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Objectives: We provide the first estimate of HIV prevalence among trans and gender‐diverse people living in England and compare outcomes of people living with HIV according to gender identity. Methods: We analysed a comprehensive national HIV cohort and a nationally representative self‐reported survey of people accessing HIV care in England (Positive Voices). Gender identity was recorded using a two‐step question co‐designed with community members and civil society. Responses were validated by clinic follow‐up and/or self‐report. Population estimates were obtained from national government offices. Results: In 2017, HIV prevalence among trans and gender‐diverse people was estimated at 0.46–4.78 per 1000, compared with 1.7 (95% credible interval: 1.6–1.7) in the general population. Of 94 885 people living with diagnosed HIV in England, 178 (0.19%) identified as trans or gender‐diverse. Compared with cisgender people, trans and gender‐diverse people were more likely to be London residents (57% vs. 43%), younger (median age 42 vs. 46 years), of white ethnicity (61% vs. 52%), under psychiatric care (11% vs. 4%), to report problems with self‐care (37% vs. 13%), and to have been refused or delayed healthcare (23% vs. 11%). Antiretroviral uptake and viral suppression were high in both groups. Conclusions: HIV prevalence among trans and gender‐diverse people living in England is relatively low compared with international estimates. Furthermore, no inequalities were observed with regard to HIV care. Nevertheless, trans and gender‐diverse people with HIV report poorer mental health and higher levels of discrimination compared with cisgender people. [ABSTRACT FROM AUTHOR]

Objectives: Bivalent original/BA.4-5 and monovalent XBB.1.5 mRNA boosters were offered to UK healthcare workers (HCWs) in the autumn of 2023. We aimed to estimate booster vaccine effectiveness (VE) and post-infection immunity among the SIREN HCW cohort over the subsequent 6-month period of XBB.1.5 and JN.1 variant circulation., Methods: Between October 2023 to March 2024, 2867 SIREN study participants tested fortnightly for SARS-CoV-2 and completed symptoms questionnaires. We used multi-state models, adjusted for vaccination, prior infection, and demographic covariates, to estimate protection against mild/asymptomatic and moderate SARS-CoV-2 infection., Results: Half of the participants (1422) received a booster during October 2023 (280 bivalent, 1142 monovalent), and 536 (19%) had a PCR-confirmed infection over the study period. Bivalent booster VE was 15.1% (-55.4 to 53.6%) at 0-2 months and 4.2% (-46.4 to 37.3%) at 2-4 months post-vaccination. Monovalent booster VE was 44.2% (95% CI 21.7 to 60.3%) at 0-2 months, and 24.1% (-0.7 to 42.9%) at 2-4 months. VE was greater against moderate infection than against mild/asymptomatic infection, but neither booster showed evidence of protection after 4 months. Controlling for vaccination, compared to an infection >2 years prior, infection within the past 6 months was associated with 58.6% (30.3 to 75.4%) increased protection against moderate infection and 38.5% (5.8 to 59.8%) increased protection against mild/asymptomatic infection., Conclusions: Monovalent XBB.1.5 boosters provided short-term protection against SARS-CoV-2 infection, particularly against moderate symptoms. Vaccine formulations that target the circulating variant may be suitable for inclusion in seasonal vaccination campaigns among HCWs., Competing Interests: Declaration of Competing Interest All authors have completed the ICJME uniform disclosure form at: https://www.icmje.org/disclosure-of-interest/ and declare: CSB and SH report grant funding from the NIHR HPRU; CSB reports participation in an ad-hoc one-off market research advisory on a variety of infection topics; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

To develop a core outcome set for Achilles tendinopathy (COS-AT) for use in clinical trials we performed a five-step process including (1) a systematic review of available outcome measurement instruments, (2) an online survey on truth and feasibility of the available measurement instruments, (3) an assessment of the methodological quality of the selected outcome measurement instruments, (4) an online survey on the outcome measurement instruments as COS and (5) a consensus in-person meeting. Both surveys were completed by healthcare professionals and patients. The Outcome Measures in Rheumatology guidelines with a 70% threshold for consensus were followed. We identified 233 different outcome measurement instruments from 307 included studies; 177 were mapped within the International Scientific Tendinopathy Symposium Consensus core domains. 31 participants (12 patients) completed the first online survey (response rate 94%). 22/177 (12%) outcome measurement instruments were deemed truthful and feasible and their measurement properties were evaluated. 29 participants (12 patients) completed the second online survey (response rate 88%) and three outcome measurement instruments were endorsed: the Victorian Institute of Sports Assessment-Achilles questionnaire, the single-leg heel rise test and evaluating pain after activity using a Visual Analogue Scale (VAS, 0-10). 12 participants (1 patient) attended the final consensus meeting, and 1 additional outcome measurement instrument was endorsed: evaluating pain during activity/loading using a VAS (0-10). It is recommended that the identified COS-AT will be used in future clinical trials evaluating the effectiveness of an intervention. This will facilitate comparing outcomes of intervention strategies, data pooling and further progression of knowledge about AT. As COS-AT is implemented, further evidence on measurement properties of included measures and new outcome measurement instruments should lead to its review and refinement., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate if daily treatment with glyceryl trinitrate (GTN) ointment, over 24 weeks combined with a 12-week eccentric exercise programme is more effective for chronic mid-portion Achilles tendinopathy than placebo ointment and eccentric exercise., Methods: This was a single-site randomised double-blind placebo-controlled trial at an acute hospital, Dublin, Ireland. Patients with chronic mid-portion Achilles tendinopathy were randomised to either 24 weeks of daily GTN ointment or placebo ointment. Both groups received an identical 12-week eccentric exercise programme. The primary outcome measure was the Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire at 24 weeks, which measures pain, function and activity. Secondary outcomes included pain severity, self-reported physical function, calf muscle function, pressure pain thresholds and ultrasound changes. Statistical analyses were performed according to intention-to-treat principles., Results: 76 patients (30 women; 46 men, mean age±SD, 45.6±8.2 years) were recruited for the trial. Significant improvements in VISA-A scores occurred in both groups at 6-week, 12-week and 24-week follow-up. The increase was not significantly different between groups, adjusted mean between-group difference from baseline to week 6, -1.33 (95% CI -6.96 to 4.31); week 12, -1.25 (95% CI -8.0 to 5.49) and week 24, -3.8 (95% CI -10.6 to 3.0); negative values favour GTN. There was no significant between-group difference in any of the secondary outcome measures at 6, 12 and 24 weeks., Conclusions: Adding daily GTN ointment over 24 weeks to a 12-week eccentric exercise programme did not improve pain, function and activity level in patients with chronic mid-portion Achilles tendinopathy when compared with placebo ointment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The protection of fourth dose mRNA vaccination against SARS-CoV-2 is relevant to current global policy decisions regarding ongoing booster roll-out. We aimed to estimate the effect of fourth dose vaccination, prior infection, and duration of PCR positivity in a highly-vaccinated and largely prior-COVID-19 infected cohort of UK healthcare workers., Methods: Participants underwent fortnightly PCR and regular antibody testing for SARS-CoV-2 and completed symptoms questionnaires. A multi-state model was used to estimate vaccine effectiveness (VE) against infection from a fourth dose compared to a waned third dose, with protection from prior infection and duration of PCR positivity jointly estimated., Findings: 1298 infections were detected among 9560 individuals under active follow-up between September 2022 and March 2023. Compared to a waned third dose, fourth dose VE was 13.1% (95% CI 0.9 to 23.8) overall; 24.0% (95% CI 8.5 to 36.8) in the first 2 months post-vaccination, reducing to 10.3% (95% CI -11.4 to 27.8) and 1.7% (95% CI -17.0 to 17.4) at 2-4 and 4-6 months, respectively. Relative to an infection >2 years ago and controlling for vaccination, 63.6% (95% CI 46.9 to 75.0) and 29.1% (95% CI 3.8 to 43.1) greater protection against infection was estimated for an infection within the past 0-6, and 6-12 months, respectively. A fourth dose was associated with greater protection against asymptomatic infection than symptomatic infection, whilst prior infection independently provided more protection against symptomatic infection, particularly if the infection had occurred within the previous 6 months. Duration of PCR positivity was significantly lower for asymptomatic compared to symptomatic infection., Interpretation: Despite rapid waning of protection, vaccine boosters remain an important tool in responding to the dynamic COVID-19 landscape; boosting population immunity in advance of periods of anticipated pressure, such as surging infection rates or emerging variants of concern., Funding: UK Health Security Agency, Medical Research Council, NIHR HPRU Oxford, Bristol, and others., Competing Interests: We declare no competing interests. DCr reports participation on steering groups for the SIREN Scotland trial and TAVI UK trial and is a trustee of the Medical Schools Council of the UK. DDA reports attendance and travel expenses for MRC board/panel meetings and is a member of the Scientific Pandemic Influenza Advisory Committee, the steering group for SIREN Scotland; the MRC Infection Immunity board, the MRC Population Health Science Group, the MRC Better Methods for Better Research Panel, and the Joint Biosecurity Centre/UKHSA Data Science Advisory Board. CSB and SH report grant funding from the NIHR HPRU. CSB reports participation in an ad-hoc one-off market research advisory on a variety of infection topics., (Crown Copyright © 2023 Published by Elsevier Ltd.)

Tendinopathy and enthesitis share clinical, anatomical, and molecular parallels. However, their relationship is complex, presenting challenges in diagnosis and treatment. The biomechanics underlying these pathologies, together with relative immune and stromal contributions to pathology, are characterised by crucial comparative elements. However, methodologies used to study enthesitis and tendinopathy have been divergent, which could account for discrepancies in how these conditions are perceived and treated. In this Review, we summarise key clinical parallels between these two common presentations in musculoskeletal medicine and address factors that currently preclude development of more effective therapeutics. Furthermore, we describe molecular similarities and disparities that govern pathological mechanisms in tendinopathy and enthesitis, thus informing translational studies and treatment strategies., Competing Interests: Declaration of interests IBM has received consulting fees from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Causeway Therapeutics, Evelo Biosciences, Janssen, Eli Lilly, MoonLake, Novartis, Pfizer, and UCB. SS has received consultancy fees from AbbVie, Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, GSK, Janssen, Eli Lilly, Novartis, Pfizer, and UCB. NLM has received consulting fees from AbbVie, Causeway Therapeutics, Novartis, GSK, and Stryker. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: There is increasing interest in the use of electronic health records (EHRs) to improve the efficiency and cost-effectiveness of clinical trials, including the capture of outcome measures., Main Text: We describe our experience of using EHRs to capture the primary outcome measure - HIV infection or the diagnosis of HIV infection - in two randomised HIV prevention trials conducted in the UK. PROUD was a clinic-based trial evaluating pre-exposure prophylaxis (PrEP), and SELPHI was an internet-based trial evaluating HIV self-testing kits. The EHR was the national database of HIV diagnoses in the UK, curated by the UK Health Security Agency (UKHSA). In PROUD, linkage to the UKHSA database was performed at the end of the trial and identified five primary outcomes in addition to the 30 outcomes diagnosed by the participating clinics. Linkage also produced an additional 345 person-years follow-up, an increase of 27% over clinic-based follow-up. In SELPHI, new HIV diagnoses were primarily identified via UKHSA linkage, complemented by participant self-report through internet surveys. Rates of survey completion were low, and only 14 of the 33 new diagnoses recorded in the UKHSA database were also self-reported. Thus UKHSA linkage was essential for capturing HIV diagnoses and the successful conduct of the trial., Conclusions: Our experience of using the UKHSA database of HIV diagnoses as a source of primary outcomes in two randomised trials in the field of HIV prevention was highly favourable and encourages the use of a similar approach in future trials in this disease area., (© 2023. The Author(s).)

Objectives: Late HIV diagnosis (CD4 <350 cells/mm 3 ) is a key public health metric. In an era of more frequent testing, the likelihood of HIV diagnosis occurring during seroconversion, when CD4 counts may dip below 350, is greater. We applied a correction, considering markers of recent infection, and re-assessed 1-year mortality following late diagnosis., Methods: We used national epidemiological and laboratory surveillance data from all people diagnosed with HIV in England, Wales, and Northern Ireland (EW&NI). Those with a baseline CD4 <350 were reclassified as 'not late' if they had evidence of recent infection (recency test and/or negative test within 24 months). A correction factor (CF) was the number reclassified divided by the number with a CD4 <350., Results: Of the 32 227 people diagnosed with HIV in EW&NI between 2011 and 2019 with a baseline CD4 (81% of total), 46% had a CD4 <350 (uncorrected late diagnosis rate): 34% of gay and bisexual men (GBM), 65% of heterosexual men, and 56% of heterosexual women. Accounting for recency test and/or prior negative tests gave a 'corrected' late diagnosis rate of 39% and corresponding CF of 14%. The CF increased from 10% to 18% during 2011-2015, then plateaued, and was larger among GBM (25%) than heterosexual men and women (6% and 7%, respectively). One-year mortality among people diagnosed late was 329 per 10 000 after reclassification (an increase from 288/10 000)., Conclusions: The case-surveillance definition of late diagnosis increasingly overestimates late presentation, the extent of which differs by key populations. Adjustment of late diagnosis is recommended, particularly for frequent testers such as GBM., (© 2022 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Frozen shoulder is a common debilitating disorder characterized by shoulder pain and progressive loss of shoulder movement. Frozen shoulder is frequently associated with other systemic conditions or occurs following periods of immobilization, and has a protracted clinical course, which can be frustrating for patients as well as health-care professionals. Frozen shoulder is characterized by fibroproliferative tissue fibrosis, whereby fibroblasts, producing predominantly type I and type III collagen, transform into myofibroblasts (a smooth muscle phenotype), which is accompanied by inflammation, neoangiogenesis and neoinnervation, resulting in shoulder capsular fibrotic contractures and the associated clinical stiffness. Diagnosis is heavily based on physical examination and can be difficult depending on the stage of disease or if concomitant shoulder pathology is present. Management consists of physiotherapy, therapeutic modalities such as steroid injections, anti-inflammatory medications, hydrodilation and surgical interventions; however, their effectiveness remains unclear. Facilitating translational science should aid in development of novel therapies to improve outcomes among individuals with this debilitating condition., (© 2022. Springer Nature Limited.)

We compare two multi-state modelling frameworks that can be used to represent dates of events following hospital admission for people infected during an epidemic. The methods are applied to data from people admitted to hospital with COVID-19, to estimate the probability of admission to intensive care unit, the probability of death in hospital for patients before and after intensive care unit admission, the lengths of stay in hospital, and how all these vary with age and gender. One modelling framework is based on defining transition-specific hazard functions for competing risks. A less commonly used framework defines partially-latent subpopulations who will experience each subsequent event, and uses a mixture model to estimate the probability that an individual will experience each event, and the distribution of the time to the event given that it occurs. We compare the advantages and disadvantages of these two frameworks, in the context of the COVID-19 example. The issues include the interpretation of the model parameters, the computational efficiency of estimating the quantities of interest, implementation in software and assessing goodness of fit. In the example, we find that some groups appear to be at very low risk of some events, in particular intensive care unit admission, and these are best represented by using 'cure-rate' models to define transition-specific hazards. We provide general-purpose software to implement all the models we describe in the flexsurv R package, which allows arbitrarily flexible distributions to be used to represent the cause-specific hazards or times to events.

Widespread vaccination campaigns have changed the landscape for COVID-19, vastly altering symptoms and reducing morbidity and mortality. We estimate trends in mortality by month of admission and vaccination status among those hospitalised with COVID-19 in England between March 2020 to September 2021, controlling for demographic factors and hospital load. Among 259,727 hospitalised COVID-19 cases, 51,948 (20.0%) experienced mortality in hospital. Hospitalised fatality risk ranged from 40.3% (95% confidence interval 39.4-41.3%) in March 2020 to 8.1% (7.2-9.0%) in June 2021. Older individuals and those with multiple co-morbidities were more likely to die or else experienced longer stays prior to discharge. Compared to unvaccinated people, the hazard of hospitalised mortality was 0.71 (0.67-0.77) with a first vaccine dose, and 0.56 (0.52-0.61) with a second vaccine dose. Compared to hospital load at 0-20% of the busiest week, the hazard of hospitalised mortality during periods of peak load (90-100%), was 1.23 (1.12-1.34). The prognosis for people hospitalised with COVID-19 in England has varied substantially throughout the pandemic and according to case-mix, vaccination, and hospital load. Our estimates provide an indication for demands on hospital resources, and the relationship between hospital burden and outcomes., (© 2022. The Author(s).)

Introduction: Understanding the effectiveness and durability of protection against SARS-CoV-2 infection conferred by previous infection and COVID-19 is essential to inform ongoing management of the pandemic. This study aims to determine whether prior SARS-CoV-2 infection or COVID-19 vaccination in healthcare workers protects against future infection., Methods and Analysis: This is a prospective cohort study design in staff members working in hospitals in the UK. At enrolment, participants are allocated into cohorts, positive or naïve, dependent on their prior SARS-CoV-2 infection status, as measured by standardised SARS-CoV-2 antibody testing on all baseline serum samples and previous SARS-CoV-2 test results. Participants undergo monthly antibody testing and fortnightly viral RNA testing during follow-up and based on these results may move between cohorts. Any results from testing undertaken for other reasons (eg, symptoms, contact tracing) or prior to study entry will also be captured. Individuals complete enrolment and fortnightly questionnaires on exposures, symptoms and vaccination. Follow-up is 12 months from study entry, with an option to extend follow-up to 24 months.The primary outcome of interest is infection with SARS-CoV-2 after previous SARS-CoV-2 infection or COVID-19 vaccination during the study period. Secondary outcomes include incidence and prevalence (both RNA and antibody) of SARS-CoV-2, viral genomics, viral culture, symptom history and antibody/neutralising antibody titres., Ethics and Dissemination: The study was approved by the Berkshire Research Ethics Committee, Health Research Authority (IRAS ID 284460, REC reference 20/SC/0230) on 22 May 2020; the vaccine amendment was approved on 12 January 2021. Participants gave informed consent before taking part in the study.Regular reports to national and international expert advisory groups and peer-reviewed publications ensure timely dissemination of findings to inform decision making., Trial Registration Number: ISRCTN11041050., Competing Interests: Competing interests: MZ has unremunerated positions as ISIRV Chair, Member of NERVTAG, SAGE and JCVI and codirector NIHR HPRU, Imperial College London. TB receives funding from the UKRI for the SIREN study. MR’s team in the UKHSA Immunisation Department provides vaccine manufacturers (including Pfizer) with postmarketing surveillance reports about pneumococcal and meningococcal disease which the companies are required to submit to the UK Licensing authority in compliance with their Risk Management Strategy. A cost recovery charge is made for these reports. Other authors have no competing interests to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Crescents are not a well recognised feature of diabetic nephropathy. We present two cases of patients presenting with a rapid decline in renal function and subacute onset of nephrotic syndrome. Glomerulonephritis screening was negative, and renal biopsy revealed non-necrotising cellular crescents and typical features of late-stage diabetic nephropathy. We review the literature for diabetic nephropathy with crescents and explore possible underlying mechanisms., (© 2022 Royal Australasian College of Physicians.)

The physiological effects of physical exercise are ubiquitously reported as beneficial to the cardiovascular and musculoskeletal systems. Exercise is widely promoted by medical professionals to aid both physical and emotional wellbeing; however, mechanisms through which this is achieved are less well understood. Despite numerous beneficial attributes, certain types of exercise can inflict significant significant physiological stress. Several studies document a key relationship between exercise and immune activation. Activation of the innate immune system occurs in response to exercise and it is proposed this is largely mediated by cytokine signalling. Cytokines are typically classified according to their inflammatory properties and evidence has shown that cytokines expressed in response to exercise are diverse and may act to propagate, modulate or mitigate inflammation in musculoskeletal health. The review summarizes the existing literature on the relationship between exercise and the immune system with emphasis on how exercise-induced cytokine expression modulates inflammation and the immune response., (© 2022. The Author(s).)

Background: Migrant populations are overrepresented among persons diagnosed with HIV in the European Union and the European Economic Area. Understanding the timing of HIV acquisition (premigration or postmigration) is crucial for developing public health interventions and for producing reliable estimates of HIV incidence and the number of people living with undiagnosed HIV infection. We summarize a recently proposed method for determining the timing of HIV acquisition and apply it to both real and simulated data., Methods: The considered method combines estimates from a mixed model, applied to data from a large seroconverters' cohort, with biomarker measurements and individual characteristics to derive probabilities of premigration HIV acquisition within a Bayesian framework. The method is applied to a subset of data from the European Surveillance System (TESSy) and simulated data., Findings: Simulation study results showed good performance with the probabilities of correctly classifying a premigration case or a postmigration case being 87.4% and 80.4%, respectively. Applying the method to TESSy data, we estimated the proportions of migrants who acquired HIV in the destination country were 31.9%, 37.1%, 45.3%, and 45.2% for those originating from Africa, Europe, Asia, and other regions, respectively., Conclusions: Although the considered method was initially developed for cases with multiple biomarkers' measurements, its performance, when applied to data where only one CD4 count per individual is available, remains satisfactory. Application of the method to TESSy data, estimated that a substantial proportion of HIV acquisition among migrants occurs in destination countries, having important implications for public health policy and programs., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: A target to eliminate HIV transmission in England by 2030 was set in early 2019. This study aimed to estimate trends from 2013 to 2019 in HIV prevalence, particularly the number of people living with undiagnosed HIV, by exposure group, ethnicity, gender, age group, and region. These estimates are essential to monitor progress towards elimination., Methods: A Bayesian synthesis of evidence from multiple surveillance, demographic, and survey datasets relevant to HIV in England was used to estimate trends in the number of people living with HIV, the proportion of people unaware of their HIV infection, and the corresponding prevalence of undiagnosed HIV. All estimates were stratified by exposure group, ethnicity, gender, age group (15-34, 35-44, 45-59, or 60-74 years), region (London, or outside of London) and year (2013-19)., Findings: The total number of people living with HIV aged 15-74 years in England increased from 83 500 (95% credible interval 80 200-89 600) in 2013 to 92 800 (91 000-95 600) in 2019. The proportion diagnosed steadily increased from 86% (80-90%) to 94% (91-95%) during the same time period, corresponding to a halving in the number of undiagnosed infections from 11 600 (8300-17 700) to 5900 (4400-8700) and in undiagnosed prevalence from 0·29 (0·21-0·44) to 0·14 (0·11-0·21) per 1000 population. Similar steep declines were estimated in all subgroups of gay, bisexual, and other men who have sex with men and in most subgroups of Black African heterosexuals. The pace of reduction was less pronounced for heterosexuals in other ethnic groups and people who inject drugs, particularly outside London; however, undiagnosed prevalence in these groups has remained very low., Interpretation: The UNAIDS target of diagnosing 90% of people living with HIV by 2020 was reached by 2016 in England, with the country on track to achieve the new target of 95% diagnosed by 2025. Reductions in transmission and undiagnosed prevalence have corresponded to large scale-up of testing in key populations and early diagnosis and treatment. Additional and intensified prevention measures are required to eliminate transmission of HIV among the communities that have experienced slower declines than other subgroups, despite having very low prevalences of HIV., Funding: UK Medical Research Council and Public Health England., Competing Interests: Declaration of interests HM was a PHE technical advisor on the UK National Institute for Health and Care Excellence pending guideline on Reducing sexually transmitted infections (GID-NG10142). All other authors declare no competing interests., (This is an open access article under the CC BY-NC-ND license.)

Background: The 7-valent and 13-valent pneumococcal conjugate vaccines (PCVs) were introduced into the UK childhood immunization program in 2006 and 2010, respectively, with high effectiveness and resulting in both direct and indirect protection. We describe the epidemiology of invasive pneumococcal disease (IPD) in adults with human immunodeficiency virus (HIV) in England following the introduction of both PCVs., Methods: Data on a national cohort of people with HIV were linked to confirmed IPD cases in adults aged ≥ 15 years during 1999-2017. Date of HIV infection was estimated using a CD4 slope decline algorithm., Results: Among 133 994 adults with HIV, 1453 developed IPD during 1999-2017, with 70% (1016/1453) developing IPD ≥ 3 months after their HIV diagnosis. IPD and HIV were codiagnosed within 90 days in 345 (24%) individuals. A missed opportunity for earlier HIV diagnosis was identified in 6% (89/1453), mostly in earlier years. IPD incidence in people with HIV increased from 147/100 000 in 1999 to 284/100 000 in 2007 before declining and stabilizing between 92 and 113/100 000 during 2014-2017. Mean annual IPD incidence was lower among those receiving antiretroviral therapy during 2014-17 (68 vs 720/100 000; incidence rate ratio [IRR] 9.3; 95% confidence interval [CI], 7.3-11.8; P < .001) and was markedly lower in those with a suppressed viral load (50 vs 523/100 000; IRR 10.4; 95% CI, 7.6-14.1; P < .001). The latter group still had 4.5-fold higher (95% CI, 3.8-5.3; P < .001) IPD incidence compared to the general population (11.2/100 000)., Conclusions: IPD incidence among people with HIV reduced after PCV13 introduction and has remained stable. Adults presenting with IPD should continue to be tested for HIV infection., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Screening for SARS-CoV-2 antibodies is under way in some key worker groups; how this adds to self-reported COVID-19 illness is unclear. In this study, we investigate the association between self-reported belief of COVID-19 illness and seropositivity., Methods: Cross-sectional study of three key worker streams comprising (A) Police and Fire & Rescue (2 sites) (B) healthcare workers (1 site) and (C) healthcare workers with previously positive PCR result (5 sites). We collected self-reported signs and symptoms of COVID-19 and compared this with serology results from two SARS-CoV-2 immunoassays (Roche Elecsys® and EUROIMMUN)., Results: Between 01 and 26 June, we recruited 2847 individuals (Stream A: 1,247, Stream B: 1,546 and Stream C: 154). Amongst those without previous positive PCR tests, 687/2,579 (26%) reported belief they had COVID-19, having experienced compatible symptoms; however, only 208 (30.3%) of these were seropositive on both immunoassays. Both immunoassays had high sensitivities relative to previous PCR positivity (>93%); there was also limited decline in antibody titres up to 110 days post symptom onset. Symptomatic but seronegative individuals had differing symptom profiles and shorter illnesses than seropositive individuals., Conclusion: Non-COVID-19 respiratory illness may have been mistaken for COVID-19 during the outbreak; laboratory testing is more specific than self-reported key worker beliefs in ascertaining past COVID-19 disease., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Increased understanding of whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection is an urgent requirement. We aimed to investigate whether antibodies against SARS-CoV-2 were associated with a decreased risk of symptomatic and asymptomatic reinfection., Methods: A large, multicentre, prospective cohort study was done, with participants recruited from publicly funded hospitals in all regions of England. All health-care workers, support staff, and administrative staff working at hospitals who could remain engaged in follow-up for 12 months were eligible to join The SARS-CoV-2 Immunity and Reinfection Evaluation study. Participants were excluded if they had no PCR tests after enrolment, enrolled after Dec 31, 2020, or had insufficient PCR and antibody data for cohort assignment. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2-4 weeks) and completed questionnaires every 2 weeks on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive, or previous positive PCR or antibody test) or negative cohort (antibody negative, no previous positive PCR or antibody test). The primary outcome was a reinfection in the positive cohort or a primary infection in the negative cohort, determined by PCR tests. Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, or possible) and symptom-status, depending on the hierarchy of evidence. Primary infections in the negative cohort were defined as a first positive PCR test and seroconversions were excluded when not associated with a positive PCR test. A proportional hazards frailty model using a Poisson distribution was used to estimate incidence rate ratios (IRR) to compare infection rates in the two cohorts., Findings: From June 18, 2020, to Dec 31, 2020, 30 625 participants were enrolled into the study. 51 participants withdrew from the study, 4913 were excluded, and 25 661 participants (with linked data on antibody and PCR testing) were included in the analysis. Data were extracted from all sources on Feb 5, 2021, and include data up to and including Jan 11, 2021. 155 infections were detected in the baseline positive cohort of 8278 participants, collectively contributing 2 047 113 person-days of follow-up. This compares with 1704 new PCR positive infections in the negative cohort of 17 383 participants, contributing 2 971 436 person-days of follow-up. The incidence density was 7·6 reinfections per 100 000 person-days in the positive cohort, compared with 57·3 primary infections per 100 000 person-days in the negative cohort, between June, 2020, and January, 2021. The adjusted IRR was 0·159 for all reinfections (95% CI 0·13-0·19) compared with PCR-confirmed primary infections. The median interval between primary infection and reinfection was more than 200 days., Interpretation: A previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection, with median protective effect observed 7 months following primary infection. This time period is the minimum probable effect because seroconversions were not included. This study shows that previous infection with SARS-CoV-2 induces effective immunity to future infections in most individuals., Funding: Department of Health and Social Care of the UK Government, Public Health England, The National Institute for Health Research, with contributions from the Scottish, Welsh and Northern Irish governments., Competing Interests: Declaration of interests We declare no competing interests., (Crown copyright © 2021 Published by Elsevier Ltd. All rights reserved.)

Tendinopathy describes a complex multifaceted pathology of the tendon, characterized by pain, decline in function and reduced exercise tolerance. The most common overuse tendinopathies involve the rotator cuff tendon, medial and lateral elbow epicondyles, patellar tendon, gluteal tendons and the Achilles tendon. The prominent histological and molecular features of tendinopathy include disorganization of collagen fibres, an increase in the microvasculature and sensory nerve innervation, dysregulated extracellular matrix homeostasis, increased immune cells and inflammatory mediators, and enhanced cellular apoptosis. Although diagnosis is mostly achieved based on clinical symptoms, in some cases, additional pain-provoking tests and imaging might be necessary. Management consists of different exercise and loading programmes, therapeutic modalities and surgical interventions; however, their effectiveness remains ambiguous. Future research should focus on elucidating the key functional pathways implicated in clinical disease and on improved rehabilitation protocols.

Objective: To produce a best evidence synthesis of the clinical effects of topical glyceryl trinitrate (GTN) in the treatment of tendinopathies., Design: A systematic review of published randomised controlled trials (RCTs) of the use of GTN in patients with tendinopathy., Data Sources: MEDLINE, Embase, Scopus and CINAHL from database inception to January 2018., Methods: We examined RCTs comparing the effects of topical GTN with either placebo or other treatments on tendinopathy. Overall quality of each eligible study was determined based on a combined assessment of internal validity, external validity and precision. The level of evidence for each assessed parameter was rated based on the system by van Tulder et al ., Results: A total of 10 eligible RCTs were identified including patients with tendinopathy of the rotator cuff (n=4), wrist extensors (n=3), Achilles (n=2) and patellar (n=1) tendons. For all tendinopathies, improvements in pain were significant when comparing GTN versus placebo in the short term (<8 weeks; poor evidence). Significant improvements in midterm outcomes for treatment with GTN versus placebo included the following: patient satisfaction (strong evidence); chances of being asymptomatic with activities of daily living (strong evidence); range of movement (moderate evidence); strength (moderate evidence); pain (at night and with activity; poor evidence) and local tenderness (poor evidence). Patients treated with topical GTN reported a higher incidence of headaches than those who received placebo (moderate evidence)., Conclusions and Relevance: Treatment of tendinopathies with topical GTN for up to 6 months appears to be superior to placebo and may therefore be a useful adjunct to the treating healthcare professions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Since October 2015 up to September 2016, HIV diagnoses fell by 32% compared with October 2014-September 2015 among men who have sex with men (MSM) attending selected London sexual health clinics. This coincided with high HIV testing volumes and rapid initiation of treatment on diagnosis. The fall was most apparent in new HIV testers. Intensified testing of high-risk populations, combined with immediately received anti-retroviral therapy and a pre-exposure prophylaxis (PrEP) programme, may make elimination of HIV achievable., (This article is copyright of The Authors, 2017.)

We report a previously undescribed inflammatory lesion consisting of deposition of activated complement (C3d and C9neo) in association with major histocompatibility complex type II (MHC2)-positive activated microglia in choroid plexus villi exhibiting classical fibrous thickening of the pericapillary filtration membrane. The proportion of villi affected ranged from 5% to 90% in 56 adult subjects with diseases of the CNS and 11 subjects with no preexisting disease of the CNS. In 3 of the 4 children studied, 2% or less of examined villi showed stromal thickening, complement deposition, and the presence of MHC2-positive microglia; in adults, the proportion of villi affected increased with age. Other features of the lesion included loss of capillaries and failure by macrophages to clear extracellular particulate electron-dense material by clathrin-mediated phagocytosis. This choroid plexus lesion may relate pathogenetically to age-related macular degeneration and to Alzheimer disease, 2 other conditions with no known risk factors other than increasing age. All 3 conditions are characterized by the presence of damaged capillaries, inflammatory extracellular aggregates of mixed molecular composition and defective clearance of the deposits by macrophages., (© 2016 Oxford University Press OR American Association of Neuropathologists.)

Unlabelled: Diabetic renal disease is characterized by accumulation of extracellular matrix, glomerulosclerosis, and tubulointerstitial fibrosis. Connective tissue growth factor (CTGF) is implicated in these changes, as it contributes to new matrix synthesis and is increased in the diabetic kidney. CTGF also inhibits mesangial matrix degradation through up-regulation of the tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). In a non-human primate model of diabetes, we determined whether the level of renal CTGF protein before development of albuminuria correlated with renal matrix and TIMP-1 changes and whether renal CTGF predicts progression to albuminuria., Methods: In a group of diabetic (n=9) and control (n=6) baboons after a 5-year duration of diabetes, renal tissue CTGF and TIMP-1 were detected by immunohistochemistry and compared with glomerular basement membrane (GBM) thickness and mesangial volume measurements from electron photomicrographs of renal biopsies. Urinary albumin levels were measured at 5 and 10 years of diabetes., Results: GBM thickness, CTGF protein, and TIMP-1 protein were increased after 5 years of diabetes (each P<.05). Tubular fibronectin scores correlated with tubular CTGF scores (r=0.72, P=.002). In diabetic animals, GBM thickness correlated with tubular and total CTGF levels (P=.002 and P=.04, respectively), whereas mesangial cell and total matrix volume correlated with glomerular TIMP-1 (P=.02 and P=.01, respectively). Tubular CTGF scores (P=.008) and GBM thickness (P=.03) at 5 years in diabetes each predicted the degree of albuminuria at 10 years., Conclusions: These results suggest that early increases in renal CTGF protein contribute to incipient diabetic nephropathy and that renal CTGF may have utility as an early marker for progression to dysfunction in the diabetic kidney.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of antibodies directed against self antigens. Immune complex glomerulonephritis (GN) is one of the most serious complications of this disorder and can lead to potentially fatal renal failure. The aetiology of SLE is complex and multifactorial, characterized by interacting environmental and genetic factors. Here we examine the nature of the renal pathology in mycobacteria-treated non-obese diabetic (NOD) mice, in order to assess its suitability as a model for studying the aetiopathogenesis of, and possible treatment options for, lupus nephritis (LN) in humans. Both global and segmental proliferative lesions, characterized by increased mesangial matrix and cellularity, were demonstrated on light microscopy, and lesions varied in severity from very mild mesangiopathic GN through to obliteration of capillary lumina and glomerular sclerosis. Mixed isotype immune complexes (IC) consisting of immunoglobulin G (IgG), IgM, IgA and complement C3c were detected using direct immunofluorescence. They were deposited in multiple sites within the glomeruli, as confirmed by electron microscopy. The GN seen in mycobacteria-treated NOD mice therefore strongly resembles the pathology seen in human LN, including mesangiopathic, mesangiocapillary and membranous subclasses of LN. The development of spontaneous mixed isotype IC in the glomeruli of some senescent NOD mice suggests that mycobacterial exposure is accelerating, rather than inducing, the development of GN in this model.

Thirteen cases of various natures, selected from a collection shown and discussed at Ultrapath VI, are presented in quiz format for recognition or diagnosis.