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Abstract Our ability to forecast epidemics far into the future is constrained by the many complexities of disease systems. Realistic longer-term projections may, however, be possible under well-defined scenarios that specify the future state of critical epidemic drivers. Since December 2020, the U.S. COVID-19 Scenario Modeling Hub (SMH) has convened multiple modeling teams to make months ahead projections of SARS-CoV-2 burden, totaling nearly 1.8 million national and state-level projections. Here, we find SMH performance varied widely as a function of both scenario validity and model calibration. We show scenarios remained close to reality for 22 weeks on average before the arrival of unanticipated SARS-CoV-2 variants invalidated key assumptions. An ensemble of participating models that preserved variation between models (using the linear opinion pool method) was consistently more reliable than any single model in periods of valid scenario assumptions, while projection interval coverage was near target levels. SMH projections were used to guide pandemic response, illustrating the value of collaborative hubs for longer-term scenario projections.

Background: Reproductive coercion (RC) is a type of abuse where a partner intentionally attempts to interfere with fertility through deception or violence, often by manipulating one's contraceptive use or reproductive decision-making. Cross-sectional studies on the magnitude of RC across sub-Saharan Africa have noted associations with contraceptive use. No studies have longitudinally examined RC experiences as related to future contraceptive dynamics, including discontinuation or forgoing use altogether., Methods: Two rounds of longitudinal population-based cohorts across eight sites in sub-Saharan Africa, from November 2020 to January 2023, were used to prospectively examine past-year RC's impact on future contraceptive dynamics (discontinuation and switching vs. continuation for contraceptive users at baseline; adoption vs. continued non-use for contraceptive non-users at baseline) using bivariate and multivariable multinomial and logistic regression., Findings: Minimal differences in women's past-year RC experiences were observed over a two-year period. In many settings, RC prevalence decreased. Only in Uganda did past-year RC increase between rounds (15.8% to 17.8%). RC's impact on contraceptive dynamics over one year differed by setting. In Burkina Faso, women with past-year RC had a three-fold increased risk of discontinuing contraception, as compared to continuing (RRR = 2.63; 95% CI = 1.28-5.42; p<0.01). In Uganda, past-year RC was marginally associated with reduced odds of contraceptive adoption, compared to continued non-use (p<0.1)., Interpretation: In this first longitudinal study of RC, trajectories varied across settings, as did RC's impact on contraception, affirming the importance of context. Future work should clarify RC trajectories and drivers thereof. Providers must be aware of RC leading to potential discontinuation. Contraceptive provision must be flexible and reflect women's life circumstances, including partner dynamics., Funding: This work was supported, in whole, by the Bill & Melinda Gates Foundation [INV-046501 and INV-009639]. Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission., Competing Interests: None., (© 2024 The Authors.)

Background: Donor interventions, including medications, protocols, and medical devices administered to donors, can enhance transplantable organ quality and quantity and maximize transplantation success. However, there is paucity of high-quality evidence about their effectiveness, in part because of ethical, practical, and regulatory challenges, and lack of guidance about conduct of donor intervention randomized controlled trials (RCTs)., Methods: With the vision to develop authoritative guidance for conduct of donor intervention RCTs, we convened a workshop of Canadian-United Kingdom experts in organ donation and transplantation ethics, research, and policy to identify stakeholders, explore unique challenges, and develop research agenda to inform future work in this promising field., Results: Donor intervention trials should consider perspectives of broad group of stakeholders including donors, transplant recipients, and their families; researchers in donation and transplantation; research ethics boards; and healthcare providers and administrators involved in donation and transplantation. Unique challenges include (1) research ethics (living versus deceased status of the donor at the time of intervention, intervention versus outcomes assessment in different individuals, harm-benefit analysis in donors versus recipients, consent, and impact on research bystanders); (2) outcome data standardization and linkage; and (3) regulatory and governance considerations., Conclusions: Donor intervention RCTs hold potential to benefit organ transplantation outcomes but face unique research ethics, outcome data, and regulatory challenges. By developing research agenda to address these challenges, our workshop was an important first step toward developing Canada-United Kingdom guidance for donor intervention RCTs that are poised to improve the quality and availability of transplantable organs., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Existing estimates of adolescent sexual and reproductive health (ASRH) behaviors may be a gross undercount given the sensitivity of this behavior in Indian culture. The objective of this study was to estimate ASRH behaviors in Rajasthan, India using direct questions and the best friend approach that seeks to reduce social desirability bias., Methods: We used population-based data of adolescents aged 15-19 in Rajasthan collected between September and December 2022. Data include whether the respondent and her closest female friend ever had a partner, ever had sex, ever used contraception, and were currently using contraception. We estimated respondent and best friend ASRH outcomes separately, overall and among unmarried adolescents for whom we anticipate social desirability bias is greatest., Results: The best friend approach performed well, with method assumptions largely met even before adjustments. Respondent and best friend estimates were similar among all adolescents except for current contraceptive use, which was higher for friends (though not significantly so). However, we observed large differences in ASRH behaviors between unmarried respondents and friends, with a significantly higher percentage of friends who ever had a partner (4.3% respondents, 11.6% friends), and a slightly higher percentage who ever had sex (2.4%, 3.8%) and who were currently using contraception (17.0%, 19.7% among those in need of contraception)., Conclusions: We observed potential benefits of using the best friend methodology in estimating premarital sexual activity, but further work is needed to refine social network-based measures of sensitive adolescent behaviors in larger study samples to better understand ASRH needs., (© 2024. The Author(s).)

Reproductive coercion (RC) is any intentional behavior that interferes with another's reproductive decision-making or pregnancy outcome. This study aims to qualitatively examine RC experiences and perceptions among women and men in Ethiopia, Nigeria (Kano and Anambra States), and Uganda. This is a secondary analysis utilizing qualitative data from the Women's and Girls' Empowerment in Sexual and Reproductive Health study. Across sites, focus group discussions (38 groups; n=320 participants) and in-depth interviews (n=120) were conducted, recorded, and transcribed. Transcripts were loaded into Atlas.ti, and quotes describing experiences of reproductive control or abuse were coded as "reproductive coercion." RC quotes were input into a matrix for thematic analysis. Emergent RC themes included indirect reproductive pressures, direct family planning interference, concurrent experiences of violence, and responses to RC. Indirect reproductive pressures included tactics to both promote and prevent pregnancy, while direct interference centered on pregnancy promotion. Women who were not compliant with their partners' reproductive demands were often subjected to violence from multiple actors (i.e., parents, in-laws, community members) in addition to their partners. Despite concurrent forms of violence, women across sites resisted RC by using contraceptives covertly, choosing to abort, or leaving their abusive partnerships. Women and men across sites indicated that men were highly influential in fertility. RC behaviors were a mechanism of control over desired reproductive outcomes, which were often rooted in perceptions of childbearing as social status. Findings indicate a need for more nuanced community interventions targeting social norms, as well as improved RC screening and response within health services., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Arteriovenous fistulas are considered the best option for haemodialysis provision, but as many as 30% fail to mature or suffer early failure., Objective: To assess the feasibility of performing a randomised controlled trial that examines whether, by informing early and effective salvage intervention of fistulas that would otherwise fail, Doppler ultrasound surveillance of developing arteriovenous fistulas improves longer-term arteriovenous fistula patency., Design: A prospective multicentre observational cohort study (the 'SONAR' study)., Setting: Seventeen haemodialysis centres in the UK., Participants: Consenting adults with end-stage renal disease who were scheduled to have an arteriovenous fistula created., Intervention: Participants underwent Doppler ultrasound surveillance of their arteriovenous fistulas at 2, 4, 6 and 10 weeks after creation, with clinical teams blinded to the ultrasound surveillance findings., Main Outcome Measures: Fistula maturation at week 10 defined according to ultrasound surveillance parameters of representative venous diameter and blood flow (wrist arteriovenous fistulas: ≥ 4 mm and > 400 ml/minute; elbow arteriovenous fistulas: ≥ 5 mm and > 500 ml/minute). Mixed multivariable logistic regression modelling of the early ultrasound scan data was used to predict arteriovenous fistula non-maturation by 10 weeks and fistula failure at 6 months., Results: A total of 333 arteriovenous fistulas were created during the study window (47.7% wrist, 52.3% elbow). By 2 weeks, 37 (11.1%) arteriovenous fistulas had failed (thrombosed), but by 10 weeks, 219 of 333 (65.8%) of created arteriovenous fistulas had reached maturity (60.4% wrist, 67.2% elbow). Persistently lower flow rates and venous diameters were observed in those fistulas that did not mature. Models for arteriovenous fistulas' non-maturation could be optimally constructed using the week 4 scan data, with fistula venous diameter and flow rate the most significant variables in explaining wrist fistula maturity failure (positive predictive value 60.6%, 95% confidence interval 43.9% to 77.3%), whereas resistance index and flow rate were most significant for elbow arteriovenous fistulas (positive predictive value 66.7%, 95% confidence interval 48.9% to 84.4%). In contrast to non-maturation, both models predicted fistula maturation much more reliably [negative predictive values of 95.4% (95% confidence interval 91.0% to 99.8%) and 95.6% (95% confidence interval 91.8% to 99.4%) for wrist and elbow, respectively]. Additional follow-up and modelling on a subset ( n  = 192) of the original SONAR cohort (the SONAR-12M study) revealed the rates of primary, assisted primary and secondary patency arteriovenous fistulas at 6 months were 76.5, 80.7 and 83.3, respectively. Fistula vein size, flow rate and resistance index could identify primary patency failure at 6 months, with similar predictive power as for 10-week arteriovenous fistula maturity failure, but with wide confidence intervals for wrist (positive predictive value 72.7%, 95% confidence interval 46.4% to 99.0%) and elbow (positive predictive value 57.1%, 95% confidence interval 20.5% to 93.8%). These models, moreover, performed poorly at identifying assisted primary and secondary patency failure, likely because a subset of those arteriovenous fistulas identified on ultrasound surveillance as at risk underwent subsequent successful salvage intervention without recourse to early ultrasound data., Conclusions: Although early ultrasound can predict fistula maturation and longer-term patency very effectively, it was only moderately good at identifying those fistulas likely to remain immature or to fail within 6 months. Allied to the better- than-expected fistula patency rates achieved (that are further improved by successful salvage), we estimate that a randomised controlled trial comparing early ultrasound-guided intervention against standard care would require at least 1300 fistulas and would achieve only minimal patient benefit., Trial Registration: This trial is registered as ISRCTN36033877 and ISRCTN17399438., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR135572) and is published in full in Health Technology Assessment ; Vol. 28, No. 24. See the NIHR Funding and Awards website for further award information.

Background: Little is known about postabortion care (PAC) services in Burkina Faso, despite PAC's importance as an essential and life-saving component of emergency obstetric care. This study aims to evaluate PAC service availability, readiness, and accessibility in Burkina Faso., Methods: Data for this study come from the Performance Monitoring for Action (PMA) Burkina Faso project and the Harmonized Health Facility Assessment (HHFA) conducted by the Institut de Recherche en Sciences de la Santé and the Ministry of Health. PMA data from a representative sample of women aged 15-49 (n = 6,385) were linked via GPS coordinates to HHFA facility data (n = 2,757), which included all public and private health facilities in Burkina Faso. We assessed readiness to provide basic and comprehensive PAC using the signal functions framework. We then calculated distance to facilities and examined percent within 5 kms of a facility with any PAC, basic PAC, and comprehensive PAC overall and by women's background characteristics., Results: PAC services were available in 46.4% of health facilities nationwide; only 38.3% and 35.0% of eligible facilities had all basic and comprehensive PAC signal functions, respectively. Removal of retained products of conception was the most common missing signal function for both basic and comprehensive PAC, followed by provision of any contraception (basic) or any LARC (comprehensive). Nearly 85% of women lived within 5 km of a facility providing any PAC services, while 50.5% and 17.4% lived within 5 km of a facility providing all basic PAC and all comprehensive PAC signal functions, respectively. Women with more education, greater wealth, and those living in urban areas had greater odds of living within 5 km of a facility with offering PAC, basic PAC, or comprehensive PAC., Conclusions: Results indicate a need for increased PAC availability and readiness, prioritizing basic PAC services at the primary level-the main source of care for many women-which would reduce structural disparities in access. The current deficiencies in PAC signal a need for broader strengthening of the primary healthcare services in Burkina Faso to reduce the burden of unsafe abortion-related morbidity and mortality while improving maternal health outcomes more broadly., (© 2024. The Author(s).)

Background: Postabortion care (PAC), which is an essential element of emergency obstetric care, is underresearched in Niger. The study aims to assess the availability, readiness, and accessibility of facility-based PAC services in Niger., Methods: This study uses female and facility data from Performance Monitoring for Action Niger. The female data include a nationally representative sample of women aged 15-49 (n = 3,696). Using GPS coordinates, these female data were linked to a sample of public and private facilities (n = 258) that are expected to provide PAC. We assessed PAC availability and facility readiness to provide basic and comprehensive PAC using the signal functions framework, overall and by facility type. We then calculated the distance between women and their closest facility and estimated the proportion of women living within five kilometers (5 km) of a facility providing any PAC, basic PAC, and comprehensive PAC, overall and by women's background characteristics., Results: Only 36.4% and 14% of eligible facilities had all basic and comprehensive PAC signal functions, respectively. Oxytocics and laparotomy were the most missing signal function for basic and comprehensive PAC, respectively. Private facilities were the least ready to provide the full range of PAC services. While 47% of women lived within 5 km of a facility providing any PAC services, only 33.4% and 7.9% lived within 5 km of a facility providing all basic and all comprehensive PAC signal functions, respectively. Women who were divorced/widowed, had higher levels of education, and were living in urban areas had increased odds of living within 5 km of a facility with any or basic PAC. Women who were never married had increased odds of living within 5 km of a facility with comprehensive PAC, while urban residence was fully predictive of living within 5 km of a facility with comprehensive PAC., Conclusions: This study found PAC availability and readiness to be insufficient in Niger, with inadequate and disparate accessibility to facilities providing PAC services. We recommended stakeholders ensure stock of essential commodities and availability of PAC services at primary facilities in order to mitigate the negative maternal health repercussions of unsafe abortion in this setting., (© 2023. The Author(s).)

The T cells of the immune system can target tumors and clear solid cancers following tumor-infiltrating lymphocyte (TIL) therapy. We used combinatorial peptide libraries and a proteomic database to reveal the antigen specificities of persistent cancer-specific T cell receptors (TCRs) following successful TIL therapy for stage IV malignant melanoma. Remarkably, individual TCRs could target multiple different tumor types via the HLA A ∗ 02:01-restricted epitopes EAAGIGILTV, LLLGIGILVL, and NLSALGIFST from Melan A, BST2, and IMP2, respectively. Atomic structures of a TCR bound to all three antigens revealed the importance of the shared x-x-x-A/G-I/L-G-I-x-x-x recognition motif. Multi-epitope targeting allows individual T cells to attack cancer in several ways simultaneously. Such "multipronged" T cells exhibited superior recognition of cancer cells compared with conventional T cell recognition of individual epitopes, making them attractive candidates for the development of future immunotherapies., Competing Interests: Declaration of interests The authors have patents granted and pending on T cell recognition of cancer via Melan A, BST2, and/or IMP2., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The Democratic Republic of Congo (DRC) legalized abortion in 2018 to preserve health and pledged to provide quality postabortion care (PAC), yet little is known about the availability of abortion care services and if facilities are prepared to provide them; even less is known about the accessibility of these services. Using facility and population-based data in Kinshasa and Kongo Central, this study examined the availability of abortion services, readiness of facilities to provide them, and inequities in access., Methods: Data on 153 facilities from the 2017-2018 DRC Demographic and Health Survey Service Provision Assessment (SPA) were used to examine signal functions and readiness of facilities to provide services across three abortion care domains (termination of pregnancy, basic treatment of abortion complications, and comprehensive treatment of abortion complications). To examine PAC and medication abortion provision before and after abortion decriminalization, we compared estimates from the 2017-2018 SPA facilities to estimates from the Performance Monitoring for Action (PMA) data collected in 2021 (n = 388). Lastly, we assessed proximity to PAC and medication abortion using PMA by geospatially linking facilities to representative samples of 2,326 and 1,856 women in Kinshasa and Kongo Central, respectively., Results: Few facilities had all the signal functions under each abortion care domain, but most facilities had many of the signal functions: overall readiness scores were > 60% for each domain. In general, readiness was higher among referral facilities compared to primary facilities. The main barriers to facility readiness were stock shortages of misoprostol, injectable antibiotics, and contraception. Overall, provision of services was higher post-decriminalization. Access to facilities providing PAC and medication abortion was almost universal in urban Kinshasa, but patterns in rural Kongo Central showed a positive association with education attainment and wealth., Conclusion: Most facilities had many of the necessary signal functions to provide abortion services, but the majority experienced challenges with commodity availability. Inequities in accessibility of services also existed. Interventions that address supply chain challenges may improve facility readiness to provide abortion care services, and further efforts are needed to narrow the gap in accessibility, especially among poor women from rural settings., (© 2023. The Author(s).)

Objectives: Among nationally representative cross-sections of women in need of contraception from Burkina Faso, Côte d'Ivoire and Kenya, we aimed to: (1) examine the intersection of past-year physical/sexual intimate partner violence (IPV), emotional IPV and reproductive coercion (RC) and (2) assess the impact of physical/sexual IPV, emotional IPV and RC on women's contraceptive use outcomes, including current contraceptive use, method type and covert use., Design: The present analysis uses cross-sectional female data collected in Burkina Faso (December 2020-March 2021), Côte d'Ivoire (October-November 2021) and Kenya (November-December 2020)., Settings: Burkina Faso, Côte d'Ivoire and Kenya PARTICIPANTS: Analytical samples were restricted to partnered women with contraceptive need who completed a violence module (Burkina Faso n=1863; Côte d'Ivoire n=1105; Kenya n=3390)., Primary and Secondary Outcome Measures: The exposures of interest-past-year emotional IPV, physical/sexual IPV and RC-were assessed using abridged versions of the Revised Conflict and Tactics Scale-2 and Reproductive Coercion Scale, respectively. Outcomes of interest included current contraceptive use, contraceptive method type (female controlled vs male compliant), and covert contraceptive use, and used standard assessments., Results: Across sites, 6.4% (Côte d'Ivoire) to 7.8% (Kenya) of women in need of contraception experienced RC; approximately one-third to one-half of women experiencing RC reported no other violence forms (31.7% in Burkina Faso to 45.8% in Côte d'Ivoire), whereas physical/sexual IPV largely occurred with emotional IPV. In multivariable models, RC was consistently associated with covert use (Burkina Faso: aOR 2.84 (95% CI 1.21 to 6.64); Côte d'Ivoire: aOR 4.45 (95% CI 1.76 to 11.25); Kenya: aOR 5.77 (95% CI 3.51 to 9.46)). Some IPV in some settings was also associated with covert use (emotional IPV, Burkina Faso: aOR 2.99 (95% CI 1.56 to 5.74); physical/sexual, Kenya: aOR 2.35 (95% CI 1.33 to 4.17))., Conclusions: Across settings, covert use is a critical strategy for women experiencing RC. Country policies must recognise RC as a unique form of violence with profound implications for women's reproductive health., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Reproductive coercion (RC) is a type of abuse where a partner asserts control over a woman's reproductive health trajectories. Recent research emphasizes that RC experiences may differ within and across low- and middle-income countries (LMICs), as compared to higher income contexts, given social pressures surrounding childbearing. To date, nationally representative surveys have lacked comprehensive measures for RC, leading to gaps in understanding its prevalence and risk factors. Across eight LMICs (10 sites), we aimed to (1) validate the RC Scale; (2) calculate prevalence of RC and specific behaviors; and (3) assess correlates of RC., Methods: This analysis leverages cross-sectional Performance Monitoring for Action (PMA) data collected from November 2020 to May 2022. Analyses were limited to women in need of contraception (Burkina Faso n = 2767; Côte d'Ivoire n = 1561; Kongo Central, Democratic Republic of Congo (DRC) n = 830; Kinshasa, DRC n = 846; Kenya n = 4588; Kano, Nigeria n = 535; Lagos, Nigeria n = 612; Niger n = 1525; Rajasthan, India n = 3017; Uganda n = 2020). Past-year RC was assessed via five items adapted from the original RC Scale and previously tested in LMICs. Confirmatory factor analysis examined fit statistics by site. Per-item and overall prevalence were calculated. Site-specific bivariate and multivariable logistic regression examined RC correlates across the socioecological framework., Results: Confirmatory factor analysis confirmed goodness of fit across all sites, with moderate internal consistency (alpha range: 0.66 Cote d'Ivoire-0.89 Kinshasa, DRC/Lagos, Nigeria). Past-year reported prevalence of RC was highest in Kongo Central, DRC (20.3%) and lowest in Niger (3.1%). Prevalence of individual items varied substantially by geography. Polygyny was the most common RC risk factor across six sites (adjusted odds ratio (aOR) range: 1.59-10.76). Increased partner education levels were protective in Kenya and Kano, Nigeria (aOR range: 0.23-0.67). Other assessed correlates differed by site., Conclusions: Understanding RC prevalence and behaviors is central to providing woman-centered reproductive care. RC was most strongly correlated with factors at the partner dyad level; future research is needed to unpack the relative contributions of relationship power dynamics versus cultural norms surrounding childbearing. Family planning services must recognize and respond to women's immediate needs to ensure RC does not alter reproductive trajectories, including vulnerability to unintended pregnancy., (© 2023. The Author(s).)

Background: Huntingtin (htt) protein is an essential regulator of nervous system function through its various neuroprotective and pro-survival functions, and loss of wild-type htt function is implicated in the etiology of Huntington's disease. While its pathological role is typically understood as a toxic gain-of-function, some neuronal phenotypes also result from htt loss. Therefore, it is important to understand possible roles for htt in other physiological circumstances., Objective: To elucidate the role of htt in the context of ethanol exposure, we investigated how loss of htt impacts behavioral and physiological responses to ethanol in Drosophila., Methods: We tested flies lacking htt for ethanol sensitivity and tolerance, preference for ethanol using capillary feeder assays, and recovery of mobility after intoxication. Levels of dopamine neurotransmitter and numbers of dopaminergic cells in brains lacking dhtt were also measured., Results: We found that dhtt-null flies are both less sensitive and more tolerant to ethanol exposure in adulthood. Moreover, flies lacking dhtt are more averse to alcohol than controls, and they recover mobility faster following acute ethanol intoxication. We showed that dhtt mediates these effects at least in part through the dopaminergic system, as dhtt is required to maintain normal levels of dopamine in the brain and normal numbers of dopaminergic cells in the adult protocerebrum., Conclusions: Our results demonstrate that htt regulates the physiological response to ethanol and indicate a novel neuroprotective role for htt in the dopaminergic system, raising the possibility that it may be involved more generally in the response to toxic stimuli.

This study aims to estimate induced abortion incidence and safety in Burkina Faso using direct and indirect methods, overall and by women's background characteristics. Data come from a nationally representative survey of reproductive aged women (n = 6,388). To address social desirability bias in abortion reporting, we asked about respondents' closest female friends' experience with abortion. The one-year abortion incidence in 2020 for respondents was 4.0 (95% CI 2.2-5.9) per 1,000 women aged 15-49 while the adjusted friend incidence was 22.9 (95% CI 15.8-30.0). Although not significant, abortion incidence was higher for adolescents, unmarried women, those with higher education, and those in urban areas among both respondents and their friends. Approximately nine out of ten abortions were unsafe (90% respondents, 95% friends), with respondent and friend findings suggesting higher risk of unsafe abortion among older women, less educated women, and women residing in rural areas. Despite recent increases in contraceptive use and continued legal restrictions, abortion remains common in Burkina Faso and is largely unsafe, with evidence of potential disparities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Bell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Abortion is a legally restricted, yet common reproductive life event among women in Burkina Faso; however, women's abortion experiences vary greatly depending on their social and economic capital, partner involvement, and level of knowledge. We sought to classify women's abortion care-seeking experiences across the life course and social conditions into typologies using qualitative data., Methods: An initial quantitative survey among a nationally representative sample of women ages 15-49 years collected information on women's induced abortion experiences. Women who reported an abortion in the last 10 years were asked if they would agree to participate in a subsequent in-depth interview (IDI) to learn more about their abortion experience. Twenty-five women, identified via purposive sampling, completed an IDI. Using a process of typology construction, we identified attributes of each woman's condition at the time of her abortion and aspects of her abortion experience, created a matrix of attributes and cases, and identified emerging relationships. Three types were identified through this process., Results: Twenty-three IDIs were analyzed, and women's abortion experiences were grouped into three types: abortion to delay childbearing in adolescence; abortion to space childbirth among women in union; abortion to avoid childbearing among single mothers. Two cases were identified as outliers. Cases were grouped based on the context of their pregnancy, the reason for the abortion and involved decision-makers, and their patterns of care-seeking, including methods and sources used., Conclusion: Structural inequities related to gender and wealth were prominent forces shaping women's abortion experiences. Comprehensive sexuality education coupled with community-based interventions to promote gender-equitable relationships and address social stigma related to women's sexuality could reduce reproductive coercion and unintended pregnancies., (© 2022. The Author(s).)

Background: Global evidence indicates increases in gender-based violence (GBV) during the COVID-19 pandemic following mitigation measures, such as stay at home orders. Indirect effects of the pandemic, including income loss, strained social support, and closed or inaccessible violence response services, may further exacerbate GBV and undermine help-seeking. In Kenya and Burkina Faso, as in many settings, GBV was prevalent prior to the COVID-19 pandemic. Studies specific to COVID-impact on GBV in Kenya indicate mixed results and there remains a lack of evidence from Burkina Faso. Our study takes a comprehensive lens by addressing both intimate partner violence (IPV) and non-partner household abuse through the COVID-19 pandemic in two priority settings., Methods: Annual, national cross-sections of women ages 15-49 completed survey data collection in November-December 2020 and December 2020-March 2021; the GBV module was limited to one woman per household [Kenya n = 6715; Burkina n = 4065]. Descriptive statistics, Venn diagrams, and logistic and multinomial regression characterized prevalence of IPV and other household abuse, frequency relative to the COVID-19 pandemic, help-seeking behaviors, and predictors of IPV and household abuse across the socioecological framework., Results: In both settings, past-year IPV prevalence exceeded non-partner household abuse (Kenya: 23.5% IPV, 11.0% household ; Burkina Faso: 25.7% IPV, 16.2% household ). Over half of those affected in each setting did not seek help; those that did turned first to family. Among those with past-year experiences, increased frequency since COVID-19 was noted for IPV (16.0% Burkina Faso ; 33.6% Kenya ) and household violence (14.3% Burkina Faso ; 26.2% Kenya ). Both context-specific (i.e., financial autonomy in Burkina Faso) and universal (i.e., COVID-related income loss) risk factors emerged., Conclusion: Past-year IPV and household violence against women in Kenya and Burkina Faso were prevalent, and in some cases, intensified during the COVID-19 pandemic. Across settings, help-seeking from formal services was notably low, likely reflecting shame, blame, and stigmatization identified as barriers in pre-COVID literature. Both primary prevention and survivor-centered support services, including those related to economic empowerment, should be integrated within COVID-recovery efforts, and extended into the post-pandemic period to fully meet women's safety needs., (© 2022. The Author(s).)

Background: Women's sexual health is generally defined and explored solely in relation to reproductive capacity, and often omits elements of sexual function and/or dysfunction. Concerted focus is given to women's health during pregnancy; however, women's sexual health is largely neglected after childbirth. This scoping review explored how the sexual health of postpartum women has been defined, measured, and researched in low- and middle-income countries (LMICs)., Methods: Articles eligible for review were those that investigated women's sexual health during the first 12 months postpartum and were conducted among women aged 15-49 in LMICs. Eligibility was further restricted to studies that were published within the last 20 years (2001-2021). The initial PubMed search identified 812 articles, but upon further eligibility review, 97 remained. At this time, the decision was made to focus this review only on articles addressing sexual function and/or dysfunction, which yielded 46 articles. Key article characteristics were described and analyzed by outcome., Results: Of the final included articles, five studies focused on positive sexual health, 13 on negative sexual health, and the remaining 28 on both positive and negative sexual health or without specified directionality. The most common outcome examined was resumption of sex after childbirth. Most studies occurred within sub-Saharan Africa (n = 27), with geographic spread throughout the Middle East (n = 10), Asia (n = 5), North Africa (n = 3), and cross-geography (n = 1); notably, all five studies on positive sexual health were conducted in Iran. Negative sexual health outcomes included vaginismus, dyspareunia, episiotomy, perineal tears, prolapse, infection, obstetric fistula, female genital cutting, postnatal pain, uterine prolapse, coercion to resume sex, sexual violence, and loss of sexual desire/arousal. Most studies were quantitative, though eight qualitative studies elucidated the difficulties women endured in receiving information specific to sexual health and hesitance in seeking help for sexual morbidities in the postpartum period., Conclusions: Overall, the evidence base surrounding women's sexual health in the postpartum period within LMICs remains limited, with most studies focusing solely on the timing of resumption of sex. Integration of sexual health counseling into postnatal care and nonjudgmental service provision can help women navigate these bodily changes and ultimately improve their sexual health., (© 2022. The Author(s).)

Background: In low-incidence countries, tuberculosis mainly affects migrants, mostly resulting from reactivation of latent tuberculosis infection (LTBI) acquired in high-incidence countries before migration. A nationwide primary care-based LTBI testing and treatment programme for migrants from high-incidence countries was therefore established in high tuberculosis incidence areas in England. We aimed to assess the effectiveness of this programme., Methods: We did a retrospective, population-based cohort study of migrants who registered in primary care between Jan 1, 2011, and Dec 31, 2018, in 55 high-burden areas with programmatic LTBI testing and treatment. Eligible individuals were aged 16-35 years, born in a high-incidence country, and had entered England in the past 5 years. Individuals who tested interferon-γ release assay (IGRA)-negative were advised about symptoms of tuberculosis, whereas those who tested IGRA-positive were clinically assessed to rule out active tuberculosis and offered preventive therapy. The primary outcome was incident tuberculosis notified to the national Enhanced Tuberculosis Surveillance system., Findings: Our cohort comprised 368 097 eligible individuals who had registered in primary care, of whom 37 268 (10·1%) were tested by the programme. 1446 incident cases of tuberculosis were identified: 166 cases in individuals who had IGRA testing (incidence 204 cases [95% CI 176-238] per 100 000 person-years) and 1280 in individuals without IGRA testing (82 cases [77-86] per 100 000 person-years). Overall, in our primary analysis including all diagnosed tuberculosis cases, a time-varying association was identified between LTBI testing and treatment and lower risk of incident tuberculosis (hazard ratio [HR] 0·76 [95% CI 0·63-0·91]) when compared with no testing. In stratified analysis by follow-up period, the intervention was associated with higher risk of tuberculosis diagnosis during the first 6 months of follow-up (9·93 [7·63-12·9) and a lower risk after 6 months (0·57 [0·41-0·79]). IGRA-positive individuals had higher risk of tuberculosis diagnosis than IGRA-negative individuals (31·9 [20·4-49·8]). Of 37 268 migrants who were tested, 6640 (17·8%) were IGRA-positive, of whom 1740 (26·2%) started preventive treatment. LTBI treatment lowered the risk of tuberculosis: of 135 incident cases in the IGRA-positive cohort, seven cases were diagnosed in the treated group (1·87 cases [95% CI 0·89-3·93] per 1000 person-years) and 128 cases were diagnosed in the untreated group (10·9 cases [9·16-12·9] per 1000 person-years; HR 0·14 [95% CI 0·06-0·32])., Interpretation: A low proportion of eligible migrants were tested by the programme and a small proportion of those testing positive started treatment. Despite this, programmatic LTBI testing and treatment of individuals migrating to a low-incidence region is effective at diagnosing active tuberculosis earlier and lowers the long-term risk of progression to tuberculosis. Increasing programme participation and treatment rates for those testing positive could substantially impact national tuberculosis incidence., Funding: National Institute for Health Research Health Protection Research Unit in Respiratory Infections., Competing Interests: Declaration of interests AL is named inventor on patents pertaining to T-cell-based diagnosis, including current and second-generation IGRA technologies and flow-cytometric diagnosis and prognosis of tuberculosis infection and disease; some of these patents were assigned by the University of Oxford (Oxford, UK) to Oxford Immunotec, resulting in the T-SPOT.TB test with royalty entitlements for the University of Oxford and AL. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Competing interests: I have read and understood BMJ policy on declaration of interests and have no interests to declare.

Introduction: Practitioners have anecdotally hinted at a possible association between gastroesophageal reflux disease (GERD) and vesicoureteral reflux (VUR). We sought to identify an association in diagnosis between GERD and VUR using a population-based dataset in a well-defined geographic area covered by a single-payer healthcare system., Methods: A retrospective review of individuals aged 0-16 years registered in the Nova Scotia Medical Service Insurance database from January 1997 to December 2012 was completed. Presence of GERD and VUR were ascertained based on billing codes. The baseline prevalence of GERD and VUR was calculated for this population for the same time period. Proportions of VUR patients with and without GERD were compared. The risk of being diagnosed with VUR in patients with GERD controlling for sex was calculated., Results: Of 404 300 patients identified, 6.6% had a diagnosis of GERD (n=27 092), 0.33% had a diagnosis of VUR (n=1348), and 0.08% were diagnosed with both (n=327). Among patients with VUR, the prevalence of GERD was 24.3% compared to 6.6% in patients without VUR (p<0.0001). Among patients with GERD, the prevalence of VUR was 1.2% compared to 0.27% in patients without (p<0.0001). The risk of being diagnosed with VUR was higher in the presence of GERD (odds ratio [OR] 4.49; 95% confidence interval [CI] 3.96-5.09; p<0.0001), irrespective of sex., Conclusions: The odds of being diagnosed with VUR is more than 4.5 times higher in an individual with GERD. The clinical significance of this association remains to be explored.

Optimal red cell transfusion support in myelodysplastic syndromes (MDS) has not been tested and established. The aim of this study was to demonstrate feasibility of recruitment and follow-up in an outpatient setting with an exploratory assessment of quality of life (QoL) outcomes (EORTC QLQ-C30 and EQ-5D-5L). We randomised MDS patients to standardised transfusion algorithms comparing current restrictive transfusion thresholds (80 g/l, to maintain haemoglobin 85-100 g/l) with liberal thresholds (105 g/l, maintaining 110-125 g/l). The primary outcomes were measures of compliance to transfusion thresholds. Altogether 38 patients were randomised (n = 20 restrictive; n = 18 liberal) from 12 participating sites in UK, Australia and New Zealand. The compliance proportion for the intention-to-treat population was 86% (95% confidence interval 75-94%) and 99% (95-100%) for restrictive and liberal arms respectively. Mean pre-transfusion haemoglobin concentrations for restrictive and liberal arms were 80 g/l (SD6) and 97 g/l (SD7). The total number of red cell units transfused on study was 82 in the restrictive and 192 in the liberal arm. In an exploratory analysis, the five main QoL domains were improved for participants in the liberal compared to restrictive arm. Our findings support the feasibility and need for a definitive trial to evaluate the effect of different red cell transfusion thresholds on patient-centred outcomes., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: In the UK, several hundred patients notified with tuberculosis (TB) die every year. The aim of this article is to describe trends in deaths among notified TB patients, explore risk factors associated with death and compare all-cause mortality in TB patients with age-specific mortality rates in the general UK population., Methods: We used 2001-2014 data from UK national TB surveillance to explore trends and risk factors for death, and population mortality data to compare age-specific death rates among notified TB patients with annual death rates in the UK general population., Results: The proportion of TB patients in the UK who died each year declined steadily from 7.1% in 2002 to 5.5% in 2014. One in five patients (21.3%) was diagnosed with TB post-mortem. Where information was available, almost half of the deaths occurred within 2 months of starting treatment. Risk factors for death included demographic, disease-specific and social risk factors. Age had by far the largest effect, with patients aged ≥80 years having a 70 times increased risk of death compared with those aged <15 years. In contrast, excess mortality determined by incidence ratios comparing all-cause mortality among TB patients with that of the general population was highest among children and the working-age population (15-64 years old)., Conclusions: Efforts to control TB and improve diagnosis and treatment outcomes in the UK need to be sustained. Control efforts need to focus on socially deprived and vulnerable groups. There is a need for further in-depth analysis of deaths of TB patients in the UK to identify potentially preventable factors., Competing Interests: Conflict of interest: D. Pedrazzoli has nothing to disclose. Conflict of interest: K. Kranzer has nothing to disclose. Conflict of interest: H.L. Thomas has nothing to disclose. Conflict of interest: M.K. Lalor has nothing to disclose., (Copyright ©ERS 2019.)

Human infection with Mycobacterium bovis is reported infrequently in the United Kingdom. Most cases involve previous consumption of unpasteurized milk. We report a rare occurrence of 2 incidents of cat-to-human transmission of M. bovis during a cluster of infection in cats.

The incidence of multidrug-resistant tuberculosis (MDR-TB) is routinely reported by the Public Health England, UK, but prevalence better represents burden. To estimate MDR-TB prevalence, and identify the factors associated with acquired resistance and unsuccessful outcomes in people managed by the health services. We included notified MDR-TB cases prevalent between 2010 and 2014. Multivariable logistic regression was used to identify the factors associated with acquisition of resistance and unsuccessful outcomes. The social risk factors (SRFs) recorded were alcohol, drug misuse, homelessness and incarceration. Between 2010 and 2014, there were 2.3-3.1 times more prevalent than incident cases each year, with an increasing prevalence-to-incidence ratio over time; 86% of prevalent cases were foreign-born, and 15% had an SRF. Overall, 11% of MDR-TB cases acquired resistance, including 18% of those with SRFs and 22% of UK-born MDR-TB cases acquired resistance. Half of the cases completed treatment by 24 months; those with SRFs, extensive drug resistance or acquired resistance were less likely to complete treatment. The number of prevalent cases is higher than incident cases, and increases over time, so a focus on prevalent cases enables better planning for services to support patients. We recommend that additional support be provided for those at risk of acquiring resistance, including those with SRFs. .

Background: The epidemiology of tuberculosis (TB) is changing in the United Kingdom and globally. Childhood TB is a key indicator of recent transmission and provides a marker of wider TB control. We describe the recent epidemiology of childhood TB in the United Kingdom, how this compares to TB in adults, and document changes with time., Methods: TB cases notified in the United Kingdom between 2000 and 2015 were categorized as children (<15 years of age) or adults (≥15 years of age). Descriptive analyses were carried out on demographic, clinical and microbiologic data. We carried out logistic regressions to identify risk factors associated with children having no microbiologic confirmation., Results: In the study period, 6293 TB cases (5%) in the United Kingdom were notified in children. Childhood TB incidence declined from 487 cases in 2000 (3.4 per 100,000) to 232 cases (2.0 per 100,000) in 2015. The majority (68%) of children with TB were UK born, with a high proportion of Pakistani (24%) and Black-African (22%) ethnicity. Sixty-four percent of children had pulmonary disease. Culture confirmation was low (24%). Children who were younger, UK born and those with extrapulmonary disease were less likely to have microbiologically confirmed TB. A high proportion (87%) of children completed treatment at last-recorded outcome, with few deaths (39 cases; 0.7%)., Conclusions: The incidence of TB in children in the United Kingdom has decreased in the past 16 years, with the majority of children completing TB treatment. Ongoing monitoring of childhood TB will provide a measure of the effectiveness of the national TB program.

Objectives: Tuberculosis (TB) is a serious re-emergent public health problem in the UK. In response to rising case incidence a National TB Strain-Typing Service based on molecular strain-typing was established. This facilitates early detection and investigation of clusters, targeted public health action, and prevention of further transmission. We review the added public health value of investigating molecular TB strain-typed (ST) clusters., Methods: A structured questionnaire for each ST cluster investigated in England between 1 January 2010 and 30 June 2013 was completed. Questions related to epidemiological links and public health action and the perceived benefits of ST cluster investigation., Results: There were 278 ST cluster investigations (CIs) involving 1882 TB cases. Cluster size ranged from 2 to 92. CIs identified new epidemiological links in 36% of clusters; in 18% STs were discordant refuting transmission thought to have occurred. Additional public health action was taken following 23% of CI., Conclusions: We found positive benefits of TB molecular ST and CI, in identifying new epidemiological links between cases and taking public health action and in refuting transmission and saving resources. This needs to be translated to a decrease in transmission to provide evidence of public health value in this low prevalence high resource setting., (Copyright © 2019. Published by Elsevier Ltd.)

Background: In January 2016, clinical TB guidance in the UK changed to no longer recommend screening contacts of non-pulmonary, non-laryngeal (ETB) index cases. However, no new evidence was cited for this change, and there is evidence that screening these contacts may be worthwhile. The objective of this study was to estimate the cost-effectiveness of screening contacts of adult ETB cases and adult pulmonary or laryngeal TB (PTB) cases in London, UK., Methods: We carried out a cross-sectional analysis of data collected on TB index cases and contacts in the London TB register and an economic evaluation using a static model describing contact tracing outcomes. Incremental cost-effectiveness ratios (ICERs) were calculated using no screening as the baseline comparator. All adult TB cases (≥15 years old) in London from 2012 to 2015, and their contacts, were eligible (2465/5084 PTB and 2559/6090 ETB index cases were included)., Results: Assuming each contact with PTB infects one person/month, the ICER of screening contacts of ETB cases was £78 000/quality-adjusted life-years (QALY) (95% CI 39 000 to 140 000), and screening contacts of PTB cases was £30 000/QALY (95% CI 18 000 to 50 000). The ICER of screening contacts of ETB cases was £30 000/QALY if each contact with PTB infects 3.4 people/month. Limitations of this study include the use of self-reported symptomatic periods and lack of knowledge about onward transmission from PTB contacts., Conclusions: Screening contacts of ETB cases in London was almost certainly not cost-effective at any conventional willingness-to-pay threshold in England, supporting recent changes to National Institute for Health and Care Excellence national guidelines., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Genotyping provides the opportunity to better understand tuberculosis (TB) transmission. We utilized strain typing data to assess trends in the proportion of clustering and identify the characteristics of individuals and clusters associated with recent United Kingdom (UK) transmission. In this retrospective cohort analysis, we included all culture-confirmed strain-typed TB notifications from the UK between 2010 and 2015 to estimate the proportion of patients that clustered over time. We explored the characteristics of patients in a cluster using multivariable logistic regression. Overall, 58.5% of TB patients were concentrated in 2,701 clusters. The proportion of patients in a cluster decreased between 2010 (58.7%) and 2015 (55.3%) (P = 0.001). Being a clustered patient was associated with being male and UK-born, having pulmonary disease, having a previous TB diagnosis, and having a history of drug misuse or imprisonment. Our results suggest that TB transmission in the UK decreased between 2010 and 2015, during which time TB incidence also decreased. Targeted cluster investigation and extended contact tracing should be aimed at persons at risk of being in a transmission chain, including UK-born individuals with social risk factors in clusters with a high proportion of patients having pulmonary disease.

Improving access to tuberculosis (TB) care and ensuring early diagnosis are two major aims of the WHO End TB strategy and the Collaborative TB Strategy for England. This study describes risk factors associated with diagnostic delay among TB cases in England. We conducted a retrospective cohort study of TB cases notified to the Enhanced TB Surveillance System in England between 2012 and 2015. Diagnostic delay was defined as more than 4 months between symptom onset and treatment start date. Multivariable logistic regression was used to identify demographic and clinical factors associated with diagnostic delay. Between 2012 and 2015, 22 422 TB cases were notified in England and included in the study. A third (7612) of TB cases had a diagnostic delay of more than 4 months. Being female, aged 45 years and older, residing outside of London and having extra-pulmonary TB disease were significantly associated with a diagnostic delay in the multivariable model (aOR = 1.2, 1.2, 1.2, 1.3, 1.8, respectively). This study identifies demographic and clinical factors associated with diagnostic delay, which will inform targeted interventions to improve access to care and early diagnosis among these groups, with the ultimate aim of helping reduce transmission and improve treatment outcomes for TB cases in England.

Background: Following nearly two decades of increasing tuberculosis in the UK, TB incidence decreased by 32% from 2011 to 2015. Explaining this reduction is crucial to informing ongoing TB control efforts., Methods: We stratified TB cases notified in the UK and TB cases averted in the UK through pre-entry screening (PES) between 2011 and 2015 by country of birth and time since arrival. We used population estimates and migration data to establish denominators, and calculated incidence rate ratios (IRRs) between 2011 and 2015. We calculated the contribution of changing migrant population sizes, PES and changes in TB rates to the reduction in TB notifications., Results: TB IRRs fell in all non-EU migrant and UK-born populations between 2011 and 2015 (0.61; 95%  CI 0.59 to 0.64 and 0.78; 0.73 to 0.83 respectively), with the greatest decrease in recent non-EU migrants (0.54; 0.48 to 0.61). 61.9% of the reduction in TB notifications was attributable to decreases in TB rates, 33.4% to a fall in the number of recent/mid-term non-EU migrants and 11.4% to PES. A small increase in notifications in EU-born migrants offset the reduction by 6.6%., Conclusions: Large decreases in TB rates in almost all populations accounted for the majority of the reduction in TB notifications, providing evidence of the impact of recent interventions to improve UK TB control. The particularly large decrease in TB rates in recent non-EU migrants provides evidence of the effectiveness of screening interventions that target this population. These findings will inform ongoing improvements to TB control., Competing Interests: Competing interests: DZ is head of the Tuberculosis Screening Unit at Public Health England and has shared responsibilities for quality assurance within the UK pre-entry screening programme and leading on the national latent TB screening programme in England. SRA is head of the Public Health England National TB Programme Office. Other authors have no competing interests to declare., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

In Europe, the agricultural biogas sector is currently undergoing fast developments, and cattle manure constitutes an important feedstock. Batch dry digester processes with leachate recirculation prove to be particularly interesting for small-scale plants. However, their startup being relatively slow, the process could be facilitated by co-digestion with energy crops. In this study, Miscanthus x giganteus was chosen for its high biomass yields and low input requirements. The carbohydrate accessibility of this lignocellulosic biomass is limited but may be improved with alkali pretreatment. The efficiency of lime (CaO) pretreatment with low water addition on the biochemical methane potential (BMP) of miscanthus was investigated through two experimental designs (CaO concentrations ranged between 2.5 and 17.5% and pretreatment lasted 1, 3, or 5 days). The pretreated miscanthus was then co-digested with cattle manure in dry leach bed reactors. CaO pretreatments led to a 14⁻37% improvement of miscanthus BMP, and a 67⁻227% increase in the first-order kinetics constant; a high contact time was shown to favor methane production. According to these results and to industrial requirements, miscanthus was pretreated with 5 and 10% CaO for 5 days, then co-digested with manure in dry leach bed reactors. Nevertheless, the promising results of the BMP tests were not validated. This could be related to the high water absorption capacity of miscanthus.

Peptide-MHC (pMHC) multimers have become the "gold standard" for the detection and isolation of antigen-specific T-cells but recent evidence shows that normal use of these reagents can miss fully functional T-cells that bear T-cell receptors (TCRs) with low affinity for cognate antigen. This issue is particularly pronounced for anticancer and autoimmune T-cells as self-reactive T-cell populations are enriched for low-affinity TCRs due to the removal of cells with higher affinity receptors by immune tolerance mechanisms. Here, we stained a wide variety of self-reactive human T-cells using regular pMHC staining and an optimized technique that included: (i) protein kinase inhibitor (PKI), to prevent TCR triggering and internalization, and (ii) anti-fluorochrome antibody, to reduce reagent dissociation during washing steps. Lymphocytes derived from the peripheral blood of type 1 diabetes patients were stained with pMHC multimers made with epitopes from preproinsulin (PPI), insulin-β chain, glutamic acid decarboxylase 65 (GAD65), or glucose-6-phospate catalytic subunit-related protein (IGRP) presented by disease-risk allelles HLA A*02:01 or HLA*24:02. Samples from ankylosing spondylitis patients were stained with a multimerized epitope from vasoactive intestinal polypeptide receptor 1 (VIPR1) presented by HLA B*27:05. Optimized procedures stained an average of 40.5-fold ( p  = 0.01, range between 1.4 and 198) more cells than could be detected without the inclusion of PKI and cross-linking anti-fluorochrome antibody. Higher order pMHC dextramers recovered more cells than pMHC tetramers in parallel assays, and standard staining protocols with pMHC tetramers routinely recovered less cells than functional assays. HLA A*02:01-restricted PPI-specific and HLA B*27:05-restricted VIPR1-specific T-cell clones generated using the optimized procedure could not be stained by standard pMHC tetramer staining. However, these clones responded well to exogenously supplied peptide and endogenously processed and presented epitopes. We also showed that anti-fluorochrome antibody-conjugated magnetic beads enhanced staining of self-reactive T-cells that could not be stained using standard protocols, thus enabling rapid ex vivo isolation of autoimmune T-cells. We, therefore, conclude that regular pMHC tetramer staining is generally unsuitable for recovering self-reactive T-cells from clinical samples and recommend the use of the optimized protocols described herein.

We used whole-genome sequencing (WGS) to delineate transmission networks and investigate the benefits of WGS during cluster investigation.We included clustered cases of multidrug-resistant (MDR) tuberculosis (TB)/extensively drug-resistant (XDR) TB linked by mycobacterial interspersed repetitive unit variable tandem repeat (MIRU-VNTR) strain typing or epidemiological information in the national cluster B1006, notified between 2007 and 2013 in the UK. We excluded from further investigation cases whose isolates differed by greater than 12 single nucleotide polymorphisms (SNPs). Data relating to patients' social networks were collected.27 cases were investigated and 22 had WGS, eight of which (36%) were excluded as their isolates differed by more than 12 SNPs to other cases. 18 cases were ruled into the transmission network based on genomic and epidemiological information. Evidence of transmission was inconclusive in seven out of 18 cases (39%) in the transmission network following WGS and epidemiological investigation.This investigation of a drug-resistant TB cluster illustrates the opportunities and limitations of WGS in understanding transmission in a setting with a high proportion of migrant cases. The use of WGS should be combined with classical epidemiological methods. However, not every cluster will be solvable, regardless of the quality of genomic data., Competing Interests: Conflict of interest: None declared., (Copyright ©ERS 2018.)

Background: Accurate estimates of tuberculosis (TB) mortality are required to monitor progress towards the World Health Organization End TB goal of reducing TB deaths by 95% by 2035. We compared TB death data for England and Wales from the national surveillance system (Enhanced Tuberculosis Surveillance System [ETS]) and the vital registration system from the Office for National Statistics (ONS)., Methods: TB cases notified in ETS were matched to deaths in ONS (dONS) with International Classification of Diseases, Tenth Revision (ICD-10) codes indicating that TB caused/contributed to the death (A15-A19). Deaths captured in one but not both systems were assessed to identify if ONS captured all TB deaths and if there was under-notification of TB in ETS. We stratified deaths into active TB, TB sequelae, incidental deaths and not TB., Results: Between 2005 and 2015, there were fewer deaths in ETS (dETS) than dONS with ICD-10 codes A15-A19 (n = 4207 vs. n = 6560); 57% of dETS were recorded as dONS and 53% of dONS were notified to ETS. A total of 9289 deaths were identified from dETS and dONS: 64% were due to active TB, 23% were TB sequelae, 6% were incidental and 7% were not TB., Conclusions: TB deaths in ETS and ONS differ substantially. Almost one third of TB deaths recorded by ONS are not due to active TB; this can be amended through coding changes.

Background: ESBL-producing Enterobacteriaceae (ESBLPE) are increasing in prevalence worldwide and are more difficult to treat than non-ESBLPE. Their prevalence in the UK general population is unknown, as the only previous UK ESBLPE faecal colonization study involved patients with diarrhoea., Objectives: To estimate the prevalence of CTX-M ESBLPE faecal colonization in the general adult population of England in 2014, and investigate risk factors., Methods: A stratified random sample of 58 337 registered patients from 16 general practices within four areas of England were invited to participate by returning faeces specimens and self-completed questionnaires. Specimens were tested for ESBLPE and carbapenemase-producing Enterobacteriaceae (CPE)., Results: 2430 individuals participated (4% of those invited). The estimated prevalence of colonization with CTX-M ESBLPE in England was 7.3% (95% CI 5.6%-9.4%) (Shropshire 774 participants, 4.9% colonization; Southampton City 740 participants, 9.2%; Newham 612 participants, 12.7%; Heart of Birmingham 234 individuals, 16.0%) and was particularly high in: those born in Afghanistan (10 participants, 60.0% colonization, 95% CI 29.7%-84.2%); those born on the Indian subcontinent (India, Pakistan, Bangladesh or Sri Lanka) (259 participants, 25.0% colonization, 95% CI 18.5%-32.9%); travellers to South Asia (India, Pakistan, Bangladesh, Sri Lanka or Nepal) in the last year (140 participants, 38.5% colonization, 95% CI 27.8%-50.5%); and healthcare domestics (8 participants, unweighted 37.5% colonization, 95% CI 8.5%-75.5%). Risk factors identified included: being born in the Indian subcontinent (aOR 5.4, 95% CI 3.0-9.7); travel to South Asia (aOR 2.9, 95% CI 1.8-4.8) or to Africa, China, South or Central America, South East or Pacific Asia or Afghanistan (aOR 2.6, 95% CI 1.7-4.1) in the last year; and working as a healthcare domestic (aOR 6.2, 95% CI 1.3-31). None of the 48 participants who took co-amoxiclav in the last year was colonized with CTX-M ESBLPE. blaCTX-M-15 accounted for 66% of CTX-M ESBLPE positives. 0.1% (two participants) were colonized with CPE., Conclusions: CTX-M ESBLPE are established in the general population in England and prevalence is particularly high in people from certain countries of birth or with recent travel. We recommend that these findings be taken into account in guidance on the empirical management of patients presenting with a likely Enterobacteriaceae infection.

Contact tracing is a key part of tuberculosis prevention and care, aiming to hasten diagnosis and prevent transmission. The proportion of case-contact pairs for which recent transmission occurred and the typical timespans between the index case and their contact accessing care are not known; we aimed to calculate these. We analysed individual-level TB contact tracing data, collected in London from 20/01/2011-31/12/2015, linked to tuberculosis surveillance and MIRU-VNTR 24-locus strain-typing information. Of pairs of index cases and contacts diagnosed with active tuberculosis, 85/314 (27%) had strain typing data available for both. Of these pairs, 79% (67/85) shared indistinguishable isolates, implying probable recent transmission. Of pairs in which both contact and the index case had a social risk factor, 11/11 (100%) shared indistinguishable isolates, compared to 55/75 (75%) of pairs in which neither had a social risk factor (P = 0.06). The median time interval between the index case and their contact accessing care was 42 days (IQR: 16, 96). As over 20% of pairs did probably not involve recent transmission between index case and contact, the effectiveness of contact tracing is not necessarily limited to those circumstances where the index case has transmitted disease to their close contacts.