staphylococcus aureus bacteremia (SAB) may be related or unrelated to the infection. In SAB therapeutics research, the length of follow-up should be optimized to capture most attributable deaths and minimize nonattributable deaths. We performed a secondary analysis of a systematic review to describe attributable mortality in SAB over time. Methods We systematically searched Medline, Embase, and Cochrane Database of Systematic Reviews from 1 January 1991 to 7 May 2021 for human observational studies of SAB. To be included in this secondary analysis, the study must have reported attributable mortality. Two reviewers extracted study data and assessed risk of bias independently. Pooling of study estimates was not performed due to heterogeneity in the definition of attributable deaths. Results Twenty-four observational cohort studies were included. The median proportion of all-cause deaths that were attributable to SAB was 77% (interquartile range [IQR], 72%–89%) at 1 month and 62% (IQR, 58%–75%) at 3 months. At 1 year, this proportion was 57% in 1 study. In 2 studies that described the rate of increase in mortality over time, 2-week follow-up captured 68 of 79 (86%) and 48 of 57 (84%) attributable deaths that occurred by 3 months. By comparison, 1-month follow-up captured 54 of 57 (95%) and 56 of 60 (93%) attributable deaths that occurred by 3 months in 2 studies. Conclusions The proportion of deaths that are attributable to SAB decreases as follow-up lengthens. Follow-up duration between 1 and 3 months seems optimal if evaluating processes of care that impact SAB mortality. Clinical Trials Registration PROSPERO CRD42021253891. [ABSTRACT FROM AUTHOR]

To evaluate whether health facility-based HIV interventions align with UNAIDS 90-90-90 targets, we performed a systematic review through the lens of UNAIDS targets. We searched 11 databases, retrieving 5201 citations with 26 eligible studies classified by country income and UNAIDS target. We analyzed whether reporting of study outcome metrics was in line with UNAIDS targets using a standardized extraction form and results were summarized in a narrative synthesis given data heterogeneity. We also assessed the quality of randomized trials with the Cochrane Risk of Bias Tool and observational studies with the Newcastle–Ottawa Scale. Stratification of interventions by country income level revealed themes in successful interventions that provide insight for scale-up in similar resource contexts. Few studies reported outcomes using metrics according to UNAIDS targets. Standardization of reporting according to the UNAIDS framework could facilitate comparability of interventions and inform country-level progress on an international scale. [ABSTRACT FROM AUTHOR]

Study of the history of medical inadmissibility and deportation of Canadian immigrants uncovers three important themes as criteria for immigration selection and control: sanitation, sanity, and moral suitability. As the understanding of human health changed with history, so too did the basis for exclusion and deportation of Canadian immigrants for medical purposes. Immigration policy mirrored then current notions of health and disease, growing in complexity as immigration policy increased its selectivity contemporaneous to increasing immigration rates. Immigration control developed from simple quarantine measures to prevent the transmission of infectious diseases from other continents, to physical and mental health inspections to prevent the propagation of hereditary dysfunction, to selection of morally fit immigrants resembling Canadian values for easy assimilation into society. Physical, mental, and moral health were key criteria in the first century of Canadian immigration policy, highlighting Canada's history of antiimmigrant sentiment through the medicalization of specific ethnic groups. [ABSTRACT FROM AUTHOR]

Background: Reaching the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets to end the HIV epidemic relies on effective interventions that engage untested HIV+ individuals and retain them in care. Evidence on community-based interventions through the lens of the targets has not yet been synthesized, reflecting a knowledge gap. We conducted a systematic review and meta-analysis to shed light on successful community-based interventions that have been effective in contributing, directly or indirectly, towards the UNAIDS 90-90-90 targets: knowledge of HIV status, linkage to care/on treatment, and viral suppression. Linkage to care was also included in this review due to the limitations of studies. Methods: We conducted a systematic review and meta-analysis of the period 2007–2018. Eleven databases were searched to identify community-based interventions designed to improve knowledge of HIV status (in particular HIV testing), linkage to care/on treatment, and/or viral suppression. Eligible studies were classified by intervention, population, country income level, outcomes and success. Success was defined as interventions demonstrating statistical significance between intervention and control group or that reached any target by proportion; 90% testing, 81% linked to care/on treatment and 73% viral suppression. Results: Of 82 eligible studies, 51.2% (42/82) reported on HIV testing (first 90), 20.7% (17/82) on linkage to care/ on treatment (second 90), and 45.1% (37/82) on viral suppression (third 90). In all, 67.1% (55/82) of studies reported success; 21 studies on the first 90, 9 towards linkage to care/on treatment, and 25 towards the third. By strategies, 36.6% deployed community workers/peers, 22% used combined test and treat strategies, 12.2% used educational methods, 8.5% used mobile testing, 7.3% used campaigns and 13.4% used technology. For HIV testing/linkage, combined test/treat interventions were often used, for viral suppression, educational interventions and technologies were commonly deployed. Our pooled analysis suggested that deployment of community health care workers/peer workers significantly improved viral suppression (pooled OR: 1.40 95% CI 1.06–1.86). Of the studies published after 2014, 50.0% reported metrics aligned with UNAIDS targets. Conclusions: Data on linkage to care/on treatment (second target) remained weak, because many studies reported successes on the first and third targets. Stratification by targets and country income levels is informative and guides adaptation of successful interventions in comparable settings. Consistent reporting of clear metrics aligned with UNAIDS targets will aid in synergy of study data with programmatic data that will help reportage. Exploration of innovative interventions, for engagement and linkage and deployment of community/ peer workers is strongly encouraged. [ABSTRACT FROM AUTHOR]

Background: The Joint United Nations Programme on HIV/AIDS (UNAIDS) Fast-Track initiative seeks to eliminate AIDS as a health threat by 2030, with its focus on UNAIDS 90-90-90 targets. Effective policies and programs, if scaled nationally, have the potential to generate a greater impact on HIV control, yet a synthesis of successful HIV policies/programs aligned to the targets is currently unavailable. To fill this gap, we conducted a systematic review to evaluate successful HIV policies and programs to direct future interventions. Methods: For the period 2007–2018, we searched 8 databases and classified eligible studies by country income level, UNAIDS targets, intervention type, and reported outcomes. Study outcomes were classified as per UNAIDS targets; proportionally: 90% target 1, 81% target 2, and 73% target 3. Results: We retrieved 5201 citations and a final set of eight studies on policies. Break up by income: three (38%) from high income, one (12%) from middle income and four (50%) from low income. Break up by outcomes reported: 36% (4/11) focused on HIV testing, 46% (5/11) on antiretroviral therapy initiation, and 18% (2/11) on viral suppression. Across studies, UNAIDS targets were met in high-income countries, where policies and guidelines were adhered to, whereas in low and middle-income countries, non-adherence led to failure to reach the targets. Targets were also met when country infrastructure supported a targeted program and stakeholders were actively engaged. Conclusions: From the studies identified, we deduced a clear, positive correlation between implementation of policies and programs that resulted in an increase in patient awareness and an increase in partner notification with services that encouraged them, and together these resulted in increasing testing rates, and deployment of linkage/retention programs that improved retention in care. An analysis of these studies also suggests that policies, combined with the scale-up incentives, are needed to change the status quo. Incentives to improve the targets must exist; performance incentives at the health care worker level and country level incentives that could transform the nature of care. Given the complexity in reporting of targets, a one size fits all model is not a feasible option. However, the policies created a strong framework to shape future interventions. [ABSTRACT FROM AUTHOR]

Background: The viral RNA-dependent RNA polymerase (RdRp) enzymes of the Flaviviridae family are essential for viral replication and are logically important targets for development of antiviral therapeutic agents. Zika virus (ZIKV) is a rapidly re-emerging human pathogen for which no vaccine or antiviral agent is currently available.Methods: To facilitate development of ZIKV RdRp inhibitors, we have established an RdRp assay using purified recombinant ZIKV NS5 polymerase.Results: We have shown that both the hepatitis C virus (HCV) nucleoside inhibitor sofosbuvir triphosphate and a pyridoxine-derived non-nucleoside small-molecule inhibitor, DMB213, can act against ZIKV RdRp activity at IC 50 s of 7.3 and 5.2 μM, respectively, in RNA synthesis reactions catalysed by recombinant ZIKV NS5 polymerase. Cell-based assays confirmed the anti-ZIKV activity of sofosbuvir and DMB213 with 50% effective concentrations (EC 50 s) of 8.3 and 4.6 μM, respectively. Control studies showed that DMB213 did not inhibit recombinant HIV-1 reverse transcriptase and showed only very weak inhibition of HIV-1 integrase strand-transfer activity. The S604T substitution in motif B of the ZIKV RdRp, which corresponds to the S282T substitution in motif B of HCV RdRp, which confers resistance to nucleotide inhibitors, also conferred resistance to sofosbuvir triphosphate, but not to DMB213. Enzyme assays showed that DMB213 appears to be competitive with natural nucleoside triphosphate (NTP) substrates.Conclusions: Recombinant ZIKV RdRp assays can be useful tools for the screening of both nucleos(t)ide compounds and non-nucleotide metal ion-chelating agents that interfere with ZIKV replication. [ABSTRACT FROM AUTHOR]