Abstract Background Randomized controlled trials (RCTs) from low- and middle-income settings suggested that early initiation of antiretroviral therapy (ART) leads to higher mortality rates among people with HIV (PWH) who present with cryptococcal meningitis (CM). There is limited information about the impact of ART timing on mortality rates in similar people in high-income settings. Methods Data on ART-naive PWH with CM diagnosed from 1994 to 2012 from Europe/North America were pooled from the COHERE, NA-ACCORD, and CNICS HIV cohort collaborations. Follow-up was considered to span from the date of CM diagnosis to earliest of the following: death, last follow-up, or 6 months. We used marginal structural models to mimic an RCT comparing the effects of early (within 14 days of CM) and late (14–56 days after CM) ART on all-cause mortality, adjusting for potential confounders. Results Of 190 participants identified, 33 (17%) died within 6 months. At CM diagnosis, their median age (interquartile range) was 38 (33–44) years; the median CD4+ T-cell count, 19/μL (10–56/μL); and median HIV viral load, 5.3 (4.9–5.6) log10 copies/mL. Most participants (n = 157 [83%]) were male, and 145 (76%) started ART. Mimicking an RCT, with 190 people in each group, there were 13 deaths among participants with an early ART regimen and 20 deaths among those with a late ART regimen. The crude and adjusted hazard ratios comparing late with early ART were 1.28 (95% confidence interval, .64–2.56) and 1.40 (.66–2.95), respectively. Conclusions We found little evidence that early ART was associated with higher mortality rates among PWH presenting with CM in high-income settings, although confidence intervals were wide.

Background: Chronic fatigue syndrome (CFS) is relatively common and disabling. Over 8000 patients attend adult services each year, yet little is known about the outcome of patients attending NHS services.Aim: Investigate the outcome of patients with CFS and what factors predict outcome.Design: Longitudinal patient cohort.Methods: We used data from six CFS/ ME (myalgic encephalomyelitis) specialist services to measure changes in fatigue (Chalder Fatigue Scale), physical function (SF-36), anxiety and depression (Hospital Anxiety and Depression Scale) and pain (visual analogue pain rating scale) between clinical assessment and 8-20 months of follow-up. We used multivariable linear regression to investigate baseline factors associated with outcomes at follow-up.Results: Baseline data obtained at clinical assessment were available for 1643 patients, of whom 834 (51%) had complete follow-up data. There were improvements in fatigue [ mean difference from assessment to outcome: - 6.8; 95% confidence interval (CI) - 7.4 to - 6.2; P < 0.001]; physical function (4.4; 95% CI 3.0-5.8; P < 0.001), anxiety (- 0.6; 95% CI - 0.9 to - 0.3; P < 0.001), depression (- 1.6; 95% CI - 1.9 to - 1.4; P < 0.001) and pain (- 5.3; 95% CI - 7.0 to - 3.6; P < 0.001). Worse fatigue, physical function and pain at clinical assessment predicted a worse outcome for fatigue at follow-up. Older age, increased pain and physical function at assessment were associated with poorer physical function at follow-up.Conclusions: Patients who attend NHS specialist CFS/ ME services can expect similar improvements in fatigue, anxiety and depression to participants receiving cognitive behavioural therapy and graded exercise therapy in a recent trial, but are likely to experience less improvement in physical function. Outcomes were predicted by fatigue, disability and pain at assessment.

Background Epigenetic clocks are biomarkers of ageing derived from DNA methylation levels at a subset of CpG sites. The difference between age predicted by these clocks and chronological age, termed “epigenetic age acceleration”, has been shown to predict age-related disease and mortality. We aimed to assess the prognostic value of epigenetic age acceleration and a DNA methylation-based mortality risk score with all-cause mortality in a prospective clinical cohort of individuals with head and neck cancer: Head and Neck 5000. We investigated two markers of intrinsic epigenetic age acceleration ( IEAAHorvath and IEAAHannum ), one marker of extrinsic epigenetic age acceleration ( EEAA ), one optimised to predict physiological dysregulation ( AgeAccelPheno ), one optimised to predict lifespan ( AgeAccelGrim ) and a DNA methylation-based predictor of mortality ( ZhangScore ). Cox regression models were first used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations of epigenetic age acceleration with all-cause mortality in people with oropharyngeal cancer ( n = 408; 105 deaths). The added prognostic value of epigenetic markers compared to a clinical model including age, sex, TNM stage and HPV status was then evaluated. Results IEAAHannum and AgeAccelGrim were associated with mortality risk after adjustment for clinical and lifestyle factors (HRs per standard deviation [SD] increase in age acceleration = 1.30 [95% CI 1.07, 1.57; p = 0.007] and 1.40 [95% CI 1.06, 1.83; p = 0.016], respectively). There was weak evidence that the addition of AgeAccelGrim to the clinical model improved 3-year mortality prediction (area under the receiver operating characteristic curve: 0.80 vs. 0.77; p value for difference = 0.069). Conclusion In the setting of a large, clinical cohort of individuals with head and neck cancer, our study demonstrates the potential of epigenetic markers of ageing to enhance survival prediction in people with oropharyngeal cancer, beyond established prognostic factors. Our findings have potential uses in both clinical and non-clinical contexts: to aid treatment planning and improve patient stratification.

Background and aims: Recent research demonstrated that obesity and high dietary sodium intake, the two established risk factors for hypertension, were associated with each other. The objective was to investigate the potential indirect effect of sodium intake on blood pressure via body mass index (BMI). Methods and results: Using ten years data from US NHANES (2007-2016), the study included adult participants (>20 years old) who were not taking antihypertensive medications and without baseline diseases (n = 12,262). BMI was modelled as the mediator of sodium intake on systolic and diastolic blood pressure, adjusted for age, sex, socioeconomic status, smoking, drinking, physical activity, calorie intake, fluid intake and potassium intake. Mediation analysis was performed to evaluate total effect, direct effect and indirect effect via BMI. Subgroup analyses based on three age subgroups (20-40, 41-60 and >= 61 years old) were performed. The mean age was 39.29 (13.4) years and 53.1 (0.45) % were males. The mean BMI was 27.8 (6.20) kg/m(2). Overall, 1 g/d increase in sodium intake was associated with an increased systolic blood pressure by 0.36 (95% confidence interval 0.14 to 0.58) mmHg, with a direct effect (0.14 (0.09-0.19)) and an indirect effect via BMI (0.23 (0.02-0.4 4)). The indirect effect was mainly observed in participants <= 60 years old. Conclusion: Sodium intake showed both direct effect and indirect effect (via BMI) on systolic blood pressure in US NHANES. The findings provide evidence for combining sodium restriction and weight reduction measures for prevention of hypertension. Cautions should be taken when generalizing the findings to other populations with lower average BMI. (C) 2021 Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University.

Objectives To confirm the association of previously reported prognostic factors with future progression of localised prostate cancer using primary care data and identify new potential prognostic factors for further assessment in prognostic model development and validation. Design Retrospective cohort study, employing Cox proportional hazards regression controlling for age, prostate specific antigen (PSA), and Gleason score, was stratified by diagnostic stage. Setting Primary care in England. Participants Males with localised prostate cancer diagnosedbetween 01/01/1987 and 31/12/2016 within the Clinical Practice ResearchDatalink database, with linked data from the National Cancer Registration andAnalysis Service and Office for National Statistics. Primary and secondary outcomes Primary outcome measure was prostate cancer mortality. Secondary outcome measures were all-cause mortality and commencing systemic therapy. Up-staging after diagnosis was not used as a secondary outcome owing to significant missing data. Results 10 901 men (mean age 74.38±9.03 years) with localised prostate cancer were followed up for a mean of 14.12 (±6.36) years. 2331 (21.38%) men underwent systemic therapy and 3450 (31.65%) died, including 1250 (11.47%) from prostate cancer. Factors associated with an increased risk of prostate cancer mortality included age; high PSA; current or ex-smoker; ischaemic heart disease; high C reactive protein; high ferritin; low haemoglobin; high blood glucose and low albumin. Conclusions This study identified several new potential prognostic factors for prostate cancer progression, as well as confirming some known prognostic factors, in an independent primary care data set. Further research is needed to develop and validate a prognostic model for prostate cancer progression.

In patient follow‐up studies, events of interest may take place between periodic clinical assessments and so the exact time of onset is not observed. Such events are known as “bounded” or “interval‐censored.” Methods for handling such events can be categorized as either (i) applying multiple imputation (MI) strategies or (ii) taking a full likelihood‐based (LB) approach. We focused on MI strategies, rather than LB methods, because of their flexibility. We evaluated MI strategies for bounded event times in a competing risks analysis, examining the extent to which interval boundaries, features of the data distribution and substantive analysis model are accounted for in the imputation model. Candidate imputation models were predictive mean matching (PMM); log‐normal regression with postimputation back‐transformation; normal regression with and without restrictions on the imputed values and Delord and Genin's method based on sampling from the cumulative incidence function. We used a simulation study to compare MI methods and one LB method when data were missing at random and missing not at random, also varying the proportion of missing data, and then applied the methods to a hematopoietic stem cell transplantation dataset. We found that cumulative incidence and median event time estimation were sensitive to model misspecification. In a competing risks analysis, we found that it is more important to account for features of the data distribution than to restrict imputed values based on interval boundaries or to ensure compatibility with the substantive analysis by sampling from the cumulative incidence function. We recommend MI by type 1 PMM.

High systolic blood pressure (SBP) causes cardiovascular disease (CVD) and is associated with mortality from other causes, but conventional multivariably-adjusted results may be confounded. Here we used a son’s SBP (>1 million Swedish men) as an instrumental variable for parental SBP and examined associations with parents’ cause-specific mortality, avoiding reverse causation. The hazard ratio for CVD mortality per SD (10.80 mmHg) of SBP was 1.49 (95% CI: 1.43, 1.56); SBP was positively associated with coronary heart disease and stroke. SBP was also associated positively with all-cause, diabetes and kidney cancer mortality, and negatively with external causes. Negative associations with respiratory-related mortality were probably confounded by smoking. Hazard ratios for other causes were imprecise or null. Diastolic blood pressure gave similar results to SBP. CVD hazard ratios were intermediate between those from conventional multivariable studies and Mendelian randomization and stronger than those from clinical trials, approximately consistent with an effect of exposure duration on effect sizes. Plots of parental mortality against offspring SBP were approximately linear, supporting calls for lower SBP targets. Results suggest that conventional multivariable analyses of mortality and SBP are not substantially confounded by reverse causation and confirm positive effects of SBP on all-cause, CVD and diabetes mortality.

BACKGROUND:The WHO elimination strategy for hepatitis C virus advocates scaling up screening and treatment to reduce global hepatitis C incidence by 80% by 2030, but little is known about how this reduction could be achieved and the costs of doing so. We aimed to evaluate the effects and cost of different strategies to scale up screening and treatment of hepatitis C in Pakistan and determine what is required to meet WHO elimination targets for incidence. METHODS:We adapted a previous model of hepatitis C virus transmission, treatment, and disease progression for Pakistan, calibrating using available data to incorporate a detailed cascade of care for hepatitis C with cost data on diagnostics and hepatitis C treatment. We modelled the effect on various outcomes and costs of alternative scenarios for scaling up screening and hepatitis C treatment in 2018-30. We calibrated the model to country-level demographic data for 1960-2015 (including population growth) and to hepatitis C seroprevalence data from a national survey in 2007-08, surveys among people who inject drugs (PWID), and hepatitis C seroprevalence trends among blood donors. The cascade of care in our model begins with diagnosis of hepatitis C infection through antibody screening and RNA confirmation. Diagnosed individuals are then referred to care and started on treatment, which can result in a sustained virological response (effective cure). We report the median and 95% uncertainty interval (UI) from 1151 modelled runs. FINDINGS:One-time screening of 90% of the 2018 population by 2030, with 80% referral to treatment, was projected to lead to 13·8 million (95% UI 13·4-14·1) individuals being screened and 350 000 (315 000-385 000) treatments started annually, decreasing hepatitis C incidence by 26·5% (22·5-30·7) over 2018-30. Prioritised screening of high prevalence groups (PWID and adults aged ≥30 years) and rescreening (annually for PWID, otherwise every 10 years) are likely to increase the number screened and treated by 46·8% and decrease incidence by 50·8% (95% UI 46·1-55·0). Decreasing hepatitis C incidence by 80% is estimated to require a doubling of the primary screening rate, increasing referral to 90%, rescreening the general population every 5 years, and re-engaging those lost to follow-up every 5 years. This approach could cost US$8·1 billion, reducing to $3·9 billion with lowest costs for diagnostic tests and drugs, including health-care savings, and implementing a simplified treatment algorithm. INTERPRETATION:Pakistan will need to invest about 9·0% of its yearly health expenditure to enable sufficient scale up in screening and treatment to achieve the WHO hepatitis C elimination target of an 80% reduction in incidence by 2030. FUNDING:UNITAID.

F. W. N. M., Bonnet, F., Cavassini, M., Abgrall, S., Berenguer, J., Wyen, C., Reiss, P., Grabmeier-Pfisterhammer, K., Guest, J. L., Shepherd, L., Teira, R., Monforte, A. D. A., Del Amo, J., Justice, A., ... Sterne, J. A. C. (2020). Cause-specific mortality after diagnosis of cancer among HIV-positive patients: a collaborative analysis of cohort studies. International Journal of Cancer, 146(11), 3134-3146. https://doi.org/10.1002/ijc.32895.

ObjectiveTo estimate the costs and outcomes associated with treating non-asthmatic adults (nor suffering from other lung-disease) presenting to primary care with acute lower respiratory tract infection (ALRTI) with oral corticosteroids compared with placebo.DesignCost-consequence analysis alongside a randomised controlled trial. Perspectives included the healthcare provider, patients and productivity losses associated with time off work.SettingFifty-four National Health Service (NHS) general practices in England.Participants398 adults attending NHS primary practices with ALRTI but no asthma or other chronic lung disease, followed up for 28 days.Interventions2× 20 mg oral prednisolone per day for 5 days versus matching placebo tablets.Outcome measuresQuality-adjusted life years using the 5-level EuroQol-5D version measured weekly; duration and severity of symptom. Direct and indirect resources related to the disease and its treatment were also collected. Outcomes were measured for the 28-day follow-up.Results198 (50%) patients received the intervention (prednisolone) and 200 (50%) received placebo. NHS costs were dominated by primary care contacts, higher with placebo than with prednisolone (£13.11 vs £10.38) but without evidence of a difference (95% CI £3.05 to £8.52). The trial medication cost of £1.96 per patient would have been recouped in prescription charges of £4.30 per patient overall (55% participants would have paid £7.85), giving an overall mean ‘profit’ to the NHS of £7.00 (95% CI £0.50 to £17.08) per patient. There was a quality adjusted life years gain of 0.03 (95% CI 0.01 to 0.05) equating to half a day of perfect health favouring the prednisolone patients; there was no difference in duration of cough or severity of symptoms.ConclusionsThe use of prednisolone for non-asthmatic adults with ALRTI, provided small gains in quality of life and cost savings driven by prescription charges. Considering the results of the economic evaluation and possible side effects of corticosteroids, the short-term benefits may not outweigh the long-term harms.Trial registration numbersEudraCT 2012-000851-15 and ISRCTN57309858; Pre-results.

People living with HIV (PLHIV) are more likely than the general population to develop AIDS-defining malignancies (ADMs) and several non-ADMs (NADMs). Information is lacking on survival outcomes and cause-specific mortality after cancer diagnosis among PLHIV. We investigated causes of death within 5 years of cancer diagnosis in PLHIV enrolled in European and North American HIV cohorts starting antiretroviral therapy (ART) 1996-2015, aged >= 16 years, and subsequently diagnosed with cancer. Cancers were grouped: ADMs, viral NADMs and nonviral NADMs. We calculated cause-specific mortality rates (MR) after diagnosis of specific cancers and compared 5-year survival with the UK and France general populations. Among 83,856 PLHIV there were 4,436 cancer diagnoses. Of 603 deaths after ADM diagnosis, 292 (48%) were due to an ADM. There were 467/847 (55%) and 74/189 (39%) deaths that were due to an NADM after nonviral and viral NADM diagnoses, respectively. MR were higher for diagnoses between 1996 and 2005 versus 2006-2015: ADMs 102 (95% CI 92-113) per 1,000 years versus 88 (78-100), viral NADMs 134 (106-169) versus 111 (93-133) and nonviral NADMs 264 (232-300) versus 226 (206-248). Estimated 5-year survival for PLHIV diagnosed with liver (29% [19-39%]), lung (18% [13-23%]) and cervical (75% [63-84%]) cancer was similar to general populations. Survival after Hodgkin's lymphoma diagnosis was lower in PLHIV (75% [67-81%]). Among ART-treated PLHIV diagnosed with cancer, MR and causes of death varied by cancer type, with mortality highest for liver and lung cancers. Deaths within 5 years of NADM diagnoses were more likely to be from cancer than AIDS.

Objectives To estimate trends in HIV testing, positivity and prevalence in UK primary care for 2000–2015 as part of a wider investigation into reasons for late diagnosis of HIV. Design Retrospective cohort study using the Clinical Practice Research Datalink (CPRD) which is derived from computerised clinical records produced during consultations in primary care. Setting 404 general practices in England. Participants 5 979 598 adults aged ≥16 years registered between 2000 and 2015 with 45 093 761 person years of observation. Outcomes Annual HIV testing rates, proportion of positive tests and prevalence of HIV-infected people recorded in primary care 2000–2015. Results HIV testing in primary care increased from 2000 to 2010, but then declined. Testing was higher in females than in males and in those aged 16–44 years compared with older adults. Rates per 100 000 in women aged 16–44 years were 177 (95% CI 167 to 188); 1309 (95% CI 1282 to 1336); 1789 (95% CI 1757 to 1821) and 839 (95% CI 817 to 862) in 2000, 2005, 2010 and 2015, respectively, and for non-pregnant women: 22.5 (95% CI 19 to 26); 134 (95% CI 125 to 143); 262 (95% CI 250 to 275); 190 (95% CI 179 to 201). For men aged 16–44 years rates were: 26 (95% CI 22 to 29); 107 (95% CI 100 to 115); 196 (95% CI 185 to 206); 137 (95% CI 127 to 146). Over the study period, there were approximately two positive results per 1000 HIV tests. Men were eightfold more likely to test positive than women. The percentage of HIV diagnoses among adults recorded in CPRD may be as low as 55% in London and 67% in the rest of the UK. Conclusions HIV testing rates in primary care peaked in 2010 and subsequently declined. Access to testing was higher for women despite the prevalence of HIV being higher in men. Implications and further research needed Opportunities remain in primary care for increasing HIV testing to prevent costly late diagnoses and decrease HIV transmission. Interventions to improve targeting of tests and increase adherence to HIV testing guidelines are needed in primary care.

Abstract Objective To evaluate the effects of four drug (quadruple) versus three drug (triple) combination antiretroviral therapies in treatment naive people with HIV, and explore the implications of existing trials for clinical practice and research. Design Systematic review and meta-analysis of randomised controlled trials. Data sources PubMed, EMBASE, CENTRAL, Web of Science, and the Cumulative Index to Nursing and Allied Health Literature from March 2001 to December 2016 (updated search in PubMed and EMBASE up to June 2018); and reference lists of eligible studies and related reviews. Study selection Randomised controlled trials comparing quadruple with triple combination antiretroviral therapies in treatment naive people with HIV and evaluating at least one effectiveness or safety outcome. Review methods Outcomes of interest included undetectable HIV-1 RNA, CD4 T cell count, virological failure, new AIDS defining events, death, and severe adverse effects. Random effects meta-analyses were conducted. Results Twelve trials (including 4251 people with HIV) were eligible. Quadruple and triple combination antiretroviral therapies had similar effects on all relevant effectiveness and safety outcomes, with no point estimates favouring quadruple therapy. With the triple therapy as the reference group, the risk ratio was 0.99 (95% confidence interval 0.93 to 1.05) for undetectable HIV-1 RNA, 1.00 (0.90 to 1.11) for virological failure, 1.17 (0.84 to 1.63) for new AIDS defining events, 1.23 (0.74 to 2.05) for death, and 1.09 (0.89 to 1.33) for severe adverse effects. The mean difference in CD4 T cell count increase between the two groups was −19.55 cells/μL (−43.02 to 3.92). In general, the results were similar, regardless of the specific regimens of combination antiretroviral therapies, and were robust in all subgroup and sensitivity analyses. Conclusion In this study, effects of quadruple combination antiretroviral therapy were not better than triple combination antiretroviral therapy in treatment naive people with HIV. This finding lends support to current guidelines recommending the triple regimen as first line treatment. Further trials on this topic should be conducted only when new research is justified by adequate systematic reviews of the existing evidence. However, this study cannot exclude the possibility that quadruple cART would be better than triple cART when new classes of antiretroviral drugs are made available.

Background: An increasing number of HIV-positive individuals now start antiretroviral therapy (ART) with high CD4 cell counts. We investigated whether this makes restoration of CD4 and CD8 cell counts and the CD4:CD8 ratio during virologically suppressive ART to median levels seen in HIV-uninfected individuals more likely and whether restoration depends on gender, age, and other individual characteristics. Methods: We determined median and quartile reference values for CD4 and CD8 cell counts and their ratio using cross-sectional data from 2309 HIV-negative individuals. We used longitudinal measurements of 60,997 HIV-positive individuals from the Antiretroviral Therapy Cohort Collaboration in linear mixed-effects models. Results: When baseline CD4 cell counts were higher, higher long-term CD4 cell counts and CD4:CD8 ratios were reached. Highest long-term CD4 cell counts were observed in middle-aged individuals. During the first 2 years, median CD8 cell counts converged toward median reference values. However, changes were small thereafter and long-term CD8 cell count levels were higher than median reference values. Median 8-year CD8 cell counts were higher when ART was started with <250 CD4 cells/mm3. Median CD4:CD8 trajectories did not reach median reference values, even when ART was started at 500 cells/mm3. Discussion: Starting ART with a CD4 cell count of ≥500 cells/mm3 makes reaching median reference CD4 cell counts more likely. However, median CD4:CD8 ratio trajectories remained below the median levels of HIV-negative individuals because of persisting high CD8 cell counts. To what extent these subnormal immunological responses affect specific clinical endpoints requires further investigation.

To better understand hepatitis C virus (HCV) epidemiology in Punjab state, India, we estimated the distribution of HCV antibody positivity (anti-HCV+) using a 2013–2014 HCV household seroprevalence survey. Household anti-HCV+ clustering was investigated (a) by individual-level multivariable logistic regression, and (b) comparing the observed frequency of households with multiple anti-HCV+ persons against the expected, simulated frequency assuming anti-HCV+ persons are randomly distributed. Village/ward-level clustering was investigated similarly. We estimated household-level associations between exposures and the number of anti-HCV+ members in a household (N = 1593 households) using multivariable ordered logistic regression. Anti-HCV+ prevalence was 3.6% (95% confidence interval 3.0–4.2%). Individual-level regression (N = 5543 participants) found an odds ratio of 3.19 (2.25–4.50) for someone being anti-HCV+ if another household member was anti-HCV+. Thirty households surveyed had ⩾2 anti-HCV+ members, whereas 0/1000 (P < 0.001) simulations had ⩾30 such households. Excess village-level clustering was evident: 10 villages had ⩾6 anti-HCV+ members, occurring in 31/1000 simulations (P = 0.031). The household-level model indicated the number of household members, living in southern Punjab, lower socioeconomic score, and a higher proportion having ever used opium/bhuki were associated with a household’s number of anti-HCV+ members. Anti-HCV+ clusters within households and villages in Punjab, India. These data should be used to inform screening efforts.

The World Health Organization (WHO) recently produced guidelines advising a treat‐all policy for HCV to encourage widespread treatment scale‐up for achieving HCV elimination. We modelled the prevention impact achieved (HCV infections averted [IA]) from initiating this policy compared with treating different subgroups at country, regional and global levels. We assessed what country‐level factors affect impact. A dynamic, deterministic HCV transmission model was calibrated to data from global systematic reviews and UN data sets to simulate country‐level HCV epidemics with ongoing levels of treatment. For each country, the model projected the prevention impact (in HCV IA per treatment undertaken) of initiating four treatment strategies; either selected randomly (treat‐all) or targeted among people who inject drugs (PWID), people aged ≥35, or those with cirrhosis. The IA was assessed over 20 years. Linear regression was used to identify associations between IA per treatment and demographic factors. Eighty‐eight countries (85% of the global population) were modelled. Globally, the model estimated 0.35 (95% credibility interval [95%CrI]: 0.16‐0.61) IA over 20 years for every randomly allocated treatment, 0.30 (95%CrI: 0.12‐0.53) from treating those aged ≥35 and 0.28 (95%CrI: 0.12‐0.49) for those with cirrhosis. Globally, treating PWID achieved 1.27 (95%CrI: 0.68‐2.04) IA per treatment. The IA per randomly allocated treatment was positively associated with a country's population growth rate and negatively associated with higher HCV prevalence among PWID. In conclusion, appreciable prevention benefits could be achieved from WHO’s treat‐all strategy, although greater benefits per treatment can be achieved through targeting PWID. Higher impact will be achieved in countries with high population growth.

Lycopene and green tea consumption have been observationally associated with reduced prostate cancer risk, but the underlying mechanisms have not been fully elucidated. We investigated the effect of factorial randomisation to a 6‐month lycopene and green tea dietary advice or supplementation intervention on 159 serum metabolite measures in 128 men with raised PSA levels (but prostate cancer‐free), analysed by intention‐to‐treat. The causal effects of metabolites modified by the intervention on prostate cancer risk were then assessed by Mendelian randomisation, using summary statistics from 44,825 prostate cancer cases and 27,904 controls. The systemic effects of lycopene and green tea supplementation on serum metabolic profile were comparable to the effects of the respective dietary advice interventions (R2 = 0.65 and 0.76 for lycopene and green tea respectively). Metabolites which were altered in response to lycopene supplementation were acetate [β (standard deviation difference vs. placebo): 0.69; 95% CI = 0.24, 1.15; p = 0.003], valine (β: −0.62; −1.03, −0.02; p = 0.004), pyruvate (β: −0.56; −0.95, −0.16; p = 0.006) and docosahexaenoic acid (β: −0.50; −085, −0.14; p = 0.006). Valine and diacylglycerol were lower in the lycopene dietary advice group (β: −0.65; −1.04, −0.26; p = 0.001 and β: −0.59; −1.01, −0.18; p = 0.006). A genetically instrumented SD increase in pyruvate increased the odds of prostate cancer by 1.29 (1.03, 1.62; p = 0.027). An intervention to increase lycopene intake altered the serum metabolome of men at risk of prostate cancer. Lycopene lowered levels of pyruvate, which our Mendelian randomisation analysis suggests may be causally related to reduced prostate cancer risk.

Background. This study was designed to review the methodology and reporting of gastric cancer prognostic models and identify potential problems in model development. Methods. This systematic review was conducted following the CHARMS checklist. MEDLINE and EMBASE were searched. Information on patient characteristics, methodological details, and models' performance was extracted. Descriptive statistics was used to summarize the methodological and reporting quality. Results. In total, 101 model developments and 32 external validations were included. The median (range) of training sample size, number of death, and number of final predictors were 360 (29 to 15320), 193 (14 to 9560), and 5 (2 to 53), respectively. Ninety-one models were developed from routine clinical data. Statistical assumptions were reported to be checked in only nine models. Most model developments (94/101) used complete-case analysis. Discrimination and calibration were not reported in 33 and 55 models, respectively. The majority of models (81/101) have never been externally validated. None of the models have been evaluated regarding clinical impact. Conclusions. Many prognostic models have been developed, but their usefulness in clinical practice remains uncertain due to methodological shortcomings, insufficient reporting, and lack of external validation and impact studies. Impact. Future research should improve methodological and reporting quality and emphasize more on external validation and impact assessment.

Background The risk of acute kidney injury (AKI) attributable to renin angiotensin aldosterone (RAAS) inhibitors and diuretics remains unclear. Methods We conducted a prospective cohort study using the Clinical Practice Research Datalink (2008–2015) linked to Hospital Episode Statistics – Admitted Patient Care and Office for National Statistics mortality data. Patients were included if they had one or more chronic diagnoses requiring medication. Exposed patients had a first ever prescription for RAAS inhibitors/diuretics during the study period. AKI risk associated with exposure was determined by multivariable Cox regression, propensity score-adjusted Cox regression and a prior event rate ratio (PERR) analysis. Results One hundred forty thousand nine hundred fifty-two individuals were included. Increased AKI risk in the exposed group was demonstrated in both the multivariable and propensity score-adjusted cox regressions (HR 1.23 (95% CI 1.04–1.45) and HR 1.24 (1.05–1.47) respectively). The PERR analysis provided a similar overall hazard ratio with a wider confidence interval (HR 1.29 (0.94–1.63)). The increased AKI risk in the exposed group was present only in those receiving two or more antihypertensives. Absolute AKI risk was small. Conclusions RAAS inhibitors/diuretics result in an increased risk of AKI. The absolute increase in AKI risk is small, however, and needs to be considered in the context of any potential benefits.