Hematopoietic stem cell transplantation and vasculopathy associated with STAT3-dominant-negative hyper-IgE syndrome

Dominant negative mutations in the transcription-factor STAT3 underlie the rare primary immunodeficiency Job's syndrome. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) has shown promise in correction of the underlying immunological defect, with one report suggesting HSCT can prevent development of wider connective tissue complications. Here, we report the case of a 26 year old male who developed an acute ST-elevation myocardial infarction due to coronary artery ectasia and thrombosis, occurring despite pediatric allogeneic HSCT for STAT3-HIES and a predicted 10-year conventional cardiovascular risk of 0.1%. Vasculopathy associated with STAT3-HIES may persist or arise following HSCT and can precipitate life-threatening complications. This has implications for counseling and vascular surveillance, and highlights the need for further studies to determine the risk, pathogenesis, and optimal management of the vasculopathy associated with STAT3-HIES

Barriers to the management of sexual dysfunction among people with psychosis: analysis of qualitative data from the REMEDY trial

Background: More than half of people who use antipsychotic medication for psychosis report having sexual dysfunction. The REMEDY trial aimed to find out if switching antipsychotic medication provides an effective way to reduce sexual dysfunction among people with psychosis. We set out to recruit 216 participants over a two-year period, but recruitment was stopped after an extended 12-month pilot phase, during which we recruited only 10 participants. As part of a nested process evaluation, we conducted qualitative interviews with front-line clinicians to examine barriers to recruitment to the trial. Methods: We developed a semi-structured interview schedule to explore staff views on factors that influenced whether they referred potential participants to the study. We interviewed a purposive sample of 51 staff from four National Health Service (NHS) Trusts in England, ensuring a range of different backgrounds, seniority, and levels of involvement in the trial. Audio recordings of interviews were transcribed for verbatim, and data were analysed using an inductive approach to thematic analysis. Results: Nine interconnected themes were generated. Six themes concerned barriers to recruitment; including; prioritising patients’ mental stability, mutual discomfort and embarrassment about discussing a “taboo” subject, and concerns about unintended consequences of asking people with psychosis about their sexual functioning. Three themes, including the quality of treatment relationships and strategies for opening dialogue suggested ways to improve recognition of these “hidden” side effects. Conclusion: The identification and management of sexual dysfunction among people with psychosis are not priorities for mental health services in England at this time. Many staff working in front-line services feel unprepared and uncomfortable asking people with psychosis about these problems. While greater use of screening tools may improve the identification of sexual dysfunction among people with psychosis, the evaluation and implementation of interventions to manage them will continue to be challenging unless NHS leaders and senior clinicians demonstrate greater commitment to changing current clinical practice. Trial registration: Current Controlled Trials ISRCTN12307891

Barriers to the management of sexual dysfunction among people with psychosis: analysis of qualitative data from the REMEDY trial

Background: More than half of people who use antipsychotic medication for psychosis report having sexual dysfunction. The REMEDY trial aimed to find out if switching antipsychotic medication provides an effective way to reduce sexual dysfunction among people with psychosis. We set out to recruit 216 participants over a two-year period, but recruitment was stopped after an extended 12-month pilot phase, during which we recruited only 10 participants. As part of a nested process evaluation, we conducted qualitative interviews with front-line clinicians to examine barriers to recruitment to the trial. Methods: We developed a semi-structured interview schedule to explore staff views on factors that influenced whether they referred potential participants to the study. We interviewed a purposive sample of 51 staff from four National Health Service (NHS) Trusts in England, ensuring a range of different backgrounds, seniority, and levels of involvement in the trial. Audio recordings of interviews were transcribed for verbatim, and data were analysed using an inductive approach to thematic analysis. Results: Nine interconnected themes were generated. Six themes concerned barriers to recruitment; including; prioritising patients’ mental stability, mutual discomfort and embarrassment about discussing a “taboo” subject, and concerns about unintended consequences of asking people with psychosis about their sexual functioning. Three themes, including the quality of treatment relationships and strategies for opening dialogue suggested ways to improve recognition of these “hidden” side effects. Conclusion: The identification and management of sexual dysfunction among people with psychosis are not priorities for mental health services in England at this time. Many staff working in front-line services feel unprepared and uncomfortable asking people with psychosis about these problems. While greater use of screening tools may improve the identification of sexual dysfunction among people with psychosis, the evaluation and implementation of interventions to manage them will continue to be challenging unless NHS leaders and senior clinicians demonstrate greater commitment to changing current clinical practice. Trial registration: Current Controlled Trials ISRCTN12307891

Switching antipsychotic medication to reduce sexual dysfunction in people with psychosis: the REMEDY RCT

BackgroundSexual dysfunction is common among people who are prescribed antipsychotic medication for psychosis. Sexual dysfunction can impair quality of life and reduce treatment adherence. Switching antipsychotic medication may help, but the clinical effectiveness and cost-effectiveness of this approach is unclear.ObjectiveTo examine whether or not switching antipsychotic medication provides a clinically effective and cost-effective method to reduce sexual dysfunction in people with psychosis.DesignA two-arm, researcher-blind, pilot randomised trial with a parallel qualitative study and an internal pilot phase. Study participants were randomised to enhanced standard care plus a switch of antipsychotic medication or enhanced standard care alone in a 1?:?1 ratio. Randomisation was via an independent and remote web-based service using dynamic adaptive allocation, stratified by age, gender, Trust and relationship status.SettingNHS secondary care mental health services in England.ParticipantsPotential participants had to be aged ??18 years, have schizophrenia or related psychoses and experience sexual dysfunction associated with the use of antipsychotic medication. We recruited only people for whom reduction in medication dosage was ineffective or inappropriate. We excluded those who were acutely unwell, had had a change in antipsychotic medication in the last 6 weeks, were currently prescribed clozapine or whose sexual dysfunction was believed to be due to a coexisting physical or mental disorder.InterventionsSwitching to an equivalent dose of one of three antipsychotic medications that are considered to have a relatively low propensity for sexual side effects (i.e. quetiapine, aripiprazole or olanzapine). All participants were offered brief psychoeducation and support to discuss their sexual health and functioning.Main outcome measuresThe primary outcome was patient-reported sexual dysfunction, measured using the Arizona Sexual Experience Scale. Secondary outcomes were researcher-rated sexual functioning, mental health, side effects of medication, health-related quality of life and service utilisation. Outcomes were assessed 3 and 6 months after randomisation. Qualitative data were collected from a purposive sample of patients and clinicians to explore barriers to recruitment.Sample sizeAllowing for a 20% loss to follow-up, we needed to recruit 216 participants to have 90% power to detect a 3-point difference in total Arizona Sexual Experience Scale score (standard deviation 6.0 points) using a 0.05 significance level.ResultsThe internal pilot was discontinued after 12 months because of low recruitment. Ninety-eight patients were referred to the study between 1 July 2018 and 30 June 2019, of whom 10 were randomised. Eight (80%) participants were followed up 3 months later. Barriers to referral and recruitment included staff apprehensions about discussing side effects, reluctance among patients to switch medication and reticence of both staff and patients to talk about sex.LimitationsInsufficient numbers of participants were recruited to examine the study hypotheses.ConclusionsIt may not be possible to conduct a successful randomised trial of switching antipsychotic medication for sexual functioning in people with psychosis in the NHS at this time.Future workResearch examining the acceptability and effectiveness of adjuvant phosphodiesterase inhibitors should be considered.Trial registrationCurrent Controlled Trials ISRCTN12307891.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 44. See the NIHR Journals Library website for further project information

Multivitamins and minerals modulate whole-body energy metabolism and cerebral blood-flow during cognitive task performance:a double-blind, randomised, placebo-controlled trial

BACKGROUND: The brain is by far the most metabolically active organ in the body, with overall energy expenditure and local blood-supply closely related to neural activity. Both energy metabolism and cerebral vaso-dilation are dependent on adequate micronutrient status. This study investigated whether supplementation with ascending doses of multi-vitamin/minerals could modulate the metabolic and cerebral blood-flow consequences of performing cognitive tasks that varied in difficulty. METHODS: In this randomised, double-blind, placebo-controlled, parallel-groups study 97 healthy females (25-49 y), who were not selected on the basis of any nutritional parameters, received either placebo or one of two doses of multivitamins/minerals. Cerebral blood-flow (CBF) parameters in the frontal cortex, and total energy expenditure (TotalEnergy), carbohydrate and fat oxidation (CarbOxi/FatOxi), were measured during 5 tasks of graded cognitive difficulty and a control task (5 min per task) using Near-infrared spectroscopy (NIRS) and Indirect calorimetry of exhaled pulmonary gas (ICa) respectively. Assessments took place 60 min after the first dose and following eight weeks supplementation. RESULTS: During task performance supplementation with the first dose of micronutrients led to a dose-dependent increase in TotalEnergy and FatOxi throughout the post-dose assessment period following the higher dose, and increases in the total concentration of haemoglobin, a proxy measure for CBF, during task performance following the lower dose of vitamins/minerals (also containing coenzyme-Q10). Chronic supplementation over 8 weeks led to a dose-dependent increase in TotalEnergy during the task period. There were no interpretable effects on mood or cognitive performance. CONCLUSIONS: These results show that acute supplementation with micronutrients in healthy adults can modulate metabolic parameters and cerebral blood flow during cognitive task performance, and that the metabolic consequences are sustained during chronic supplementation. These findings suggest that both brain function and metabolism are amenable to micronutrient supplementation, even in adults who are assumed to have nutritional status typical of the population. TRIAL REGISTRATION: ClinicalTrials.gov - NCT02381964

Additional file 1: Figure S1. of Multivitamins and minerals modulate whole-body energy metabolism and cerebral blood-flow during cognitive task performance: a double-blind, randomised, placebo-controlled trial

Exploratory analysis of the effects of differing task demands on ratings of mental fatigue/difficulty and all physiological variables, irrespective of treatment. Table S1. Mean scores (+SEM) averaged across Day 1 and Day 56 from the exploratory analysis of the effects of differing task demands on ratings of mental fatigue/difficulty and all physiological variables, irrespective of treatment. Table S2. Means (+SEM) of ICa data obtained during the 5 min pre-task resting period, the control tapping task and 5 task periods on Day 1 and Day 56. Table S3. Cognitive task performance scores (mean plus SEM) on Day 1 and Day 56. Table S4. Subjective difficulty and mental fatigue data (+SEM) from Day 1 and Day 56. (DOC 328 kb

Effect of Glyburide vs Subcutaneous Insulin on Perinatal Complications Among Women With Gestational Diabetes: A Randomized Clinical Trial.

Randomized trials have not focused on neonatal complications of glyburide for women with gestational diabetes. To compare oral glyburide vs subcutaneous insulin in prevention of perinatal complications in newborns of women with gestational diabetes. The Insulin Daonil trial (INDAO), a multicenter noninferiority randomized trial conducted between May 2012 and November 2016 (end of participant follow-up) in 13 tertiary care university hospitals in France including 914 women with singleton pregnancies and gestational diabetes diagnosed between 24 and 34 weeks of gestation. Women who required pharmacologic treatment after 10 days of dietary intervention were randomly assigned to receive glyburide (n=460) or insulin (n=454). The starting dosage for glyburide was 2.5 mg orally once per day and could be increased if necessary 4 days later by 2.5 mg and thereafter by 5 mg every 4 days in 2 morning and evening doses, up to a maximum of 20 mg/d. The starting dosage for insulin was 4 IU to 20 IU given subcutaneously 1 to 4 times per day as necessary and increased according to self-measured blood glucose concentrations. The primary outcome was a composite criterion including macrosomia, neonatal hypoglycemia, and hyperbilirubinemia. The noninferiority margin was set at 7% based on a 1-sided 97.5% confidence interval. Among the 914 patients who were randomized (mean age, 32.8 [SD, 5.2] years), 98% completed the trial. In a per-protocol analysis, 367 and 442 women and their neonates were analyzed in the glyburide and insulin groups, respectively. The frequency of the primary outcome was 27.6% in the glyburide group and 23.4% in the insulin group, a difference of 4.2% (1-sided 97.5% CI, -∞ to 10.5%; P=.19). This study of women with gestational diabetes failed to show that use of glyburide compared with subcutaneous insulin does not result in a greater frequency of perinatal complications. These findings do not justify the use of glyburide as a first-line treatment. clinicaltrials.gov Identifier: NCT01731431