Early Antiretroviral Therapy Not Associated With Higher Cryptococcal Meningitis Mortality in People With Human Immunodeficiency Virus in High-Income Countries: An International Collaborative Cohort Study.

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.

Retrospective cohort study evaluating clinical, biochemical and pharmacological prognostic factors for prostate cancer progression using primary care data.

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.

Multiple imputation strategies for a bounded outcome variable in a competing risks analysis.

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.

Cause-specific mortality after diagnosis of cancer among HIV-positive patients: A collaborative analysis of cohort studies.

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.

Effects and cost of different strategies to eliminate hepatitis C virus transmission in Pakistan: a modelling analysis.

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.

Parameter estimates for trends and patterns of excess mortality among persons on antiretroviral therapy in high-income European settings.

INTRODUCTION: HIV cohort data from high-income European countries were compared with the UNAIDS Spectrum modelling parameters for these same countries to validate mortality rates and excess mortality estimates for people living with HIV (PLHIV) on antiretroviral therapy (ART). METHODS: Data from 2000 to 2015 were analysed from the Antiretroviral Therapy Cohort Collaboration (ART-CC) for Austria, Denmark, France, Italy, the Netherlands, Spain, and Switzerland. Flexible parametric models were used to compare all-cause mortality rates in the ART-CC and Spectrum. The percentage of AIDS-related deaths and excess mortality (both are the same within Spectrum) were compared, with excess mortality defined as that in excess of the general population mortality. RESULTS: Analyses included 94 026 PLHIV with 585 784 person-years of follow-up, from which there were 5515 deaths. All-cause annual mortality rates in Spectrum for 2000-2003 were 0.0121, reducing to 0.0078 in 2012-2015, whilst the ART-CC's corresponding annual mortality rates were 0.0151 [95% confidence interval (95% CI): 0.0130-0.0171] reducing to 0.0049 (95% CI: 0.0039-0.0060). The percentage of AIDS-related deaths in Spectrum was 74.7% in 2000-2003, dropping to 43.6% in 2012-2015. In the ART-CC, AIDS-related mortality constitutes 45.3% (95% CI: 38.4-52.9%) of mortality in 2000-2003 and 26.7% (95% CI: 19-46%) between 2012 and 2015. Excess mortality in the ART-CC was broadly similar to the Spectrum estimates, dropping from 75.3% (95% CI: 60.3-95.2%) in 2000-2003 to 30.7% (95% CI: 25.5-63.7%) in 2012-2015. CONCLUSION: All-cause mortality assumptions for PLHIV on ART in high-income European settings should be adjusted in Spectrum to be higher in 2000-2003 and decline more quickly to levels currently captured for recent years.

Prognostic Models for Predicting Overall Survival in Patients with Primary Gastric Cancer: A Systematic Review.

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.

Modelling the potential prevention benefits of a treat-all hepatitis C treatment strategy at global, regional and country levels: A modelling study.

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.

Quadruple versus triple combination antiretroviral therapies for treatment naive people with HIV: systematic review and meta-analysis of randomised controlled trials.

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.

Associations of mortality with own blood pressure using son's blood pressure as an instrumental variable.

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.

Qualitative evaluation of a pilot educational intervention to increase primary care HIV-testing.

BACKGROUND: UK guidelines recommend a 'routine offer of HIV testing' in primary care where HIV diagnosed prevalence exceeds 2 in 1000. However, current primary care HIV testing rates are low. Efforts to increase primary care HIV testing are needed. To examine how an educational intervention to increase HIV testing in general practice was experienced by healthcare professionals (HCPs) and to understand the perceived impacts on HIV testing. METHOD: Qualitative interviews with general practitioners (GPs) and nurses 3-months after receiving an educational intervention developed from an adapted version of the Medical Foundation for HIV and Sexual Health (MEDFASH) HIV Testing In Practice (TIPs) online educational tool which included training on HIV associated clinical indicator conditions, why, who, and how to test. The intervention was delivered in 19 high-HIV prevalence general practices in Bristol. 27 semi-structured interviews were conducted across 13 practices with 16 GPs, 10 nurses and the sexual health clinician who delivered the intervention. Transcripts were analysed thematically informed by Normalisation Process Theory. RESULTS: HCPs welcomed the opportunity to update their HIV knowledge through a tailored, interactive session. Post-training, HCPs reported increased awareness of HIV indicator conditions, confidence to offer HIV tests and consideration of HIV tests. Continued testing barriers include perceived lack of opportunity. CONCLUSIONS: This qualitative study found that HIV education is perceived as valuable in relation to perceived awareness, confidence, and consideration of HIV testing. However, repetition and support from other strategies are needed to encourage HCPs to offer HIV tests. Future interventions should consider using behaviour change theory to develop a complex intervention that addresses not only HCP capability to offer an HIV test, but also issues of opportunity and motivation.

The contribution of injection drug use to hepatitis C virus transmission globally, regionally, and at country level: a modelling study.

BACKGROUND: WHO aims to eliminate the hepatitis C virus (HCV) as a public health threat by 2030. Injection drug use is an important risk factor for HCV transmission, but its contribution to country-level and global epidemics is unknown. We estimated the contribution of injection drug use to risk for HCV epidemics globally, regionally, and at country level. METHODS: We developed a dynamic deterministic HCV transmission model to simulate country-level HCV epidemics among people who inject drugs and the general population. Each country's model was calibrated using country-specific data from UN datasets and systematic reviews on the prevalence of HCV and injection drug use. The population attributable fraction of HCV transmission associated with injection drug use was estimated-defined here as the percentage of HCV infections prevented if additional HCV transmission due to injection drug use was removed between 2018 and 2030. FINDINGS: The model included 88 countries (85% of the global population). The model predicted 0·23% (95% credibility interval [CrI] 0·16-0·31) of the global population were injection drug users in 2017, and 8% (5-12) of prevalent HCV infections were among people who currently inject drugs. Globally, if the increased risk for HCV transmission among people who inject drugs was removed, an estimated 43% (95% CrI 25-67) of incident HCV infections would be prevented from 2018 to 2030, varying regionally. This population attributable fraction was higher in high-income countries (79%, 95% CrI 57-97) than in countries of low and middle income (38%, 24-64) and was associated with the percentage of a country's prevalent HCV infections that are among people who inject drugs. INTERPRETATION: Unsafe injecting practices among people who inject drugs contribute substantially to incident HCV infections globally. Any intervention that can reduce HCV transmission among people who inject drugs will have a pronounced effect on country-level incidence of HCV. FUNDING: None.

Estimating the risk of acute kidney injury associated with use of diuretics and renin angiotensin aldosterone system inhibitors: A population based cohort study using the clinical practice research datalink.

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.

Evaluation of an educational intervention to increase HIV-testing in high HIV prevalence general practices: a pilot feasibility stepped-wedged randomised controlled trial.

BACKGROUND: HIV-infected patients often present to primary care several times with HIV-indicator conditions before diagnosis but the opportunity to test by healthcare professionals (HCPs) is frequently missed. Current HIV testing rates in primary care are low and educational interventions to facilitate HCPs to increase testing and awareness of HIV are needed. METHOD: We implemented a pilot feasibility stepped-wedged randomised controlled trial of an educational intervention in high HIV prevalence practices in Bristol. The training delivered to HCPs including General Practitioners (GP) aimed to increase HIV testing and included why, who, and how to test. The intervention was adapted from the Medical Foundation for HIV and Sexual Health HIV Testing in Practice (MEDFASH) educational tool. Questionnaires assessed HCP feedback and perceived impacts of the intervention. HIV testing rates were compared between control and intervention practices using 12 monthly laboratory totals. RESULTS: 169 HCPs (from 19 practices) received the educational intervention. 127 (75%) questionnaires were completed. Delivery of the intervention was received positively and was perceived as valuable for increasing awareness, confidence and consideration of testing, with HCPs gaining more awareness of HIV testing guidelines. The main pre-training HIV testing barrier reported by GPs was the patient not considering themselves at risk, whilst for nurses it was a concern about embarrassing or offending the patient. Most HCPs reported the intervention addressed these barriers. The HIV testing rate increased more in the control than in the intervention practices: mean difference 2.6 (95% CI 0.5,4.7) compared with 1.9 (- 0.5,4.3) per 1000 patients, respectively. The number of HIV tests across all practices increased from 1154 in the first 6 months to 1299 in the second 6 months, an annual increase in testing rate of 2.0 (0.7,3.4) from 16.3 to 18.3 per 1000 patients. CONCLUSION: There was a small increase in HIV testing rates over the study period, but this could not be attributed to the educational intervention. More effective and sustainable programmes tailored to each practice context are needed to change testing culture and HCP behaviour. Repeated training, supported by additional measures, such as testing prompts, may be needed to influence primary care HIV testing.

Developing and validating Parkinson's disease subtypes and their motor and cognitive progression.

OBJECTIVES: To use a data-driven approach to determine the existence and natural history of subtypes of Parkinson's disease (PD) using two large independent cohorts of patients newly diagnosed with this condition. METHODS: 1601 and 944 patients with idiopathic PD, from Tracking Parkinson's and Discovery cohorts, respectively, were evaluated in motor, cognitive and non-motor domains at the baseline assessment. Patients were recently diagnosed at entry (within 3.5 years of diagnosis) and were followed up every 18 months. We used a factor analysis followed by a k-means cluster analysis, while prognosis was measured using random slope and intercept models. RESULTS: We identified four clusters: (1)  fast motor progression with symmetrical motor disease, poor olfaction, cognition and postural hypotension; (2) mild motor and non-motor disease with intermediate motor progression; (3) severe motor disease, poor psychological well-being and  poor sleep with an intermediate motor progression; (4) slow motor progression with tremor-dominant, unilateral disease. Clusters were moderately to substantially stable across the two cohorts (kappa 0.58). Cluster 1 had the fastest motor progression in Tracking Parkinson's at 3.2 (95% CI 2.8 to 3.6) UPDRS III points per year while cluster 4 had the slowest at 0.6 (0.1-1.1). In Tracking Parkinson's, cluster 2 had the largest response to levodopa 36.3% and cluster 4 the lowest 28.8%. CONCLUSIONS: We have found four novel clusters that replicated well across two independent early PD cohorts and were associated with levodopa response and motor progression rates. This has potential implications for better understanding disease pathophysiology and the relevance of patient stratification in future clinical trials.

Identifying Risk of Viral Failure in Treated HIV-Infected Patients Using Different Measures of Adherence: The Antiretroviral Therapy Cohort Collaboration.

Adherence to antiretroviral therapy (ART) is critical for successful treatment of Human Immunodeficiency Virus (HIV), but comparisons across settings are difficult because adherence is measured in different ways. We examined utility of different adherence measures for identification of patients at risk of viral failure (VF). Eight cohorts in the ART Cohort Collaboration contributed data from pharmacy refills or self-report questionnaires collected between 1996 and 2013 (N = 11689). For pharmacy data (N = 7156), we examined associations of percentage adherence during the 1st year of ART with VF (>500 copies/mL) at 1 year. For self-report data (N = 4533), we examined 28-day adherence with VF based on closest viral load measure within 6 months after questionnaire date. Since adherence differed markedly by measurement type, we defined different cut-off points for pharmacy (lower <45%, medium 45⁻99%, higher 100%) and self-report (lower ≤95%, medium 96⁻99%, higher 100%) data. Adjusted odds ratios (ORs) for VF in lower and medium, compared to higher adherence groups, were 23.04 (95% CI: 18.44⁻28.78) and 3.84 (3.36⁻4.39) for pharmacy data. For self-report data, they were 3.19 (2.31⁻4.40) and 1.08 (0.80⁻1.46). Both types of measure were strongly associated with VF. Although adherence measurements over longer time-frames are preferable for prediction, they are less useful for intervention.

Usage of low dead space syringes and association with hepatitis C prevalence amongst people who inject drugs in the UK.

INTRODUCTION: Syringes with attached needles (low dead space syringes [LDSS]) retain far less blood following injection than syringes with detachable needles (high dead space syringes [HDSS]). People who inject drugs (PWID) who share needles/syringes may be less likely to acquire Hepatitis C virus (HCV) infection using LDSS, compared with HDSS, but data are limited. METHODS: Utilizing drug behavior and HCV antibody testing data from the UK 2014/2015 Unlinked Anonymous Monitoring Survey of PWID, we calculated the percentage of syringes used in the past month that were LDSS. We investigated which injecting characteristics and demographic factors were associated with 100% LDSS (against 0-99%) usage, and whether 100% LDSS use was associated with antibody HCV-status, after adjusting for confounders. RESULT: Of 2174 participants, 55% always used LDSS, 27% always used HDSS, and 17% used both LDSS and HDSS. PWID that had injected into their groin during the past month were unlikely to use LDSS, adjusted odds ratio (aOR) 0.14 (95% confidence interval 0.11-0.17), compared to those not using the groin. Those injecting crack were less likely to use LDSS than those not, aOR 0.79 (0.63-0.98). Polydrug use was negatively associated with LDSS use, aOR 0.88 (0.79-0.98) per additional drug. LDSS use was associated with lower prevalent HCV among all PWID (aOR 0.77, [0.64-0.93]), which was stronger among recent initiates (aOR 0.53 [0.30-0.94]) than among experienced PWID (aOR 0.81 [0.66-0.99]). DISCUSSION: People who inject into their groin were less likely to use LDSS. Exclusive LDSS use was associated with lower prevalence of HCV amongst PWID that started injecting recently, suggesting LDSS use is protective against HCV.

Long terms trends in CD4+ cell counts, CD8+ cell counts, and the CD4+ :  CD8+ ratio.

OBJECTIVE: Model trajectories of CD4+ and CD8+ cell counts after starting combination antiretroviral therapy (ART) and use the model to predict trends in these counts and the CD4+ : CD8+ ratio. DESIGN: Cohort study of antiretroviral-naïve HIV-positive adults who started ART after 1997 (ART Cohort Collaboration) with more than 6 months of follow-up data. METHODS: We jointly estimated CD4+ and CD8+ cell count trends and their correlation using a bivariate random effects model, with linear splines describing their population trends, and predicted the CD4+ : CD8+ ratio trend from this model. We assessed whether CD4+ and CD8+ cell count trends and the CD4+ : CD8+ ratio trend varied according to CD4+ cell count at start of ART (baseline), and, whether these trends differed in patients with and without virological failure more than 6 months after starting ART. RESULTS: A total of 39 979 patients were included (median follow-up was 53 months). Among patients with baseline CD4+ cell count at least 50 cells/µl, predicted mean CD8+ cell counts continued to decrease between 3 and 15 years post-ART, partly driving increases in the predicted mean CD4+ : CD8+ ratio. During 15 years of follow-up, normalization of the predicted mean CD4+ : CD8+ ratio (to >1) was only observed among patients with baseline CD4+ cell count at least 200 cells/µl. A higher baseline CD4+ cell count predicted a shorter time to normalization. CONCLUSION: Declines in CD8+ cell count and increases in CD4+ : CD8+ ratio occurred up to 15 years after starting ART. The likelihood of normalization of the CD4+ : CD8+ ratio is strongly related to baseline CD4+ cell count.