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HIV is a potent risk factor for tuberculosis (TB). Therefore, community-wide universal testing and treatment for HIV (UTT) could contribute to TB control, but evidence for this is limited. Community-wide TB screening can decrease population-level TB prevalence. Combining UTT with TB screening could therefore significantly impact TB control in sub-Saharan Africa, but to our knowledge there is no evidence for this combined approach. HPTN 071 (PopART) was a community-randomised trial conducted between November 2013 to July 2018; 21 Zambian and South African communities (with a total population of approximately 1 million individuals) were randomised to arms A (community-wide UTT and TB screening), B (community-wide universal HIV testing with treatment following national guidelines and TB screening), or C (standard-of-care). In a cohort of randomly selected adults (18 to 44 years) enrolled between 2013 and 2015 from all 21 communities (total size 38,474; 27,139 [71%] female; 8,004 [21%] HIV positive) and followed-up annually for 36 months to measure the population-level impact of the interventions, data on self-reported TB treatment in the previous 12 months (self-reported TB) were collected by trained research assistants and recorded using a structured questionnaire at each study visit. In this prespecified analysis of the trial, self-reported TB incidence rates were measured by calendar year between 2014 and 2017/2018. A p-value ≤0.05 on hypothesis testing was defined as reaching statistical significance. Between January 2014 and July 2018, 38,287 individuals were followed-up: 494 self-reported TB during 104,877 person-years. Overall incidence rates were similar across all arms in 2014 and 2015 (0.33 to 0.46/100 person-years). In 2016 incidence rates were lower in arm A compared to C overall (adjusted rate ratio [aRR] 0.48 [95% confidence interval (95% CI) 0.28 to 0.81; p = 0.01]), with statistical significance reached. In 2017/2018, while incidence rates were lower in arm A compared to C, statistical significance was not reached (aRR 0.58 [95% CI 0.27 to 1.22; p = 0.13]). Among people living with HIV (PLHIV) incidence rates were lower in arm A compared to C in 2016 (RR 0.56 [95% CI 0.29 to 1.08; p = 0.08]) and 2017/2018 (RR 0.50 [95% CI 0.26 to 0.95; p = 0.04]); statistical significance was only reached in 2017/2018. Incidence rates in arms B and C were similar, overall and among PLHIV. Among HIV-negative individuals, there were too few events for cross-arm comparisons. Study limitations include the use of self-report which may have been subject to under-reporting, limited covariate adjustment due to the small number of events, and high losses to follow-up over time. In this study, community-wide UTT and TB screening resulted in substantially lower TB incidence among PLHIV at population-level, compared to standard-of-care, with statistical significance reached in the final study year. There was also some evidence this translated to a decrease in self-reported TB incidence overall in the population. Reduction in arm A but not B suggests UTT drove the observed effect. Our data support the role of UTT in TB control, in addition to HIV control, in high TB/HIV burden settings. ClinicalTrials.gov: NCT01900977.

Streptococcus pneumoniae is a human pathogen that has become increasingly resistant to synthetic fluoroquinolone antibiotics that target bacterial topoisomerases. To identify pathways essential under fluoroquinolone stress and potential novel targets to revitalize use of this antibiotic class, we perform genome-wide CRISPRi-seq screens and generate antibiotic-gene essentiality signatures. Expectedly, genes involved in DNA recombination and repair become more important under fluoroquinolone-induced DNA damage, including recA , recJ , recF , recO , rexAB , and ruvAB . Surprisingly, specific downregulation of the gene encoding the histidine kinase LiaS caused fluoroquinolone hypersensitivity. LiaS is part of the LiaFSR (VraTSR) three-component regulatory system involved in cell envelope homeostasis. We show that LiaS keeps the response regulator LiaR inactive, and that liaS deletion causes LiaR hyperphosphorylation and upregulation of the LiaR regulon. We use RNA-seq to refine the LiaR regulon, highlighting the role of heat-shock response and pleiotropic regulator SpxA2 in fluoroquinolone sensitivity. Activating the LiaR-regulon by the cell envelope-targeting antibiotic bacitracin synergized with ciprofloxacin and levofloxacin, restoring sensitivity in fluoroquinolone-resistant strains in vitro. Furthermore, bacitracin/levofloxacin combination therapy is effective in vivo and improved treatment of fluoroquinolone-resistant S. pneumoniae infection in a zebrafish meningitis model. These findings offer a starting point for identification and validation of potent combination therapies to treat antibiotic-resistant pneumococcal infections. Streptococcus pneumoniae, the causative agent of pneumococcal disease, has become increasingly resistant to fluoroquinolones. Through CRISPRi-seq, the authors identify the role of the LiaFSR operon in resensitizing S. pneumoniae to fluoroquinolones.

HIV is a potent risk factor for tuberculosis (TB). Therefore, community-wide universal testing and treatment for HIV (UTT) could contribute to TB control, but evidence for this is limited. Community-wide TB screening can decrease population-level TB prevalence. Combining UTT with TB screening could therefore significantly impact TB control in sub-Saharan Africa, but to our knowledge there is no evidence for this combined approach. HPTN 071 (PopART) was a community-randomised trial conducted between November 2013 to July 2018; 21 Zambian and South African communities (with a total population of approximately 1 million individuals) were randomised to arms A (community-wide UTT and TB screening), B (community-wide universal HIV testing with treatment following national guidelines and TB screening), or C (standard-of-care). In a cohort of randomly selected adults (18 to 44 years) enrolled between 2013 and 2015 from all 21 communities (total size 38,474; 27,139 [71%] female; 8,004 [21%] HIV positive) and followed-up annually for 36 months to measure the population-level impact of the interventions, data on self-reported TB treatment in the previous 12 months (self-reported TB) were collected by trained research assistants and recorded using a structured questionnaire at each study visit. In this prespecified analysis of the trial, self-reported TB incidence rates were measured by calendar year between 2014 and 2017/2018. A p-value [less than or equal to]0.05 on hypothesis testing was defined as reaching statistical significance. Between January 2014 and July 2018, 38,287 individuals were followed-up: 494 self-reported TB during 104,877 person-years. Overall incidence rates were similar across all arms in 2014 and 2015 (0.33 to 0.46/100 person-years). In 2016 incidence rates were lower in arm A compared to C overall (adjusted rate ratio [aRR] 0.48 [95% confidence interval (95% CI) 0.28 to 0.81; p = 0.01]), with statistical significance reached. In 2017/2018, while incidence rates were lower in arm A compared to C, statistical significance was not reached (aRR 0.58 [95% CI 0.27 to 1.22; p = 0.13]). Among people living with HIV (PLHIV) incidence rates were lower in arm A compared to C in 2016 (RR 0.56 [95% CI 0.29 to 1.08; p = 0.08]) and 2017/2018 (RR 0.50 [95% CI 0.26 to 0.95; p = 0.04]); statistical significance was only reached in 2017/2018. Incidence rates in arms B and C were similar, overall and among PLHIV. Among HIV-negative individuals, there were too few events for cross-arm comparisons. Study limitations include the use of self-report which may have been subject to under-reporting, limited covariate adjustment due to the small number of events, and high losses to follow-up over time. In this study, community-wide UTT and TB screening resulted in substantially lower TB incidence among PLHIV at population-level, compared to standard-of-care, with statistical significance reached in the final study year. There was also some evidence this translated to a decrease in self-reported TB incidence overall in the population. Reduction in arm A but not B suggests UTT drove the observed effect. Our data support the role of UTT in TB control, in addition to HIV control, in high TB/HIV burden settings.

Background Identifying successful strategies to improve participant retention in longitudinal studies remains a challenge. In this study we evaluated whether non-traditional fieldworker shifts (after hours during the week and weekends) enhanced participant retention when compared to retention during traditional weekday shifts in the HPTN 071 (PopART) population cohort (PC). Methods HPTN 071 (PopART) PC participants were recruited and followed up in their homes on an annual basis by research fieldworkers over a 3-4 year period. The average number of successful follow-up visits, where a PC participant was found and retained in the study, was calculated for each of 3 visit schedules (early weekday shift, late weekday shift, and Saturday shift), and standardized to account for variation in fieldwork shift duration. We used one-way univariate analysis of variance (ANOVA) to describe differences in mean-successful visits and 95% confidence intervals between the shift types. Results Data on 16 651 successful visits were included. Successful visit rates were higher when conducting Saturday visits (14.0; 95% CI: 11.3-16.6) compared to both regular (4.5; 95% CI: 3.7-5.3) and late weekday shifts (5.3; 95% CI: 4.7-5.8) overall and in all subgroup analyses ( P <0.001). The successful visit rate was higher amongst women than men were during all shift types (3.2 vs. 1.3, p <0.001). Successful visit rates by shift type did not differ significantly by age, over time, by PC round or by community triplet. Conclusion The number of people living with HIV continues to increase annually. High quality evidence from longitudinal studies remains critical for evaluating HIV prevention and treatment strategies. This study showed a significant benefit on participant retention through introduction of Saturday shifts for home visits and these data can make an important contribution to the emerging body of evidence for improving retention in longitudinal research. Trial registration PopART was approved by the Stellenbosch University Health Research Ethics Committees (N12/11/074), London School of Hygiene and Tropical Medicine (6326) ethics committee and the Division of AIDS (DAIDS) (Protocol ID 11865). PopART was registered with ClinicalTrials.gov (registration number NCT01900977 ).

The HPTN 071(PopART) study was a community-randomised trial in Zambia and South Africa, examining the impact of combination-prevention including universal testing and treatment (UTT), on HIV-incidence. This sub-study evaluated factors associated with IPV (physical and/or sexual) to identify differences by HIV status. During 2015–16, a random subset of adults who participated in the first year of the PopART intervention were recruited and standardised questionnaires were administered. Logistic regression was performed to estimate odds ratios of factors associated with IPV. Among > 700 women studied (300 HIV-negative;400 HIV-positive), ~ 20% reported experiencing physical and/or sexual violence in the last 12-months. Sexual violence was similar by HIV status, but physical violence and reporting both physical/sexual violence was more common among HIV-positive women. Spending nights away from the community in the last 12-months was associated with higher odds of IPV among both HIV-negative (aOR 3.17, 95% CI 1.02–9.81) and HIV-positive women (aOR 1.79, 95% CI 0.99–3.24). Among HIV-positive women, financial autonomy was associated with reduced IPV (aOR:0.41,95%CI:0.23-0.75) while pregnancy in the last 12-months (aOR 2.25, 95% CI 1.07–4.74), risk of alcohol dependence (aOR 2.75, 95% CI 1.51–5.00) and risk of mental distress (aOR 2.62, 95% CI 1.33–5.16) were associated with increased IPV. Among HIV-negative women reporting sex in the last 12-months, transactional sex (aOR 3.97, 95% CI 1.02–15.37) and not knowing partner’s HIV status (aOR 3.01, 95% CI 1.24–7.29) were associated with IPV. IPV was commonly reported in the study population and factors associated with IPV differed by HIV status. The association of mobility with IPV warrants further research. The high prevalence of harmful alcohol use and mental distress, and their association with IPV among HIV-positive women require urgent attention.

Abstract Background Herpes simplex virus type 2 (HSV2) is an important cofactor for HIV acquisition and transmission. Associations between the infections are reexamined in longitudinal data from an HIV prevention trial. Methods The HPTN 071 (PopART) trial evaluated a combination prevention intervention in 21 urban communities in Zambia and South Africa. HIV incidence was measured in a cohort of approximately 2000 adults (age, 18–44 years) selected randomly from each community and followed up for 36 months. Incidence of HSV2 infection was estimated, and the effects of risk factors were examined. The association between HIV incidence and HSV2 infection was examined at individual and community levels. Results An overall 10 539 participants were HSV2 negative at baseline and retested after 36 months. Estimated HSV2 incidence was 5.4 per 100 person-years (95% CI, 5.0–5.7) for women and 2.9 per 100 person-years (95% CI, 2.6–3.2) for men. When compared with those remaining HSV2 negative, HIV incidence was higher in those who were HSV2 positive at baseline (women: adjusted rate ratio [aRR], 3.24 [95% CI, 2.50–4.20]; men: aRR, 2.57 [95% CI, 1.60–4.11]) and even higher in those who seroconverted to HSV2 during follow-up (women: aRR, 5.94 [95% CI, 4.42–7.98]; men: aRR, 8.37 [95% CI, 5.18–13.52]). At the community level, strong associations were seen between HIV incidence and HSV2 prevalence (R2 = 0.48, P < .001) and incidence (R2 = 0.36, P = .004). Conclusions There were strong associations between HIV incidence and HSV2 prevalence and incidence at individual and community levels. HSV2 control could contribute to HIV prevention.

Background: HPTN 084 is a Phase 3 randomized, double-blind, double-dummy superiority trial evaluating safety and efficacy of long-acting injectable cabotegravir (CAB) compared to daily oral TDF/FTC for HIV prevention in cisgender women. The blinded trial was stopped at a planned interim DSMB review in November 2020. Methods: HIV-uninfected PrEP eligible cisgender women were randomized 1:1 to either active CAB plus TDF/FTC placebo or active TDF/FTC plus CAB placebo. Participants received 5 weeks of daily oral product followed by intramuscular injections every eight weeks after an initial four-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF/FTC for 48 weeks after last injection. The primary endpoints were incident HIV infection and [greater than or equal to]grade 2 clinical and laboratory events. Results: Overall, 3224 participants were enrolled at sites in South Africa (n = 7), Zimbabwe (5), Uganda (3), Malawi (2), Botswana (1), Eswatini (1) and Kenya (1). Median age was 25 years (range 18, 45), 54% (n = 1754/3210) had 2+ partners in past month, 32% (n = 1019/3210) had partner with HIV or unknown status, 19% (n = 601/3190) had chlamydia and 7% (n = 211/3190) had gonorrhoea at enrolment. Participant visit completion at months 6, 12, 18, and 24 was 94%, 90%, 87% and 86%. Thirty eight incident infections were observed over 3808 person-years (HIV incidence 1.0%, 95% confidence interval [CI] 0.71, 1.37); 4 in the CAB arm (incidence 0.21, 95% CI 0.06, 0.54) and 34 in the TDF/FTC arm (incidence 1.79%, 95% CI 1.24, 2.51) (hazard ratio 0.11 [95% CI 0.04, 0.32]). Injection coverage was 93% of person-years. In a random subset of 375 TDF/FTC participants, 62% of plasma samples had detectable TDF/FTC; 46% had concentrations consistent with daily dosing. Adverse events were mild-moderate and balanced by arm. Among CAB participants, injection site reactions were more common (32% vs. 9%), but most were mild. Nausea was more common in the TDF/FTC (9%) compared to the CAB participants (5%). Pregnancy incidence was 1.3 per 100 person-years (95% CI 1.0, 1.7); no congenital anomalies were reported. Conclusions: While both products demonstrated high prevention efficacy and were safe and well tolerated; CAB was superior to TDF/FTC in preventing HIV infection in cisgender women.

Eighty-seven high-risk individuals in Thailand who had received a complete course of recombinant HBV vaccine 18–20 y ago were investigated with regard to their immunological memory. To evaluate humoral immunity, anti-HBs antibody titers were measured. Cellular immunity was determined by ELISPOT to detect HBV-specific IFN-γ–producing cells. Overall 83.9% of participants developed circulating anti-HBs (titer ≥1 mIU/mL) and 58.6% were seroprotected (titer ≥10 mIU/mL). As for cellular immunity, 50.6% were positive on ELISPOT. Moreover, there was no correlation between the level of anti-HBs and positive ELISPOT results. However, the majority of participants (81.8%) who were positive for IFN-γ–producing cells were seropositive, but only 50% of seropositive participants were ELISPOT-positive. Thus, 18–20 y after immunization, it appears that a second booster dose should be considered, especially in high-risk groups.

Staphylocoagulase (SC) secreted by Staphylococcus aureus is a potent non-proteolytic activator of the blood coagulation zymogen prothrombin and the prototype of a newly established zymogen activator and adhesion protein (ZAAP) family. The conformationally activated SC.prothrombin complex specifically cleaves fibrinogen to fibrin, which propagates the growth of bacteria-fibrin-platelet vegetations in acute bacterial endocarditis. Our recent 2.2 A X-ray crystal structures of an active SC fragment [SC(1-325)] bound to the prothrombin zymogen catalytic domain, prethrombin 2, demonstrated that SC(1-325) represents a new type of non-proteolytic activator with a unique fold. The observed insertion of the SC(1-325) N-terminus into the 'Ile 16' cleft of prethrombin 2, which triggers the activating conformational change, provided the first unambiguous structural evidence for the 'molecular sexuality' mechanism of non-proteolytic zymogen activation. Based on the SC(1-325) fold, a new family of bifunctional zymogen activator and adhesion proteins was identified that possess N-terminal domains homologous to SC(1-325) and C-terminal domains that mediate adhesion to plasma or extracellular matrix proteins. Further investigation of the ZAAP family may lead to new insights into the mechanisms of bacterial factors that hijack zymogens of the human blood coagulation and fibrinolytic systems to promote and disseminate endocarditis and other infectious diseases.

Many bacterial pathogens secrete proteins that activate host trypsinogen-like enzyme precursors, most notably the proenzymes of the blood coagulation and fibrinolysis systems 1 , 2 . Staphylococcus aureus , an important human pathogen implicated in sepsis and endocarditis 3 , secretes the cofactor staphylocoagulase, which activates prothrombin, without the usual proteolytic cleavages, to directly initiate blood clotting 4 , 5 . Here we present the 2.2 Å crystal structures of human α-thrombin and prethrombin-2 bound to a fully active staphylocoagulase variant. The cofactor consists of two domains, each with three-helix bundles; this is a novel fold that is distinct from known serine proteinase activators, particularly the streptococcal plasminogen activator streptokinase 6 . The staphylocoagulase fold is conserved in other bacterial plasma-protein-binding factors and extracellular-matrix-binding factors 7 , 8 , 9 . Kinetic studies confirm the importance of isoleucine 1 and valine 2 at the amino terminus of staphylocoagulase for zymogen activation. In addition to making contacts with the 148 loop and (pro)exosite I of prethrombin-2, staphylocoagulase inserts its N-terminal peptide into the activation pocket of bound prethrombin-2, allosterically inducing functional catalytic machinery. These investigations demonstrate unambiguously the validity of the zymogen-activation mechanism known as ‘molecular sexuality’ 10 .