Development and Evaluation of a Web-Based Family-Centered Decision Support Tool About Firearm Storage.

BACKGROUND: Many youth in the USA have access to a loaded and unlocked firearm in their home. Discussions between adult family members have the potential to positively influence firearm storage. PURPOSE: Work with firearm-owning parents to develop and obtain preliminary data about the efficacy of a family-centered decision support tool about firearm storage. METHODS: We adapted the Ottawa Personal Decision Guide for Two to the issue of firearm storage, producing the Family Safety Check-In. Subsequently, we evaluated its acceptability and impact on intentions to make a plan with their partner (or other adult sharing parental duties) about safer firearm storage. Participants were parents/guardians of at least one school-aged child, had firearms in their home, and resided in the USA (n = 402). They completed a web-based pre-test survey, were randomized to the Family Safety Check-In or an American Academy of Pediatrics (AAP) informational resource about firearm storage for families, and then completed a post-test survey. RESULTS: The Family Safety Check-In had higher ratings for acceptability (B = 1.24, 95% CI = 0.58-1.90) and appropriateness (B = 1.46, 95% CI = 0.72-2.19) than the AAP resource. Participants in the Family Safety Check-In condition also had greater intentions to make a plan with their partner about storing firearms more safely (OR = 1.90, 95% CI = 1.26-2.87). CONCLUSIONS: The Family Safety Check-In is a promising direction for harm reduction that warrants further evaluation.

The purpose of this study was to develop and obtain preliminary data about the efficacy of the Family Safety Check-In, a family-centered decision support tool about firearm storage. To develop this family-centered intervention, we adapted the Ottawa Personal Decision Guide for Two to the issue of firearm storage. Subsequently, we evaluated its acceptability and impact on intentions to make a plan with their partner (or other adult sharing parental duties) about safer firearm storage. Participants were parents/guardians of at least one school-aged child, had firearms in their home, and resided in the USA (n = 402). They completed a web-based pre-test survey, were randomized to the Family Safety Check-In or an American Academy of Pediatrics (AAP) informational resource about firearm storage for families, and then completed a post-test survey. The Family Safety Check-In had higher ratings for acceptability and appropriateness than the AAP resource. Participants in the Family Safety Check-In condition also had greater intentions to make a plan with their partner about storing firearms more safely. The Family Safety Check-In is a promising direction for harm reduction that warrants further evaluation.

Benchmarking computational variant effect predictors by their ability to infer human traits.

BACKGROUND: Computational variant effect predictors offer a scalable and increasingly reliable means of interpreting human genetic variation, but concerns of circularity and bias have limited previous methods for evaluating and comparing predictors. Population-level cohorts of genotyped and phenotyped participants that have not been used in predictor training can facilitate an unbiased benchmarking of available methods. Using a curated set of human gene-trait associations with a reported rare-variant burden association, we evaluate the correlations of 24 computational variant effect predictors with associated human traits in the UK Biobank and All of Us cohorts. RESULTS: AlphaMissense outperformed all other predictors in inferring human traits based on rare missense variants in UK Biobank and All of Us participants. The overall rankings of computational variant effect predictors in these two cohorts showed a significant positive correlation. CONCLUSION: We describe a method to assess computational variant effect predictors that sidesteps the limitations of previous evaluations. This approach is generalizable to future predictors and could continue to inform predictor choice for personal and clinical genetics.

Pediatric Acute Respiratory Distress Syndrome Severity and Health-Related Quality of Life Outcomes: Single-Center Retrospective Cohort, 2011-2017.

OBJECTIVES: To determine factors associated with health-related quality of life (HRQL) decline among pediatric acute respiratory distress syndrome (PARDS) survivors. DESIGN: Retrospective cohort study. SETTING: Academic children's hospital. PATIENTS: Three hundred fifteen children 1 month to 18 years old with an unplanned PICU admission from December 2011 to February 2017 enrolled in the hospital's Outcomes Assessment Program. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pre-admission baseline and median 6-week post-discharge HRQL were assessed using the Pediatric Quality of Life Inventory or the Functional Status II-R. Patients meeting retrospectively applied Second Pediatric Acute Lung Injury Consensus Conference criteria for PARDS were identified, and PARDS severity was classified using binary (mild/moderate, severe) and trichotomous (mild, moderate, severe) categorization for noninvasive ventilation and invasive mechanical ventilation (IMV). PARDS occurred in 41 of 315 children (13.0%). Clinically important HRQL decline (≥ 4.5 points) occurred in 17 of 41 patients (41.5%) with PARDS and 64 of 274 without PARDS (23.4%). On multivariable generalized linear regression adjusted for age, baseline Pediatric Overall Performance Category, maximum nonrespiratory Pediatric Logistic Organ Dysfunction score, diagnosis, length of stay, and time to follow-up, PARDS was associated with HRQL decline (adjusted relative risk [aRR], 1.70; 95% CI, 1.03-2.77). Four-hour and maximum PARDS severity were the only factors associated with HRQL decline. HRQL decline occurred in five of 18 patients with mild PARDS at 4 hours, five of 13 with moderate PARDS (aRR 2.35 vs. no PARDS [95% CI, 1.01-5.50]), and seven of ten with severe PARDS (aRR 2.56 vs. no PARDS [95% CI, 1.45-4.53]). The area under the receiver operating characteristic curve for discrimination of HRQL decline for IMV patients was 0.79 (95% CI, 0.66-0.91) for binary and 0.80 (95% CI, 0.69-0.93) for trichotomous severity categorization. CONCLUSIONS: HRQL decline is common among children surviving PARDS, and risk of decline is associated with PARDS severity. HRQL decline from baseline may be an efficient and clinically meaningful endpoint to incorporate into PARDS clinical trials.

Neuroradiological features of contrast-induced neurotoxicity: A systematic review and pooled analysis.

BACKGROUND: Contrast-induced neurotoxicity (CIN), is an increasingly recognised complication of endovascular procedures, presenting as a spectrum of neurological symptoms that mimic ischaemic stroke. The diagnosis of CIN remains a clinical challenge, and stereotypical imaging findings are not established. This study was conducted to characterise the neuroimaging findings in patients with CIN, to raise diagnostic awareness and improve decision making. METHODS: We performed a systematic review of PubMed and Embase databases from inception (1946/1947) to June 2023 for reports of CIN following administration of iodinated contrast media. Studies with a final diagnosis of CIN, which provided details of neuroimaging were included. All included cases were pooled and descriptive analysis was conducted. RESULTS: A total of 84 patients were included, with a median age of 64 years. A large proportion of patients had normal imaging (CT 40.8 %, MRI 53.1 %). CT abnormalities included cortical/subarachnoid hyperattenuation (42.1 %), cerebral oedema/sulcal effacement (26.3 %), and loss of grey-white differentiation (7.9 %). Frequently reported MRI abnormalities included brain parenchymal MRI signal change (40.8 %) and cerebral oedema (12.2 %), most commonly observed on FLAIR sequences (26.5 %). Characterisation of imaging findings according to anatomical location and clinical symptoms has been conducted. CONCLUSIONS: Neuroimaging is an essential part of the diagnostic workup of CIN. Analysis of the anatomical location and laterality of imaging abnormalities may suggest relationship between radiological features and actual clinical symptoms, although this remains to be confirmed with dedicated study. Radiological abnormalities, particularly CT, appear to be transient and reversible in most patients.

Use of artificial intelligence and the future of peer review.

Conducting high-quality peer review of scientific manuscripts has become increasingly challenging. The substantial increase in the number of manuscripts, lack of a sufficient number of peer-reviewers, and questions related to effectiveness, fairness, and efficiency, require a different approach. Large-language models, 1 form of artificial intelligence (AI), have emerged as a new approach to help resolve many of the issues facing contemporary medicine and science. We believe AI should be used to assist in the triaging of manuscripts submitted for peer-review publication.

Guidelines for releasing a variant effect predictor.

Computational methods for assessing the likely impacts of mutations, known as variant effect predictors (VEPs), are widely used in the assessment and interpretation of human genetic variation, as well as in other applications like protein engineering. Many different VEPs have been released to date, and there is tremendous variability in their underlying algorithms and outputs, and in the ways in which the methodologies and predictions are shared. This leads to considerable challenges for end users in knowing which VEPs to use and how to use them. Here, to address these issues, we provide guidelines and recommendations for the release of novel VEPs. Emphasising open-source availability, transparent methodologies, clear variant effect score interpretations, standardised scales, accessible predictions, and rigorous training data disclosure, we aim to improve the usability and interpretability of VEPs, and promote their integration into analysis and evaluation pipelines. We also provide a large, categorised list of currently available VEPs, aiming to facilitate the discovery and encourage the usage of novel methods within the scientific community.

Intercalated Water Drives Anomalous Thermal Expansion in the Tetragonal Zircon Structured Bismuth Vanadate BiVO4 Photocatalyst.

The thermal transformation of the tetragonal-zircon (tz-) to tetragonal-scheelite (ts-)BiVO4 was studied by in situ synchrotron X-ray diffraction, thermogravimetric analysis, and Fourier-transformed infrared spectroscopy. Upon heating, the tetragonal zircon polymorph of BiVO4 (tz-BiVO4) transitioned to the ts-polymorph between 693-773 K. Above 773 K, single phase ts-BiVO4 was observed before transitioning to the monoclinic fergusonite (mf-) polymorph upon cooling. An anomaly in thermal expansion was observed between 400-500 K, associated with the loss of intercalated H2O/NH4 + from the coprecipitation procedure. Heating tz-BiVO4 resulted in contraction of the V-O bond distance and VO4 polyhedra volume, ascribed to rotation of the tetrahedra groups. Attempts to study this by neutron diffraction failed due to the large incoherent scatter from the hydrogenous species. Efforts to remove these species while maintaining the tz-BiVO4 structure were unsuccessful, suggesting they play a role in stabilizing the tz-polymorph. The local structure of both mf-BiVO4 and tz-BiVO4 were investigated by X-ray pair distribution function analysis, revealing local distortions.

Seeing the Unseen: The Structural Influence of the Lone Pair Electrons in PbWO4.

Pair distribution function (PDF) analysis of the scheelite-type material PbWO4 reveals previously unidentified short-range structural distortions in the PbO8 polyhedra and WO4 tetrahedra not observed in the similarly structured CaWO4. These local distortions are a result of the structural influence of the Pb2+ 6s2 lone pair electrons. These are not evident from the Rietveld analysis of synchrotron X-ray or neutron powder diffraction data, nor do they strongly influence the X-ray PDF (XPDF). This illustrates the importance of neutron PDF (NPDF) in the study of such materials. First-principles density function theory (DFT) calculations show that the Pb2+ 6s2 electrons are hybridized with the O2- 2p electrons near the Fermi level. The presence of local-scale distortions has previously been neglected in studies of structure-functionality relationships in PbWO4 and other scheelite-structured photocatalytic materials, including BiVO4, and this observation opens new avenues for their optimization.

Racial and Ethnic Disparities in All-Cause and Cause-Specific Mortality Among US Youth.

Importance: Mortality rates in US youth have increased in recent years. An understanding of the role of racial and ethnic disparities in these increases is lacking. Objective: To compare all-cause and cause-specific mortality trends and rates among youth with Hispanic ethnicity and non-Hispanic American Indian or Alaska Native, Asian or Pacific Islander, Black, and White race. Design, Setting, and Participants: This cross-sectional study conducted temporal analysis (1999-2020) and comparison of aggregate mortality rates (2016-2020) for youth aged 1 to 19 years using US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database. Data were analyzed from June 30, 2023, to January 17, 2024. Main Outcomes and Measures: Pooled, all-cause, and cause-specific mortality rates per 100 000 youth (hereinafter, per 100 000) for leading underlying causes of death were compared. Injuries were classified by mechanism and intent. Results: Between 1999 and 2020, there were 491 680 deaths among US youth, including 8894 (1.8%) American Indian or Alaska Native, 14 507 (3.0%) Asian or Pacific Islander, 110 154 (22.4%) Black, 89 251 (18.2%) Hispanic, and 267 452 (54.4%) White youth. Between 2016 and 2020, pooled all-cause mortality rates were 48.79 per 100 000 (95% CI, 46.58-51.00) in American Indian or Alaska Native youth, 15.25 per 100 000 (95% CI, 14.75-15.76) in Asian or Pacific Islander youth, 42.33 per 100 000 (95% CI, 41.81-42.86) in Black youth, 21.48 per 100 000 (95% CI, 21.19-21.77) in Hispanic youth, and 24.07 per 100 000 (95% CI, 23.86-24.28) in White youth. All-cause mortality ratios compared with White youth were 2.03 (95% CI, 1.93-2.12) among American Indian or Alaska Native youth, 0.63 (95% CI, 0.61-0.66) among Asian or Pacific Islander youth, 1.76 (95% CI, 1.73-1.79) among Black youth, and 0.89 (95% CI, 0.88-0.91) among Hispanic youth. From 2016 to 2020, the homicide rate in Black youth was 12.81 (95% CI, 12.52-13.10) per 100 000, which was 10.20 (95% CI, 9.75-10.66) times that of White youth. The suicide rate for American Indian or Alaska Native youth was 11.37 (95% CI, 10.30-12.43) per 100 000, which was 2.60 (95% CI, 2.35-2.86) times that of White youth. The firearm mortality rate for Black youth was 12.88 (95% CI, 12.59-13.17) per 100 000, which was 4.14 (95% CI, 4.00-4.28) times that of White youth. American Indian or Alaska Native youth had a firearm mortality rate of 6.67 (95% CI, 5.85-7.49) per 100 000, which was 2.14 (95% CI, 1.88- 2.43) times that of White youth. Black youth had an asthma mortality rate of 1.10 (95% CI, 1.01-1.18) per 100 000, which was 7.80 (95% CI, 6.78-8.99) times that of White youth. Conclusions and Relevance: In this study, racial and ethnic disparities were observed for almost all leading causes of injury and disease that were associated with recent increases in youth mortality rates. Addressing the increasing disparities affecting American Indian or Alaska Native and Black youth will require efforts to prevent homicide and suicide, especially those events involving firearms.

Tetrahedra Rotational and Displacive Disorder in the Scheelite-Type Oxide CsReO4.

Scheelite-type metal oxides are a notable class of functional materials, with applications including ionic conductivity, photocatalysis, and the safe storage of radioactive waste. To further engineer these materials for specific applications, a detailed understanding of how their properties can change under different conditions is required─not just in the long-range average structure but also in the short-range local structure. This paper outlines a detailed investigation of the metal oxide CsReO4, which exhibits an uncommon orthorhombic Pnma pseudo-scheelite-type structure at room temperature. Using synchrotron X-ray diffraction, the average structure of CsReO4 is found to undergo a transformation from the orthorhombic Pnma pseudo-scheelite-type structure to the tetragonal I41/a scheelite-type structure at ∼440 K. In the X-ray pair distribution function analysis, lattice strain and rotations of the ReO4 tetrahedra are apparent above 440 K despite the increase in long-range average symmetry, revealing a disconnect between the structural models at different length scales. This study demonstrates how the bonding requirements and ionic radii of the A-site cation can induce disorder that is detectable at different length scales, affecting the physical properties of the material.

Pacybara: accurate long-read sequencing for barcoded mutagenized allelic libraries.

MOTIVATION: Long-read sequencing technologies, an attractive solution for many applications, often suffer from higher error rates. Alignment of multiple reads can improve base-calling accuracy, but some applications, e.g. sequencing mutagenized libraries where multiple distinct clones differ by one or few variants, require the use of barcodes or unique molecular identifiers. Unfortunately, sequencing errors can interfere with correct barcode identification, and a given barcode sequence may be linked to multiple independent clones within a given library. RESULTS: Here we focus on the target application of sequencing mutagenized libraries in the context of multiplexed assays of variant effects (MAVEs). MAVEs are increasingly used to create comprehensive genotype-phenotype maps that can aid clinical variant interpretation. Many MAVE methods use long-read sequencing of barcoded mutant libraries for accurate association of barcode with genotype. Existing long-read sequencing pipelines do not account for inaccurate sequencing or nonunique barcodes. Here, we describe Pacybara, which handles these issues by clustering long reads based on the similarities of (error-prone) barcodes while also detecting barcodes that have been associated with multiple genotypes. Pacybara also detects recombinant (chimeric) clones and reduces false positive indel calls. In three example applications, we show that Pacybara identifies and correctly resolves these issues. AVAILABILITY AND IMPLEMENTATION: Pacybara, freely available at https://github.com/rothlab/pacybara, is implemented using R, Python, and bash for Linux. It runs on GNU/Linux HPC clusters via Slurm, PBS, or GridEngine schedulers. A single-machine simplex version is also available.

Characteristics of Firearm Injury by Injury Intent: The Need for Tailored Interventions.

INTRODUCTION: While the U.S. has high quality data on firearm-related deaths, less information is available on those who arrive at trauma centers alive, especially those discharged from the emergency department. This study sought to describe characteristics of patients arriving to trauma centers alive following a firearm injury, postulating that significant differences in firearm injury intent might provide insights into injury prevention strategies. METHODS: This was a multi-center prospective cohort study of patients treated for firearm-related injuries at 128 U.S. trauma centers from 3/2021-2/2022. Data collected included patient-level sociodemographic, injury and clinical characteristics, community characteristics, and context of injury. The outcome of interest was the association between these factors and the intent of firearm injury. Measures of urbanicity, community distress, and strength of state firearm laws were utilized to characterize patient communities. RESULTS: 15,232 patients presented with firearm-related injuries across 128 centers in 41 states. Overall, 9.5% of patients died, and deaths were more common among law enforcement and self-inflicted (SI) firearm injuries (80.9% and 50.5%, respectively). These patients were also more likely to have a history of mental illness. SI firearm injuries were more common in older White men from rural and less distressed communities, whereas firearm assaults were more common in younger, Black men from urban and more distressed communities. Unintentional injuries were more common among younger patients and in states with lower firearm safety grades whereas law enforcement-related injuries occurred most often in unemployed patients with a history of mental illness. CONCLUSIONS: Injury, clinical, sociodemographic, and community characteristics among patients injured by a firearm significantly differed between intents. With the goal of reducing firearm-related deaths, strategies and interventions need to be tailored to include community improvement and services that address specific patient risk factors for firearm injury intent. LEVEL OF EVIDENCE: Level III, Prognostic/Epidemiological.

Characterizing glucokinase variant mechanisms using a multiplexed abundance assay.

BACKGROUND: Amino acid substitutions can perturb protein activity in multiple ways. Understanding their mechanistic basis may pinpoint how residues contribute to protein function. Here, we characterize the mechanisms underlying variant effects in human glucokinase (GCK) variants, building on our previous comprehensive study on GCK variant activity. RESULTS: Using a yeast growth-based assay, we score the abundance of 95% of GCK missense and nonsense variants. When combining the abundance scores with our previously determined activity scores, we find that 43% of hypoactive variants also decrease cellular protein abundance. The low-abundance variants are enriched in the large domain, while residues in the small domain are tolerant to mutations with respect to abundance. Instead, many variants in the small domain perturb GCK conformational dynamics which are essential for appropriate activity. CONCLUSIONS: In this study, we identify residues important for GCK metabolic stability and conformational dynamics. These residues could be targeted to modulate GCK activity, and thereby affect glucose homeostasis.

Minimum information and guidelines for reporting a multiplexed assay of variant effect.

Multiplexed assays of variant effect (MAVEs) have emerged as a powerful approach for interrogating thousands of genetic variants in a single experiment. The flexibility and widespread adoption of these techniques across diverse disciplines have led to a heterogeneous mix of data formats and descriptions, which complicates the downstream use of the resulting datasets. To address these issues and promote reproducibility and reuse of MAVE data, we define a set of minimum information standards for MAVE data and metadata and outline a controlled vocabulary aligned with established biomedical ontologies for describing these experimental designs.

Strengthening the Role of the NIH in the Firearm Violence Epidemic: A Modest Proposal.

This Viewpoint discusses the potential for the National Institutes of Health (NIH), the premier research entity in the world, to significantly strengthen its investment in preventing and reducing firearm-related harms.