Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Quality of life of men treated with brachytherapies for prostate cancer

Abstract Background Most studies of men undergoing treatment for prostate cancer examine physical symptoms as predictors of Quality of Life (QOL). However, symptoms vary by treatment modality in this population, and psychosocial variables, shown to be important to QOL, have rarely been examined. Litwin noted a need for analysis of QOL data in men treated for prostate cancer with different modes of therapy, as studies focusing on specific treatments will increase the homogeneity of research findings. Methods This cross-sectional study explored physical and psychosocial predictors of QOL in men receiving one of two types of radiation treatment for prostate cancer: Intensity Modulated Radiation Therapy (IMRT) + High Dose Rate (HDR) Brachytherapy or IMRT + seed implantation. Subjects completed a biographic questionnaire; quality of life measures, which were the eight subscales of the Medical Outcome Study Short Form Health Survey (SF-36); measures of physical symptoms including the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) and the Prostate Symptom Self-Report (PSSR); and measures of psychological factors, the Ways of Coping Scale (WOC), Perceived Stress Scale, the Anxiety Subscale of the SCL-90, and Strategies Used by Patients to Promote Health (SUPPH). Eight regression models including both physical and psychosocial variables were used to predict quality of life. Results Sixty-three subjects with complete data on all variables were studied. Treatment effect sizes were medium to large in predicting each of the quality of life subscales of the SF-36. Psychosocial variables were related to physical function, role function, bodily pain, general health, social function, emotional role, and mental health. Physical symptoms were related to subjects' perceived general health and mental health. Discussion The number of significant relationships among psychosocial variables and indicators of QOL exceeded the number of relationships among symptoms and QOL suggesting that psychosocial variables associate strongly with prostate cancer patients' reports of quality of life. Findings of the study may provide patients and families with knowledge that contributes to their understanding of quality of life outcomes of IMRT+ HDR and IMRT + seed implantation and their ability to make more informed treatment choices.</p

ACHESS – The Australian study of child health in same-sex families: background research, design and methodology

<p>Abstract</p> <p>Background</p> <p>There are an increasing number of children in Australia growing up with same-sex attracted parents. Although children from same-sex parent families do in general perform well on many psychosocial measures recent research is beginning to consider some small but significant differences when these children are compared with children from other family backgrounds. In particular studies suggest that there is an association between the stigma that same-sex parent families experience and child wellbeing. Research to date lacks a holistic view with the complete physical, mental and social wellbeing of children not yet addressed. In addition, most studies have focused only on families with lesbian parents and have studied only small numbers of children.</p> <p>Methods/design</p> <p>The Australian Study of Child Health in Same-Sex Families (ACHESS) is a national study that aims to determine the complete physical, mental and social wellbeing of Australian children under the age 18 years with at least one parent who self identifies as being same-sex attracted. There will be a particular focus on the impact that stigma and discrimination has on these families. Parent and child surveys will be used to collect data and will be available both online and in paper form. Measures have been chosen whenever possible that have sound conceptual underpinnings, robust psychometric properties and Australian normative data, and include the Child Health Questionnaire (CHQ), the Strengths and Difficulties Questionnaire (SDQ) and the Kessler Psychological Distress Scale (K10).</p> <p>Discussion</p> <p>ACHESS aims to be the largest study of its kind and will for the first time produce a detailed quantitative analysis of Australian children with same-sex attracted parents. By inviting participants to take part in further research it will also establish a valuable cohort of children, and their families, to launch future waves of research that will help us better understand the health and wellbeing of children with same-sex attracted parents.</p

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate