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High levels of HIV testing in men who have sex with men remain key to reducing the incidence of HIV. We aimed to assess whether the offer of a single, free HIV self-testing kit led to increased HIV diagnoses with linkage to care.SELPHI was an internet-based, open-label, randomised controlled trial that recruited participants via sexual and social networking sites. Eligibility criteria included being a man or trans woman (although trans women are reported separately); being resident in England or Wales, UK; being aged 16 years or older; having had anal intercourse with a man; not having a positive HIV diagnosis; and being willing to provide name, email address, date of birth, and consent to link to national HIV databases. Participants were randomly allocated (3:2) by computer-generated number sequence to receive a free HIV self-test kit (BT group) or to not receive this free kit (nBT group). Online surveys collected data at baseline, 2 weeks after enrolment (BT group only), 3 months after enrolment, and at the end of the study. The primary outcome was confirmed (linked to care) new HIV diagnosis within 3 months of enrolment, analysed by intention to treat. Those assessing the primary outcome were masked to allocation. This study is registered with the ISRCTN Clinical Trials Register, number ISRCTN20312003.10 111 participants (6049 in BT group and 4062 in nBT group) enrolled between Feb 16, 2017, and March 1, 2018. The median age of participants was 33 years (IQR 26-44 years); 9000 (89%) participants were White; 8118 (80%) participants were born in the UK; 81 (1%) participants were transgender men; 4706 (47%) participants were university educated; 1537 (15%) participants had never been tested for HIV; and 389 (4%) participants were taking pre-exposure prophylaxis. At enrolment, 7282 (72%) participants reported condomless anal sex with at least one male partner in the previous 3 months. In the BT group, of the 4511 participants for whom HIV testing information was available, 4263 (95%) reported having used the free HIV self-test kit within 3 months.Within 3 months of enrolment there were 19 confirmed new HIV diagnoses (0·31%) in 6049 participants in the BT group and 15 (0·37%) of 4062 in the nBT group (p=0·64).The offer of a single, free HIV self-test did not lead to increased rates of new HIV diagnoses, which could reflect decreasing HIV incidence rates in the UK. Nonetheless, the offer of a free HIV self-testing kit resulted in high HIV testing rates, indicating that self-testing is an attractive testing option for a large group of men who have sex with men.UK National Institute for Health and Care Research.

Background Incomplete antiretroviral therapy (ART) adherence has been linked to deleterious immunologic, inflammatory, and clinical consequences, even among virally suppressed ( Methods We estimated the reduction in the risk of SNAEs or death resulting from an increase in ART adherence by (1) applying existing data on the association between adherence with high residual inflammation/coagulopathy in virally suppressed PWH, and (2) using a Cox proportional hazards model derived from changes in plasma interleukin 6 (IL-6) and D-dimer from 3 randomized clinical trials. Comparatively, assuming 100% ART adherence in a PWH who achieves viral suppression, we estimated the number of persons in whom a decrease in adherence to Results Increasing ART adherence to 100% in PWH who are suppressed on ART despite imperfect adherence translated into a 6%–37% reduction in the risk of SNAEs or death. Comparatively, based on an anticipated 12% increase in IL-6, 254 and 165 PWH would need to decrease their adherence from 100% to Conclusions Modest gains in ART adherence could have clinical benefits beyond virologic suppression. Increasing ART adherence (eg, via an intervention or switch to long-acting ART) in PWH who remain virally suppressed despite incomplete adherence should be evaluated.

To estimate HIV incidence among female sex workers (FSW) in Zimbabwe: using HIV prevalence by age and number of years since started selling sex (YSSS).We pooled data from FSW aged 18-39 participating in respondent-driven sampling surveys conducted in Zimbabwe between 2011 and 2017.For each year of age, we estimated: HIV prevalence ( Pt ) and the change in HIV prevalence from the previous age ( Pt - Pt -1 ). We then estimated the rate of new HIV infections during that year of age: It = Pt - Pt -1 /(1 - Pt -1 ), and calculated HIV incidence for 18-24 and 25-39 year-olds separately as the weighted average of It . We estimated HIV incidence for FSW 1-5 years and 6-15 years since first selling sex using the same approach, and compared HIV prevalence among FSW first selling sex at their current age with the general population.Among 9906 women, 50.2% were HIV positive. Based on HIV prevalence increases by age, we estimated an HIV incidence of 6.3/100 person-years at risk (pyar) (95% confidence interval [CI] 5.3, 7.6) among 18-24 year-olds, and 3.3/100 pyar (95% CI 1.3, 4.2) among 25-39 year-olds. Based on prevalence increases by YSSS, HIV incidence was 5.3/100 pyar (95% CI 4.3, 8.5) between 1 and 5 years since first selling sex, and 2.1/100 pyar (95% CI -1.3, 7.2) between 6 and 15 years.Our analysis is consistent with very high HIV incidence among FSW in Zimbabwe, especially among those who are young and recently started selling sex. There is a critical need to engage young entrants into sex work in interventions that reduce their HIV risk.

BACKGROUND Women with HIV face challenges in engaging in HIV care post partum. We aimed to examine changes in engagement in HIV care through clinic attendance before, during, and after pregnancy, compared with matched women with HIV who had never had a recorded pregnancy. METHODS In this cohort study, we describe changes in engagement in HIV care before, during, and after pregnancy among women with HIV from the UK Collaborative HIV Cohort (CHIC) study from 25 HIV clinics in the UK with a livebirth reported to the National Surveillance of HIV in Pregnancy and Childhood between Jan 1, 2000, and Dec 31, 2017. To investigate whether changes were specific to HIV, we compared these changes to those over equivalent periods among non-pregnant women with HIV in the UK CHIC study matched for ethnicity, year of conception, age, CD4 cell count, viral suppression, and antiretroviral therapy use. Analyses were via logistic regression using generalised estimated equations with an interaction between case-control status (pregnant women vs non-pregnant women) and pregnancy or pseudo pregnancy (for non-pregnant women) stage. FINDINGS 1116 matched pairs of pregnant and non-pregnant women were included (median age 34 years [IQR 30-38], 80·1% Black African, 12·5% white). 69 330 person-months of follow-up were recorded, 25 412 in the before stage, 18 897 during, and 25 021 after pregnancy or pseudo pregnancy stages. Among pregnant women, the proportion of time engaged in care increased during pregnancy (8477 [90·5%] of 9371 person-months) and after pregnancy (10 501 [84·6%] of 12 407), compared with before pregnancy (9979 [78·5%] of 12 707). Among non-pregnant women in the control group, engagement in HIV care remained stable across the three equivalent stages (9688 [76·3%] of 12 705 person-months before pseudo pregnancy; 7463 [78·3%] of 9526 during pseudo pregnancy; and 9892 [78·4%] of 12 614 after pseudo pregnancy). The association of engagement in HIV care with pregnancy or pseudo pregnancy stage differed significantly by case-control status (pinteraction

Objectives There is increasing evidence to suggest that people living with HIV (PLWH) have significant morbidity from alcohol, recreational drug use and cigarette smoking. Our aim was to report associations of these factors with antiretroviral therapy (ART) non-adherence, viral non-suppression and subsequent viral rebound in PLWH. Methods The Antiretroviral Sexual Transmission Risk and Attitudes (ASTRA) study recruited PLWH attending eight outpatient clinics in England between February 2011 and December 2012. Data included self-reported excessive drinking (estimated consumption of > 20 units of alcohol/week), alcohol dependency (CAGE score ≥ 2 with current alcohol consumption), recreational drug use (including injection drug use in the past 3 months), and smoking status. Among participants established on ART, cross-sectional associations with ART non-adherence [missing ≥2 consecutive days of ART on ≥2 occasions in the past three months] and viral-non suppression [viral load (VL) > 50 copies/mL] were assessed using logistic regression. In participants from one centre, longitudinal associations with subsequent viral rebound (first VL > 200 copies/mL) in those on ART with VL ≤ 50 copies/mL at baseline were assessed using Cox regression during a 7-year follow-up. Results Among 3258 PLWH, 2248 (69.0%) were men who have sex with men, 373 (11.4%) were heterosexual men, and 637 (19.6%) were women. A CAGE score ≥ 2 was found in 568 (17.6%) participants, 325 (10.1%) drank > 20 units/week, 1011 (31.5%) currently smoked, 1242 (38.1%) used recreational drugs and 74 (2.3%) reported injection drug use. In each case, prevalence was much more common among men than among women. Among 2459 people on ART who started at least 6 months previously, a CAGE score ≥ 2, drinking > 20 units per week, current smoking, injection and non-injection drug use were all associated with ART non-adherence. After adjusting for demographic and socioeconomic factors, CAGE score ≥ 2 [adjusted odds ratio (aOR) = 1.52, 95% confidence interval (CI): 1.09-2.13], current smoking (aOR = 1.58, 95% CI: 1.10-2.17) and injection drug use (aOR = 2.11, 95% CI: 1.00-4.47) were associated with viral non-suppression. During follow-up of a subset of 592 people virally suppressed at recruitment, a CAGE score ≥ 2 [adjusted hazard ratio (aHR) = 1.66, 95% CI: 1.03-2.74], use of 3 or more non-injection drugs (aHR = 1.82, 95% CI: 1.12-3.57) and injection drug use (aHR = 2.73, 95% CI: 1.08-6.89) were associated with viral rebound. Conclusions Screening and treatment for alcohol, cigarette and drug use should be integrated into HIV outpatient clinics, while clinicians should be alert to the potential for poorer virological outcomes.

Background The public health impact of the coronavirus disease 2019 (COVID-19) pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. Methods Using a mathematical model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, COVID-19 disease and clinical care, we explore the public-health impact of different potential therapeutics, under a range of scenarios varying healthcare capacity, epidemic trajectories; and drug efficacy in the absence of supportive care. Results The impact of drugs like dexamethasone (delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R = 1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalization) could have much greater benefits, particularly in resource-poor settings facing large epidemics. Conclusions Advances in the treatment of COVID-19 to date have been focused on hospitalized-patients and predicated on an assumption of adequate access to supportive care. Therapeutics delivered earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.

BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection. OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone. DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978). SETTING: Multinational, multicenter trial. PARTICIPANTS: Adults hospitalized with COVID-19. INTERVENTION: Intravenous ensovibep, 600 mg, or placebo. MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90. RESULTS: An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR

BackgroundRoad traffic injuries are a significant cause of death and disability globally. However, in some countries the exact health burden caused by road traffic injuries is unknown. In Malawi, there is no central reporting mechanism for road traffic injuries and so the exact extent of the health burden caused by road traffic injuries is hard to determine. A limited number of models predict the incidence of death due to road traffic injury in Malawi. These estimates vary greatly, owing to differences in assumptions and so the health burden caused on the population by road traffic injuries remains unclear.MethodsWe use an individual based model and combine an epidemiological model of road traffic injuries with a health seeking behaviour and health system model. We provide a detailed representation of road traffic injuries in Malawi, from the onset of the injury through to the final health outcome. We also investigate the effects of an assumption made by other models, that multiple injuries do not contribute to health burden caused by road accidents.Results Our model estimates an overall average incidence of death between 23.5 to 29.8 deaths per 100,000 person years due to road traffic injuries and an average of 180,000 to 225,000 disability-adjusted life years (DALYs) per year between 2010 and 2020 in an estimated average population size of 1,364,000 over the 10-year period. Our estimated incidence of death falls within the range of other estimates currently available for Malawi, whereas our estimated number of DALYs is greater than the only other estimate available for Malawi, the GBD estimate predicting and average of 126,200 DALYs per year over the same time period. Our estimates, which account for multiple injuries, predict a 22-58% increase in overall health burden compared to the model ran as a single injury model.ConclusionsRoad traffic injuries are difficult to model with conventional modelling methods, owing to the numerous types of injuries that occur. Using an individual based model framework, we can provide a detailed representation of road traffic injuries. Our results indicate a higher health burden caused by road traffic injuries than previously estimated.

Musculoskeletal models of the lumbar spine have been developed with varying level of detail for a wide range of clinical applications. Providing consistency is ensured throughout the modelling approach, these models can be combined with other computational models and be used in predictive modelling studies to investigate bone health deterioration and the associated fracture risk. To provide precise physiological loading conditions for such predictive modelling studies, a new full-body musculoskeletal model including a detailed and consistent representation of the lower limbs and the lumbar spine was developed. The model was assessed against in-vivo measurements from the literature for a range of spine movements representative of daily living activities. Comparison between model estimations and electromyography recordings was also made for a range of lifting tasks. This new musculoskeletal model will provide a comprehensive physiological mechanical environment for future predictive finite element modelling studies on bone structural adaptation. It will be made freely available on https://simtk.org/projects/llsm/.

Objective: We investigated differences in all-cause hospitalization between key demographic groups among people with HIV in the UK in the current antiretroviral therapy (ART) era. Design/Methods: We used data from the Royal Free HIV Cohort study between 2007 and 2018. Individuals were classified into five groups: MSM, Black African men who have sex with women (MSW), MSW of other ethnicity, Black African women and women of other ethnicity. We studied hospitalizations during the first year after HIV diagnosis (Analysis-A) separately from those more than one year after diagnosis (Analysis-B). In Analysis-A, time to first hospitalization was assessed using Cox regression adjusted for age and diagnosis date. In Analysis-B, subsequent hospitalization rate was assessed using Poisson regression, accounting for repeated hospitalization within individuals, adjusted for age, calendar year, time since diagnosis. Results: The hospitalization rate was 30.7/100 person-years in the first year after diagnosis and 2.7/100 person-years subsequently; 52% and 13% hospitalizations, respectively, were AIDS-related. Compared with MSM, MSW and women were at much higher risk of hospitalization during the first year [aHR (95% confidence interval, 95% CI): 2.7 (1.7–4.3), 3.0 (2.0–4.4), 2.0 (1.3–2.9), 3.0 (2.0–4.5) for Black African MSW; other ethnicity MSW; Black African women; other ethnicity women respectively, Analysis-A] and remained at increased risk subsequently [corresponding aIRR (95% CI): 1.7 (1.2–2.4), 2.1 (1.5–2.8), 1.5 (1.1–1.9), 1.7 (1.2–2.3), Analysis-B]. Conclusion: In this setting with universal healthcare, substantial variation exists in hospitalization risk across demographic groups, both in early and subsequent periods after HIV diagnosis, highlighting the need for targeted interventions.

ObjectiveThe aim of this report is to investigate the nature of the relationship between depression and condomless sex (CLS) among gay, bisexual and other men who have sex with men (GBMSM).MethodsData are from the Antiretrovirals, Sexual Transmission Risk and Attitude (ASTRA) study of people living with HIV and attending one of eight HIV outpatient clinics in England (2011–2012) and the Attitudes to and Understanding of Risk of Acquisition of HIV (AURAH) study of HIV-negative/unknown status individuals attending one of 20 genitourinary medicine clinics in England (2013–2014). This analysis included GBMSM only. For each study, the prevalence of depressive symptoms (Patient Health Questionnaire-9 score ≥10) was presented according to three categories of sex in the past 3 months (considering anal/vaginal sex with men/women and anal sex with men in separate definitions): (1) no sex, (2) condom-protected sex only and (3) CLS. Multinomial logistic regression with ‘condom-protected sex only’ as the reference group was used to adjust for age and (for ASTRA participants) time since HIV diagnosis.ResultsThere were opposing associations of depression with recent sexual behaviour: the prevalence of depression was higher among those who reported no sex and those who reported CLS, compared with those who reported condom-protected sex only. Among the 2170 HIV-positive GBMSM in ASTRA, considering anal/vaginal sex with men/women, the prevalence of depressive symptoms was 32%, 20% and 28%, respectively, among men reporting no sex (n=783), condom-protected sex only (n=551) and CLS (n=836) (global pConclusionsDepression may be linked both to lack of sexual activity and to sexual risk taking. When investigating associations between depression and CLS, it is important to separate out individuals reporting condom-protected sex only from those reporting no sex.

To characterise health seeking behaviour (HSB) and determine its predictors amongst children in Malawi in 2016.We used the 2016 Malawi Integrated Household Survey data set. The outcome of interest was HSB, defined as seeking care at a health facility amongst people who reported one or more of a list of possible symptoms given on the questionnaire in the past two weeks. We fitted a multivariate logistic regression model of HSB using a forward step-wise selection method, with age, sex and symptoms entered as a priori variables.Of 5350 children, 1666 (32%) had symptoms in the past two weeks. Of the 1666, 1008 (61%) sought care at health facility. The children aged 5-14 years were less likely to be taken to health facilities for health care than those aged 0-4 years. Having fever vs. not having fever and having a skin problem vs. not having skin problem were associated with increased likelihood of HSB. Having a headache vs. not having a headache was associated with lower likelihood of accessing care at health facilities (AOR = 0.50, 95% CI: 0.26-0.96, P = 0.04). Children from urban areas were more likely to be taken to health facilities for health care (AOR = 1.81, 95% CI: 1.17-2.85, P = 0.008), as were children from households with a high wealth status (AOR = 1.86, 95% CI: 1.25-2.78, P = 0.02).There is a need to understand and address individual, socio-economic and geographical barriers to health seeking to increase access and use of health care and fast-track progress towards Universal Health Coverage.Caractériser le comportement de recherche de santé (CRS) et déterminer ses prédicteurs chez les enfants du Malawi en 2016. MÉTHODES: Nous avons utilisé l'ensemble de données de l'Enquête intégrée de 2016 auprès des ménages du Malawi. Le résultat d'intérêt était le CRS, défini comme la recherche de soins dans un établissement de santé chez les personnes qui ont déclaré une ou plusieurs symptômes d'une liste de possibilités figurant sur le questionnaire, dans les deux dernières semaines. Nous avons appliqué un modèle de régression logistique multivariée du CRS en utilisant une méthode de sélection par étape, avec l'âge, le sexe et les symptômes entrés comme variables a priori. RÉSULTATS: Sur 5.350 enfants, 1.666 (32%) ont présenté des symptômes au cours des deux dernières semaines. Sur les 1.666, des soins ont été cherché pour 1.008 (61%) dans un établissement de santé. Les enfants âgés de 5 à 14 ans étaient moins susceptibles d'être emmenés dans des établissements de santé pour des soins de santé que ceux âgés de 0 à 4 ans. Avoir de la fièvre par rapport à ne pas en avoir et avoir un problème de peau par rapport à ne pas en avoir étaient associés à une probabilité accrue de CRS. Avoir un mal de tête par rapport à ne pas en avoir était associé à une probabilité plus faible d'accéder aux soins dans les établissements de santé (AOR = 0,50 ; IC95%: 0,26-0,96 ; P= 0,04). Les enfants des zones urbaines étaient plus susceptibles d'être emmenés dans des établissements de santé pour des soins de santé (AOR = 1,81 ; IC95%: 1,17-2,85 ; P= 0,008), tout comme les enfants de ménages ayant une position socioéconomique plus élevée (AOR = 1,96 ; IC95%: 1,13-3,40 ; P= 0,02).Il est nécessaire de comprendre et de surmonter les obstacles individuels, socioéconomiques et géographiques à la recherche de la santé pour accroître l'accès et l'utilisation des soins de santé et accélérer les progrès vers la couverture sanitaire universelle.

To investigate the impact of serum albumin (at diagnosis and pre-operatively) on survival in patients undergoing cytoreductive surgery for advanced ovarian cancer(AOC) and whether improvement in albumin achieved following neoadjuvant chemotherapy (NACT) affects overall survival (OS).Outcomes of 441 patients who underwent cytoreduction for AOC were reviewed. Albumin was recorded at diagnosis and pre-operatively. Further analysis was performed if patients were hypoalbuminaemic at diagnosis.Analysis was stratified according to whether the patientreceived primary debulking surgery (PDS) or interval debulking surgery (IDS) and if their albumin was corrected.308 patients had a serum albumin level at diagnosis and 400 patients had a pre-operative albumin available for analysis. For patients with an albumin at diagnosis ≤ 35g/L and ≥36 g/L, median OS was 31.5 (95% CI 23.5-39.5) and 50.4 (95% CI 38.9-61.9) months respectively (P = 0.003). Followingmultivariate analysis (MVA), albumin at diagnosis remained statistically significant as an independent marker for survival, even after adjusting for cytoreductive outcome, stage and grade(p = 0.04, Hazard ratio 1.38, 95% CI 1.01-1.89).Hypoalbuminaemic patients at diagnosis achieved complete cytoreduction in 53% of cases.For PDS patients, median OS was 19.7 months (95% CI 11.5-27.9). For IDS patients, median OS was 27.9 months (n = 1).IDS patients with a corrected albumin had a median OS of 42.9 months (95% CI 31.5-54.3) (p 0.05).Hypoalbuminaemia at diagnosis is a poor prognostic factor in AOC. Normalization of serum albumin after NACT is a potential predictor of survival.

Background To reduce transmission of SARS-CoV-2, it is important to identify those who are infectious. However, little is known about what proportion of infectious people are asymptomatic and potential "silent" transmitters. We evaluated the value of COVID-19 symptoms as a marker for SARS-CoV-2 infection from a representative English survey. Methods We used data from the Office for National Statistics Coronavirus (COVID-19) Infection Survey pilot study. We estimated sensitivity, specificity, the proportion of asymptomatic cases (1 - sensitivity), positive predictive value (PPV) and negative predictive value (NPV) of COVID-19 symptoms as a marker of infection using results of the SARS-CoV-2 test as the "gold standard". Results In total, there were 36,061 individuals with a SARS-CoV-2 test between 26 April and 27 June 2020. Of these, 625 (1.7%) reported symptoms on the day of the test. There were 115 (0.32%) with a positive SARS-CoV-2 test result. Of the 115, there were 27 (23.5%) who were symptomatic and 88 (76.5%) who were asymptomatic on the day of the test. Focusing on those with specific symptoms (cough, and/or fever, and/or loss of taste/smell), there were 158 (0.43%) with such symptoms on the day of the test. Of the 115 with a positive SARS-CoV-2, there were 16 (13.9%) reporting symptoms. In contrast, 99 (86.1%) did not report specific symptoms on the day of the test. The PPV for all symptoms was 4.3% and for the specific symptoms 10.1%. The specificity and NPV of symptoms were above 98%. Conclusion COVID-19 symptoms are poor markers of SARS-CoV-2. Thus, 76.5% of this random sample who tested positive reported no symptoms, and 86.1% reported none of those specific to COVID-19. A more widespread testing programme is necessary to capture "silent" transmission and potentially prevent and reduce future outbreaks.

Summary Background Since October, 2017 (and until October, 2020), pre-exposure prophylaxis (PrEP) has only been available in England, UK, through the PrEP Impact Trial, by purchasing it from some genitourinary medicine clinics, or via online sources. Here we report changes from 2013 to 2018 in PrEP and postexposure prophylaxis (PEP) awareness and use among HIV-negative gay, bisexual, and other men who have sex with men (MSM) and assess predictors of PrEP initiation. Methods In the prospective cohort study Attitudes to, and Understanding of Risk of Acquisition of HIV 2 (AURAH2), MSM were recruited from three sexual health clinics in England: two in London and one in Brighton, UK. Men were eligible if they were aged 18 years or older and HIV-negative or of unknown HIV status. Participants self-completed a baseline paper questionnaire at one of the three clinics between July 30, 2013, and April 30, 2016, and were subsequently able to complete 4-monthly and annual online questionnaires, which were available between March 1, 2015, and March 31, 2018, and collected information on sociodemographics, health and wellbeing, HIV status, and sexual behaviours. PrEP and PEP use in the previous 12 months was obtained at baseline and in annual questionnaires. We assessed trends over calendar time in 3-month periods from first enrolment to the end of the study period (July–December, 2013, was counted as one period) in use of PrEP and PEP using generalised estimating equation logistic models. We used age-adjusted Poisson models to assess factors associated with PrEP initiation among participants who reported never having used PrEP at baseline. Findings 1162 men completed a baseline questionnaire, among whom the mean age was 34 years (SD 10·4), and of those with available data, 942 (82%) of 1150 were white, 1076 (94%) of 1150 were gay, and 857 (74%) of 1159 were university educated. 622 (54%) of 1162 men completed at least one follow-up online questionnaire, of whom 483 (78%) completed at least one annual questionnaire. Overall, PrEP use in the past year increased from 0% (none of 28 respondents) in July to December, 2013, to 43% (23 of 53) in January to March, 2018. The corresponding increase in PrEP use among men who reported condomless sex with two or more partners was from 0% (none of 13 respondents) to 78% (21 of 27). PEP use peaked in April to June, 2016, at 28% (41 of 147 respondents), but decreased thereafter to 8% (four of 53) in January to March, 2018. Among 460 men who had never used PrEP at baseline, predictors of initiating PrEP included age 40–44 years (incidence rate ratio [IRR] 4·25, 95% CI 1·14–15·79) and 45 years and older (3·59, 1·08–11·97) versus younger than 25 years; and after adjustment for age, recent HIV test (5·17, 1·89–14·08), condomless sex (5·01, 2·16–11·63), condomless sex with two or more partners (5·43, 2·99–9·86), group sex (1·69, 1·01–2·84), and non-injection chemsex-related drugs use (2·86, 1·67–4·91) in the past 3 months, PEP use (4·69, 2·83–7·79) in the past 12 months, and calendar year (Jan 1, 2017, to March 31, 2018 vs July 30, 2013, to Dec 31, 2015: 21·19, 9·48–47·35). Non-employment (0·35, 0·14–0·91) and unstable or no housing (vs homeowner 0·13, 0·02–0·95) were associated with reduced rates of PrEP initiation after adjustment for age. About half of PrEP was obtained via the internet, even after the PrEP Impact trial had started (11 [48%] of 23 respondents in January to March, 2018). Interpretation PrEP awareness and use increased substantially from 2013 to 2018 among a cohort of MSM in England. Improving access to PrEP by routine commissioning by National Health Service England could increase PrEP use among all eligible MSM, but should include public health strategies to target socioeconomic and demographic disparities in knowledge and use of PrEP. Funding National Institute for Health Research.

Summary Background The COVID-19 pandemic could lead to disruptions to provision of HIV services for people living with HIV and those at risk of acquiring HIV in sub-Saharan Africa, where UNAIDS estimated that more than two-thirds of the approximately 38 million people living with HIV resided in 2018. We aimed to predict the potential effects of such disruptions on HIV-related deaths and new infections in sub-Saharan Africa. Methods In this modelling study, we used five well described models of HIV epidemics (Goals, Optima HIV, HIV Synthesis, an Imperial College London model, and Epidemiological MODeling software [EMOD]) to estimate the effect of various potential disruptions to HIV prevention, testing, and treatment services on HIV-related deaths and new infections in sub-Saharan Africa lasting 6 months over 1 year from April 1, 2020. We considered scenarios in which disruptions affected 20%, 50%, and 100% of the population. Findings A 6-month interruption of supply of antiretroviral therapy (ART) drugs across 50% of the population of people living with HIV who are on treatment would be expected to lead to a 1·63 times (median across models; range 1·39–1·87) increase in HIV-related deaths over a 1-year period compared with no disruption. In sub-Saharan Africa, this increase amounts to a median excess of HIV deaths, across all model estimates, of 296 000 (range 229 023–420 000) if such a high level of disruption occurred. Interruption of ART would increase mother-to-child transmission of HIV by approximately 1·6 times. Although an interruption in the supply of ART drugs would have the largest impact of any potential disruptions, effects of poorer clinical care due to overstretched health facilities, interruptions of supply of other drugs such as co-trimoxazole, and suspension of HIV testing would all have a substantial effect on population-level mortality (up to a 1·06 times increase in HIV-related deaths over a 1-year period due to disruptions affecting 50% of the population compared with no disruption). Interruption to condom supplies and peer education would make populations more susceptible to increases in HIV incidence, although physical distancing measures could lead to reductions in risky sexual behaviour (up to 1·19 times increase in new HIV infections over a 1-year period if 50% of people are affected). Interpretation During the COVID-19 pandemic, the primary priority for governments, donors, suppliers, and communities should focus on maintaining uninterrupted supply of ART drugs for people with HIV to avoid additional HIV-related deaths. The provision of other HIV prevention measures is also important to prevent any increase in HIV incidence. Funding Bill & Melinda Gates Foundation.

We investigate the nature and significance of the vital but neglected “company-states” in helping to facilitate the move from contained regional international systems to the first genuinely global international system. Historically, actors like the Dutch and English East India Companies were crucial in spearheading the first wave of European expansion in Asia, Africa, and the Americas. Conceptually, company-states broaden our understanding of international actors. At a time when intra-European politics favored gradual institutional convergence on the sovereign state, the demands of extra-European expansion meanwhile gave rise to diverse competing institutions. Company-states succeeded in an era of weak sovereign states because of their relative efficiency in managing the transaction costs and principal-agent challenges of intercontinental trade and rule. Conversely, company-states later declined as they succumbed to the effects of sharpening worldwide geopolitical competition, and were displaced by increasingly powerful new European empire-building projects. This argument advances earlier work on the creation of the international system by eschewing Eurocentrism and state-centrism, and foregrounding diversity and hybridization.

Objective To investigate the characteristics and outcomes of people who initiated different antiretroviral therapy (ART) regimens during the era of integrase strand transfer inhibitors (INSTIs). Design UK-based observational cohort study. Methods UK Collaborative HIV Cohort study participants were included if they had started ART between 1 January 2012 and 30 June 2017. Virological failure was defined as the first of two consecutive plasma HIV RNA more than 50 copies/ml, at least 6 months after starting ART. Follow-up was censored at ART discontinuation, class switch or death. The risk of virological failure among those on INSTI, protease inhibitor or nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens was compared using Kaplan-Meier and Cox regression methods. Results Of 12 585 participants, 45.6% started a NNRTI, 29.0% a protease inhibitor and 25.4% an INSTI regimen. Over a median follow-up of 20.3 months (interquartile range 7.9-38.9), 7.5% of participants experienced virological failure. Compared with those starting an NNRTI regimen, people receiving INSTIs or protease inhibitors were more likely to experience virological failure: INSTI group adjusted hazard ratio 1.52, 95% confidence interval 1.19-1.95, P = 0.0009; protease inhibitor group adjusted hazard ratio 2.70, 95% confidence interval 2.27-3.21, P less than 0.0001, likelihood ratio test P less than 0.0001. Conclusion First-line INSTI regimens were associated with a lower risk of virological failure than protease inhibitor regimens but both groups were more likely to experience virological failure than those initiating treatment with a NNRTI. There is likely to be residual channelling bias resulting from selected use of INSTIs and protease inhibitors in specific clinical contexts, including in those with a perceived risk of poor adherence.

Summary Chronic and emerging infectious diseases and antimicrobial resistance remain a substantial global health threat. Microbiota are increasingly recognised to play an important role in health. Infections also have a profound effect beyond health, especially on global and local economies. To maximise health improvements, the field of infectious disease epidemiology needs to derive learning from ecology and traditional epidemiology. New methodologies and tools are transforming understanding of these systems, from a better understanding of socioeconomic, environmental, and cultural drivers of infection, to improved methods to detect microorganisms, describe the immunome, and understand the role of human microbiota. However, exploiting the potential of novel methods to improve global health remains elusive. We argue that to exploit these advances a shift is required in the teaching of infectious disease epidemiology to ensure that students are well versed in a breadth of disciplines, while maintaining core epidemiological skills. We discuss the following key points using a series of teaching vignettes: (1) integrated training in classic and novel techniques is needed to develop future scientists and professionals who can work from the micro (interactions between pathogens, their cohabiting microbiota, and the host at a molecular and cellular level), with the meso (the affected communities), and to the macro (wider contextual drivers of disease); (2) teach students to use a team-science multidisciplinary approach to effectively integrate biological, clinical, epidemiological, and social tools into public health; and (3) develop the intellectual skills to critically engage with emerging technologies and resolve evolving ethical dilemmas. Finally, students should appreciate that the voices of communities affected by infection need to be kept at the heart of their work.

Background Road traffic injuries are a significant cause of death and disability globally. However, in some countries the exact health burden caused by road traffic injuries is unknown. In Malawi, there is no central reporting mechanism for road traffic injuries and so the exact extent of the health burden caused by road traffic injuries is hard to determine. A limited number of models predict the incidence of mortality due to road traffic injury in Malawi. These estimates vary greatly, owing to differences in assumptions, and so the health burden caused on the population by road traffic injuries remains unclear. Methods We use an individual-based model and combine an epidemiological model of road traffic injuries with a health seeking behaviour and health system model. We provide a detailed representation of road traffic injuries in Malawi, from the onset of the injury through to the final health outcome. We also investigate the effects of an assumption made by other models that multiple injuries do not contribute to health burden caused by road accidents. Results Our model estimates an overall average incidence of mortality between 23.5 and 29.8 per 100,000 person years due to road traffic injuries and an average of 180,000 to 225,000 disability-adjusted life years (DALYs) per year between 2010 and 2020 in an estimated average population size of 1,364,000 over the 10-year period. Our estimated incidence of mortality falls within the range of other estimates currently available for Malawi, whereas our estimated number of DALYs is greater than the only other estimate available for Malawi, the GBD estimate predicting and average of 126,200 DALYs per year over the same time period. Our estimates, which account for multiple injuries, predict a 22–58% increase in overall health burden compared to the model ran as a single injury model. Conclusions Road traffic injuries are difficult to model with conventional modelling methods, owing to the numerous types of injuries that occur. Using an individual-based model framework, we can provide a detailed representation of road traffic injuries. Our results indicate a higher health burden caused by road traffic injuries than previously estimated.

BACKGROUND: Tixagevimab-cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab-cilgavimab versus placebo, in patients receiving remdesivir and other standard care.METHODS: In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg-cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Efficacy and safety analyses were done in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab-cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978 and the participant follow-up is ongoing.FINDINGS: From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab-cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab-cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio [RRR] 1·08 [95% CI 0·97-1·20]; p=0·21). Results were similar in the seronegative subgroup (RRR 1·14 [0·97-1·34]; p=0·13). Mortality was lower in the tixagevimab-cilgavimab group (61 [9%]) versus placebo group (86 [12%]; hazard ratio [HR] 0·70 [95% CI 0·50-0·97]; p=0·032). The composite safety outcome occurred in 178 (25%) tixagevimab-cilgavimab and 212 (30%) placebo group participants (HR 0·83 [0·68-1·01]; p=0·059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab-cilgavimab group and 38 (5%) in the placebo group.INTERPRETATION: Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab-cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower.FUNDING: US National Institutes of Health (NIH) and Operation Warp Speed.

HIV modelling and economic analyses have had a prominent role in guiding programmatic responses to HIV in sub-Saharan Africa. We reflect critically how the HIV modelling field might develop in future. We argue for HIV modelling to be more routinely aligned with national government and ministry of health priorities, recognizing their legitimate mandates and stewardship responsibilities, for HIV and other wider health programmes. We also place importance on an environment existing in which collaboration between modellers, and joint approaches to addressing modelling questions, becomes the norm rather than exception. Such an environment can accelerate translation of modelling analyses into policy formulation because areas where models agree can be prioritized for action, whereas areas over which uncertainty prevails can be slated for additional study, data collection and analysis. We also argue the need for HIV modelling to increasingly be integrated with the modelling of health needs beyond HIV, particularly in allocative efficiency analyses, where focusing on one disease over another may lead to worse health overall. Such integration may also enhance partnership with national governments whose mandates extend beyond HIV and to all of health care. Finally, we see a need for there to be substantial and equitable investment in capacity strengthening within African countries, so that African researchers will increasingly be leading modelling exercises. Building a critical mass of expertise, strengthened through external collaboration and knowledge exchange, should be the ultimate goal.

In this so-called treat-all era, antiretroviral therapy (ART) interruptions contribute to an increasing proportion of HIV infections and deaths. Many strategies to improve retention on ART cost more than standard of care. In this study, we aimed to estimate the upper-bound costs at which such interventions should be adopted.In this combined analysis, we compared the infections averted, disability-adjusted life-years (DALYs) averted, and upper-bound costs of interventions that improve ART retention in three HIV models with diverse structures, assumptions, and baseline settings: EMOD in South Africa, Optima in Malawi, and Synthesis in sub-Saharan African low-income and middle-income countries (LMICs). We modelled estimates over a 40-year time horizon, from a baseline of Jan 1, 2022, when interventions would be implemented, to Jan 1, 2062. We varied increment of ART retention (25%, 50%, 75%, and 100% retention), the extent to which interventions could be targeted towards individuals at risk of interrupting ART, and cost-effectiveness thresholds in each setting.Despite simulating different settings and epidemic trends, all three models produced consistent estimates of health benefit (ie, DALYs averted) and transmission reduction per increment in retention. The range of estimates was 1·35-3·55 DALYs and 0·12-0·20 infections averted over the 40-year time horizon per additional person-year retained on ART. Upper-bound costs varied by setting and intervention effectiveness. Improving retention by 25% among all people receiving ART, regardless of risk of ART interruption, gave an upper-bound cost per person-year of US$2-6 in Optima (Malawi), $43-68 in Synthesis (LMICs in sub-Saharan Africa), and $28-180 in EMOD (South Africa). A maximally targeted and effective retention intervention had an upper-bound cost per person-year of US$93-223 in Optima (Malawi), $871-1389 in Synthesis (LMICs in sub-Saharan Africa), and $1013-6518 in EMOD (South Africa).Upper-bound costs that could improve ART retention vary across sub-Saharan African settings and are likely to be similar to or higher than was estimated before the start of the treat-all era. Upper-bound costs could be increased by targeting interventions to those most at risk of interrupting ART.BillMelinda Gates Foundation.

Background Female sex workers (FSW) in sub-Saharan Africa are disproportionately affected by HIV and are critical to engage in HIV prevention, testing and care services. We describe the design of our evaluation of the ‘AMETHIST’ intervention, nested within a nationally-scaled programme for FSW in Zimbabwe. We hypothesise that the implementation of this intervention will result in a reduction in the risk of HIV transmission within sex work. Methods The AMETHIST intervention (Adapted Microplanning to Eliminate Transmission of HIV in Sex Transactions) is a risk-differentiated intervention for FSW, centred around the implementation of microplanning and self-help groups. It is designed to support uptake of, and adherence to, HIV prevention, testing and treatment behaviours among FSW. Twenty-two towns in Zimbabwe were randomised to receive either the Sisters programme (usual care) or the Sisters programme plus AMETHIST. The composite primary outcome is defined as the proportion of all FSW who are at risk of either HIV acquisition (HIV-negative and not fully protected by prevention interventions) or of HIV transmission (HIV-positive, not virally suppressed and not practicing consistent condom use). The outcome will be assessed after 2 years of intervention delivery in a respondent-driven sampling survey (total n = 4400; n = 200 FSW recruited at each site). Primary analysis will use the ‘RDS-II’ method to estimate cluster summaries and will adapt Hayes and Moulton’s ‘2-step’ method produce adjusted effect estimates. An in-depth process evaluation guided by our project trajectory will be undertaken. Discussion Innovative pragmatic trials are needed to generate evidence on effectiveness of combination interventions in HIV prevention and treatment in different contexts. We describe the design and analysis of such a study. Trial registration Pan African Clinical Trials Registry PACTR202007818077777. Registered on 2 July 2020.

Introduction In 2016, the WHO published recommendations increasing the number of recommended antenatal care (ANC) visits per pregnancy from four to eight. Prior to the implementation of this policy, coverage of four ANC visits has been suboptimal in many low-income settings. In this study we explore socio-demographic factors associated with early initiation of first ANC contact and attending at least four ANC visits (“ANC4+”) in Malawi using the Malawi Demographic and Health Survey (MDHS) data collected between 2004 and 2016, prior to the implementation of new recommendations. Methods We combined data from the 2004–5, 2010 and 2015–16 MDHS using Stata version 16. Participants included all women surveyed between the ages of 15–49 who had given birth in the five years preceding the survey. We conducted weighted univariate, bivariate and multivariable logistic regression analysis of the effects of each of the predictor variables on the binary endpoint of the woman attending at least four ANC visits and having the first ANC attendance within or before the four months of pregnancy (ANC4+). To determine whether a factor was included in the model, the likelihood ratio test was used with a statistical significance of P< 0.05 as the threshold. Results We evaluated data collected in surveys in 2004/5, 2010 and 2015/6 from 26386 women who had given birth in the five years before being surveyed. The median gestational age, in months, at the time of presenting for the first ANC visit was 5 (inter quartile range: 4–6). The proportion of women initiating ANC4+ increased from 21.3% in 2004–5 to 38.8% in 2015–16. From multivariate analysis, there was increasing trend in ANC4+ from women aged 20–24 years (adjusted odds ratio (aOR) = 1.27, 95%CI:1.05–1.53, P = 0.01) to women aged 45–49 years (aOR = 1.91, 95%CI:1.18–3.09, P = 0.008) compared to those aged 15–19 years. Women from richest socio-economic position ((aOR = 1.32, 95%CI:1.12–1.58, P Conclusion The proportion of women reporting ANC4+ and of key ANC interventions in Malawi have increased significantly since 2004. However, we found that most women did not access the recommended number of ANC visits in Malawi, prior to the 2016 WHO policy change which may mean that women are less likely to undertake the 2016 WHO recommendation of 8 contacts per pregnancy. Additionally, our results highlighted significant variation in coverage according to key socio-demographic variables which should be considered when devising national strategies to ensure that all women access the appropriate frequency of ANC visits during their pregnancy.

BACKGROUND: In a randomized, placebo-controlled, clinical trial, bamlanivimab, a SARS-CoV-2-neutralizing monoclonal antibody, given in combination with remdesivir, did not improve outcomes among hospitalized patients with COVID-19 based on an early futility assessment.OBJECTIVE: To evaluate the a priori hypothesis that bamlanivimab has greater benefit in patients without detectable levels of endogenous neutralizing antibody (nAb) at study entry than in those with antibodies, especially if viral levels are high.DESIGN: Randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04501978).SETTING: Multicenter trial.PATIENTS: Hospitalized patients with COVID-19 without end-organ failure.INTERVENTION: Bamlanivimab (7000 mg) or placebo.MEASUREMENTS: Antibody, antigen, and viral RNA levels were centrally measured on stored specimens collected at baseline. Patients were followed for 90 days for sustained recovery (defined as discharge to home and remaining home for 14 consecutive days) and a composite safety outcome (death, serious adverse events, organ failure, or serious infections).RESULTS: Among 314 participants (163 receiving bamlanivimab and 151 placebo), the median time to sustained recovery was 19 days and did not differ between the bamlanivimab and placebo groups (subhazard ratio [sHR], 0.99 [95% CI, 0.79 to 1.22]; sHR > 1 favors bamlanivimab). At entry, 50% evidenced production of anti-spike nAbs; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1000 ng/L. Among those without and with nAbs at study entry, the sHRs were 1.24 (CI, 0.90 to 1.70) and 0.74 (CI, 0.54 to 1.00), respectively (nominal P for interaction = 0.018). The sHR (bamlanivimab vs. placebo) was also more than 1 for those with plasma antigen or nasal viral RNA levels above median level at entry and was greatest for those without antibodies and with elevated levels of antigen (sHR, 1.48 [CI, 0.99 to 2.23]) or viral RNA (sHR, 1.89 [CI, 1.23 to 2.91]). Hazard ratios for the composite safety outcome (LIMITATION: Subgroup analysis of a trial prematurely stopped because of futility; small sample size; multiple subgroups analyzed.CONCLUSION: Efficacy and safety of bamlanivimab may differ depending on whether an endogenous nAb response has been mounted. The limited sample size of the study does not allow firm conclusions based on these findings, and further independent trials are required that assess other types of passive immune therapies in the same patient setting.PRIMARY FUNDING SOURCE: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

Background/aims Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines public–private partnership initiated the Therapeutics for Inpatients with COVID-19. Therapeutics for Inpatients with COVID-19 is a multi-arm, multi-stage platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate antiviral therapeutic agents for adults hospitalized with COVID-19. Five agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed. Methods Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. Therapeutics for Inpatients with COVID-19 utilizes a multi-arm, multi-stage design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo, the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and Data and Safety Monitoring Board schedule was developed for the study of potential therapeutic agents with limited in-human data in hospitalized patients with COVID-19. Results As of 8 August 2021, five agents have entered the Therapeutics for Inpatients with COVID-19 master protocol and a total of 1909 participants have been randomized to one of these agents or matching placebo. There were a number of challenges faced by the study team that needed to be overcome in order to successfully implement Therapeutics for Inpatients with COVID-19 across a global network of sites. These included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff and obtaining regulatory approvals across a global network of sites. Conclusion Through a robust multi-network partnership, the Therapeutics for Inpatients with COVID-19 protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required to achieve the full potential of this approach in dealing with a global outbreak.

PTU-25 Table 1 2018 2019 2020 Total FBI Referral 10 20 31 Total DFBI 2 (20%) 4 (20%) 17 (55%) Number of patients 2 2 9 Objects Batteries Toothbrush, coins Bra wire, batteries, pen, glasses, paperclip, screws, toothbrush, blades Discussion2020 demonstrated a marked increase in OGD for FBI, of which 55% were DFBI compared with 20% in preceding years. All patients were ≤40 years of age. Commonest objects were long e.g. pens or high risk e.g. batteries/razors. However, a wider variety of objects were swallowed during the pandemic.Our outcomes reflect those in published data1, with most procedures successful when objects were known to be in the stomach.DFBI is often spontaneous and stress related, rather than a suicide attempt, on a background of complex personality disorder. It is thought DFBI gives a psychological ‘gain’ in forcing care, with multiple healthcare contacts resulting from the act2.Care plans are common in other forms of DSH but lacking in DFBI. These may benefit repeat attenders, ensuring endoscopy only performed when strictly necessary and minimising the psychological gain from the act.Mental health issues have increased during the pandemic, this has impacted on already stretched endoscopy services with increase in DFBI, possibly due to decreased access to psychiatric services. This act is resource intensive and difficult to manage, a care plan should be considered after admission with DFBI.4. Birk M et al. Removal of foreign bodies in the upper gastrointestinal tract in adults: ESGE Clinical Guideline. Endoscopy. 2016:48;1-81. Poynter B et al. Hard to Swallow: A systematic review of deliberate foreign body ingestion. Gen Hosp Psych. 2011:33(5);518-524Palese C, Al-kawas F. Repeat intentional foreign body ingestion: the importance of a multidisciplinary approach. Gast & Hep. 2012: 8(7);485-489

Background UNAIDS has established new program targets for 2025 to achieve the goal of eliminating AIDS as a public health threat by 2030. This study reports on efforts to use mathematical models to estimate the impact of achieving those targets. Methods and findings We simulated the impact of achieving the targets at country level using the Goals model, a mathematical simulation model of HIV epidemic dynamics that includes the impact of prevention and treatment interventions. For 77 high-burden countries, we fit the model to surveillance and survey data for 1970 to 2020 and then projected the impact of achieving the targets for the period 2019 to 2030. Results from these 77 countries were extrapolated to produce estimates for 96 others. Goals model results were checked by comparing against projections done with the Optima HIV model and the AIDS Epidemic Model (AEM) for selected countries. We included estimates of the impact of societal enablers (access to justice and law reform, stigma and discrimination elimination, and gender equality) and the impact of Coronavirus Disease 2019 (COVID-19). Results show that achieving the 2025 targets would reduce new annual infections by 83% (71% to 86% across regions) and AIDS-related deaths by 78% (67% to 81% across regions) by 2025 compared to 2010. Lack of progress on societal enablers could endanger these achievements and result in as many as 2.6 million (44%) cumulative additional new HIV infections and 440,000 (54%) more AIDS-related deaths between 2020 and 2030 compared to full achievement of all targets. COVID-19–related disruptions could increase new HIV infections and AIDS-related deaths by 10% in the next 2 years, but targets could still be achieved by 2025. Study limitations include the reliance on self-reports for most data on behaviors, the use of intervention effect sizes from published studies that may overstate intervention impacts outside of controlled study settings, and the use of proxy countries to estimate the impact in countries with fewer than 4,000 annual HIV infections. Conclusions The new targets for 2025 build on the progress made since 2010 and represent ambitious short-term goals. Achieving these targets would bring us close to the goals of reducing new HIV infections and AIDS-related deaths by 90% between 2010 and 2030. By 2025, global new infections and AIDS deaths would drop to 4.4 and 3.9 per 100,000 population, and the number of people living with HIV (PLHIV) would be declining. There would be 32 million people on treatment, and they would need continuing support for their lifetime. Incidence for the total global population would be below 0.15% everywhere. The number of PLHIV would start declining by 2023., John Stover and co-workers assess the potential health impacts of UNAIDS’ HIV/AIDS targets., Author summary Why was this study done? The previous UNAIDS strategic plan expired in 2020, creating a need for a new plan to guide efforts for the next 5 years. Modeling contributed to the development of the new plan by assessing the epidemiological impact of proposed intervention coverage targets and estimating the financial resources needed to achieve them. What did the researchers do and find? We applied mathematical simulation models to 77 high HIV burden countries to examine the effects of the proposed intervention coverage targets on trends in new HIV infections and AIDS-related deaths. The results were extended to a total of 173 countries to provide a comprehensive global analysis. Results show that achieving the 2025 targets would reduce new annual infections by 83% (71% to 86% across regions) and AIDS-related deaths by 78% (67% to 81% across regions) by 2025 compared to 2010. Progress on societal enablers (access to justice, prevention of stigma and discrimination, and prevention of gender-based violence [GBV]) is essential to achieve these targets. Coronavirus Disease 2019 (COVID-19)–related disruptions could increase new HIV infections and AIDS-related deaths in the short term, but targets could still be achieved by 2025. What do these findings mean? Although global efforts have failed to achieve the ambitious 2020 targets, it is still possible to achieve the 2030 goal of eliminating AIDS as a public health threat. Many of the 2025 intervention coverage targets have already been achieved in some settings. Additional effort is required to accelerate progress in all countries and in all populations.

Introduction\ud Sisters with a Voice (Sisters), a programme providing community-led differentiated HIV prevention and treatment services, including condoms, HIV testing, pre-exposure prophylaxis (PrEP) and antiretroviral therapy linkage for sex workers, reached over 26,000 female sex workers (FSW) across Zimbabwe in 2020. Zimbabwe's initial Covid “lockdown” in March 2020 and associated movement restrictions interrupted clinical service provision for 6 weeks, particularly in mobile clinics, triggering the adaptation of services for the Covid-19 context and a scale up of differentiated service delivery (DSD) models. PrEP service delivery decentralized with shifts from clinical settings towards community/home-based, peer-led PrEP services to expand and maintain access. We hypothesize that peer-led community-based provision of PrEP services influenced both demand and supply-side determinants of PrEP uptake. We observed the effect of these adaptations on PrEP uptake among FSW accessing services in Sisters in 2020.\ud \ud Methods\ud New FSW PrEP initiations throughout 2020 were tracked by analysing routine Sisters programme data and comparing it with national PrEP initiation data for 2020. We mapped PrEP uptake among all negative FSW attending services in Sisters alongside Covid-19 adaptations and shifts in the operating environment throughout 2020: prior to lockdown (January–March 2020), during severe restrictions (April–June 2020), subsequent easing (July–September 2020) and during drug stockouts that followed (October–December 2020).\ud \ud Results and discussion\ud PrEP uptake in 2020 occurred at rates

BackgroundThe unprecedented public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear.Methods and FindingsWe develop a mathematical model of SARS-CoV-2 transmission, COVID-19 disease and clinical care to explore the potential public-health impact of a range of different potential therapeutics, under a range of different scenarios varying: i) healthcare capacity, ii) epidemic trajectories; and iii) drug efficacy in the absence of supportive care. In each case, the outcome of interest was the number of COVID-19 deaths averted in scenarios with the therapeutic compared to scenarios without. We find the impact of drugs like dexamethasone (which are delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalisation) could have much greater benefits, particularly in resource-poor settings facing large epidemics.ConclusionsThere is a global asymmetry in who is likely to benefit from advances in the treatment of COVID-19 to date, which have been focussed on hospitalised-patients and predicated on an assumption of adequate access to supportive care. Therapeutics that can feasibly be delivered to those earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.

Background In the 1980s debate intensified over whether there was a protective effect of high-density lipoprotein cholesterol (HDL-C) or an adverse effect of triglycerides on coronary heart disease (CHD) risk. In a 1991 paper reprinted in the IJE we suggested that the high degree of correlation between the two, together with plausible levels of measurement error, made it unlikely that conventional epidemiological approaches could contribute to causal understanding. The consensus that HDL-C was protective, popularly reified in the notion of ‘good cholesterol’, strengthened over subsequent years. Reviewing the biostatistical and epidemiological literature from before and after 1991 we suggest that within the observational epidemiology pantheon only Mendelian randomization studies—that began to appear at the same time as the initial negative randomized controlled trials—made a meaningful contribution. It is sobering to realize that many issues that appear suitable targets for epidemiological investigation are simply refractory to conventional approaches. The discipline should surely revisit this and other high-profile cases of consequential epidemiological failure—such as that with respect to vitamin E supplementation and CHD risk—rather than pass them over in silence.

Outcomes of secondary cytoreduction surgery (SCS) were evaluated for morbidity, progression free survival (PFS) and overall survival (OS) and factors influencing results were explored. Retrospective analysis of all cases of SCS for epithelial ovarian cancer (EOC) was performed from October 2010 to December 2017. 62 patients were prospectively identified as candidates for SCS and 57 underwent SCS. 20(35%) patients required bowel resection/s, 24(42%) had nodal resections and 11(19%) had extensive upper abdominal surgery. 51(89%) achieved complete cytoreduction. After a median follow-up of 30 months (range 9-95 months), median PFS was 32 months (CI 17-76 months) and median OS has not reached. Seventeen patients have died and 32 have progressed. Three patients had Clavien-Dindo grade-3 and two had grade-4 morbidity. Patients who had multi-site recurrence had shorter median PFS (

Background: Antiretroviral treatment (ART) reduces HIV infectiousness but the effect of early ART on sexual behaviour is unclear. Methods: We assessed, within the START randomized trial that enrolled HIV-positive adults with CD4+ cell count greater than 500 cells/μl, the effect of early (immediate) versus deferred ART on: condomless sex with HIV-serodifferent partners (CLS-D); all condomless sex (CLS); HIV transmission-risk sex (CLS-D-HIV risk, defined as CLS-D and: not on ART or started ART

The internal architecture of the femur and its fracture behaviour vary greatly between subjects. Femoral architecture and subsequent fracture risk are strongly influenced by load distribution during physical activities of daily living. The objective of this work is to evaluate the impact of outer cortical surface shape as a key affector of load distribution driving femoral structure and fracture behaviour. Different femur cortical shapes are generated using a statistical shape model. Their mesoscale internal architecture is predicted for the same activity regime using a structural optimisation approach previously reported by the authors and fracture under longitudinal compression is simulated. The resulting total volume of bone is similar in all geometries although substantial differences are observed in distribution between trabecular and cortical tissue. Greater neck-shaft and anteversion angles show a protective effect in longitudinal compression while a thinner shaft increases fracture risk.

BACKGROUND: For people living with HIV, major guidelines in high-income countries recommend testing for transmitted drug resistance (TDR) to guide the choice of first-line antiretroviral therapy (ART). However, individuals who fail a first-line regimen can now be switched to one of several effective regimens. Therefore, the virological and clinical benefit of TDR testing needs to be evaluated. METHODS: We included individuals from the HIV-CAUSAL Collaboration who enrolled

Objectives The aim of this study was to investigate associations between baseline characteristics and CD4 cell count response on first-line antiretroviral therapy and risk of virological failure (VF) with or without drug resistance. Methods We conducted an analysis of UK Collaborative HIV Cohort data linked to the UK HIV Drug Resistance Database. Inclusion criteria were viral sequence showing no resistance prior to initiation of first-line efavirenz + tenofovir disoproxil fumarate + emtricitabine and virological suppression within 6 months. Outcomes of VF (≥200 copies/mL) with or without drug resistance were assessed using a competing risks approach fitted jointly with a model for CD4 cell count recovery. Hazard ratios for each VF outcome were estimated for baseline CD4 cell count and viral load and characteristics of CD4 cell count response using latent variables on a standard normal scale. Results A total of 3640 people were included with 338 VF events; corresponding viral sequences were available in 134 with ≥1 resistance mutation in 36. VF with resistance was associated with lower baseline CD4 (0.30, 0.09–0.62), lower CD4 recovery (0.04, 0.00–0.17) and higher CD4 variability (4.40, 1.22–12.68). A different pattern of associations was observed for VF without resistance, but the strength of these results was less consistent across sensitivity analyses. Cumulative incidence of VF with resistance was estimated to be >2% at 3 years for baseline CD4 ≥350 cells/μL. Conclusion Lower baseline CD4 cell count and suboptimal CD4 recovery are associated with VF with drug resistance. People with low CD4 cell count before ART or with suboptimal CD4 recovery on treatment should be a priority for regimens with high genetic barrier to resistance.

Background: Many individuals failing first-line antiretroviral therapy (ART) in sub-Saharan Africa never initiate second-line ART or do so after significant delay. For people on ART with a viral load more than 1000 copies/ml, the WHO recommends a second viral load measurement 3 months after the first viral load and enhanced adherence support. Switch to a second-line regimen is contingent upon a persistently elevated viral load more than 1000 copies/ml. Delayed second-line switch places patients at increased risk for opportunistic infections and mortality. Methods: To assess the potential benefits of a simplified second-line ART switch strategy, we use an individual-based model of HIV transmission, progression and the effect of ART which incorporates consideration of adherence and drug resistance, to compare predicted outcomes of two policies, defining first-line regimen failure for patients on efavirenz-based ART as either two consecutive viral load values more than 1000 copies/ml, with the second after an enhanced adherence intervention (implemented as per current WHO guidelines) or a single viral load value more than 1000 copies/ml. We simulated a range of setting-scenarios reflecting the breadth of the sub-Saharan African HIV epidemic, taking into account potential delays in defining failure and switch to second-line ART. Findings: The use of a single viral load more than 1000 copies/ml to define ART failure would lead to a higher proportion of persons with nonnucleoside reverse-transcriptase inhibitor resistance switched to second-line ART [65 vs. 48%; difference 17% (90% range 14–20%)], resulting in a median 18% reduction in the rate of AIDS-related death over setting scenarios (90% range 6–30%; from a median of 3.1 to 2.5 per 100 person-years) over 3 years. The simplified strategy also is predicted to reduce the rate of AIDS conditions by a median of 31% (90% range 8–49%) among people on first-line ART with a viral load more than 1000 copies/ml in the past 6 months. For a country of 10 million adults (and a median of 880 000 people with HIV), we estimate that this approach would lead to a median of 1322 (90% range 67–3513) AIDS deaths averted per year over 3 years. For South Africa this would represent around 10 215 deaths averted annually. Interpretation: As a step towards reducing unnecessary mortality associated with delayed second-line ART switch, defining failure of first-line efavirenz-based regimens as a single viral load more than 1000 copies/ml should be considered.

Recent evidence has suggested that chemsex (the use of mephedrone, crystal methamphetamine and γ -hydroxybutyrate/ γ -butryolactone (GHB/GBL) to enable, enhance and prolong sexual interactions) has increased among men having sex with men (MSM) attending sexual health clinics in large UK cities. To date there has been no data from the UK or Europe that describes changes in chemsex over time within a cohort of MSM.The prospective cohort study, Attitudes to and Understanding Risk of Acquisition of HIV over Time (AURAH2), collected online questionnaire data from HIV negative or undiagnosed MSM (at enrolment) from 2015 to 2018, recruited from sexual health clinics. We aim to investigate changes in chemsex, three individual drugs associated with chemsex, frequency of chemsex sessions and measures of sexual behaviour, among the cohort of MSM over the study's 3 year follow-up period.In total 622 MSM completed at least one online questionnaire for the AURAH2 study, of which 400 (64.3%) were still engaged with the study within the last six months of follow-up. Prevalence of chemsex significantly declined during the follow-up from 31.8% (198/622) at the first online questionnaire, to 11.1% (8/72; p 0.001) at the 9th. This decline was reflected in the proportion of MSM reporting use of two of the three individual chemsex drugs: mephedrone use had significantly declined from 25.2% at the first online questionnaire to 9.7% (p 0.001) at the 9th, GHB/GBL use had also declined from 19.9% to 8.3% (p = 0.001). While crystal methamphetamine use declined, but not significantly (11.1%-6.9% [p = 0.289]). Most measures of sexual behaviour (any anal sex, group sex, recent HIV test and bacterial STI) also tended to decline over the follow-up period, with the exception of CLAI with more than one and more than two partners.Chemsex and use of two individual chemsex drugs (mephedrone and GHB/GBL) significantly declined over time among individuals in the study, alongside most measures of sexual behaviour with the exception of those related to CLAI. Focusing health promotion and HIV prevention, such as awareness of post-exposure prophylaxis (PEP) and access to pre-exposure prophylaxis (PrEP), on MSM that report chemsex, and in particular problematic chemsex, would be highly beneficial, potentially only necessary for a relatively short period of time for individuals, and could have long term benefits for HIV and STI prevention.

Since 1919, world leaders have sought to uphold and advance international order by sponsoring a succession of global security hierarchies, understood as authoritative arrangements that are global in scope and dedicated to mitigating international security challenges. These hierarchies have progressively broadened in the inclusivity of their security referents. Explicitly racist and civilizational answers to the question ‘security for whom’ have given way to more cosmopolitan visions of security hierarchy. The scope of the challenges these hierarchies have aimed to mitigate (‘security from what’) has also broadened, alongside the intrusiveness of the measures (‘security through which means’) licenced to manage them. The progression towards more inclusive, ambitious and intrusive global security hierarchies has nevertheless evolved in tension with the parallel globalization of both nationalism and the sovereign state system. These countervailing influences – in conjunction with the recent worldwide resurgence of illiberal forces – now threaten the prospective longevity of today’s United Nation (UN)-centric cosmopolitan global security hierarchy.

Objective: Extensive antiretroviral therapy scale-up is expected to prevent onward transmission of HIV by reducing the overall community viral load. Despite multiple studies about predictors of detectable viral load derived from clinical setting, to date, no study has established such predictors using a population-based viral load survey in a sub-Saharan African hyperendemic setting to inform interventions designed to halt HIV transmission. We used one of Africa's largest prospective cohorts in rural KwaZulu-Natal Province, South Africa, to establish the key sociodemographic, behavioral and community predictors of unsuppressed viral load at the population level. Methods: We collected 5454 viral load measurements from a population-based viral load survey of 3892 women living with HIV from a rural population during 2011, 2013 and 2014. Multilevel logistic regression models were fitted to examine the risk predictors of unsuppressed viral load. Results: Among women living with HIV in this population, the prevalence of unsuppressed viral load was 69% in 2011, 58% in 2013 and 53% in 2014. Although time since HIV infection was associated with lower risk for virologic detection [adjusted odds ratio (aOR) = 0.91,0.87–0.94], young women (aOR = 2.59,1.47–4.55) with extensive external migration history (aOR = 1.25,1.02–1.54), greater number of sexual partners (aOR = 1.30,1.02–1.67), and longer history of residing in an HIV incidence hotspot community were more likely to experience unsuppressed viral load (aOR = 1.12,1.06–1.19). Conclusion: Young women, number of sexual partners, transiency and longer residence in an HIV hotspot community are important determinants of unsuppressed viral load in a hyperendemic rural African setting. To substantially reduce the persistently high transmission potential in these settings, targeted interventions to address these risk factors will be essential for both individual and population health gains.

BackgroundCOVID-19 mitigation strategies have been challenging to implement in resource-limited settings such as Malawi due to the potential for widespread disruption to social and economic well-being. Here we estimate the clinical severity of COVID-19 in Malawi, quantifying the potential impact of intervention strategies and increases in health system capacity.MethodsThe infection fatality ratios (IFR) in Malawi were estimated by adjusting reported IFR for China accounting for demography, the current prevalence of comorbidities and health system capacity. These estimates were input into an age-structured deterministic model, which simulated the epidemic trajectory with non-pharmaceutical interventions. The impact of a novel therapeutic agent and increases in hospital capacity and oxygen availability were explored, given different assumptions on mortality rates.FindingsThe estimated age-specific IFR in Malawi are higher than those reported for China, however the younger average age of the population results in a slightly lower population-weighted IFR (0.48%, 95% uncertainty interval [UI] 0.30% – 0.72% compared with 0.60%, 95% CI 0.4% – 1.3% in China). The current interventions implemented, (i.e. social distancing, workplace closures and public transport restrictions) could potentially avert 3,100 deaths (95% UI 1,500 – 4,500) over the course of the epidemic. Enhanced shielding of people aged ≥ 60 years could avert a further 30,500 deaths (95% UI 17,500 – 45,600) and halve ICU admissions at the peak of the outbreak. Coverage of face coverings of 60% under the assumption of 50% efficacy could be sufficient to control the epidemic. A novel therapeutic agent, which reduces mortality by 0.65 and 0.8 for severe and critical cases respectively, in combination with increasing hospital capacity could reduce projected mortality to 2.55 deaths per 1,000 population (95% UI 1.58 – 3.84).ConclusionThe risks due to COVID-19 vary across settings and are influenced by age, underlying health and health system capacity.Summary BoxWhat is already known?As COVID-19 spreads throughout Sub-Saharan Africa, countries are under increasing pressure to protect the most vulnerable by suppressing spread through, for example, stringent social distancing measures or shielding of those at highest risk away from the general population.There are a number of studies estimating infection fatality ratio due to COVID-19 but none use data from African settings. The estimated IFR varies across settings ranging between 0.28-0.99%, with higher values estimated for Europe (0.77%, 95% CI 0.55 – 0.99%) compared with Asia (0.46%, 95% CI 0.38 – 0.55).The IFR for African settings are still unknown, although several studies have highlighted the potential for increased mortality due to comorbidities such as HIV, TB and malaria.There are a small number of studies looking at the impact of non-pharmaceutical interventions in Africa, particularly South Africa, but none to date have combined this with country-specific estimates of IFR adjusted for comorbidity prevalence and with consideration to the prevailing health system constraints and the impact of these constraints on mortality rates.What are the new findings?After accounting for the health system constraints and differing prevalences of underlying comorbidities, the estimated infection fatality ratio (IFR) for Malawi (0.48%, 95% uncertainty interval 0.30% – 0.72%) is within the ranges reported for the Americas, Asia and Europe (overall IFR 0.70, 95% CI 0.57 – 0.82, range 0.28 – 0.89).Introducing enhanced shielding of people aged ≥ 60 years could avert up to 30,500 deaths (95% UI 17,500 – 45,600) and significantly reduce demand on ICU admissions.Maintaining coverage of face coverings at 60%, under the assumption of 50% efficacy, could be sufficient to control the epidemic.Combining the introduction of a novel therapeutic agent with increases in hospital capacity could reduce projected mortality to 2.55 deaths per 1,000 population (95% UI 1.58 – 3.84).What do the new findings imply?Adjusting estimates of COVID-19 severity to account for underlying health is crucial for predicting health system demands.A multi-pronged approach to controlling transmission, including face coverings, increasing hospital capacity and using new therapeutic agents could significantly reduce deaths to COVID-19, but is not as effective as a theoretical long-lasting lockdown.

Background: Lumbar Disc Degeneration (LDD) is associated with recurrent low back pain (LBP) (symptomatic). However, in some instances of LDD, people do not experience LBP (asymptomatic). Research question: As a step towards understanding why some people with LDD experience LBP and others do not, the primary aim of this study was to examine differences in anticipatory (APA) and compensatory postural adjustments (CPA), between symptomatic LDD patients (LDD pain) and asymptomatic LDD controls (LDD no pain) during postural perturbation. The secondary aim was to determine simultaneous differences in mental health, disability and quality of life status. Methods: 3 T MRI was used to acquire T2 weighted images (L1-S1) from LDD no pain (n = 34) and LDD pain groups (n = 34). In this observational study, responses to predicted and unpredicted forward perturbations were examined using three dimensional motion capture. A Mann Whitney U test was conducted to examine group differences in sagittal spine and lower limb kinematics (integrated angular displacements during four established APA and CPA time intervals), anxiety, depression, disability and quality of life. Results: The LDD pain group exhibited lower hip and knee displacements (p = 0.049−0.040) than the LDD no pain group during predicted and unpredicted perturbation. The LDD pain group also exhibited higher compensatory lumbar displacement than the LDD no pain group (p = 0.040−0.005) in the predicted condition but there was no difference observed in the unpredicted condition. The LDD pain group experienced higher levels of depression, anxiety and disability (p < 0.0001) and lower quality of life (p = 0.0001) than LDD controls. Significance: Symptomatic LDD patients are different from LDD controls; they exhibit different kinematic strategies, levels of disability, anxiety, depression and quality of life. Effective care may benefit from evaluating and targeting these differences.