Sertraline for anxiety in adults with a diagnosis of autism (STRATA): study protocol for a pragmatic, multicentre, double-blind, placebo-controlled randomised controlled trial.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to manage anxiety in adults with an autism diagnosis. However, their effectiveness and adverse effect profile in the autistic population are not well known. This trial aims to determine the effectiveness and cost-effectiveness of the SSRI sertraline in reducing symptoms of anxiety and improving quality of life in adults with a diagnosis of autism compared with placebo and to quantify any adverse effects. METHODS: STRATA is a two-parallel group, multi-centre, pragmatic, double-blind, randomised placebo-controlled trial with allocation at the level of the individual. It will be delivered through recruiting sites with autism services in 4 regional centres in the United Kingdom (UK) and 1 in Australia. Adults with an autism diagnosis and a Generalised Anxiety Disorder Assessment (GAD-7) score ≥ 10 at screening will be randomised 1:1 to either 25 mg sertraline or placebo, with subsequent flexible dose titration up to 200 mg. The primary outcome is GAD-7 scores at 16 weeks post-randomisation. Secondary outcomes include adverse effects, proportionate change in GAD-7 scores including 50% reduction, social anxiety, obsessive-compulsive symptoms, panic attacks, repetitive behaviours, meltdowns, depressive symptoms, composite depression and anxiety, functioning and disability and quality of life. Carer burden will be assessed in a linked carer sub-study. Outcome data will be collected using online/paper methods via video call, face-to-face or telephone according to participant preference at 16, 24 and 52 weeks post-randomisation, with brief safety checks and data collection at 1-2, 4, 8, 12 and 36 weeks. An economic evaluation to study the cost-effectiveness of sertraline vs placebo and a QuinteT Recruitment Intervention (QRI) to optimise recruitment and informed consent are embedded within the trial. Qualitative interviews at various times during the study will explore experiences of participating and taking the trial medication. DISCUSSION: Results from this study should help autistic adults and their clinicians make evidence-based decisions on the use of sertraline for managing anxiety in this population. TRIAL REGISTRATION: ISRCTN, ISRCTN15984604 . Registered on 08 February 2021. EudraCT 2019-004312-66. ANZCTR ACTRN12621000801819. Registered on 07 April 2021.

Remote Monitoring of Visual Function in Patients with Maculopathy: The Aphelion Study.

INTRODUCTION: Remote monitoring of vision, using tools such as the shape discrimination hyperacuity (SDH) test, can detect disease activity in patients with maculopathy. We determined the in-clinic accuracy and repeatability of three myVisionTrack expanded version (mVTx) tests for self-testing of visual acuity (VA) and contrast sensitivity. METHODS: Aphelion, a single-arm, prospective study conducted at two sites in the USA, included adults with any maculopathy and a baseline VA of 0.7 log of minimum angle of resolution (logMAR) (Snellen 20/100) or better. Participants completed the mVTx tests (tumbling E, Landolt C, contrast sensitivity, and SDH) and standard clinical tests (near and distance Early Treatment Diabetic Retinopathy Study [ETDRS] charts and the Pelli-Robson contrast sensitivity chart). Test-retest repeatability and agreement between the mVTx tests and the corresponding clinical test were assessed by Bland-Altman analyses. Participants also completed a usability survey. RESULTS: The mean age of the 122 participants was 67 years. The most common diagnosis was age-related macular degeneration (42% of patients). The tumbling E test had a test-retest 95% limit of agreement (LoA) of ± 0.18 logMAR; the Landolt C test, ± 0.23 logMAR; the SDH test, ± 0.24 logMAR; and the contrast sensitivity test, ± 0.32 log contrast threshold (logCT). Compared with the distance ETDRS chart, the LoA was ± 0.35 logMAR for the tumbling E test (mean difference, - 0.07 logMAR) and ± 0.39 logMAR for the Landolt C test (mean difference, 0.03 logMAR). For the contrast sensitivity test, the LoA compared with the Pelli-Robson chart was ± 0.30 logCT (mean difference, - 0.25 logCT). Most participants (85%) reported that they learned the tests quickly. The tumbling E test scored the highest on ease of use. CONCLUSION: The mVTx tests of VA are accurate and repeatable, supporting their potential use alongside the SDH test to detect disease progression remotely between clinic visits.

A model-based approach for historical borrowing, with an application to neovascular age-related macular degeneration.

Bayesian historical borrowing has recently attracted growing interest due to the increasing availability of historical control data, as well as improved computational methodology and software. In this article, we argue that the statistical models used for borrowing may be suboptimal when they do not adjust for differing factors across historical studies such as covariates, dosing regimen, etc. We propose an alternative approach to address these shortcomings. We start by constructing a historical model based on subject-level historical data to accurately characterize the control treatment by adjusting for known between trials differences. This model is subsequently used to predict the control arm response in the current trial, enabling the derivation of a model-informed prior for the treatment effect parameter of another (potentially simpler) model used to analyze the trial efficacy (i.e. the trial model). Our approach is applied to neovascular age-related macular degeneration trials, employing a cross-sectional regression trial model, and a longitudinal non-linear mixed-effects drug-disease-trial historical model. The latter model characterizes the relationship between clinical response, drug exposure and baseline covariates so that the derived model-informed prior seamlessly adapts to the trial population and can be extrapolated to a different dosing regimen. This approach can yield a more accurate prior for borrowing, thus optimizing gains in efficiency (e.g. increasing power or reducing the sample size) in future trials.

Testing adults by questionnaire for social and communication disorders, including autism spectrum disorders, in an adult mental health service population.

OBJECTIVES: Autism is difficult to identify in adults due to lack of validated self-report questionnaires. We compared the effectiveness of the autism-spectrum quotient (AQ) and the Ritvo autism-Asperger's diagnostic scale-revised (RAADS-R) questionnaires in adult mental health services in two English counties. METHODS: A subsample of adults who completed the AQ and RAADS-R were invited to take part in an autism diagnostic observation schedule (ADOS Module 4) assessment with probability of selection weighted by scores on the questionnaires. RESULTS: There were 364 men and 374 women who consented to take part. Recorded diagnoses were most commonly mood disorders (44%) and mental and behavioural disorders due to alcohol/substance misuse (19%), and 4.8% (95% CI [2.9, 7.5]) were identified with autism (ADOS Module 4 10+). One had a pre-existing diagnosis of autism; five (26%) had borderline personality disorders (all female) and three (17%) had mood disorders. The AQ and RAADS-R had fair test accuracy (area under receiver operating characteristic [ROC] curve 0.77 and 0.79, respectively). AQ sensitivity was 0.79 (95% CI [0.54, 0.94]) and specificity was 0.77 (95% CI [0.65, 0.86]); RAADS-R sensitivity was 0.75 (95% CI [0.48, 0.93]) and specificity was 0.71 (95% CI [0.60, 0.81]). CONCLUSIONS: The AQ and RAADS-R can guide decisions to refer adults in mental health services to autism diagnostic services.

The Prevalence of Diabetes in Autistic Persons: A Systematic Review.

BACKGROUND: It has been proposed that autistic individuals are at an increased risk of type 1 and type 2 diabetes. Improved understanding of diabetes prevalence in autistic persons will help inform resource allocation for diabetes-related public health measures for this patient group. OBJECTIVE: To conduct a systematic review of published literature pertaining to type 1 and type 2 diabetes prevalence in autistic individuals, including comparison with their non-autistic peers. METHODS: Eligibility criteria included studies investigating the prevalence of diabetes in autistic individuals, as well as having been published in the English language. A systematic search of online databases (MEDLINE, PsycINFO, CINAHL, EMBASE and PubMed) was conducted on 4th April 2020. Additional approaches included the ancestry method, grey literature searches and expert consultation. Studies were qualitatively analysed with reporting quality appraised. RESULTS: 19 eligible studies were identified, 7 of which provided type-specific diabetes prevalence data. Of 15 studies that included a non-autistic control group, 9 reported a higher diabetes prevalence among autistic persons, with a statistically significant difference in 4 studies. Studies demonstrating a higher diabetes prevalence in autistic groups had higher average study population sizes and reporting quality ratings. CONCLUSION: It is uncertain whether diabetes is significantly more prevalent in autistic persons relative to their non-autistic peers, though larger studies suggest a trend in this direction. Nevertheless, diabetes is a significant public health issue for the autistic community, which may require a tailored approach for identification and management. Prospero database registration number: CRD42019122176.

Cardiovascular Safety and All-Cause Mortality of Methoxy Polyethylene Glycol-Epoetin Beta and Other Erythropoiesis-Stimulating Agents in Anemia of CKD: A Randomized Noninferiority Trial.

BACKGROUND AND OBJECTIVES: Erythropoiesis-stimulating agents correct anemia of CKD but may increase cardiovascular risk. We compared cardiovascular outcomes and all-cause mortality associated with monthly methoxy polyethylene glycol-epoetin beta with those of the shorter-acting agents epoetin alfa/beta and darbepoetin alfa in patients with anemia of CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a multicenter, open-label, noninferiority trial in which patients were randomized to receive methoxy polyethylene glycol-epoetin beta or reference erythropoiesis-stimulating agents, stratified by maintenance or correction treatment status and C-reactive protein level. The trial had a prespecified noninferiority margin of 1.20 for the hazard ratio (HR) for the primary end point (a composite of all-cause mortality, nonfatal myocardial infarction or stroke, adjudicated by an independent blinded committee). This trial is registered with ClinicalTrials.gov, number NCT00773513. RESULTS: In total, 2818 patients underwent randomization, received methoxy polyethylene glycol-epoetin beta or a reference agent, and were followed for a median of 3.4 years (maximum, 8.4 years). In the modified intention-to-treat analysis, a primary end point event occurred in 640 (45.4%) patients in the methoxy polyethylene glycol-epoetin beta arm, and 644 (45.7%) in the reference arm (HR 1.03; 95% confidence interval [95% CI], 0.93 to 1.15, P=0.004 for noninferiority). All-cause mortality was not different between treatment groups (HR 1.06; 95% CI, 0.94 to 1.19). Results in patient subgroups on dialysis or treated in the correction or maintenance settings were comparable to the primary analysis. CONCLUSIONS: In patients with anemia of CKD, once-monthly methoxy polyethylene glycol-epoetin beta was noninferior to conventional, shorter-acting erythropoiesis-stimulating agents with respect to rates of major adverse cardiovascular events or all-cause mortality.

RAS Mutation Status Confers Prognostic Relevance in Patients Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) with peritoneal carcinomatosis is an increasingly prevalent disease that carries significant mortality if left untreated. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in this patient population is associated with improved outcomes but high morbidity. We sought to study the prognostic significance of the known genomic driver, RAS, in patients with mCRC undergoing CRS/HIPEC to allow for improved assessment of risk-benefit ratio in this patient population. METHODS: Patients undergoing CRS/HIPEC for mCRC between 2010 and 2017 at our institution were identified. Patient demographics, RAS mutation status, perioperative morbidity, overall survival (OS), and relapse-free survival (RFS) were evaluated. RESULTS: Forty-seven patients met inclusion criteria. RAS mutant versus RAS wild-type groups were well matched with no difference in the clinicopathologic factors between groups. RAS mutation was associated with decreased RFS but no difference in OS. CONCLUSIONS: RAS mutation is an independent marker of early recurrence in patients undergoing CRS/HIPEC for mCRC and may identify patients who do not derive benefit from this high-risk procedure.

Efficacy and Long-Term Safety of C.E.R.A. Maintenance in Pediatric Hemodialysis Patients with Anemia of CKD.

BACKGROUND AND OBJECTIVES: The study was conducted to identify a conversion factor for switching from previous erythropoiesis-stimulating agents (ESAs) to continuous erythropoietin receptor activator-methoxy polyethylene glycol-epoetin beta (C.E.R.A.) and to document the efficacy and long-term safety of C.E.R.A. in pediatric patients with anemia of CKD undergoing hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this open-label, multicenter study, patients aged 6-17 years, with stable chronic anemia of CKD, undergoing hemodialysis received C.E.R.A. every 4 weeks, at a starting dose determined by previous weekly epoetin alfa/beta or darbepoetin dosing. After a 16-week dose-titration and a 4-week evaluation period, patients with stable hemoglobin could enter a 1-year optional safety extension. RESULTS: A total of 64 patients were enrolled. A conversion factor (4 µg every 4 weeks for each weekly dose of 125 IU epoetin alfa/beta or 0.55 µg darbepoetin) was identified that allowed patients to maintain hemoglobin within target levels on switching to C.E.R.A. from another ESA. Using this conversion factor, the adjusted mean change in hemoglobin from baseline to evaluation was -0.09 g/dl (95% confidence interval, -0.45 to 0.26); 81% of patients maintained hemoglobin within 10.0-12.0 g/dl and 75% maintained hemoglobin within 1.0 g/dl of baseline. Results were consistent across age groups (6-11 and 12-17 years) and previous ESA. Thirty-seven patients entered the safety extension period and 17 completed 73 weeks of treatment. Most withdrawals were for kidney transplantation. A total of 70% of patients had hemoglobin within 10.0-12.0 g/dl at last observation, and 62% were within ±1.0 g/dl of baseline. Safety was similar to studies in adult patients, with no new signal detected. CONCLUSIONS: Using a defined conversion factor, 4-weekly C.E.R.A. was efficacious in maintaining hemoglobin levels in pediatric patients with stable anemia of CKD undergoing hemodialysis, switching from maintenance treatment with epoetin alfa/beta or darbepoetin. Safety was consistent with the known C.E.R.A. safety profile in adults.

Nursing associates.

I think this role will give people a brilliant opportunity to enter the care service, obtain qualifications and develop a career. The degree pathway prevents some individuals from entering nursing. We must encourage people into the profession and support this - we need more people bedside with patients.

Methodology and reporting of systematic reviews and meta-analyses of observational studies in psychiatric epidemiology: systematic review.

BACKGROUND: Relatively little is known of the use of systematic review and synthesis methods of non-randomised psychiatric epidemiological studies, which play a vital role in aetiological research, planning and policy-making. AIMS: To evaluate reviews of psychiatric epidemiological studies of functional mental disorders that employed synthesis methods such as systematic review or meta-analysis, or other forms of quantitative review. METHOD: We searched the literature to identify appropriate reviews published during the period 1996 to April 2009. Selected reviews were evaluated using published review guidelines. RESULTS: We found 106 reviews in total, of which 38 (36%) did not mention method of data abstraction from primary studies at all. Many failed to mention study quality, publication bias, bias and confounding. In 73 studies that performed a meta-analysis, 58 (79%) tested for heterogeneity and of these, 47 found significant heterogeneity. Studies that detected heterogeneity made some allowance for this. A major obstacle facing reviewers is the wide variation between primary studies in the use of instruments to measure outcomes and in sampling methods used. CONCLUSIONS: Many deficiencies found in systematic reviews are potentially remediable, although synthesis of primary study findings in a field characterised by so many sources of heterogeneity will remain challenging.

Prevalence of psychiatric disorder in Europe: the potential and reality of meta-analysis.

BACKGROUND: Within the European Mental Health Status Project, over 200 psychiatric surveys concerning members of the European Union (plus Norway) were examined for their potential for meta-analysis with regard to prevalence of psychiatric disorders and basic demographic and social variables. The diversity of samples, methods, analysis and presentation was such that only data derived from GHQ-12 and CIDI studies could be used, and those relating to sex differentials only. METHODS: The statistical program "Stata" was used to compute odds ratios (with confidence intervals) for individual studies, and to produce fixed and random effects estimates of the pooled odds ratio for all studies together, and a measure of heterogeneity. Forrest Plots were also produced. RESULTS: Analysis of GHQ-12 data with a cut-off point of 4, indicating a current or recent "probable mental health problem", showed, as expected, that women had higher prevalence rates than men. However, there was a relatively high heterogeneity score, suggesting that these studies may not be measuring the same thing. Analysis of CIDI results showed homogeneity for major depressive disorder within the last 12 months, with the risk for men about half of that for women. CONCLUSIONS: In terms of advancing epidemiological knowledge, the results are trivial, at most confirming what is already well known. However, the study shows the potential for pooled analysis, with much greater power in epidemiological investigation if consistency could be achieved in research. Various ways in which this might be done are discussed. It also shows the value of personal knowledge and personal networks in fields which are not well handled by electronic literature databases.