Chromatin conformation, gene transcription, and nucleosome remodeling as an emergent system.

In single cells, variably sized nanoscale chromatin structures are observed, but it is unknown whether these form a cohesive framework that regulates RNA transcription. Here, we demonstrate that the human genome is an emergent, self-assembling, reinforcement learning system. Conformationally defined heterogeneous, nanoscopic packing domains form by the interplay of transcription, nucleosome remodeling, and loop extrusion.

Review article: Efficacy of cyproheptadine in the management of serotonin toxicity following deliberate self-poisoning - A systematic review.

Serotonin toxicity is a potentially fatal condition caused by increased serotonergic activity in the central nervous system. Cyproheptadine, a serotonergic antagonist, is recommended for treatment; however, there is a lack of evidence to support its use. The present study aimed to evaluate the evidence for the use of cyproheptadine in the management of serotonin toxicity following deliberate self-poisoning.

"In the spectrum of people who are healthy": Views of individuals at risk of dementia on using neurotechnology for cognitive enhancement.

Neurotechnological cognitive enhancement has become an area of intense scientific, policy, and ethical interest. However, while work has increasingly focused on ethical views of the general public, less studied are those with personal connections to cognitive impairment. Using a mixed-methods design, we surveyed attitudes regarding implantable neurotechnological cognitive enhancement in individuals who self-identified as having increased likelihood of developing dementia (n=25; 'Our Study'), compared to a nationally representative sample of Americans (n=4726; 'Pew Study').

Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells.

Background: Metabolism is error prone. For instance, the reduced forms of the central metabolic cofactors nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH), can be converted into redox-inactive products, NADHX and NADPHX, through enzymatically catalyzed or spontaneous hydration. The metabolite repair enzymes NAXD and NAXE convert these damaged compounds back to the functional NAD(P)H cofactors.

Differences in anxiety, depression and pain experience among adults with chronic low back pain as a function of nicotine product use.

The landscape of nicotine use in the United States (US) has continued to evolve, with electronic cigarette use (hereafter e-cigarette) becoming more evident in recent years. Patterns of dual nicotine use, or using combustible nicotine in conjunction with e-cigarettes, may increase dependence on nicotine, continued exposure to toxins, and corresponding health risks. One of the most prevalent health problems related to nicotine use is the experience of chronic pain.

Functional analysis of SRY variants in individuals with 46,XY Differences of Sex Development.

In mammals, male sexual development is initiated by the expression of the Sex-determining-Region-Y (SRY) gene. SRY contains a highly conserved High Mobility Group (HMG) box essential for DNA binding and activity. Variants in SRY cause Differences of Sex Development (DSD), accounting for 10-15% of 46,XY gonadal dysgenesis cases.

Formation of I+III supercomplex rescues respiratory chain defects.

Mitochondrial electron transport chain (ETC) complexes partition between free complexes and quaternary assemblies known as supercomplexes (SCs). However, the physiological requirement for SCs and the mechanisms regulating their formation remain controversial. Here, we show that genetic perturbations in mammalian ETC complex III (CIII) biogenesis stimulate the formation of a specialized extra-large SC (SC-XL) with a structure of I+III, resolved at 3.

Generation and heterozygous repair of human iPSC lines from two individuals with the neurodevelopmental disorder, TRAPPC4 deficiency.

A rare neurodevelopmental disorder has been linked to a well-conserved splice site variant in the TRAPPC4 gene (c.454 + 3A > G), which causes mis-splicing of TRAPPC4 transcripts and reduced levels of TRAPPC4 protein. Patients present with severe progressive neurological symptoms including seizures, microcephaly, intellectual disability and facial dysmorphism.

Validation of Pediatric Sequential Organ Failure Assessment (pSOFA) Scores to Predict Critical Events in the Pediatric Intensive Care Unit.

Objective: To determine the prognostic value of the Pediatric Sequential Organ Failure Assessment (pSOFA) to discriminate critical events, including code events and intubations, in the pediatric intensive care unit (PICU).

Methods: We performed an observational cohort study of all critical events in a quaternary care PICU between 5/2020 and 4/2023. Critical events were extracted from our hospital communications platform and from the electronic health record (EHR).

Options for pediatric heart valve replacement.

Heart valve replacement is indicated for children with irreparable heart valve disease. These replacements come in a variety of forms including mechanical, xenograft tissue, allograft tissue, and autograft tissue valves. These options each have unique benefits and risks profiles.

Continuous frusemide infusion versus intermittent bolus therapy in paediatric intensive care: A single centre retrospective study.

Objective: Frusemide is a common diuretic administered to critically ill children intravenously, by either continuous infusion (CI) or intermittent bolus (IB). We aim to describe the characteristics of children who receive intravenous frusemide, patterns of use, and incidence of acute kidney injury (AKI), and to investigate factors associated with commencing CI.

Design: Retrospective observational study.

Heritable polygenic editing: the next frontier in genomic medicine?

Polygenic genome editing in human embryos and germ cells is predicted to become feasible in the next three decades. Several recent books and academic papers have outlined the ethical concerns raised by germline genome editing and the opportunities that it may present. To date, no attempts have been made to predict the consequences of altering specific variants associated with polygenic diseases.

Videolaryngoscopy in paediatrics: in search of the clinical evidence.

Despite the numerous recent trials, systematic reviews and meta-analyses have not conclusively shown superiority of videolaryngoscopy over other techniques for tracheal intubation of children. Clinical trials have shown significant differences using various outcome measures, but the overall clinical evidence remains weak. An international group of experts is currently working on developing good clinical research practice guidelines for paediatric airway management research, with the ultimate aim of identifying a core set of outcomes to be applied to develop future robust and comparable trials.

Extracorporeal Cardiopulmonary Resuscitation Outcomes in Pre-Glenn Single Ventricle Infants: Analysis of A Ten-Year Dataset.

Background: While several studies have reported on outcomes of extracorporeal membrane oxygenation (ECMO) in patients with single ventricle physiology, few studies have described outcomes of extracorporeal cardiopulmonary resuscitation (ECPR) in this unique population. The objective of this study was to determine survival and risk factors for mortality after ECPR in single ventricle patients prior to superior cavopulmonary anastomosis, using a large sample from the Extracorporeal Life Support Organization (ELSO) Registry.

Methods: We included single ventricle patients who underwent ECPR for in-hospital cardiac arrest (IHCA) between January 2012 and December 2021.

Lack of correlation between school reopening and trends in adult COVID-19 hospitalisations and death rates during the Delta and early Omicron periods: an ecological analysis of five countries.

Objectives: In this ecological study, we describe SARS-CoV-2 case incidence for school age and adult populations, COVID-19 hospitalisation and death rates during Delta and the early Omicron periods, before and after schools reopened in five countries.

Methods: Data were extracted from government websites. Cases and COVID-19 hospitalisation and death incidence rates were calculated during the Delta and early Omicron periods in Australia, Canada, Denmark, Finland and the United Kingdom, for two weeks preceding and six weeks after schools reopened.

Structure guided modification of 2-chloro-5-(ethyl-phenyl-sulfamoyl)-N-[2-(2-oxo-pyrrolidin-1-yl)-phenyl]-benzamide to afford selective inhibitors of Cryptosporidium parvum N-myristoyltransferase.

Cryptosporidium parvum is a protozoan parasite that causes severe diarrheal illness in children and each year nearly 50,000 children under age 5 die due to the disease. Despite tremendous research efforts, there remains a lack of effective therapies and vaccines. Novel inhibitors against N-myristoyltransferase of C.

Evaluating a 12-week aerobic exercise intervention in adults with persisting post-concussive symptoms.

Background: Although guidelines support aerobic exercise in sub-acute mild traumatic brain injury (mTBI), evidence for adults with persisting post-concussive symptoms (PPCS) after mTBI is lacking. The objective was to evaluate the impact of a sub-symptom threshold aerobic exercise intervention on overall symptom burden and quality of life in adults with PPCS.

Methods: This prospective cohort study was nested within the ACTBI Trial (Aerobic Exercise for treatment of Chronic symptoms following mild Traumatic Brain Injury).

Ionizing radiation improves skin bacterial dysbiosis in cutaneous T-cell lymphoma.

Introduction: Cutaneous T-cell lymphoma (CTCL) is closely associated with the host microbiome. While recent evidence suggests that shifts in specific bacterial taxa are associated with response to UV-B, a form of non-ionizing radiation, the impact of ionizing radiation (IR) has not been investigated.

Methods: 16S rRNA and gene amplicon sequencing were performed on DNA extracted from swabs of lesional/non-lesional skin of 12 CTCL patients before/after TSEBT or local IR and from 25 matched healthy controls (HC).

No Vaccine, No Organ? Ethics of Vaccine Mandates for Pediatric Transplant.

Many transplant programs worldwide are likely to impose vaccine mandates for pediatric solid organ transplant candidates; some already do. Three potential benefits that advocates invoke to justify mandates are improved patient outcomes, efficient organ allocation, and contributions to community protection. We show that none of these benefits can justify mandates.

Developing alert thresholds and self-management advice for people receiving immune checkpoint inhibitors: a Multinational Association for Supportive Care in Cancer modified Delphi survey.

Background: Remote monitoring using electronic patient-reported outcomes (ePROs) may help identify immune-related adverse events (irAEs) and direct self-management. There is no consensus regarding thresholds to alert providers about potentially severe irAEs or when to instigate evidence-based self-management. We aimed to develop consensus around alert thresholds and self-management advice for side-effects suggestive of an irAE which can be deployed as part of remote monitoring systems.

Intracerebroventricular B7-H3-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial.

Diffuse intrinsic pontine glioma (DIPG) is a fatal central nervous system (CNS) tumor that confers a median survival of 11 months. As B7-H3 is expressed on pediatric CNS tumors, we conducted BrainChild-03, a single-center, dose-escalation phase 1 clinical trial of repetitive intracerebroventricular (ICV) dosing of B7-H3-targeting chimeric antigen receptor T cells (B7-H3 CAR T cells) for children with recurrent or refractory CNS tumors and DIPG. Here we report results from Arm C, restricted to patients with DIPG.

Enhanced D614G and Omicron Variants Antibody Persistence in Infants at 2 Months of Age Following Maternal mRNA Booster Vaccination During Pregnancy or Postpartum.

Background: Following maternal COVID-19 vaccination, the persistence of antibodies in sera and breast milk for mothers and infants is not well characterized. We sought to describe the persistence of antibodies through 2 months after delivery in maternal and infant serum and breast milk following maternal COVID-19 mRNA vaccination and to examine differences by receipt of booster dose during pregnancy or postpartum.

Methods: This is a prospective cohort study with enrollment from July 2021 to January 2022 at 9 US academic sites.

Effectiveness of mRNA COVID-19 vaccines and hybrid immunity in preventing SARS-CoV-2 infection and symptomatic COVID-19 among adults in the United States.

Background: Understanding protection against SARS-CoV-2 infection by vaccine and hybrid immunity is important for informing public health strategies as new variants emerge.

Methods: We analyzed data from three cohort studies spanning September 1, 2022-July 31, 2023, to estimate COVID-19 vaccine effectiveness (VE) against SARS-CoV-2 infection and symptomatic COVID-19 among adults with and without prior infection in the United States. Participants collected weekly nasal swabs, irrespective of symptoms, annual blood draws, and completed periodic surveys, which included vaccination status and prior infection history.

A genome-wide scan of non-coding RNAs and enhancers for refractive error and myopia.

Refractive error (RE) and myopia are complex polygenic conditions with the majority of genome-wide associated genetic variants in non-exonic regions. Given this, and the onset during childhood, gene-regulation is expected to play an important role in its pathogenesis. This prompted us to explore beyond traditional gene finding approaches.