A Novel Protection and Repair Skincare Regimen Shows Efficacy for Improving Environmental Skin Aging.

BACKGROUND: Skin aging is accelerated by environmental exposures including solar radiation and pollutants. Thus, protecting skin from environmental exposure and repairing ensuing damage is essential for keeping skin healthy and appearing youthful. PURPOSE: To evaluate the clinical benefits of a novel skincare regimen designed to provide comprehensive environmental protection in the daytime and repair environmentally damaged skin at night. METHODS: Thirty participants, including males and females, with mild-to-moderate extrinsic aging, were enrolled in a 12-week single-site study. Participants used the regimen (The Essential Six, RATIONALE, Victoria, Australia) comprised of 3 products to protect the skin in the morning and 3 products to repair the skin at night. Participants were seen at baseline and evaluated for efficacy and tolerability at weeks 2, 6, and 12. Non-invasive measurements to evaluate hydration, transepidermal water loss, skin tone, and elasticity were conducted. RESULTS: The dermatologist investigator noted across-the-board improvement in all evaluated parameters, except deep wrinkles. By week 12, there were statistically significant (P<0.001) improvements in radiance (43%), tactile roughness (48%), visual roughness (44%), firmness (32%), clarity/even skin tone (21%), and overall appearance (29%). Fine lines improved 16% at week 12 (P=0.002). Participant self-assessment revealed statistically significant and progressive improvement in all evaluated parameters over time. No tolerability issues were identified by the investigator, while a small number of participants reported mild stinging and some dryness that resolved over time. This was likely due to the high concentration of active ingredients found in this regimen. Corneometry revealed improved skin hydration of 28% as early as week 2. CONCLUSION: The data presented confirms that this novel protection and repair regimen improves the appearance of environmentally aged skin. J Drugs Dermatol. 2024;23(10):866-872. doi:10.36849/JDD.8274.

Changes in sleep patterns in people with a history of depression during the COVID-19 pandemic: a natural experiment.

BACKGROUND: The COVID-19 pandemic, while a major stressor, increased flexibility in sleep-wake schedules. OBJECTIVES: To investigate the impact of the pandemic on sleep patterns in people with a history of depression and identify sociodemographic, clinical or genetic predictors of those impacts. METHODS: 6453 adults from the Australian Genetics of Depression Study (45±15 years; 75% women) completed surveys before (2016-2018) and during the pandemic (2020-2021). Participants were assigned to 'short sleep' (<6 hours), 'optimal sleep' (6-8 hours) or 'long sleep' (>8 hours). We focused on those having prepandemic 'optimal sleep'. FINDINGS: Pre pandemic, the majority (70%, n=4514) reported optimal sleep, decreasing to 49% (n=3189) during the pandemic. Of these, 57% maintained optimal sleep, while 16% (n=725) shifted to 'short sleep' and 27% (n=1225) to 'long sleep'. In group comparisons 'optimal-to-short sleep' group had worse prepandemic mental health and increased insomnia (p's<0.001), along with an elevated depression genetic score (p=0.002). The 'optimal-to-long sleep' group were slightly younger and had higher distress (p's<0.05), a greater propensity to being evening types (p<0.001) and an elevated depression genetic score (p=0.04). Multivariate predictors for 'optimal-to-short sleep' included reported stressful life events, psychological or somatic distress and insomnia severity (false discovery rate-corrected p values<0.004), while no significant predictors were identified for 'optimal-to-long sleep'. CONCLUSION AND IMPLICATIONS: The COVID-19 pandemic, a natural experiment, elicited significant shifts in sleep patterns among people with a history of depression, revealing associations with diverse prepandemic demographic and clinical characteristics. Understanding these dynamics may inform the selection of interventions for people with depression facing major challenges.

Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial.

BACKGROUND: Motor neuron disease represents a group of progressive and incurable diseases that are characterised by selective loss of motor neurons, resulting in an urgent need for rapid identification of effective disease-modifying therapies. The MND SMART trial aims to test the safety and efficacy of promising interventions efficiently and definitively against a single contemporaneous placebo control group. We now report results of the stage two interim analysis for memantine and trazodone. METHODS: MND SMART is an investigator-led, phase 3, double-blind, placebo-controlled, multiarm, multistage, randomised, adaptive platform trial recruiting at 20 hospital centres in the UK. Individuals older than 18 years with a confirmed diagnosis of either amyotrophic lateral sclerosis classified by the revised El Escorial criteria, primary lateral sclerosis, progressive muscular atrophy, or progressive bulbar palsy, regardless of disease duration, were eligible for screening. Participants were randomised (1:1:1) to receive oral trazodone 200 mg once a day, oral memantine 20 mg once a day, or matched placebo using a computer-generated minimisation algorithm delivered via a secure web-based system. Co-primary outcome measures were clinical functioning, measured by rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R), and survival. Comparisons were conducted in four stages, with predefined criteria for stopping at the end of stages one and two. We report interim analysis from the stage two results, which was done when 100 participants per group (excluding long survivors, defined as >8 years since diagnosis at baseline) completed a minimum of 12 months of follow-up for the candidate investigational medicinal products. The trial is registered on the European Clinical Trials Registry, 2019-000099-41, and ClinicalTrials.gov, NCT04302870, and is ongoing. FINDINGS: Between Feb 27, 2020, and July 24, 2023 (database lock for interim analysis two), 554 people with a motor neuron disease were randomly allocated to memantine (183 [33%]), trazodone (185 [33%]), or placebo (186 [34%]). The primary interim analysis population comprised 530 participants, of whom 175 (33%) had been allocated memantine, 175 (33%) had been allocated trazodone, and 180 (34%) had been allocated placebo. Over 12 months of follow-up, the mean rate of change per month in ALSFRS-R was -0·650 for memantine, -0·625 for trazodone, and -0·655 for placebo (memantine versus placebo estimated mean difference 0·033, one-sided 90% CI lower level -0·085; one-sided p=0·36; trazodone vs placebo: 0·065, -0·051; one-sided p=0·24). The one-sided p values were both above the significance threshold of 10%, indicating that neither memantine nor trazodone groups met the criteria for continuation. There were 483 participants with at least one adverse event (145 [77%] on placebo, 170 [91%] on memantine, and 168 [90%] on trazodone). There were 88 participants with at least one serious adverse event (37 [20%] on memantine, 27 [14%] on trazodone, and 24 [13%] on placebo). A total of 11 serious adverse event led to treatment discontinuation. There was no survival difference between comparisons, with 49 deaths in the memantine group, 52 deaths in the trazodone group, and 48 deaths in the placebo group. INTERPRETATION: Neither memantine nor trazodone improved efficacy outcomes compared with placebo. This result is sufficiently powered to warrant no further testing of trazodone or memantine in motor neuron disease at the doses evaluated in this study. The multiarm multistage design shows important benefits in reducing the time, cost, and participant numbers to reach a definitive result. FUNDING: The Euan MacDonald Centre, MND Scotland, My Name'5 Doddie Foundation, and Baillie Gifford.

IL-1 Signal Inhibition in Alcohol-Related Hepatitis: A Randomized, Double-Blind, Placebo-Controlled Trial of Canakinumab.

BACKGROUND AND AIMS: Short-term mortality in alcohol-related hepatitis (AH) is high, and no current therapy results in durable benefit. A role for interleukin (IL)-1ß has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1ß, in the treatment of patients with AH. METHODS: Participants with biopsy-confirmed AH and discriminant function ≥32 but Model for End-Stage Liver Disease ≤27 were randomly allocated 1:1 to receive either CAN 3 mg/kg or placebo (PBO). Liver biopsies were taken before and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analyzed by the modified intention-to-treat principle. RESULTS: Fifty-seven participants were randomized: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data were evaluable from 48 participants. In CAN-treated participants, 14 (58%) of 24 demonstrated histological improvement compared with 10 (42%) of 24 in the PBO group (P = .25). There was no improvement in prognostic scores of liver function. Four (7%) of the 55 participants died within 90 days, 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (P = .04). CONCLUSIONS: CAN therapy in severe AH participants with Model for End-Stage Liver Disease ≤27 did not alter biochemical or clinical outcomes compared with PBO. Nonsignificant histological improvements did not translate into clinical benefit. EudraCT, Number: 2017-003724-79; ClinicalTrials.gov, Number: NCT03775109.

Glycated haemoglobin is a major predictor of disease severity in patients with NAFLD.

OBJECTIVES: Currently, non-invasive scoring systems to stage the severity of non-alcoholic fatty liver disease (NAFLD) do not consider markers of glucose control (glycated haemoglobin, HbA1c); this study aimed to define the relationship between HbA1c and NAFLD severity in patients with and without type 2 diabetes. RESEARCH DESIGN AND METHODS: Data were obtained from 857 patients with liver biopsy staged NAFLD. Generalized-linear models and binomial regression analysis were used to define the relationships between histological NAFLD severity, age, HbA1c, and BMI. Paired biopsies from interventional studies (n = 421) were used to assess the impact of change in weight, HbA1c and active vs. placebo treatment on improvements in steatosis, non-alcoholic steatohepatitis (NASH), and fibrosis. RESULTS: In the discovery cohort (n = 687), risk of severe steatosis, NASH and advanced fibrosis correlated positively with HbA1c, after adjustment for obesity and age. These data were endorsed in a separate validation cohort (n = 170). Predictive modelling using HbA1c and age was non-inferior to the established non-invasive biomarker, Fib-4, and allowed the generation of HbA1c, age, and BMI adjusted risk charts to predict NAFLD severity. Following intervention, reduction in HbA1c was associated with improvements in steatosis and NASH after adjustment for weight change and treatment, whilst fibrosis change was only associated with weight change and treatment. CONCLUSIONS: HbA1c is highly informative in predicting NAFLD severity and contributes more than BMI. Assessments of HbA1c must be a fundamental part of the holistic assessment of patients with NAFLD and, alongside age, can be used to identify patients with highest risk of advanced disease.

Epidemias de significação e políticas de saúde global: Do fim da AIDS ao fim da ampliação da resposta global da AIDS.

RESUMONas últimas quatro décadas e meia, a história da pandemia de HIV passou por várias fases que podem ser pensadas como ondas distintas em termos da resposta social e política que a pandemia gerou. Ao longo dessa história, houve batalhas importantes sobre os significados e interpretações que a resposta à pandemia produziu. Mas, especialmente na última década, parece haver uma crescente desconexão entre as alegações de sucesso feitas por muitas agências globais de saúde e formuladores de políticas e a realidade empírica que essas alegações encobrem. Este comentário argumenta que a 'ampliação' ('scale-up') da resposta à pandemia essencialmente chegou ao fim e enfatiza a importância de um debate político mais honesto sobre o estado atual da resposta global ao HIV. Argumenta que, a fim de melhor definir os rumos que tal resposta deve tomar no futuro, exige que pensemos criticamente sobre as formas como essa resposta se desenvolveu historicamente, que reconheçamos os avanços significativos alcançados nas últimas décadas, mas também que reconheçamos a encruzilhada a que chegou em meados da década de 2020.

Markers of positive affect and brain state synchrony discriminate melancholic from non-melancholic depression using naturalistic stimuli.

Melancholia has been proposed as a qualitatively distinct depressive subtype associated with a characteristic symptom profile (psychomotor retardation, profound anhedonia) and a better response to biological therapies. Existing work has suggested that individuals with melancholia are blunted in their display of positive emotions and differ in their neural response to emotionally evocative stimuli. Here, we unify these brain and behavioural findings amongst a carefully phenotyped group of seventy depressed participants, drawn from an established Australian database (the Australian Genetics of Depression Study) and further enriched for melancholia (high ratings of psychomotor retardation and anhedonia). Melancholic (n = 30) or non-melancholic status (n = 40) was defined using a semi-structured interview (the Sydney Melancholia Prototype Index). Complex facial expressions were captured whilst participants watched a movie clip of a comedian and classified using a machine learning algorithm. Subsequently, the dynamics of sequential changes in brain activity were modelled during the viewing of an emotionally evocative movie in the MRI scanner. We found a quantitative reduction in positive facial expressivity amongst participants with melancholia, combined with differences in the synchronous expression of brain states during positive epochs of the movie. In non-melancholic depression, the display of positive affect was inversely related to the activity of cerebellar regions implicated in the processing of affect. However, this relationship was reduced in those with a melancholic phenotype. Our multimodal findings show differences in evaluative and motoric domains between melancholic and non-melancholic depression through engagement in ecologically valid tasks that evoke positive emotion. These findings provide new markers to stratify depression and an opportunity to support the development of targeted interventions.

Stigmatisation and resistance processes: Reflections on the field of HIV research and an agenda for contemporary stigma studies.

Stigmatisation processes constitute key barriers to effectively addressing the HIV pandemic. In this article, we provide a critical overview of this field's current state of the art, highlighting some key emerging issues that merit greater research attention in the future to ensure that contemporary research on stigmatisation and resistance processes continues to engage with changing social and political circumstances. We look at how resistance to stigma has developed in the context of HIV and highlight some of the most important programmatic strategies that have emerged over the history of the pandemic. We present the key concepts of 'moral panics' and 'necropolitics', and we articulate them in relation to new global phenomena that deepen the processes of stigmatisation. Moreover, we identify an agenda for investigation which merits greater attention in future research, intervention, and advocacy: 1) changing political environments, neoliberalism, growing political polarisation, and the rise of political extremism; 2) the rise of the information age, technological change, and social media; and 3) rebuilding civil society and governmental responses to stigma.

Healthcare interactions prior to first hospital admission with alcohol-related liver disease.

BACKGROUND AND AIMS: To examine the healthcare contacts of patients in the year before an index admission to hospital with alcohol-related liver disease (ArLD) to identify where opportunities for earlier identification of alcohol use disorders (AUD) and ArLD and intervention may occur. METHODS: A retrospective cohort study using the regional database encompassing NHS organisations across North West London (344 general practitioner [GP] practices, 4 acute hospital trusts and 2 mental health and community health trusts). Patients who had an index admission with ArLD were identified through healthcare coding and compared with a control cohort. Healthcare contacts, blood tests and AUD testing in the year preceding admission were measured. RESULTS: The ArLD cohort had 1494 participants with an index hospital admission with ArLD. The control cohort included 4462 participants. In the year preceding an index admission with ArLD, 91% of participants had at least one contact with primary care with an average of 2.97 (SD 2.45) contacts; 80% (n = 1199/1494) attended ED, 68% attended an outpatient clinic, and 42% (n = 628/1494) had at least one inpatient admission. Only 9% of the ArLD (137/1494) had formal testing for AUD. Abnormal bilirubin and platelets were more common in the ArLD than the control cohort 25% (138/560) and 28% (231/837), respectively, v 1% (12/1228) and 1% (20/1784). CONCLUSIONS: Prior to an index admission with ArLD patients have numerous interactions with all healthcare settings, indicating missed opportunities for early identification and treatment.

Clozapine Efficacy and Adverse Drug Reactions Among a Nationwide Study of 1021 Australians Prescribed Clozapine: The ClozaGene Study.

BACKGROUND AND HYPOTHESIS: The ClozaGene Study is a nationwide cohort of adults who have been treated with clozapine. While clozapine is indicated in the management of treatment-resistant schizophrenia, it is associated with a considerable adverse drug reaction (ADR) burden, and not all patients achieve adequate symptomatic response. The current study focuses on self-reported experiences of clozapine use and response, clozapine-associated ADRs, and mental health comorbidity. STUDY DESIGN: A total of 1021 participants (41.0% female; aged 46.2 ±â€…10.6 years [range 18-66]) were recruited via a mail-out based on prescriptions for clozapine. Participants completed a self-report questionnaire. STUDY RESULTS: Most participants (90.1%, n = 912) were living with schizophrenia while 41.5% reported a lifetime diagnosis of depression, 15.6% bipolar disorder, and 8.1% schizoaffective disorder. Clozapine was currently prescribed to 944 (92.5%) participants and 37.8% of these participants self-reported currently taking additional antipsychotic medication. Nearly 3 quarters of participants living with schizophrenia reported that clozapine helped control their schizophrenia symptoms moderately to very well. The most commonly reported ADRs were sialorrhea (80.3%), weight gain (71.0%), constipation (56.9%), and sedation (52.8%). The prevalence of clozapine cessation due to clozapine-induced myocarditis and neutropenia was 1% and 0.4%, respectively. CONCLUSIONS: Our findings highlight the high rate of psychotic and metabolic symptoms and ADRs among adults prescribed clozapine in the general Australian population. Future genomic analyses will focus on identifying genetic variants influencing clozapine treatment response and side effects.

Surgeon Performance as a Predictor for Patient-Reported Outcomes After Arthroscopic Partial Meniscectomy.

Background: Surgeon performance has been investigated as a factor affecting patient outcomes after orthopaedic procedures to improve transparency between patients and providers. Purpose/Hypothesis: The purpose of this study was to identify whether surgeon performance influenced patient-reported outcomes (PROMs) 1 year after arthroscopic partial meniscectomy (APM). It was hypothesized that there would be no significant difference in PROMs between patients who underwent APM from various surgeons. Study Design: Case-control study; Level of evidence, 3. Methods: A prospective cohort of 794 patients who underwent APM between 2018 and 2019 were included in the analysis. A total of 34 surgeons from a large multicenter health care center were included. Three multivariable models were built to determine whether the surgeon-among demographic and meniscal pathology factors-was a significant variable for predicting the Knee injury and Osteoarthritis Outcome Score (KOOS)-Pain subscale, the Patient Acceptable Symptom State (PASS), and a 10-point improvement in the KOOS-Pain at 1 year after APM. Likelihood ratio (LR) tests were used to determine the significance of the surgeon variable in the models. Results: The 794 patients were identified from the multicenter hospital system. The baseline KOOS-Pain score was a significant predictor of outcome in the 1-year KOOS-Pain model (odds ratio [OR], 2.1 [95% CI, 1.77-2.48]; P < .001), the KOOS-Pain 10-point improvement model (OR, 0.57 [95% CI, 0.44-0.73), and the 1-year PASS model (OR, 1.42 [95% CI, 1.15-1.76]; P = .002) among articular cartilage pathology (bipolar medial cartilage) and patient-factor variables, including body mass index, Veterans RAND 12-Item Health Survey-Mental Component Score, and Area Deprivation Index. The individual surgeon significantly impacted outcomes in the 1-year KOOS-Pain mixed model in the LR test (P = .004). Conclusion: Patient factors and characteristics are better predictors for patient outcomes 1 year after APM than surgeon characteristics, specifically baseline KOOS-Pain, although an individual surgeon influenced the 1-Year KOOS-Pain mixed model in the LR test. This finding has key clinical implications; surgeons who wish to improve patient outcomes after APM should focus on improving patient selection rather than improving the surgical technique. Future research is needed to determine whether surgeon variability has an impact on longer-term patient outcomes.

Angle-resolved optical spectroscopy of photonic cellulose nanocrystal films reveals the influence of additives on the mechanism of kinetic arrest.

Cellulose nanocrystals (CNCs) are rod-like nanoparticles whose chiral self-assembly into photonic films has been promoted as a sustainable source of colouration. Upon drying, an aqueous CNC suspension passes through two regimes: first, a liquid phase, where the CNCs self-organise into a cholesteric liquid crystal, followed by a kinetically-arrested phase, where the helicoidal structure compresses upon loss of solvent, resulting in a solid film with vibrant structural colour. The transition between these two regimes plays an important role in the visual appearance of photonic CNC films, but details on when and how kinetic arrest occurs have remained elusive. In this work, we combine angle-resolved optical spectroscopy of photonic films (approx. 100 vol% CNC) with a model for compressed helicoidal structures to retrieve the suspension conditions during kinetic arrest (approx. 10 vol% CNC). This analysis indicates a shift in the mechanism of kinetic arrest from a glass transition at lower ionic strength to gelation at higher ionic strength, explaining the trends in domain size and film colour. In contrast, neutral additives (glucose, poly(ethylene glycol)) appear to primarily reduce the compression upon drying without affecting cholesteric behaviour, as supported by a general analytical model. These findings deepen our understanding of CNC co-assembly with various commonly-used additives, enabling better control over the production of multifunctional structurally coloured materials.

Translating the potential of the urine steroid metabolome to stage NAFLD (TrUSt-NAFLD): study protocol for a multicentre, prospective validation study.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) affects approximately one in four individuals and its prevalence continues to rise. The advanced stages of NAFLD with significant liver fibrosis are associated with adverse morbidity and mortality outcomes. Currently, liver biopsy remains the 'gold-standard' approach to stage NAFLD severity. Although generally well tolerated, liver biopsies are associated with significant complications, are resource intensive, costly, and sample only a very small area of the liver as well as requiring day case admission to a secondary care setting. As a result, there is a significant unmet need to develop non-invasive biomarkers that can accurately stage NAFLD and limit the need for liver biopsy. The aim of this study is to validate the use of the urine steroid metabolome as a strategy to stage NAFLD severity and to compare its performance against other non-invasive NAFLD biomarkers. METHODS AND ANALYSIS: The TrUSt-NAFLD study is a multicentre prospective test validation study aiming to recruit 310 patients with biopsy-proven and staged NAFLD across eight centres within the UK. 150 appropriately matched control patients without liver disease will be recruited through the Oxford Biobank. Blood and urine samples, alongside clinical data, will be collected from all participants. Urine samples will be analysed by liquid chromatography-tandem mass spectroscopy to quantify a panel of predefined steroid metabolites. A machine learning-based classifier, for example, Generalized Matrix Relevance Learning Vector Quantization that was trained on retrospective samples, will be applied to the prospective steroid metabolite data to determine its ability to identify those patients with advanced, as opposed to mild-moderate, liver fibrosis as a consequence of NAFLD. ETHICS AND DISSEMINATION: Research ethical approval was granted by West Midlands, Black Country Research Ethics Committee (REC reference: 21/WM/0177). A substantial amendment (TrUSt-NAFLD-SA1) was approved on 26 November 2021. TRIAL REGISTRATION NUMBER: ISRCTN19370855.

Safety and Efficacy of Mucograft Porcine Collagen Bioengineered Acellular Dermal Matrix as a Spacer Graft in Lower Eyelid Elevation Surgery.

Background: Recent regulatory changes have limited the access to a widely used commercially available bioengineered acellular dermal matrix (BADM) product as a spacer graft in the surgical correction of lower eyelid retraction. We report our off-label usage of Mucograft, a porcine BADM, as an alternative BADM. Methods: A retrospective review was conducted of patients undergoing bilateral lower lid surgery with Mucograft (12 eyes) at a single institution. Results: For the six patients, there was a mean lower lid elevation of 1.93 mm, without any serious complications. There was greater elevation of the lower lid position for the Mucograft group compared with four septo-retractor control patients (1.93 versus 0.94mm, P = 0.008). Conclusion: Mucograft performed satisfactorily, and further investigation is warranted regarding its longer-term safety and efficacy.

Mental Imagery to Reduce Alcohol-related harm in patients with alcohol use disorder and alcohol-related liver damaGE: the MIRAGE randomised pilot trial results.

OBJECTIVE: The healthcare burden of alcohol-related liver disease (ARLD) is increasing. ARLD and alcohol use disorder (AUD) is best managed by reduction or cessation of alcohol use, but effective treatments are lacking. We tested whether people with ARLD and AUD admitted to hospital could be recruited to and retained in a trial of Functional Imagery Training (FIT), a psychological therapy that uses mental imagery to reduce alcohol craving. We conducted a multicentre randomised pilot trial of treatment as usual (TAU) versus FIT+TAU in people admitted to hospital with ARLD and AUD. DESIGN: Participants were randomised to TAU (a single session of brief intervention) or FIT+TAU (TAU with one hospital-based FIT session then eight telephone sessions over 6 months). Pilot outcomes included recruitment rate and retention at day 180. Secondary outcomes included fidelity of FIT delivery, alcohol use, and severity of alcohol dependence. RESULTS: Fifty-four participants (mean age 49; 63% male) were recruited and randomised, 28 to TAU and 26 to FIT+TAU. The retention rate at day 180 was 43%. FIT was delivered adequately by most alcohol nurses. 50% of intervention participants completed FIT sessions 1 and 2. There were no differences in alcohol use or severity of alcohol dependence between treatment groups at day 180. CONCLUSION: Participants with ARLD and AUD could be recruited to a trial of FIT versus FIT+TAU. However, retention at day 180 was suboptimal. Before conducting a definitive trial of FIT in this patient group, modifications in the intervention and recruitment/retention strategy must be tested. TRIAL REGISTRATION NUMBER: ISRCTN41353774.

Islet transplantation outcomes in type 1 diabetes and transplantation of HLA-DQ8/DR4: results of a single-centre retrospective cohort in Canada.

Background: In solid organ transplantation, HLA matching between donor and recipient is associated with superior outcomes. In islet transplantation, an intervention for Type 1 diabetes, HLA matching between donor and recipient is not performed as part of allocation. Susceptibility to Type 1 diabetes is associated with the presence of certain HLA types. This study was conducted to determine the impact of these susceptibility antigens on islet allograft survival. Methods: This is a single-centre retrospective cohort study. This cohort of transplant recipients (n = 268) received islets from 661 donor pancreases between March 11th, 1999 and August 29th, 2018 at the University of Alberta Hospital (Edmonton, AB, Canada). The frequency of the Type 1 diabetes susceptibility HLA antigens (HLA-A24, -B39, -DQ8, -DQ2 and-DQ2-DQA1∗05) in recipients and donors were determined. Recipient and donor HLA antigens were examined in relation to time to first C-peptide negative status/graft failure or last observation point. Taking into account multiple transplants per patient, we fitted a Gaussian frailty survival analysis model with baseline hazard function stratified by transplant number, adjusted for cumulative islet dose and other confounders. Findings: Across all transplants recipients of donors positive for HLA-DQ8 had significantly better graft survival (adjusted HRs 0.33 95% CI 0.17-0.66; p = 0.002). At first transplant only, donors positive for HLA-DQ2-DQA1∗05 had inferior graft survival (adjusted HR 1.96 95% CI 1.10-3.46); p = 0.02), although this was not significant in the frailty analysis taking multiple transplants into account (adjusted HR 1.46 95% CI 0.77-2.78; p = 0.25). Other HLA antigens were not associated with graft survival after adjustment for confounders. Interpretation: Our findings suggest islet transplantation from HLA-DQ8 donors is associated with superior graft outcomes. A donor positive for HLA-DQ2-DQA1∗05 at first transplant was associated with inferior graft survival but not when taking into account multiple transplants per recipient. The relevance of HLA-antigens on organ allocation needs further evaluation and inclusion in islet transplant registries and additional observational and interventional studies to evaluate the role of HLA-DQ8 in islet graft survival are required. Funding: None.

Modeling Risk Factors for Intraindividual Variability: A Mixed-Effects Beta-Binomial Model Applied to Cognitive Function in Older People in the English Longitudinal Study of Ageing.

Cognitive functioning in older age profoundly impacts quality of life and health. While most research on cognition in older age has focused on mean levels, intraindividual variability (IIV) around this may have risk factors and outcomes independent of the mean value. Investigating risk factors associated with IIV has typically involved deriving a summary statistic for each person from residual error around a fitted mean. However, this ignores uncertainty in the estimates, prohibits exploring associations with time-varying factors, and is biased by floor/ceiling effects. To address this, we propose a mixed-effects location scale beta-binomial model for estimating average probability and IIV in a word recall test in the English Longitudinal Study of Ageing. After adjusting for mean performance, an analysis of 9,873 individuals across 7 (mean = 3.4) waves (2002-2015) found IIV to be greater at older ages, with lower education, in females, with more difficulties in activities of daily living, in later birth cohorts, and when interviewers recorded issues potentially affecting test performance. Our study introduces a novel method for identifying groups with greater IIV in bounded discrete outcomes. Our findings have implications for daily functioning and care, and further work is needed to identify the impact for future health outcomes.