Analysis of time to regulatory approval in an exception from informed consent trial in trauma patients.

Background: The interactive media-based approach to community consultation and public disclosure (CC/PD), a key step when conducting exception from informed consent (EFIC) clinical trials, is intended to be completed in 4 months. This analysis characterizes the process, from initiation of CC/PD activities to institutional review board approval, to better understand the barriers and how these can be mitigated.

Methods: This is a retrospective post hoc analysis of data collected as part of the CC/PD campaigns conducted for a large trial involving up to 90 trauma centers in the United States.

MR1 presents vitamin B6-related compounds for recognition by MR1-reactive T cells.

The major histocompatibility complex class I related protein (MR1) presents microbially derived vitamin B2 precursors to mucosal-associated invariant T (MAIT) cells. MR1 can also present other metabolites to activate MR1-restricted T cells expressing more diverse T cell receptors (TCRs), some with anti-tumor reactivity. However, knowledge of the range of the antigen(s) that can activate diverse MR1-reactive T cells remains incomplete.

Identifying the Mechanisms of a Peripherally Limited Exercise Phenotype in Patients With Heart Failure With Preserved Ejection Fraction.

Background: We identified peripherally limited patients using cardiopulmonary exercise testing and measured skeletal muscle oxygen transport and utilization during invasive single leg exercise testing to identify the mechanisms of the peripheral limitation.

Methods: Forty-five patients with heart failure with preserved ejection fraction (70±7 years, 27 females) completed seated upright cardiopulmonary exercise testing and were defined as having a (1) peripheral limitation to exercise if cardiac output/oxygen consumption (VO) was elevated (≥6) or 5 to 6 with a stroke volume reserve >50% (n=31) or (2) a central limitation to exercise if cardiac output/VO slope was ≤5 or 5 to 6 with stroke volume reserve <50% (n=14). Single leg knee extension exercise was used to quantify peak leg blood flow (Doppler ultrasound), arterial-to-venous oxygen content difference (femoral venous catheter), leg VO, and muscle oxygen diffusive conductance.

Lung-delivered IL-10 therapy elicits beneficial effects via immune modulation in organic dust exposure-induced lung inflammation.

Efficacious therapeutic options capable of resolving inflammatory lung disease associated with environmental and occupational exposures are lacking. This study sought to determine the preclinical therapeutic potential of lung-delivered recombinant interleukin (IL)-10 therapy following acute organic dust exposure in mice. Here, C57BL/6J mice were intratracheally instilled with swine confinement organic dust extract (ODE) (12.

Thiophene-based lipids for mRNA delivery to pulmonary and retinal tissues.

Lipid nanoparticles (LNPs) largely rely on ionizable lipids to yield successful nucleic acid delivery via electrostatic disruption of the endosomal membrane. Here, we report the identification and evaluation of ionizable lipids containing a thiophene moiety (Thio-lipids). The Thio-lipids can be readily synthesized via the Gewald reaction, allowing for modular lipid design with functional constituents at various positions of the thiophene ring.

Leveraging electronic health records and knowledge networks for Alzheimer's disease prediction and sex-specific biological insights.

Identification of Alzheimer's disease (AD) onset risk can facilitate interventions before irreversible disease progression. We demonstrate that electronic health records from the University of California, San Francisco, followed by knowledge networks (for example, SPOKE) allow for (1) prediction of AD onset and (2) prioritization of biological hypotheses, and (3) contextualization of sex dimorphism. We trained random forest models and predicted AD onset on a cohort of 749 individuals with AD and 250,545 controls with a mean area under the receiver operating characteristic of 0.

Safety and Efficacy of Apitegromab in Patients With Spinal Muscular Atrophy Types 2 and 3: The Phase 2 TOPAZ Study.

Background And Objectives: Currently approved therapies for spinal muscular atrophy (SMA) reverse the degenerative course, leading to better functional outcome, but they do not address the impairment arising from preexisting neurodegeneration. Apitegromab, an investigational, fully human monoclonal antibody, inhibits activation of myostatin (a negative regulator of skeletal muscle growth), thereby preserving muscle mass. The phase 2 TOPAZ trial assessed the safety and efficacy of apitegromab in individuals with later-onset type 2 and type 3 SMA.

Manufacturing and Functional Characterization of Bioengineered Liver Grafts for Extracorporeal Liver Assistance in Acute Liver Failure.

Acute Liver Failure (ALF) is a life-threatening illness characterized by the rapid onset of abnormal liver biochemistries, coagulopathy, and the development of hepatic encephalopathy. Extracorporeal bioengineered liver (BEL) grafts could offer a bridge therapy to transplant or recovery. The present study describes the manufacture of clinical scale BELs created from decellularized porcine-derived liver extracellular matrix seeded entirely with human cells: human umbilical vein endothelial cells (HUVECs) and primary human liver cells (PHLCs).

Full-length Isoform Sequencing for Resolving the Molecular Basis of Charcot-Marie-Tooth 2A.

Objectives: Transcript sequencing of patient-derived samples has been shown to improve the diagnostic yield for solving cases of suspected Mendelian conditions, yet the added benefit of full-length long-read transcript sequencing is largely unexplored.

Methods: We applied short-read and full-length transcript sequencing and mitochondrial functional studies to a patient-derived fibroblast cell line from an individual with neuropathy that previously lacked a molecular diagnosis.

Results: We identified an intronic homozygous c.

Efficient prime editing in mouse brain, liver and heart with dual AAVs.

Realizing the promise of prime editing for the study and treatment of genetic disorders requires efficient methods for delivering prime editors (PEs) in vivo. Here we describe the identification of bottlenecks limiting adeno-associated virus (AAV)-mediated prime editing in vivo and the development of AAV-PE vectors with increased PE expression, prime editing guide RNA stability and modulation of DNA repair. The resulting dual-AAV systems, v1em and v3em PE-AAV, enable therapeutically relevant prime editing in mouse brain (up to 42% efficiency in cortex), liver (up to 46%) and heart (up to 11%).

Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice.

Sickle-cell disease (SCD) is caused by an A·T-to-T·A transversion mutation in the β-globin gene (HBB). Here we show that prime editing can correct the SCD allele (HBB) to wild type (HBB) at frequencies of 15%-41% in haematopoietic stem and progenitor cells (HSPCs) from patients with SCD. Seventeen weeks after transplantation into immunodeficient mice, prime-edited SCD HSPCs maintained HBB levels and displayed engraftment frequencies, haematopoietic differentiation and lineage maturation similar to those of unedited HSPCs from healthy donors.

hSSB1 (NABP2/OBFC2B) modulates the DNA damage and androgen-induced transcriptional response in prostate cancer.

Background: Activation and regulation of androgen receptor (AR) signaling and the DNA damage response impact the prostate cancer (PCa) treatment modalities of androgen deprivation therapy (ADT) and radiotherapy. Here, we have evaluated a role for human single-strand binding protein 1 (hSSB1/NABP2) in modulation of the cellular response to androgens and ionizing radiation (IR). hSSB1 has defined roles in transcription and maintenance of genome stability, yet little is known about this protein in PCa.

Hypothermia or Machine Perfusion in Kidney Donors.

Background: Therapeutic hypothermia in brain-dead organ donors has been shown to reduce delayed graft function in kidney recipients after transplantation. Data are needed on the effect of hypothermia as compared with machine perfusion on outcomes after kidney transplantation.

Methods: At six organ-procurement facilities in the United States, we randomly assigned brain-dead kidney donors to undergo therapeutic hypothermia (hypothermia group), ex situ kidney hypothermic machine perfusion (machine-perfusion group), or both (combination-therapy group).

Early intervention with ColdZyme mouth spray after self-diagnosis of common cold: A randomized, double-blind, placebo-controlled study.

Background: Previous clinical and in vitro investigations have supported the efficacy of a glycerol throat spray containing cold-adapted cod trypsin (ColdZyme) against respiratory viruses causing the common cold bycreating a protective mucosal barrier shown to deactivate common cold virus in vitro and decrease pharyngeal rhinovirus load.

Methods And Findings: This was a double-blind, randomized, parallel-group, placebo-controlled study conducted at 10 German sites to evaluate the efficacy of the medical device ColdZyme, a glycerol mouth spray containing cold-adapted cod trypsin for a naturally occurring common cold versus placebo spray. Adults experiencing a minimum of three common colds during the previous year, but otherwise healthy, were enrolled to begin treatment with the mouth spray or placebo six times daily at first sign of a common cold.

Academic Health Centers and Humanitarian Crises: One Health System's Response to Unaccompanied Children at the Border.

University of California Health (UCH) provided a system-wide, rapid response to the humanitarian crisis of unaccompanied children crossing the southern U.S. border in the midst of the COVID-19 pandemic in 2021.

Early intervention with a glycerol throat spray containing cold-adapted cod trypsin after self-diagnosis of common cold: A randomised trial.

Background: A glycerol throat spray containing cold-adapted cod trypsin (GCTS) deactivates common cold virus in vitro and decreases pharyngeal rhinovirus load after inoculation in humans. We relied on early self-diagnosis and evaluated two different scales to detect a treatment effect in naturally occurring common colds.

Methods: Adults were enrolled in this randomised, prospective, parallel group, single-blind study to begin treatment six times daily at first sign of a common cold or were assigned to a non-treated group.

Adaptation of a Simulation Model and Checklist to Assess Pediatric Emergency Care Performance by Prehospital Teams.

Introduction: Simulation tools to assess prehospital team performance and identify patient safety events are lacking. We adapted a simulation model and checklist tool of individual paramedic performance to assess prehospital team performance and tested interrater reliability.

Methods: We used a modified Delphi process to adapt 3 simulation cases (cardiopulmonary arrest, seizure, asthma) and checklist to add remote physician direction, target infants, and evaluate teams of 2 paramedics and 1 physician.

Cognitive Outcome 1 Year After Mild Traumatic Brain Injury: Results From the TRACK-TBI Study.

Background And Objectives: The objectives of this study were to develop and establish concurrent validity of a clinically relevant definition of poor cognitive outcome 1 year after mild traumatic brain injury (mTBI), to compare baseline characteristics across cognitive outcome groups, and to determine whether poor 1-year cognitive outcome can be predicted by routinely available baseline clinical variables.

Methods: Prospective cohort study included 656 participants ≥17 years of age presenting to level 1 trauma centers within 24 hours of mTBI (Glasgow Coma Scale score 13-15) and 156 demographically similar healthy controls enrolled in the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Poor 1-year cognitive outcome was defined as cognitive impairment (below the ninth percentile of normative data on ≥2 cognitive tests), cognitive decline (change score [1-year score minus best 2-week or 6-month score] exceeding the 90% reliable change index on ≥2 cognitive tests), or both.

The collective effect of finite-sized inhomogeneities on the spatial spread of populations in two dimensions.

The dynamics of a population expanding into unoccupied habitat has been primarily studied for situations in which growth and dispersal parameters are uniform in space or vary in one dimension. Here, we study the influence of finite-sized individual inhomogeneities and their collective effect on front speed if randomly placed in a two-dimensional habitat. We use an individual-based model to investigate the front dynamics for a region in which dispersal or growth of individuals is reduced to zero (obstacles) or increased above the background (hotspots), respectively.

Functional characterization of a bioengineered liver after heterotopic implantation in pigs.

Organ bioengineering offers a promising solution to the persistent shortage of donor organs. However, the progression of this technology toward clinical use has been hindered by the challenges of reconstituting a functional vascular network, directing the engraftment of specific functional cell types, and defining appropriate culture conditions to concurrently support the health and phenotypic stability of diverse cell lineages. We previously demonstrated the ability to functionally reendothelialize the vasculature of a clinically scaled decellularized liver scaffold with human umbilical vein endothelial cells (HUVECs) and to sustain continuous perfusion in a large animal recovery model.

Evaluation of Clinical, Gram Stain, and Microbiological Cure Outcomes in Men Receiving Azithromycin for Acute Nongonococcal Urethritis: Discordant Cures Are Associated With Mycoplasma genitalium Infection.

Background: In men with nongonococcal urethritis (NGU), clinicians and patients rely on clinical cure to guide the need for additional testing/treatment and when to resume sex, respectively; however, discordant clinical and microbiological cure outcomes do occur. How accurately clinical cure reflects microbiological cure in specific sexually transmitted infections (STIs) is unclear.

Methods: Men with NGU were tested for Neisseria gonorrhoeae, Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Trichomonas vaginalis, urethrotropic Neisseria meningitidis ST-11 clade strains, and Ureaplasma urealyticum (UU).

Rapid Assessment and Containment of Transmission in Postacute Care Settings-Orange County, California, 2019.

Background: , a multidrug-resistant yeast, can spread rapidly in ventilator-capable skilled-nursing facilities (vSNFs) and long-term acute care hospitals (LTACHs). In 2018, a laboratory serving LTACHs in southern California began identifying species of that were detected in urine specimens to enhance surveillance of , and was identified in February 2019 in a patient in an Orange County (OC), California, LTACH. Further investigation identified at 3 associated facilities.