Incidence of Cardiometabolic Diseases in People With and Without Human Immunodeficiency Virus in the United Kingdom: A Population-Based Matched Cohort Study.

BACKGROUND: Evidence on the risk of cardiovascular disease (CVD) and CVD risk factors in people with human immunodeficiency virus (PWH) is limited. We aimed to identify the risk of composite CVD, individual CVD events, and common risk factors. METHODS: This was a nationwide, population-based, cohort study comparing adult (≥18 years old) PWH with people without human immunodeficiency virus (HIV) matched on age, sex, ethnicity, and location. The primary outcome was composite CVD comprising stroke, myocardial infarction, peripheral vascular disease, ischemic heart disease, and heart failure. The secondary outcomes were individual CVD events, hypertension, diabetes, chronic kidney disease (CKD), and all-cause mortality. Cox proportional hazard regression models were used to examine the risk of each outcome. RESULTS: We identified 9233 PWH and matched them with 35 721 HIV-negative individuals. An increased risk was found for composite CVD (adjusted hazard ratio [aHR], 1.50; 95% confidence interval [CI], 1.28-1.77), stroke (aHR, 1.42; 95% CI, 1.08-1.86), ischemic heart disease (aHR, 1.55; 95% CI, 1.24-1.94), hypertension (aHR, 1.37; 95% CI, 1.23-1.53), type 2 diabetes (aHR, 1.28; 95% CI, 1.09-1.50), CKD (aHR, 2.42; 95% CI, 1.98-2.94), and all-cause mortality (aHR, 2.84; 95% CI, 2.48-3.25). CONCLUSIONS: PWH have a heightened risk for CVD and common CVD risk factors, reinforcing the importance for regular screening for such conditions.

Does milk intake promote prostate cancer initiation or progression via effects on insulin-like growth factors (IGFs)? A systematic review and meta-analysis.

PURPOSE: To establish whether the association between milk intake and prostate cancer operates via the insulin-like growth factor (IGF) pathway (including IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3). METHODS: Systematic review, collating data from all relevant studies examining associations of milk with IGF, and those examining associations of IGF with prostate cancer risk and progression. Data were extracted from experimental and observational studies conducted in either humans or animals, and analyzed using meta-analysis where possible, with summary data presented otherwise. RESULTS: One hundred and seventy-two studies met the inclusion criteria: 31 examining the milk-IGF relationship; 132 examining the IGF-prostate cancer relationship in humans; and 10 animal studies examining the IGF-prostate cancer relationship. There was moderate evidence that circulating IGF-I and IGFBP-3 increase with milk (and dairy protein) intake (an estimated standardized effect size of 0.10 SD increase in IGF-I and 0.05 SD in IGFBP-3 per 1 SD increase in milk intake). There was moderate evidence that prostate cancer risk increased with IGF-I (Random effects meta-analysis OR per SD increase in IGF-I 1.09; 95% CI 1.03, 1.16; n = 51 studies) and decreased with IGFBP-3 (OR 0.90; 0.83, 0.98; n = 39 studies), but not with other growth factors. The IGFBP-3 -202A/C single nucleotide polymorphism was positively associated with prostate cancer (pooled OR for A/C vs. AA = 1.22; 95% CI 0.84, 1.79; OR for C/C vs. AA = 1.51; 1.03, 2.21, n = 8 studies). No strong associations were observed for IGF-II, IGFBP-1 or IGFBP-2 with either milk intake or prostate cancer risk. There was little consistency within the data extracted from the small number of animal studies. There was additional evidence to suggest that the suppression of IGF-II can reduce tumor size, and contradictory evidence with regards to the effect of IGFBP-3 suppression on tumor progression. CONCLUSION: IGF-I is a potential mechanism underlying the observed associations between milk intake and prostate cancer risk.

Comprehensive geriatric assessment for older adults admitted to hospital.

BACKGROUND: Comprehensive geriatric assessment (CGA) is a multi-dimensional, multi-disciplinary diagnostic and therapeutic process conducted to determine the medical, mental, and functional problems of older people with frailty so that a co-ordinated and integrated plan for treatment and follow-up can be developed. This is an update of a previously published Cochrane review. OBJECTIVES: We sought to critically appraise and summarise current evidence on the effectiveness and resource use of CGA for older adults admitted to hospital, and to use these data to estimate its cost-effectiveness. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, three other databases, and two trials registers on 5 October 2016; we also checked reference lists and contacted study authors. SELECTION CRITERIA: We included randomised trials that compared inpatient CGA (delivered on geriatric wards or by mobile teams) versus usual care on a general medical ward or on a ward for older people, usually admitted to hospital for acute care or for inpatient rehabilitation after an acute admission. DATA COLLECTION AND ANALYSIS: We followed standard methodological procedures expected by Cochrane and Effective Practice and Organisation of Care (EPOC). We used the GRADE approach to assess the certainty of evidence for the most important outcomes. For this update, we requested individual patient data (IPD) from trialists, and we conducted a survey of trialists to obtain details of delivery of CGA. We calculated risk ratios (RRs), mean differences (MDs), or standardised mean differences (SMDs), and combined data using fixed-effect meta-analysis. We estimated cost-effectiveness by comparing inpatient CGA versus hospital admission without CGA in terms of cost per quality-adjusted life year (QALY) gained, cost per life year (LY) gained, and cost per life year living at home (LYLAH) gained. MAIN RESULTS: We included 29 trials recruiting 13,766 participants across nine, mostly high-income countries. CGA increases the likelihood that patients will be alive and in their own homes at 3 to 12 months' follow-up (risk ratio (RR) 1.06, 95% confidence interval (CI) 1.01 to 1.10; 16 trials, 6799 participants; high-certainty evidence), results in little or no difference in mortality at 3 to 12 months' follow-up (RR 1.00, 95% CI 0.93 to 1.07; 21 trials, 10,023 participants; high-certainty evidence), decreases the likelihood that patients will be admitted to a nursing home at 3 to 12 months follow-up (RR 0.80, 95% CI 0.72 to 0.89; 14 trials, 6285 participants; high-certainty evidence) and results in little or no difference in dependence (RR 0.97, 95% CI 0.89 to 1.04; 14 trials, 6551 participants; high-certainty evidence). CGA may make little or no difference to cognitive function (SMD ranged from -0.22 to 0.35 (5 trials, 3534 participants; low-certainty evidence)). Mean length of stay ranged from 1.63 days to 40.7 days in the intervention group, and ranged from 1.8 days to 42.8 days in the comparison group. Healthcare costs per participant in the CGA group were on average GBP 234 (95% CI GBP -144 to GBP 605) higher than in the usual care group (17 trials, 5303 participants; low-certainty evidence). CGA may lead to a slight increase in QALYs of 0.012 (95% CI -0.024 to 0.048) at GBP 19,802 per QALY gained (3 trials; low-certainty evidence), a slight increase in LYs of 0.037 (95% CI 0.001 to 0.073), at GBP 6305 per LY gained (4 trials; low-certainty evidence), and a slight increase in LYLAH of 0.019 (95% CI -0.019 to 0.155) at GBP 12,568 per LYLAH gained (2 trials; low-certainty evidence). The probability that CGA would be cost-effective at a GBP 20,000 ceiling ratio for QALY, LY, and LYLAH was 0.50, 0.89, and 0.47, respectively (17 trials, 5303 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Older patients are more likely to be alive and in their own homes at follow-up if they received CGA on admission to hospital. We are uncertain whether data show a difference in effect between wards and teams, as this analysis was underpowered. CGA may lead to a small increase in costs, and evidence for cost-effectiveness is of low-certainty due to imprecision and inconsistency among studies. Further research that reports cost estimates that are setting-specific across different sectors of care are required.

Source apportionment of trace contaminants in urban sewer catchments.

Sampling and analysis of Water Framework Directive priority chemicals were undertaken in nine urban catchments across the UK. Over 9000 samples were collected from a number of different catchment sources including tap water, domestic waste water, surface water runoff, trade discharges, town centre and light industrial estate wastewaters. Determinands included trace metals, polyaromatic hydrocarbons (PAHs), persistent organic pollutants and a number of common pharmaceuticals. Loads of the chemicals from each catchment entering the local wastewater treatment works (WwTW) were estimated and were shown to be relatively consistent between different catchments, after taking population into account. A Monte Carlo mixing model was used to combine the concentrations and flows from the different catchment sources and to predict concentrations and loads entering the WwTW. Based on the model output, the significance of the different sources could be evaluated. The study highlighted the importance of domestic wastewater as a source of contaminants, including metals and trace organic substances (such as ethylenediaminetetraacetic acid (EDTA), bisphenol A, nonylphenol and tributyl tin (TBT)). Concentrations in trade discharges were important in some locations in the case of nonylphenol, EDTA, TBT, as well as for some metals such as copper, zinc and nickel. Contributions to the total load from town centre and light industrial estate sources were generally less than 10% of the total.

The risk of mental illness in people living with HIV in the UK: a propensity score-matched cohort study.

BACKGROUND: Prevalence of mental illness is higher in people living with HIV than in the general population, but the incidence of composite mental illness and its components is unclear. We aimed to identify the risk of incident mental illness along with individual conditions of depression, anxiety, and severe mental illness in people living with HIV in the UK. METHODS: Data for this population-based cohort were extracted from the IQVIA Medical Research Database, a nationally representative UK-based database of primary care electronic health records. We included adults (aged ≥18 years) living with HIV, matched with adults without HIV using propensity score matching (1:1 ratio). The primary outcome was composite mental illness comprising a diagnosis of depression, anxiety, or severe mental illness. Secondary outcomes were individual mental health conditions. Cox proportional hazard regression models were used to compare the risk of each outcome between people with and without HIV. Each model excluded those with the outcome at baseline. Individuals were followed up prospectively. The study period was from Jan 1, 2000, to Jan 1, 2020. FINDINGS: Of 7167 people living with HIV without mental illness at baseline, 586 developed a mental illness (incidence rate 19·6 per 1000 person-years) compared with 418 of 7167 people without HIV (incidence rate 12·1 per 1000 person-years), resulting in an adjusted hazard ratio (HR) of 1·63 (95% CI 1·44-1·85). People living with HIV had higher incidence rates for depression (15·4 per 1000 person-years), anxiety (7·2 per 1000 person-years), and severe mental illness (1·6 per 1000 person-years) compared with people without HIV (7·9, 5·0, and 0·6 per 1000 person-years, respectively), with adjusted HRs of 1·94 (95% CI 1·68-2·24) for depression, 1·38 (1·15-1·66) for anxiety, and 2·18 (1·41-3·39) for severe mental illness. INTERPRETATION: People living with HIV have an increased risk for developing composite mental illness, depression, anxiety, and severe mental illness compared with people without HIV. People living with HIV should be regularly screened for mental illness; however, there is a strong need to improve prevention of mental illness in people living with HIV and for more outreach programmes to ensure that no groups of people living with HIV are being underdiagnosed. FUNDING: None.

The importance of over-the-counter-sales and product format in the environmental exposure assessment of active pharmaceutical ingredients.

When assessing the environmental exposure of active pharmaceutical ingredients (APIs), the mass contributed from over the counter (OTC) sales are often not included due to difficulty obtaining this data and topical formats are overlooked completely. This study presents a comprehensive approach, investigating the significance of OTC and topical applications as sources of API releases to wastewater, in addition to temporal and subnational variations in use in the UK. The study provides methods to obtain and make use of OTC sales data which can be applied widely. The calculated releases to wastewater compared well with influent concentrations measured at several UK wastewater treatment plants (WWTPs). Consistent overestimation was observed, attributed to a number of factors, including in-sewer removal. OTC sales were found to make up a large proportion of the mass of ibuprofen (76%) and diclofenac (35%) consumed and topical formats were also found to be vital, contributing disproportionately to wastewater loadings per unit mass of ibuprofen and diclofenac used (43% and 99% of the total mass released, respectively). Releases of the APIs investigated did not vary temporally, but regional variation was significant and where possible should be considered for the most accurate exposure assessment of pharmaceuticals.

The removal of pharmaceuticals during wastewater treatment: Can it be predicted accurately?

The presence of active pharmaceutical ingredients (APIs) in the environment is of growing concern and effluents from wastewater treatment works (WwTWs) are one of the major sources. This research combines the outputs of a multimillion pound UK program of work to evaluate the fate of APIs in the wastewater treatment process. A combination of analysis of measured data and modelling has been applied to 18 APIs, representing a wide range of medicinal application and physico-chemical characteristics. Some isomers (for atorvastatin) and metabolites (for sertraline, carbamazepine and erythromycin) were also included. High variability was observed between removal rates for individual APIs between WwTW, which after statistical analysis could not be explained by the nominal WwTW process (e.g. activated sludge or trickling filter). Nor was there a clear relationship between API removal and physico-chemical parameters such as pKa, charge or log Kow. A publically available sewage process model, SimpleTreat 4.0 which has been rigorously validated and is now being used for exposure assessment with REACH legislation for organic chemicals and within the Biocidal Products Regulation by the European Medicines Agency for APIs, was used to estimate removal rates with which to compare with measured data. SimpleTreat provided estimates of removal rates within ±30% of observed values for the majority of the APIs measured, with the use of readily available WwTW specific parameters such as flow, total suspended solids and BOD data. The data and correlations provided in this study provide support for any future considerations regarding the management of API discharge to the aquatic environment.

Active pharmaceutical ingredients entering the aquatic environment from wastewater treatment works: A cause for concern?

This work reports on the variation in wastewater treatment works (WwTW) influent concentrations of a wide variety of active pharmaceutical ingredients (APIs), their removal efficiency, effluent concentrations and potential risks to the aquatic environment. The research is based on data generated from two large UK-wide WwTW monitoring programmes. Taking account of removal of parent compound from the aqueous phase during treatment in combination with estimates of dilution available it is possible to prioritise the APIs of greatest risk of exceeding estimates of predicted no effect concentrations (PNEC) in receiving waters for all WwTW in the UK. The majority of substances studied were removed to a high degree, although with significant variation, both within and between WwTW. Poorer removal (between influent and effluent) was observed for ethinyloestradiol, diclofenac, propranolol, the macrolide antibiotics, fluoxetine, tamoxifen and carbamazepine. All except the last two of these substances were present in effluents at concentrations higher than their respective estimated PNEC (based on measurement of effluents from 45 WwTW on 20 occasions). Based on available dilution data as many as 890 WwTW in the UK (approximately 13% of all WwTW) may cause exceedances of estimated riverine PNECs after mixing of their effluents with receiving waters. The overall degree of risk is driven by the toxicity value selected, which in itself is controlled by the availability of reliable and relevant ecotoxicological data and consequently the safety factors applied. The dataset and discussion, provides information to assist in the future management of these types of chemicals.

Developing the WCRF International/University of Bristol Methodology for Identifying and Carrying Out Systematic Reviews of Mechanisms of Exposure-Cancer Associations.

Background: Human, animal, and cell experimental studies; human biomarker studies; and genetic studies complement epidemiologic findings and can offer insights into biological plausibility and pathways between exposure and disease, but methods for synthesizing such studies are lacking. We, therefore, developed a methodology for identifying mechanisms and carrying out systematic reviews of mechanistic studies that underpin exposure-cancer associations.Methods: A multidisciplinary team with expertise in informatics, statistics, epidemiology, systematic reviews, cancer biology, and nutrition was assembled. Five 1-day workshops were held to brainstorm ideas; in the intervening periods we carried out searches and applied our methods to a case study to test our ideas.Results: We have developed a two-stage framework, the first stage of which is designed to identify mechanisms underpinning a specific exposure-disease relationship; the second stage is a targeted systematic review of studies on a specific mechanism. As part of the methodology, we also developed an online tool for text mining for mechanism prioritization (TeMMPo) and a new graph for displaying related but heterogeneous data from epidemiologic studies (the Albatross plot).Conclusions: We have developed novel tools for identifying mechanisms and carrying out systematic reviews of mechanistic studies of exposure-disease relationships. In doing so, we have outlined how we have overcome the challenges that we faced and provided researchers with practical guides for conducting mechanistic systematic reviews.Impact: The aforementioned methodology and tools will allow potential mechanisms to be identified and the strength of the evidence underlying a particular mechanism to be assessed. Cancer Epidemiol Biomarkers Prev; 26(11); 1667-75. ©2017 AACR.

An investigation of the variation in the transition bias among various animal mitochondrial DNA.

The transition:transversion ratio (ts/tv) is known to be very high in human mitochondrial DNA, but we have little information about this ratio in other species. Here we investigate the transition bias in animal mitochondrial DNA using single nucleotide polymorphism data at four-fold degenerate sites. We investigate this pattern of polymorphism in the cytochrome b gene (cyt-b) in 70 species using a total of 1823 mutations. We show that most species show a bias towards transitions but that the ratio varies significantly between species. There is little evidence for variation within orders or genera and between closely related species such as the great apes. The majority of the variation appears to be at a higher phylogenetic levels: between orders and classes. We test whether the variation in ts/tv ratio could be due to variation in the metabolic rate by considering whether the ratio is correlated to base composition. We find no evidence that the metabolic rate affects the ts/tv ratio. We also investigate the relative frequencies of C to T or T to C (C<-->T) mutations and A to G or G to A (A<-->G) mutations. We show that overall they occur at significantly different frequencies, and that there is significant variation in their relative frequency between species and between classes. We find no evidence in support of the hypothesis that this variation could be due to different metabolic rates.

Concentrations of trace substances in sewage sludge from 28 wastewater treatment works in the UK.

Concentrations of trace substances in sewage sludge have been measured in a survey of 28 wastewater treatment works (WwTWs) in the UK carried out over a period of 12months. Approximately 250 samples were analysed for more than 40 trace contaminants, including trace metals, pharmaceuticals, polycyclic aromatic hydrocarbons (PAHs), 'emerging' and regulated organic pollutants. All substances investigated were found to be present in at least some of the sludges sampled. Concentrations were relatively homogenous across all the WwTWs, irrespective of the treatment process, influent and effluent concentrations, and the location of the sludge sampling point within each works. Analysis of the results against existing regulatory and proposed thresholds suggested that levels are mostly below the limits set in the Sewage Sludge Directive, and proposed new limits for sludge used in agriculture. Predicted soil concentrations after application of sewage sludge to land were below the predicted no effect concentrations (PNEC) for all determinands. Predicted concentrations of pharmaceuticals in soil were also below thresholds deemed to indicate negligible environmental risk.

Social isolation and diurnal cortisol patterns in an ageing cohort.

BACKGROUND: Social isolation may operate as a psychosocial stressor which disrupts functioning of the hypothalamic-pituitary-adrenocortical axis. METHODS: Using data from the MRC National Survey of Health and Development, we tested whether living alone, not being married and social network size were associated with diurnal cortisol patterns at 60-64 years. We hypothesised that recent onset compared with long-term isolation would be more strongly associated with cortisol awakening response, cortisol decline over the day and evening cortisol. Models were adjusted for sex, smoking, body mass index, alcohol intake, psychological distress and financial difficulties. RESULTS: Those widowed within the last three years had a 36% (95%CI 6%, 73%) higher night time cortisol than those who were currently married. Those newly living alone also had a higher night time cortisol and flatter diurnal slope than those living with others. CONCLUSION: Independently of multiple behavioural and psychosocial correlates, recent onset of social isolation is related to diurnal cortisol patterns that increase the risk of morbidity and mortality.

Performance of UK wastewater treatment works with respect to trace contaminants.

This study examined the performance of 16 wastewater treatment works to provide an overview of trace substance removal in relation to meeting the objectives of the Water Framework Directive (WFD). Collection and analysis of over 2400 samples including sewage influent, process samples at different stages in the treatment process and final effluent has provided data on the performance of current wastewater treatment processes and made it possible to evaluate the need for improved effluent quality. Results for 55 substances, including metals, industrial chemicals and pharmaceuticals are reported. Data for sanitary parameters are also provided. A wide range of removal efficiencies was observed. Removal was not clearly related to the generic process type, indicating that other operational factors tend to be important. Nonetheless, removals for many substances of current concern were high. Despite this, current proposals for stringent water quality standards mean that further improvements in effluent quality are likely to be required.

How well should laboratories perform in proficiency tests.

The long-term performance of laboratories is examined using results from three proficiency testing programmes in the water and environmental monitoring sector. A medium term proficiency test pass rate of greater than approximately 75% is suggested as a minimum target for routine analysis to demonstrate fitness for purpose. This pass rate is proposed as a practical yardstick to be used by QA managers and accreditation bodies. This recommendation is contingent on a laboratory's continued and largely uninterrupted participation in a PT programme.