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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.

BACKGROUND: The use of a combination of the integrase inhibitor, cabotegravir, and the non-nucleoside reverse transcriptase inhibitor, rilpivirine, in a long-acting injectable form is being considered as an antiretroviral treatment option for people with HIV in sub-Saharan Africa. We aimed to model the effects of injectable cabotegravir-rilpivirine to help to inform its potential effectiveness and cost-effectiveness under different possible policies for its introduction. METHODS: We used an existing individual-based model of HIV to predict the effects of introducing monthly injections of cabotegravir-rilpivirine for people with HIV in low-income settings in sub-Saharan Africa. We evaluated policies in the context of 1000 setting scenarios that reflected characteristics of HIV epidemics and programmes in sub-Saharan Africa. We compared three policies for introduction of injectable cabotegravir-rilpivirine with continued use of dolutegravir-based oral regimens for: all individuals on antiretroviral therapy (ART); individuals with a recently measured viral load of more than 1000 copies per mL (signifying poor adherence to oral drugs, and often associated with drug resistance); and individuals with a recently measured viral load of less than 1000 copies per mL (a group with a lower prevalence of pre-existing drug resistance). We also did cost-effectiveness analysis, taking a health system perspective over a 10 year period, with 3% discounting of disability-adjusted life-years (DALYs) and costs. A cost-effectiveness threshold of US$500 per DALY averted was used to establish if a policy was cost-effective. FINDINGS: In our model, all policies involving the introduction of injectable cabotegravir-rilpivirine were predicted to lead to an increased proportion of people with HIV on ART, increased viral load suppression, and decreased AIDS-related mortality, with lesser benefits in people with a recently measured viral load of less than 1000 copies per mL. Its introduction is also predicted to lead to increases in resistance to integrase inhibitors and non-nucleoside reverse transcriptase inhibitors if introduced in all people with HIV on ART or in those with a recently measured viral load of less than 1000 copies per mL, but to a lesser extent if introduced in people with more than 1000 copies per mL due to concentration of its use in people less adherent to oral therapy. Consistent with the effect on AIDS-related mortality, all approaches to the introduction of injectable cabotegravir-rilpivirine are predicted to avert DALYs. Assuming a cost of $120 per person per year, use of this regimen in people with a recently measured viral load of more than 1000 copies per mL was borderline cost-effective (median cost per DALY averted across setting scenarios $404). The other approaches considered for its use are unlikely to be cost-effective unless the cost per year of injectable cabotegravir-rilpivirine is considerably reduced. INTERPRETATION: Our modelling suggests that injectable cabotegravir-rilpivirine offers potential benefits; however, to be a cost-effective option, its introduction might need to be carefully targeted to individuals with HIV who might otherwise have suboptimal adherence to ART. As data accumulate from trials and implementation studies, such findings can be incorporated into the model to better inform on the full consequences of policy alternatives. FUNDING: Bill & Melinda Gates Foundation, including through the HIV Modelling Consortium (OPP1191655).

Background: Preexposure prophylaxis (PrEP) with tenofovir and emtricitabine can prevent new HIV-1 infections, but there is a concern that use of PrEP could increase HIV drug resistance resulting in loss of treatment options. We compared standardized outcomes from three independent mathematical models simulating the impact of PrEP on HIV transmission and drug resistance in sub-Saharan African countries. Methods: All models assume that people using PrEP receive an HIV test every 3-6 months. The models vary in structure and parameter choices for PrEP coverage, effectiveness of PrEP (at different adherence levels) and the rate with which HIV drug resistance emerges and is transmitted. Results: Themodels predict that the use of PrEP in conjunction with antiretroviral therapy will result in a lower prevalence of HIVthanwhen only antiretroviral therapy is used.With or without PrEP, all models suggest that HIV drug resistance will increase over the next 20 years due to antiretroviral therapy. PrEP will increase the absolute prevalence of drug resistance in the total population by less than 0.5%andamongst infected individuals by at most 7%. Twenty years after the introduction of PrEP, the majority of drug-resistant infections is due to antiretroviral therapy (50-63% across models), whereas 40-50% will be due to transmission of drug resistance, and less than 4% to the use of PrEP. Conclusion: HIV drug resistance resulting from antiretroviral therapy is predicted to far exceed that resulting from PrEP. Concern over drug resistance should not be a reason to limit the use of PrEP.

Background Expanding statin use may help to alleviate the excess burden of atherosclerotic cardiovascular disease in people living with HIV (PLHIV). Pravastatin and pitavastatin are preferred agents due to their lack of substantial interaction with antiretroviral therapy. We aimed to evaluate the cost‐effectiveness of pravastatin and pitavastatin for the primary prevention of atherosclerotic cardiovascular disease among PLHIV in the United States. Methods We developed a microsimulation model that randomly selected (with replacement) individuals from the Data‐collection on Adverse Effects of Anti‐HIV Drugs study with follow‐up between 2013 and 2016. Our study population was PLHIV aged 40 to 75 years, stable on antiretroviral therapy, and not currently using lipid‐lowering therapy. Direct medical costs and quality‐adjusted life‐years (QALYs) were assigned in annual cycles and discounted at 3% per year. We assumed a willingness‐to‐pay threshold of $100,000/QALY gained. The interventions assessed were as follows: (1) treating no one with statins; (2) treating everyone with generic pravastatin 40 mg/day (drug cost $236/year) and (3) treating everyone with branded pitavastatin 4 mg/day (drug cost $2,828/year). The model simulated each individual’s probability of experiencing atherosclerotic cardiovascular disease over 20 years. Results Persons receiving pravastatin accrued 0.024 additional QALYs compared with those not receiving a statin, at an incremental cost of $1338, giving an incremental cost‐effectiveness ratio of $56,000/QALY gained. Individuals receiving pitavastatin accumulated 0.013 additional QALYs compared with those using pravastatin, at an additional cost of $18,251, giving an incremental cost‐effectiveness ratio of $1,444,000/QALY gained. These findings were most sensitive to the pill burden associated with daily statin administration, statin costs, statin efficacy and baseline atherosclerotic cardiovascular disease risk. In probabilistic sensitivity analysis, no statin was optimal in 5.2% of simulations, pravastatin was optimal in 94.8% of simulations and pitavastatin was never optimal. Conclusions Pravastatin was projected to be cost‐effective compared with no statin. With substantial price reduction, pitavastatin may be cost‐effective compared with pravastatin. These findings bode well for the expanded use of statins among PLHIV in the United States. To gain greater confidence in our conclusions it is important to generate strong, HIV‐specific estimates on the efficacy of statins and the quality‐of‐life burden associated with taking an additional daily pill.

BACKGROUND: LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19.METHODS: In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5.RESULTS: On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47).CONCLUSIONS: Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).

BACKGROUND: Globally, trans people are disproportionately affected by HIV, but research on strategies to increase testing are limited. SELPHI is a randomised-controlled-trial (RCT) of 10,135 cis men, trans men, and trans women reporting lifetime anal intercourse with male partners (cis or trans), evaluating whether the offer of free HIV self-testing (HIVST) increases diagnosis. This subgroup analysis from the SELPHI RCT aims to describe key HIVST outcomes and HIVST acceptability for trans people. METHODS: SELPHI recruited using social networking and trans focused social media. Participants were randomised 60/40 to baseline HIVST (Biosure™) (BT) vs no baseline HIVST (nBT); and at 3-months (if completed the survey and reported recent CAI) 50/50 to 3-monthly HIVST (RT) vs no repeat HIVST (nRT). Outcomes were self-reported through online surveys. We conducted a qualitative study of semi-structured peer-led participant interviews (n = 20) exploring HIVST motivations and experiences. These were analysed using a framework approach. FINDINGS: SELPHI recruited and randomised 118 trans men and trans women (94 trans men, 24 trans women), of whom 20 (16 trans men, 4 trans women) underwent the second randomisation. Median age at baseline was 29 (IQR: 22, 37), 79% were white, 79% were UK born, 37% had degree level education, and 31% had never tested for HIV. 62% (n = 59) of trans men completed the 3-month survey, but survey completion by trans women in nBT was too low (1/11) for randomised comparison. In trans men HIV testing uptake by 3 months was significantly higher in BT (95% 36/38) vs nBT (29%, 6/21) (RR=3.32 (1.68, 6.55) p

Public health organisations typically recommend a minimum amount of moderate intensity activities such as walking or cycling for two and a half hours a week, combined with some more demanding physical activity on at least 2 days a week to maintain a healthy musculoskeletal condition. For populations at risk of bone loss in the lumbar spine, these guidelines are particularly relevant. However, an understanding of how these different activities are influential in maintaining vertebral bone health is lacking. A predictive structural finite element modelling approach using a strain-driven algorithm was developed to study mechanical stimulus and bone adaptation in the lumbar spine under various physiological loading conditions. These loading conditions were obtained with a previously developed full-body musculoskeletal model for a range of daily living activities representative of a healthy lifestyle. Activities of interest for the simulations include moderate intensity activities involving limited spine movements in all directions such as, walking, stair ascent and descent, sitting down and standing up, and more demanding activities with large spine movements during reaching and lifting tasks. For a combination of moderate and more demanding activities, the finite element model predicted a trabecular and cortical bone architecture representative of a healthy vertebra. When more demanding activities were removed from the simulations, areas at risk of bone degradation were observed at all lumbar levels in the anterior part of the vertebral body, the transverse processes and the spinous process. Moderate intensity activities alone were found to be insufficient in providing a mechanical stimulus to prevent bone degradation. More demanding physical activities are essential to maintain bone health in the lumbar spine.

Introduction Routine viral load (VL) testing among persons living with Human Immunodeficiency Virus (PLHIV) enables earlier detection of sub-optimal antiretroviral therapy (ART) adherence and for appropriate management of treatment failure. Since adoption of this policy by Zimbabwe in 2016, the extent of implementation is unclear. Therefore we set out to determine among PLHIV ever enrolled on ART from 2004–2017 and in ART care for ≥12 months at health facilities providing ART in Zimbabwe: numbers (proportions) with VL testing uptake, VL suppression and subsequently switched to 2nd-line ART following confirmed virologic failure. Materials and methods We used retrospective data from the electronic Patient Monitoring System (ePMS) in which PLHIV on ART are registered at 525 public and 4 private health facilities. Results Among the 392,832 PLHIV in ART care for ≥12 months, 99,721 (25.4%) had an initial VL test done and results available of whom 81,932 (82%) were virally suppressed. Among those with a VL>1000 copies/mL; 6,689 (37.2%) had a follow-up VL test and 4,086 (61%) had unsuppressed VLs of whom only 1,749 (42.8%) were switched to 2nd-line ART. Lower age particularly adolescents (10–19 years) were more likely (ARR 1.34; 95%CI: 1.25–1.44) to have virologic failure. Conclusion The study findings provide insights to implementation gaps including limitations in VL testing; low identification of high- risk PLHIV in care and lack of prompt utilization of test results. The use of electronic patient-level data has demonstrated its usefulness in assessing the performance of the national VL testing program. By end of 2017 implementation of VL testing was sub-optimal, and virological failure was relatively common, particularly among adolescents. Of concern is evidence of failure to act on VL test results that were received. A quality improvement initiative has been planned in response to these findings and its effect on patient management will be monitored.

Background Weight gain effects of individual antiretroviral drugs are not fully understood. We investigated associations between a prespecified clinically significant increase (>7%) in body-mass index (BMI) and contemporary antiretroviral use. Methods The International Cohort Consortium of Infectious Diseases (RESPOND) is a prospective, multicohort collaboration, including data from 17 well established cohorts and over 29 000 people living with HIV. People with HIV under prospective follow-up from Jan 1, 2012, and older than 18 years were eligible for inclusion. Each cohort contributed a predefined minimum number of participants related to the size of the specific cohort (with a minimum of 1000 participants). Participants were required to have CD4 cell counts and HIV viral load measurement in the 12 months before or within 3 months after baseline. For all antiretroviral drugs received at or after RESPOND entry, changes from pre-antiretroviral BMI levels (baseline) were considered at each BMI measurement during antiretroviral treatment. We used logistic regression to identify individual antiretrovirals that were associated with first occurrence of a more than 7% increase in BMI from pre-antiretroviral BMI. We adjusted analyses for time on antiretrovirals, pre-antiretroviral BMI, demographics, geographical region, CD4 cell count, viral load, smoking status, and AIDS at baseline. Findings 14 703 people were included in this study, of whom 7863 (53middot5%) had a more than 7% increase in BMI. Compared with lamivudine, use of dolutegravir (odds ratio [OR] 1middot27, 95% CI 1middot17-1middot38), raltegravir (1middot37, 1middot20-1middot56), and tenofovir alafenamide (1middot38, 1middot22-1middot35) was significantly associated with a more than 7% BMI increase, as was low pre-antiretroviral BMI (2middot10, 1middot91-2middot31 for underweight vs healthy weight) and Black ethnicity (1middot61, 1middot47-1middot76 vs White ethnicity). Higher CD4 count was associated with a reduced risk of BMI increase (0middot97, 0middot96-0middot98 per 100 cells per mu L increase). Relative to lamivudine, dolutegravir without tenofovir alafenamide (OR 1middot21, 95% CI 1middot19-1middot32) and tenofovir alafenamide without dolutegravir (1middot33, 1middot15-1middot53) remained independently associated with a more than 7% increase in BMI; the associations were higher when dolutegravir and tenofovir alafenamide were used concomitantly (1middot79, 1middot52-2middot11, and 1middot70, 1middot44-2middot01, respectively). Interpretation Clinicians and people with HIV should be aware of associations between weight gain and use of dolutegravir, tenofovir alafenamide, and raltegravir, particularly given the potential consequences of weight gain, such as insulin resistance, dyslipidaemia, and hypertension. Funding The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort and The University of Cologne HIV Cohorts, ViiV Healthcare, and Gilead Sciences. Copyright (c) 2021 Elsevier Ltd. All rights reserved.

Objective: To describe the spectrum of ICD-10 classified causes for hospitalisations occurring between 2011/2012 and 2018 in a cohort of PLHIV.Methods: This sub-study includes 798 HIV-positive individuals participating in the Antiretroviral, Sexual Transmission Risk and Attitudes (ASTRA) questionnaire study who were recruited from a large London centre. A medical record review identified the occurrence and causes of hospitalisation from the date of questionnaire completion (2011-2012) until 1 June 2018. Up to five causes were classified by an HIV clinician using the ICD-10 system.Results: There were 274 hospitalisations in 153 people (rate=5.8/100 person-years; 95% CI: 5.1, 6.5). Causes were wide-ranging; the most common were circulatory (16.8%), digestive (13.1%), respiratory (11.7%), infectious diseases (11.0%), injury/poisoning (10.6%), genitourinary diseases (9.9%) and neoplasms (9.1%). A tenth (27/274) of hospitalisations were related to at least one AIDS-defining illness. Median duration of hospitalisation was 5 days. At the time of hospitalisation, median CD4 count was high (510 cells/µl; IQR: 315-739), while median CD4 nadir was relatively low (113 cells/µl; IQR: 40-239). At admission, half of individuals (51%) had a previous AIDS-defining illness and 21% had viral load >50 copies/ml. Individuals admitted for infectious diseases were particularly likely to have unfavourable clinical characteristics (low CD4, viral non-suppression, not on ART, previous AIDS).Conclusions: In the modern cART era, the spectrum of causes of hospitalisation in PLHIV in the UK is wide-ranging, highlighting the importance of holistic care for PLHIV, including prevention, early detection and treatment of comorbidities.

Objectives As a step towards the comprehensive evaluation of movement in patients with low back pain, the aim of this study is to design a marker set (three rigid segment spine, pelvic and lower limb model) and evaluate the reliability and minimal detectable change (MDC) of this marker set in healthy adults during gait and sit to stand (STS) tasks using three dimensional motion capture. Results The ‘Imperial Spine’ marker set was used to assess relative peak angles during gait and STS tasks using the minimum recommended sample size (n = 10) for reliability studies with minimum Intraclass Correlation Coefficient (ICC) of 0.70, optimum ICC 0.90 and 9 trials replicated per subject per task. Intra- and inter-tester reliability between an experienced and inexperienced user was examined. ICC, mean, standard error (SEM), Bland Altman 95% limits of agreement (LOA) and MDC were computed. ICC values demonstrated excellent intra- and inter-tester reliability in both tasks, particularly in the sagittal plane (majority ICCs > 0.80). SEM measurements were lower in gait (0.8–5.5°) than STS tasks (1°-12.6°) as were MDC values. LOA demonstrated good agreement. The ‘Imperial Spine’ marker set is reliable for use in healthy adults during functional tasks. Future evaluation in patients is required.

Background We describe the spectrum of ICD-10 classified causes for hospitalisations occurring between 2011 and 2018 in a cohort of people living with HIV (PLHIV). Methods This sub-study includes 798 PLHIV participating in the Antiretroviral, Sexual Transmission Risk and Attitudes (ASTRA) questionnaire study who were recruited from a large London centre. A medical record review identified the occurrence and causes of hospitalisation from the date of questionnaire completion (February–December 2011) until 1 June 2018. Up to five causes were classified by an HIV clinician using the ICD-10 system. Results There were 274 hospitalisations in 153 people (rate = 5.8/100 person-years; 95% CI: 5.1, 6.5). Causes were wide-ranging; the most common were circulatory (16.8%), digestive (13.1%), respiratory (11.7%), infectious diseases (11.0%), injury/poisoning (10.6%), genitourinary diseases (9.9%) and neoplasms (9.1%). A tenth (27/274) of hospitalisations were related to at least one AIDS-defining illness. Median duration of hospitalisation was 5 days (IQR 2–9). At the time of hospitalisation, median CD4 count was high (510 cells/μl; IQR: 315–739), while median CD4 nadir was relatively low (113 cells/μl; IQR: 40–239). At admission, half of individuals (51%) had a previous AIDS-defining illness and 21% had viral load > 50 copies/ml. Individuals admitted for infectious diseases were particularly likely to have unfavourable HIV-related clinical characteristics (low CD4, viral non-suppression, not on antiretroviral therapy (ART), previous AIDS). Conclusions In the modern combination antiretroviral therapy era, the spectrum of causes of hospitalisation in PLHIV in the UK is wide-ranging, highlighting the importance of holistic care for PLHIV, including prevention, early detection and treatment of comorbidities.

Female sex workers (FSW) are prioritised for increased access to pre-exposure prophylaxis (PrEP), although rates of uptake remain sub-optimal, particularly across Southern Africa. In the first two years of its availability in Zimbabwe, 37.1% of FSW in trial sites initiated PrEP and received at least one re-supply. We conducted a qualitative study on perceptions of PrEP among 19 early users selected from sites with varying rates of PrEP initiation. Narrative interviews examined the pathways taken by FSW from hearing about PrEP, through their decision to start taking it, and early experiences. FSW appreciated PrEP's introduction within familiar and trusted "friendly" services tailored for sex workers and valued positive encouragement from clinic staff and peers over negative influence from family members. They also found PrEP difficult to understand at first, and feared side effects and rare adverse complications described in information leaflets. While FSW identified individual strategies for remembering to take their medication, they also relied on structured peer adherence support, leading some FSW to actively promote the method to other FSW as "PrEP champions". Information on how early users experience a new prevention technology such as PrEP can inform design of interventions that leverage existing support structures and target key barriers.

Introduction People living with HIV (PLHIV) have an elevated risk of atherosclerotic cardiovascular disease (CVD) compared to their HIV‐negative peers. Expanding statin use may help alleviate this burden. However, the choice of statin in the context of antiretroviral therapy is challenging. Pravastatin and pitavastatin improve cholesterol levels in PLHIV without interacting substantially with antiretroviral therapy. They are also more expensive than most statins. We evaluated the cost‐effectiveness of pravastatin and pitavastatin for the primary prevention of CVD among PLHIV in Thailand who are not currently using lipid‐lowering therapy. Methods We developed a discrete‐state microsimulation model that randomly selected (with replacement) individuals from the TREAT Asia HIV Observational Database cohort who were aged 40 to 75 years, receiving antiretroviral therapy in Thailand, and not using lipid‐lowering therapy. The model simulated each individual’s probability of experiencing CVD. We evaluated: (1) treating no one with statins; (2) treating everyone with pravastatin 20mg/day (drug cost 7568 Thai Baht ($US243)/year) and (3) treating everyone with pitavastatin 2 mg/day (drug cost 8182 Baht ($US263)/year). Direct medical costs and quality‐adjusted life‐years (QALYs) were assigned in annual cycles over a 20‐year time horizon and discounted at 3% per year. We assumed the Thai healthcare sector perspective. Results Pravastatin was estimated to be less effective and less cost‐effective than pitavastatin and was therefore dominated (extended) by pitavastatin. Patients receiving pitavastatin accumulated 0.042 additional QALYs compared with those not using a statin, at an extra cost of 96,442 Baht ($US3095), giving an incremental cost‐effectiveness ratio of 2,300,000 Baht ($US73,812)/QALY gained. These findings were sensitive to statin costs and statin efficacy, pill burden, and targeting of PLHIV based on CVD risk. At a willingness‐to‐pay threshold of 160,000 Baht ($US5135)/QALY gained, we estimated that pravastatin would become cost‐effective at an annual cost of 415 Baht ($US13.30)/year and pitavastatin would become cost‐effective at an annual cost of 600 Baht ($US19.30)/year. Conclusions Neither pravastatin nor pitavastatin were projected to be cost‐effective for the primary prevention of CVD among PLHIV in Thailand who are not currently using lipid‐lowering therapy. We do not recommend expanding current use of these drugs among PLHIV in Thailand without substantial price reduction.

Background: The ongoing coronavirus disease 2019 (COVID-19) pandemic is a major global threat. Several mathematical modelling studies have investigated the spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), along with the effectiveness of interventions to interrupt transmission nationally in the UK and elsewhere. Methods: We present a mathematical model for the transmission of SARS-CoV2 in London. The model was parametrised using data on notified cases, deaths, contacts, and mobility to analyse the epidemic in the UK capital. We investigated the impact of multiple non pharmaceutical interventions (NPIs) and combinations of these measures on future incidence of COVID-19. Findings: Immediate action at the early stages of an epidemic in the affected districts would have tackled spread. While an extended lockdown is highly effective, other measures such as shielding older populations, universal testing and facemasks can all potentially contribute to a reduction of infections and deaths. However, based on current evidence it seems unlikely they will be as effective as continued lockdown. In order to achieve elimination and lift lockdown within 5 months, the best strategy seems to be a combination of weekly universal testing, contact tracing and use of facemasks, with concurrent lockdown. This approach could potentially reduce deaths by 76% compared with continued lockdown alone. Interpretation: A combination of NPIs such as universal testing, contact tracing and mask use while under lockdown would be associated with least deaths and infections. This approach would require high uptake and sustained local effort but it is potentially feasible as may lead to elimination in a relatively short time scale.

The energy absorption and structural isolation performance of axially-compressed sandwich structures constructed with stiff face plates separated with an auxetic lattice core metamaterial is studied. Advances in additive manufacturing increasingly allow bespoke, carefully designed, structures to be included within the core lattice to enhance mechanical performance. Currently, the internal structure of the lattice core is deliberately disrupted geometrically to engineer suitable post-buckling behaviour under quasi-static loading. The desirable properties of a high fundamental stiffness and a practically zero underlying stiffness in the post-buckling range ensure that energy may be absorbed within a limited displacement and that any transfer of strain to an attached structure is minimized as far as is feasible. It is demonstrated that such disruptions can be arranged to enhance the panel performance. The concept may be extended to promote cellular buckling where the internal lattice buckles with densification occurring at defined locations and in sequence to absorb energy while maintaining a low underlying mechanical stiffness.

Introduction Uptake of early infant HIV diagnosis (EID) varies widely across sub-Saharan African settings. We evaluated the potential clinical impact and cost-effectiveness of universal maternal HIV screening at infant immunization visits, with referral to EID and maternal antiretroviral therapy (ART) initiation. Methods Using the CEPAC-Pediatric model, we compared two strategies for infants born in 2017 in Cote d'Ivoire (CI), South Africa (SA), and Zimbabwe: (1) existing EID programmes offering six-week nucleic acid testing (NAT) for infants with known HIV exposure (EID), and (2) EID plus universal maternal HIV screening at six-week infant immunization visits, leading to referral for infant NAT and maternal ART initiation (screen-and-test). Model inputs included published Ivoirian/South African/Zimbabwean data: maternal HIV prevalence (4.8/30.8/16.1%), current uptake of EID (40/95/65%) and six-week immunization attendance (99/74/94%). Referral rates for infant NAT and maternal ART initiation after screen-and-test were 80%. Costs included NAT ($24/infant), maternal screening ($10/mother-infant pair), ART ($5 to 31/month) and HIV care ($15 to 190/month). Model outcomes included mother-to-child transmission of HIV (MTCT) among HIV-exposed infants, and life expectancy (LE) and mean lifetime per-person costs for children with HIV (CWH) and all children born in 2017. We calculated incremental cost-effectiveness ratios (ICERs) using discounted (3%/year) lifetime costs and LE for all children. We considered two cost-effectiveness thresholds in each country: (1) the per-capita GDP ($1720/6380/2150) per year-of-life saved (YLS), and (2) the CEPAC-generated ICER of offering 2 versus 1 lifetime ART regimens (e.g. offering second-line ART; $520/500/580/YLS). Results With EID, projected six-week MTCT was 9.3% (CI), 4.2% (SA) and 5.2% (Zimbabwe). Screen-and-test decreased total MTCT by 0.2% to 0.5%, improved LE by 2.0 to 3.5 years for CWH and 0.03 to 0.07 years for all children, and increased discounted costs by $17 to 22/child (all children). The ICER of screen-and-test compared to EID was $1340/YLS (CI), $650/YLS (SA) and $670/YLS (Zimbabwe), below the per-capita GDP but above the ICER of 2 versus 1 lifetime ART regimens in all countries. Conclusions Universal maternal HIV screening at immunization visits with referral to EID and maternal ART initiation may reduce MTCT, improve paediatric LE, and be of comparable value to current HIV-related interventions in high maternal HIV prevalence settings like SA and Zimbabwe.

Background. Metamodels can simplify complex health policy models and yield instantaneous results to inform policy decisions. We investigated the predictive validity of linear regression metamodels used to support a real-time decision-making tool that compares infant HIV testing/screening strategies. Methods. We developed linear regression metamodels of the Cost-Effectiveness of Preventing AIDS Complications Pediatric (CEPAC-P) microsimulation model used to predict life expectancy and lifetime HIV-related costs/person of two infant HIV testing/screening programs in South Africa. Metamodel performance was assessed with cross-validation and Bland-Altman plots, showing between-method differences in predicted outcomes against their means. Predictive validity was determined by the percentage of simulations in which the metamodels accurately predicted the strategy with the greatest net health benefit (NHB) as projected by the CEPAC-P model. We introduced a zone of indifference and investigated the width needed to produce between-method agreement in 95% of the simulations. We also calculated NHB losses from “wrong” decisions by the metamodel. Results. In cross-validation, linear regression metamodels accurately approximated CEPAC-P-projected outcomes. For life expectancy, Bland-Altman plots showed good agreement between CEPAC-P and the metamodel (within 1.1 life-months difference). For costs, 95% of between-method differences were within $65/person. The metamodels predicted the same optimal strategy as the CEPAC-P model in 87.7% of simulations, increasing to 95% with a zone of indifference of 0.24 life-months ( ∼ 7 days). The losses in health benefits due to “wrong” choices by the metamodel were modest (range: 0.0002–1.1 life-months). Conclusions. For this policy question, linear regression metamodels offered sufficient predictive validity for the optimal testing strategy as compared with the CEPAC-P model. Metamodels can simulate different scenarios in real time, based on sets of input parameters that can be depicted in a widely accessible decision-support tool.

Background There is little information on the prevalence of recreational drug use among UK heterosexual men and women, in particular on use of drugs associated with ‘chemsex’ within gay communities. The aim of this study was to examine among HIV-negative and HIV-positive heterosexual men and women in England: (i) the prevalence of recreational drug use (including use of drugs associated with chemsex), (ii) socio-economic/lifestyle correlates of drug use, and (iii) the association of drug use with sexual behavior measures and mental health symptoms. Methods Data are from the AURAH study of HIV-negative individuals attending sexual health clinics across England (2013–2014) and the ASTRA study of HIV-positive individuals attending HIV outpatient clinics in England (2011–2012). Prevalence of recreational drug use (past three months) and associations are presented separately among the four sample groups: HIV-negative (N = 470) and HIV-positive (N = 373) heterosexual men and HIV-negative (N = 676) and HIV-positive (N = 637) women. Results The age standardized prevalence of any drug use was 22.9%, 17.1%, 15.3%, and 7.1% in the four sample groups respectively. In all groups, cannabis was the drug most commonly used (range from 4.7% to 17.9%) followed by cocaine (1.6% to 8.5%). The prevalence of use of drugs associated with chemsex was very low among HIV-negative participants (1.0% heterosexual men, 0.2% women) and zero among HIV-positive men and women. In age-adjusted analysis, factors linked to drug use overall and/or to cannabis and cocaine use specifically in the four sample groups included Black/mixed Caribbean and white (vs. Black/mixed African) ethnicity, lower level of education , cigarette smoking, and higher risk alcohol consumption. Associations of recreational drug use with measures of condomless sex, depression, and anxiety were observed in the four groups, but were particularly strong/apparent among women. Conclusion Providers need to be aware of cannabis and cocaine use and its potential link with sexual risk behavior and symptoms of depression and anxiety among heterosexual men and women attending sexual health and HIV clinics.

We assessed attitudes to disclosure to new sexual partners and association with sexual behaviours among HIV-diagnosed gay, bisexual, and other men who have sex with men (GBMSM) in the UK Antiretrovirals, Sexual Transmission Risk and Attitudes (ASTRA) study in 2011-12. Among 1373 GBMSM diagnosed with HIV for ≥3 months and reporting sex in the past three months (84% on antiretroviral therapy (ART), 75% viral load (VL) ≤50c/mL), 56.3% reported higher sexual disclosure ("agree" or "tend to agree" with "I'd expect to tell a new partner I'm HIV-positive before we have sex"). GBMSM on ART with self-reported undetectable VL had lower disclosure than those on ART without self-reported undetectable VL and those not on ART. Higher sexual disclosure was associated with higher prevalence of CLS in the past three months; this was due to its association with CLS with other HIV-positive partners. Higher sexual disclosure was more common among GBMSM who had CLS with other HIV-positive partners only (72.1%) compared to those who had higher-risk CLS with HIV-serodifferent partners (55.6%), other CLS with HIV-serodifferent partners (45.9%), or condom-protected sex only (47.6%). Findings suggest mutual HIV-disclosure and HIV-serosorting were occurring in this population. Knowledge of VL status may have impacted on disclosure to sexual partners.

BACKGROUND: The integrase inhibitor dolutegravir is being considered in several countries in sub-Saharan Africa instead of efavirenz for people initiating antiretroviral therapy (ART) because of superior tolerability and a lower risk of resistance emergence. WHO requested updated modelling results for its 2019 Antiretroviral Guidelines update, which was restricted to the choice of dolutegravir or efavirenz in new ART initiators. In response to this request, we modelled the risks and benefits of alternative policies for initial first-line ART regimens.METHODS: We updated an existing individual-based model of HIV transmission and progression in adults to consider information on the risk of neural tube defects in women taking dolutegravir at time of conception, as well as the effects of dolutegravir on weight gain. The model accounted for drug resistance in determining viral suppression, with consequences for clinical outcomes and mother-to-child transmission. We sampled distributions of parameters to create various epidemic setting scenarios, which reflected the diversity of epidemic and programmatic situations in sub-Saharan Africa. For each setting scenario, we considered the situation in 2018 and compared ART initiation policies of an efavirenz-based regimen in women intending pregnancy, and a dolutegravir-based regimen in others, and a dolutegravir-based regimen, including in women intending pregnancy. We considered predicted outcomes over a 20-year period from 2019 to 2039, used a 3% discount rate, and a cost-effectiveness threshold of US$500 per disability-adjusted life-year (DALY) averted.FINDINGS: Considering updated information on risks and benefits, a policy of ART initiation with a dolutegravir-based regimen rather than an efavirenz-based regimen, including in women intending pregnancy, is predicted to bring population health benefits (10 990 DALYs averted per year) and to be cost-saving (by $2·9 million per year), leading to a reduction in the overall population burden of disease of 16 735 net DALYs per year for a country with an adult population size of 10 million. The policy involving ART initiation with a dolutegravir-based regimen in women intending pregnancy was cost-effective in 87% of our setting scenarios and this finding was robust in various sensitivity analyses, including around the potential negative effects of weight gain.INTERPRETATION: In the context of a range of modelled setting scenarios in sub-Saharan Africa, we found that a policy of ART initiation with a dolutegravir-based regimen, including in women intending pregnancy, was predicted to bring population health benefits and be cost-effective, supporting WHO's strong recommendation for dolutegravir as a preferred drug for ART initiators.FUNDING: Bill & Melinda Gates Foundation.

Objectives To establish the positive predictive values of pre-operative identification with CT imaging of metastatic diaphragm disease in surgically managed cases of advanced ovarian cancer (AOC). Additionally, we have assessed the post-operative morbidity and survival following diaphragmatic surgical intervention in a large regional cancer centre in the United Kingdom. Study design A retrospective review of all cases of AOC with metastatic diaphragm disease surgically treated at the Pan-Birmingham Gynaecological Cancer Centre, UK between 1st August 2007 and 29th February 2016. Results A total of 536 women underwent surgery for primary AOC. Diaphragm disease was evident intra-operatively in 215/536 (40.1%) and 85/536 women (15.9%) underwent a procedure involving their diaphragm. Of these 85 cases, 38 peritoneal strippings (38/85, 44.7%), 31 partial diaphragmatic resections (31/85, 35.6%) and 16 electro-surgical ablations (16/85, 18.9%) were performed. There were no significant differences in post-operative complications between the three different diaphragmatic surgical groups. Of those patients who underwent peritoneal stripping or partial diaphragm resection, 12% were upstaged to stage 4A by virtue of pleural invasion. The positive predictive value for pre-operative radiological identification of diaphragmatic disease was 78.6%. CT imaging failed to detect diaphragmatic involvement despite obvious diaphragm disease during surgery in 29.4% of cases, giving a low negative predictive value of 64.8%. The sensitivity and specificity for CT imaging in detecting diaphragm disease was 44.3% and 93.8%, respectively. Conclusions Diaphragmatic disease is often discovered in AOC. However, pre-operative assessment with CT imaging is not reliable in accurately detecting diaphragm involvement. Therefore, all patients with AOC should be regarded as in potential need for diaphragm surgery and their operation undertaken in cancer centres with adequate expertise in upper abdominal surgery. If there is a suspicion of diaphragm muscle invasion during diaphragmatic peritonectomy, the muscle should be partially resected. This will lead to potential upstaging of disease to stage 4A and therefore, to suitability for targeted therapy. In our Centre, the surgical removal of diaphragmatic disease did not significantly increase surgical morbidity.

BackgroundNon-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) are increased in populations with immune dysfunction, including people living with HIV; however, there is little evidence for to what degree immunological and virological factors differently affect NHL and HL risk.MethodsData from the Data Collection on Adverse events of Anti-HIV Drugs Study cohort were analyzed to identify independent risk factors for NHL and HL using hazard ratios (HRs), focusing on current and cumulative area under the curve (AUC) measures of immunological and virological status. Variables with different associations with NHL and HL were identified using marginal Cox models. All statistical tests were two-sided.ResultsAmong 41 420 people followed for 337 020 person-years, 392 developed NHL (incidence rate = 1.17/1000 person-years of follow-up [PYFU], 95% confidence interval [CI] = 1.06 to 1.30) and 149 developed HL (incidence rate = 0.44/1000 PYFU, 95% CI = 0.38 to 0.52). Higher risk of both NHL and HL was associated with lower current CD4 cell count (adjusted HR [aHR] of NHL for CD4 599 cells/mm3 = 8.08, 95% CI = 5.63 to 11.61; HL = 4.58, 95% CI = 2.22 to 9.45), whereas higher current HIV viral load (aHR of NHL for HIV-VL >1000 vs ConclusionsCD4 depletion increased risk of both types of lymphomas while current and accumulated HIV-VL was associated with NHL only. This suggests that NHL development is related to both CD4 cell depletion and added immune dysfunction derived from ongoing HIV replication. This latter factor was not associated with HL risk.

Summary Background In the UK, HIV incidence among men who have sex with men (MSM) has remained high for several years, despite widespread use of antiretroviral therapy and high rates of virological suppression. Pre-exposure prophylaxis (PrEP) has been shown to be highly effective in preventing further infections in MSM, but its cost-effectiveness is uncertain. Methods In this modelling study and economic evaluation, we calibrated a dynamic, individual-based stochastic model, the HIV Synthesis Model, to multiple data sources (surveillance data provided by Public Health England and data from a large, nationally representative survey, Natsal-3) on HIV among MSM in the UK. We did a probabilistic sensitivity analysis (sampling 22 key parameters) along with a range of univariate sensitivity analyses to evaluate the introduction of a PrEP programme with sexual event-based use of emtricitabine and tenofovir for MSM who had condomless anal sexual intercourse in the previous 3 months, a negative HIV test at baseline, and a negative HIV test in the preceding year. The main model outcomes were the number of HIV infections, quality-adjusted life-years (QALYs), and costs. Findings Introduction of such a PrEP programme, with around 4000 MSM initiated on PrEP by the end of the first year and almost 40 000 by the end of the 15th year, would result in a total cost saving (£1·0 billion discounted), avert 25% of HIV infections (42% of which would be directly because of PrEP), and lead to a gain of 40 000 discounted QALYs over an 80-year time horizon. This result was particularly sensitive to the time horizon chosen, the cost of antiretroviral drugs (for treatment and PrEP), and the underlying trend in condomless sex. Interpretation This analysis suggests that the introduction of a PrEP programme for MSM in the UK is cost-effective and possibly cost-saving in the long term. A reduction in the cost of antiretroviral drugs (including the drugs used for PrEP) would substantially shorten the time for cost savings to be realised. Funding National Institute for Health Research.

Bone functional tissue adaptation is a multiaspect physiological process driven by interrelated mechanical and biological stimuli which requires the combined activity of osteoclasts and osteoblasts. In previous work, the authors developed a phenomenological mesoscale structural modelling approach capable of predicting internal structure of the femur based on daily activity loading, which relied on the iterative update of the cross-sectional areas of truss and shell elements representative of trabecular and cortical bones, respectively. The objective of this study was to introduce trabecular reorientation in the phenomenological model at limited computational cost. To this aim, a metamodel derived from poroelastic microscale continuum simulations was used to predict the functional adaptation of a simplified proximal structural femur model. Clear smooth trabecular tracts are predicted to form in the regions corresponding to the main trabecular groups identified in literature, at minimal computational cost.

The aim of this study was to determine whether the age-adjusted Charlston co-morbidity index (ACCI) can predict post-operative complications, adjuvant chemotherapy usage and overall survival (OS) in patients with advanced epithelial ovarian cancer (AOC) treated with neoadjuvant chemotherapy (NACT). A review was performed of all cytoreductive surgeries performed between 16/8/07-3/2/14 for AOC at a UK Cancer Centre. All surgeries were stratified by ACCI into three groups: Low (0-1), Intermediate (2-3) and High (≥4). Of the 293 cases the ACCI distribution was: 74 (25.26%) low, 164 (55.97%) intermediate and 55 (18.77%) high. Patients with a high ACCI were less likely to receive adjuvant chemotherapy (p = .023), more likely to receive fewer adjuvant cycles (p = .0057) but no more likely to experience complications. Median OS for patients with a low, intermediate and high ACCI was 44.58 (95%CI 36.98-52.19), 34.65 (95%CI 29.48-39.82) and 33.37 (95%CI 17.47-49.27) months. ACCI was associated with OS (p .01) confirmed on multivariate analysis (p = .03). The ACCI is, therefore, a marker of survival in these patients and predicts adjuvant chemotherapy usage. Impact statement The Age-Adjusted Charlston Co-morbidity Index has previously been identified as a predictor of survival in both medical and surgical conditions. Recently it has also been validated in patients undergoing primary cytoreductive surgery for advanced ovarian cancer. This study is the first to validate the Age-Adjusted Charlston Co-morbidity Index in patients undergoing cytoreductive surgery following neoadjuvant chemotherapy. Our findings demonstrate that it can be used to not only predict overall survival in women undergoing debulking surgery after neo-adjuvant chemotherapy but also predicts the uptake and commencement of adjuvant chemotherapy. Such findings are important considerations to enable an informed patient choice regarding interval surgery in the more co-morbid patients. More importantly, although the ACCI can be used as a marker of overall survival, even in the most co-morbid of patients there remains a significant survival advantage following surgery to the extent that it should not be contraindicated in this cohort. The ACCI is being increasingly incorporated into various clinical trials as a standard demographic measure and this study validates its inclusion in patients undergoing interval debulking surgery.

OBJECTIVE: HIV transmission is ongoing among men who have sex with men (MSM) in the UK. Sex without a condom (condomless sex, CLS) is the main risk factor. We investigated the prevalence of and factors associated with types of CLS. METHODS: Cross-sectional questionnaire study in UK HIV clinics in 2011/2012 (ASTRA). MSM diagnosed with HIV for ≥3 months reported on anal and vaginal sex, CLS with HIV-serodifferent partners (CLS-D) and CLS with HIV-seroconcordant (CLS-C) partners in the previous 3 months. Mutually exclusive sexual behaviours were as follows: (1) Higher HIV risk CLS-D (not on antiretroviral therapy (ART) or clinic-recorded viral load(VL) >50 c/mL), (2) Other CLS-D, (3) CLS-C without CLS-D, (4) Condom-protected sex only and (5) No anal or vaginal sex. Associations were examined of sociodemographic, HIV-related, lifestyle, and other sexual measures with the five categories of sexual behaviour. We examined the prevalence of higher HIV risk CLS-D incorporating (in addition to ART and VL) time on ART, ART non-adherence, and recent sexually transmitted infections (STIs). RESULTS: Among 2189 HIV-diagnosed MSM (87% on ART), prevalence of any CLS in the past 3 months was 38.2% (95% CI 36.2% to 40.4%) and that of any CLS-D was 16.3% (14.8%–17.9%). The five-category classification was as follows: (1) Higher HIV risk CLS-D: 4.2% (3.5% to 5.2%), (2) Other CLS-D: 12.1% (10.8% to 13.5%), (3) CLS-C without CLS-D: 21.9% (20.2% to 23.7%), (4) Condom-protected sex only: 25.4% (23.6% to 27.3%) and (5) No anal or vaginal sex: 36.4% (34.3% to 38.4%). Compared with men who reported condom-protected sex only, MSM who reported any CLS in the past 3 months had higher prevalence of STIs, chemsex-associated drug use, group sex, higher partner numbers, and lifetime hepatitis C. Prevalence of higher HIV risk CLS-D ranged from 4.2% to 7.5% according to criteria included. CONCLUSION: CLS was prevalent among HIV-diagnosed MSM, but CLS-D with higher HIV transmission risk was overall low. CLS-D is no longer the most appropriate measure of HIV transmission risk behaviour among people with diagnosed HIV; accounting for VL is important.

International Relations scholars have turned to China’s tributary system to broaden our understanding of international systems beyond the ‘states-under-anarchy’ model derived from European history. This scholarship forms the inspiration and foil for this article, which refines International Relations scholars’ conceptualizations of how international hierarchy arose and endured in East Asia during the Manchu Qing Dynasty — China’s last and most territorially expansive imperial dynasty. I argue that existing conceptions of East Asian hierarchy overstate the importance of mutual identification between the region’s Confucian monarchies in sustaining Chinese hegemony. Instead, we can understand Qing China’s dominance only once we recognize the Manchus as a ‘barbarian’ dynasty, which faced unique challenges legitimating its rule domestically and internationally. As ‘barbarian’ conquerors, Manchus did not secure their rule by simply conforming to pre-existing Sinic cultural norms. Instead, like other contemporary Eurasian empires, they maintained dominance through strategies of heterogeneous contracting. Domestically, they developed customized legitimacy scripts tailored to win the allegiance of the empire’s diverse communities. Internationally, meanwhile, the Manchus strategically appropriated existing Confucian norms and practices of tributary diplomacy in ways that mitigated — but did not eliminate — Confucian vassals’ resentment of ‘barbarian’ domination. East Asian hierarchy may have been more peaceful than Westphalian anarchy, but the absence of war masks a more coercive reality where the appearance of Confucian conformity obscured more fractious relations between Qing China and even its ostensibly most loyal vassals.