SETD1B-associated neurodevelopmental disorder.

BACKGROUND: Dysfunction of histone methyltransferases and chromatin modifiers has been implicated in complex neurodevelopmental syndromes and cancers. SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. Previous reports of patients with rare variants in SETD1B describe a distinctive phenotype that includes seizures, global developmental delay and intellectual disability. METHODS: Two of the patients described herein were identified via genome-wide and exome-wide testing, with microarray and research-based exome, through the CAUSES (Clinical Assessment of the Utility of Sequencing and Evaluation as a Service) Research Clinic at the University of British Columbia. The third Vancouver patient had clinical trio exome sequencing through Blueprint Genetics. The fourth patient underwent singleton exome sequencing in Nantes, with subsequent recruitment to this cohort through GeneMatcher. RESULTS: Here we present clinical reports of four patients with rare coding variants in SETD1B that demonstrate a shared phenotype, including intellectual disability, language delay, conserved musculoskeletal findings and seizures that may be treatment-refractory. We include supporting evidence from next-generation sequencing among a cohort of paediatric patients with epilepsy. CONCLUSION: Rare coding variants in SETD1B can cause a diagnosable syndrome and could contribute as a risk factor for epilepsy, autism and other neurodevelopmental phenotypes. In the long term, some patients may also be at increased risk for cancers and other complex diseases. Thus, longitudinal studies are required to further elucidate the precise role of SETD1B in neurodevelopmental disorders and other systemic disease.

Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

The Exploration of the GWOT Combat Amputee's Experience With Longitudinal Care: A Qualitative Study.

INTRODUCTION: Contemporary advances in combat medicine have allowed greater numbers of wounded service members to survive their injuries. An estimated 1,705 combat veterans sustained major lower or upper extremity amputations between 2001 and 2017 during the Global War on Terror. This study intends to answer the following question utilizing a qualitative study design: What were the common and abnormal experiences of the Global War on Terror combat amputees relative to their mechanism of injury, perception of injury, and systems of care utilized during their recovery and rehabilitation process?. METHODS: During the months of December 2022 and January 2023, individual semi-structured interviews were conducted with U.S. Marines that served in the Global War on Terror (total n = 10). Deductive and inductive approaches were employed to identify codes, themes, and meta-themes in the data. RESULTS: All participants deployed to Afghanistan between the years 2010 and 2014 and were assigned to the following military occupational specialties: Explosive Ordnance Disposal technicians (total n = 2); combat engineers (total n = 2); and infantrymen (total n = 6). Analysis of data collected from interviews highlighted these key observations: (1) Themes in the combat amputee experience include support, systems of care, and mindset and (2) the themes synergistically contribute to the meta-themes mental health and pain and vice versa. As all participants were subjected to a blast mechanism of injury, it is difficult to determine if this played a role in deviating rehabilitation and recovery processes. Perception of injury and how well participants adapted to their new lifestyle, meaning how optimistic they were, appeared to play a significant role in recovery. Participants had mixed feelings about the care they had received but generally spoke favorably of military hospitals and were frustrated with the Veteran Affairs, and there was no clear consensus on their relationship with civilian health care, though most participants chose to seek most of their care through the Veteran Affairs. CONCLUSION: Based on the research question, this study found an intricate relationship between mental health, pain, and the experiences of the participants regarding their care and rehabilitation. However, the nature of qualitative research makes it impossible to determine generalizations that can be used to create meaningful change to address improving combat amputee veteran care. Further research into long-term health outcomes based on hypotheses not evaluated in existing literature would further improve the ability of health care providers to care for this unique patient population.

Conditional approval: discussion points from the PSI conditional approval expert group.

The European Agency for the Evaluation of Medicinal Products has recently completed the consultation of a draft guidance on how to implement conditional approval. This route of application is available for orphan drugs, emergency situations and serious debilitating or life-threatening diseases. Although there has been limited experience in implementing conditional approval to date, PSI (Statisticians in the Pharmaceutical Industry) sponsored a meeting of pharmaceutical statisticians with an interest in the area to discuss potential issues. This article outlines the issues raised and resulting discussions, based on the group's interpretation of the legislation. Conditional approval seems to fit well with the accepted regulatory strategy in HIV. In oncology, conditional approval may be most likely when (a) compelling phase II data are available using accepted clinical outcomes (e.g. progression/recurrence-free survival or overall survival) and Phase III has been planned or started, or (b) when data are available using a surrogate endpoint for clinical outcome (e.g. response rate or biochemical measures) from a single-arm study in rare tumours with high response, compared with historical data. The use of interim analyses in Phase III for supporting conditional approval raises some challenging issues regarding dissemination of information, maintenance of blinding, potential introduction of bias, ethics, switching, etc.

Intravenous ketamine sedation for painful oncology procedures.

BACKGROUND: The aim of the study was to determine the efficacy and adverse effects of intravenous (i.v.) ketamine sedation administered by nonanesthetist physicians for painful procedures. METHODS: A single-agent, procedural sedation protocol using titrated doses of ketamine i.v. (maximum 2 mg.kg(-1)) was conducted in outpatient pediatric oncology patients undergoing lumbar puncture (LP), bone marrow biopsy/aspiration (BMBx/A) or combination (LP/BMBx/A) in a tertiary care setting. The efficacy of analgesia and sedation (ability to perform the procedure), procedure duration, recovery time and the occurrence of adverse events are described. RESULTS: Fifty-eight subjects of a median age of 5 years (1-13) and median weight of 20 kg (10.5-68) underwent 119 sedations. An LP was performed in 73% of cases, a BMBx/A in 13% and LP/BMBx/A in 13%. Efficacy was 100% and the mean dose of ketamine was 1.3 mg.kg(-1) (0.4). The mean duration of the procedure was 6.6 min (4.2) and the recovery time was 11 min (4-45). Two subjects (1.7%) had a hypoxemia (SpO2 of <94%). No major airway complications occurred. The prevalence of hypertension (systolic > 20% at 5 min) was 54%. The median pain visual analogue score (VAS) for an observer was 0 (range 0-3) and caregiver was 0 (range 0-4). The median VAS for satisfaction (observer) was 10 (range 7-10) and caregiver VAS was also 10 (range 5-10). At 24 h after discharge, the incidence of bad dreams was 3.3%; vomiting, 10.8%; and abnormal behavior, 4.2%. CONCLUSION: Ketamine i.v. up to 2 mg.kg(-1) is an effective sedative for oncology procedures using a defined protocol.

More than a sore mouth: patients' experience of oral mucositis.

PURPOSE/OBJECTIVES: To explore patients' experience of chemotherapy-induced oral mucositis. DESIGN: Interpretive descriptive, phenomenologic. SETTING: The cancer center of a metropolitan teaching hospital in South Australia. SAMPLE: A purposive sample of six participants undergoing intensive cytotoxic therapy associated with autologous hematopoietic stem cell transplantation. METHODS: Patients were interviewed at different stages of their treatment trajectory and asked to relate their experience of oral mucositis as it developed and resolved. FINDINGS: Participants' reports indicated three distinct phases representing linear time in the course of their mucositis: the preparatory phase, the peak phase, and the persisting phase. Five themes further abstracted were the presence of nurses, therapeutic interventions, manifestations of mucositis, the distress of eating (and not eating), and whether the treatment was worthwhile. CONCLUSIONS: Oral mucositis is much more than a sore mouth. The effects of mucositis are widespread and can have a marked effect on patients' psychological well-being. IMPLICATIONS FOR NURSING: Care centers often focus on pain control through pharmacologic intervention and overlook the effects of other sequelae. Nurses' role in helping patients to cope with mucositis should encompass more than providing pharmacologic pain relief.