A meta-analysis on the diagnostic utility of ultrasound in pediatric distal forearm fractures.

Pediatric distal forearm fractures, comprising 30% of musculoskeletal injuries in children, are conventionally diagnosed using radiography. Ultrasound has emerged as a safer diagnostic tool, eliminating ionizing radiation, enabling bedside examinations with real-time imaging, and proving effective in non-hospital settings. The objective of this study is to evaluate the diagnostic efficacy of ultrasound for detecting distal forearm fractures in the pediatric population. A systematic review and meta-analysis were conducted through a comprehensive literature search in PubMed, Scopus, Web of Science, and Embase databases until October 1, 2023, following established guidelines. Eligible studies, reporting diagnostic accuracy measures of ultrasound in pediatric patients with distal forearm fractures, were included. Relevant data elements were extracted, and data analysis was performed. The analysis included 14 studies with 1377 patients, revealing pooled sensitivity and specificity of 94.5 (95% CI 92.7-95.9) and 93.5 (95% CI 89.6-96.0), respectively. Considering pre-test probabilities of 25%, 50%, and 75% for pediatric distal forearm fractures, positive post-test probabilities were 83%, 44%, and 98%, while negative post-test probabilities were 2%, 6%, and 15%, respectively. The bivariate model indicated significantly higher diagnostic accuracy in the subgroup with trained ultrasound performers vs. untrained performers (p = 0.03). Furthermore, diagnostic accuracy was significantly higher in the subgroup examining radius fractures vs. ulna fractures (p < 0.001), while no significant differences were observed between 4-view and 6-view ultrasound subgroups or between radiologist ultrasound interpreters and non-radiologist interpreters. This study highlighted ultrasound's reliability in detecting pediatric distal forearm fractures, emphasizing the crucial role of expertise in precisely confirming fractures through ultrasound examinations.

Comparison of literature mining tools for variant classification: Through the lens of 50 RYR1 variants.

PURPOSE: The American College of Medical Genetics and Genomics and the Association for Molecular Pathology have outlined a schema that allows for systematic classification of variant pathogenicity. Although gnomAD is generally accepted as a reliable source of population frequency data and ClinGen has provided guidance on the utility of specific bioinformatic predictors, there is no consensus source for identifying publications relevant to a variant. Multiple tools are available to aid in the identification of relevant variant literature, including manually curated databases and literature search engines. We set out to determine the utility of 4 literature mining tools used for ascertainment to inform the discussion of the use of these tools. METHODS: Four literature mining tools including the Human Gene Mutation Database, Mastermind, ClinVar, and LitVar 2.0 were used to identify relevant variant literature for 50 RYR1 variants. Sensitivity and precision were determined for each tool. RESULTS: Sensitivity among the 4 tools ranged from 0.332 to 0.687. Precision ranged from 0.389 to 0.906. No single tool retrieved all relevant publications. CONCLUSION: At the current time, the use of multiple tools is necessary to completely identify the literature relevant to curate a variant.

The name and frame matters when it comes to public support of opioid prevention programs.

BACKGROUND: Opioid overdose is the second leading cause of accidental death. Safe Consumption Sites (SCSs) are very effective harm reduction, but skepticism persists in the U.S. In four U.S. states, legislative attempts failed, except for Rhode Island's "Harm Reduction Center," (HRC), and New York City's "Overdose Prevention Centers" (OPP). METHODS: We hypothesized that compassion naming and framing would rate higher than safety/security or just-the-facts framing. Our mixed methods design included focus groups and a randomized experiment with an online panel of representative U.S. adults. All rated the title, description, and two or more images related to the program. Focus groups discussed impressions. RESULTS: Of four packets seen (SCS, OPP, HRC, and SIF), OPP was the clear favorite in both studies. Unexpectedly, offering facts and statistics improved favorability. Compassionate language was a primary driver of favorability, followed by life-saving medical messaging. Imagery of people helping and smiling was liked best. Focus groups' primary concern was about "their backyards," but also, they desired to save lives and reduce suffering. CONCLUSION: Stigma drove opposition to SCSs, as did conservative political affiliation. We provide finalized marketing packets which will reduce stigma and generate public support for SCSs.

Disparities in computed tomography utilization for pediatric blunt trauma: a systematic review and meta-analysis comparing pediatric and non-pediatric trauma centers.

Pediatric blunt trauma is a major cause of morbidity and mortality, and computed tomography (CT) imaging is vital for accurate evaluation and management. Pediatric trauma centers (PTCs) have selective CT practices, while non-PTCs may differ, resulting in potential variations in CT utilization. The objective of this study is to delineate disparities in CT utilization for pediatric blunt trauma patients between PTCs and non-PTCs. A systematic review and meta-analysis were conducted following established guidelines, searching PubMed, Scopus, and Web of Science up to March 3, 2023. All studies examining CT utilization in the management of pediatric (aged < 21 years) blunt trauma and specifying the type of trauma center(s) were included, and data were extracted and analyzed using STATA software version 17.0. An analysis of 30 studies revealed significant variations in CT scan utilization among pediatric blunt trauma patients across different types of trauma centers. PTCs exhibited lower pooled rates of abdominopelvic CT scans (35.4% vs. 44.9%, p < 0.01), cranial CT scans (36.9% vs. 42.9%, p < 0.01), chest CT scans (14.5% vs. 25.4%, p < 0.01), and cervical spine CT scans (23% vs. 45%, p < 0.01) compared to adult or mixed trauma centers (ATCs/MTCs). PTCs had a pooled rate of 54% for receiving at least one CT scan, while ATCs/MTCs had a higher rate of 69.3% (p < 0.05). The studies demonstrated considerable heterogeneity. These findings underscore the need to conduct further research to understand the reasons for the observed variations and to promote appropriate imaging usage, minimize radiation exposure, and encourage collaboration between pediatric and adult trauma centers.

The enhancement of CRISPR/Cas9 gene editing using metformin.

The CRISPR/Cas9 technology is a revolutionary tool that can be used to edit the genome. Specifically, the genome of hematopoietic stem cells (HSCs) could be edited to correct monogenic blood disorders as well as produce immunotherapies. However, the efficiency of editing HSCs remains low. To overcome this hurdle, we set out to investigate the use of metformin, an FDA-approved drug, to enhance gene modification. We assessed the effect of metformin on the growth of two hematopoietic cell lines: a myeloid-erythroid leukemic cell line (K562 cells) representative of the myeloid population and an immortalized T lymphocyte cell line (Jurkat cells) representative of the lymphoid population. No significant difference in growth patterns was observed in concentrations up to 10 mM metformin in both cell lines. We then assessed the ability of two different concentrations of metformin (0.001 mM or 1 mM), based on our observations, to enhance both (1) the cutting efficiency of Cas9 and (2) the targeting efficiency with the use of a donor DNA repair template. The cutting efficiency of Cas9 was significantly enhanced in a total of five guide RNAs (four specific to a platelet locus and one specific to an erythroid locus) following treatment. In addition, an enhancement in targeting was observed with the use of a GFP-containing donor DNA repair template with both concentrations. Overall, a greater than two-fold increase in GFP expression was noted in cells treated with metformin. This suggests that metformin, an FDA-approved drug, could be added to existing protocols to enhance CRISPR/Cas9 gene editing.

A systematic review and meta-analysis of incidental findings in computed tomography scans for pediatric trauma patients.

PURPOSE: To quantitatively synthesize and report the frequency and category of incidental findings on Computed Tomography (CT) scans in pediatric trauma patients. METHODS: A thorough literature search was carried out in PubMed, Scopus, and Web of Science databases until March 6, 2023, in adherence to the preferred reporting items for systematic review and meta-analyses (PRISMA) guidelines. Studies describing incidental findings on CT scans in trauma patients ≤21 years were included. Incidental findings were grouped into three categories: Category 1 (requiring immediate or urgent evaluation or treatment), Category 2 (likely benign but which may require outpatient follow-up), and Category 3 (benign anatomic variants or pathologic findings that do not require follow-up or intervention). RESULTS: Seven studies were included in this study, which revealed a combined rate of 27.10 % of incidental findings with notable heterogeneity among the studies. Aggregated frequencies were 10.15 % for Category 1, 32.18 % for Category 2 and 51.44 % for Category 3. Subgroup meta-analysis on abdominal CT scans showed a higher pooled incidence of incidental findings at 47.17 %, but with lower heterogeneity than the general meta-analysis. CONCLUSION: The study underscores the prevalence of incidental findings in pediatric trauma patients undergoing CT scans. The categorization of these findings provides useful information for clinicians in determining appropriate follow-up and management strategies.

Genome-wide identification of dominant polyadenylation hexamers for use in variant classification.

Polyadenylation is an essential process for the stabilization and export of mRNAs to the cytoplasm and the polyadenylation signal hexamer (herein referred to as hexamer) plays a key role in this process. Yet, only 14 Mendelian disorders have been associated with hexamer variants. This is likely an under-ascertainment as hexamers are not well defined and not routinely examined in molecular analysis. To facilitate the interrogation of putatively pathogenic hexamer variants, we set out to define functionally important hexamers genome-wide as a resource for research and clinical testing interrogation. We identified predominant polyA sites (herein referred to as pPAS) and putative predominant hexamers across protein coding genes (PAS usage >50% per gene). As a measure of the validity of these sites, the population constraint of 4532 predominant hexamers were measured. The predominant hexamers had fewer observed variants compared to non-predominant hexamers and trimer controls, and CADD scores for variants in these hexamers were significantly higher than controls. Exome data for 1477 individuals were interrogated for hexamer variants and transcriptome data were generated for 76 individuals with 65 variants in predominant hexamers. 3' RNA-seq data showed these variants resulted in alternate polyadenylation events (38%) and in elongated mRNA transcripts (12%). Our list of pPAS and predominant hexamers are available in the UCSC genome browser and on GitHub. We suggest this list of predominant hexamers can be used to interrogate exome and genome data. Variants in these predominant hexamers should be considered candidates for pathogenic variation in human disease, and to that end we suggest pathogenicity criteria for classifying hexamer variants.

A non-canonical mechanism of GPCR activation.

The goal of designing safer, more effective drugs has led to tremendous interest in molecular mechanisms through which ligands can precisely manipulate signaling of G-protein-coupled receptors (GPCRs), the largest class of drug targets. Decades of research have led to the widely accepted view that all agonists-ligands that trigger GPCR activation-function by causing rearrangement of the GPCR's transmembrane helices, opening an intracellular pocket for binding of transducer proteins. Here we demonstrate that certain agonists instead trigger activation of free fatty acid receptor 1 by directly rearranging an intracellular loop that interacts with transducers. We validate the predictions of our atomic-level simulations by targeted mutagenesis; specific mutations which disrupt interactions with the intracellular loop convert these agonists into inverse agonists. Further analysis suggests that allosteric ligands could regulate signaling of many other GPCRs via a similar mechanism, offering rich possibilities for precise control of pharmaceutically important targets.

Clinical and molecular heterogeneity of syndromic hypothalamic hamartoma.

Two children are presented who have a distinct syndrome of multiple buccolingual frenula, a stiff and short fifth finger with small nails, a hypothalamic hamartoma, mild to moderate neurological impairment, and mild endocrinological symptoms. No variant assessed to be pathogenic or likely pathogenic was detected in the GLI3 gene in either child. This syndrome appears to be distinct from the inherited Pallister-Hall syndrome associated with GLI3 variants, which is characterized by hypothalamic hamartoma, mesoaxial polydactyly, and other anomalies. In the individuals described here, manifestations outside of the central nervous system were milder and the mesoaxial polydactyly, which is common in individuals with Pallister-Hall syndrome, was absent. Instead, these children had multiple buccolingual frenula together with the unusual appearance of the fifth digit. It remains unclear whether these two individuals represent a separate nosologic entity or if they represent a milder manifestation of one of the more severe syndromes associated with a hypothalamic hamartoma.

The effect of histone deacetylase inhibitors on the efficiency of the CRISPR/Cas9 system.

The CRISPR/Cas9 technology is a prominent genome-editing tool capable of producing a double-strand break in the genome. However, the modification of hematopoietic stem cells via the homology-directed repair pathway is still inefficient. Therefore, we hypothesize that histone deacetylase inhibitors, such as valproic acid (VPA) and sodium butyrate (NaB), could enhance HDR efficiency by increasing the accessibility of the genome-editing machinery. To address the potential utilization of HDAC inhibitors therapeutically, we began by assessing the effect of VPA and NaB on two cell lines representative of the two hematopoietic stem cell lineages. No statistically significant effect on cell growth or viability was observed at concentrations as high as 5 mM. At a concentration as low as 0.005 mM NaB, an enhancement in CRISPR cutting efficiency was evidenced in both cell lines. This enhancement did not appear to be locus-specific. However, an enhancement in cutting efficiency following VPA treatment does appear to be. HDR efficiency was enhanced greater than two-fold with the use of 0.005 mM VPA. These results are promising and suggest the consideration of treatment with an HDAC inhibitor in CRISPR/Cas9 genome editing protocols.

Towards accountability-centred practices: governance in OSCEs subordinating patient and practitioner clinical experience.

New public management ideals and standards have become increasingly adhered to in health professions education; this is particularly apparent in high-stakes assessment, as a gateway to practice. Using an Institutional Ethnographic approach, we looked at the work involved in running high-stakes Objective Structured Clinical Exams (OSCEs) throughout an academic year including use of observations, interviews and textual analysis. In our results, we describe three types of 'work'-standardising work, defensibility work and accountability work-summarising these in the discussion as an Accountability Circuit, which shows the organising role of texts on people's work processes. We show how this form of governance mandates a shift towards accountability-centred practices, away from practices which are person-centred; this lens on accountability-centring during high-stakes assessments invites critique of the often-unquestioned emphasis of new public management in health professions education.

Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor.

BACKGROUND: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. METHODS: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (change in low density lipoprotein cholesterol). RESULTS: MK-0616 displayed high affinity (Ki = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84-103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple-oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43-85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. CONCLUSIONS: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.

Are GP training opportunities in Northern Ireland widening or closing the gap on health inequalities? An analysis of Northern Ireland deprivation data.

BACKGROUND: Increasing the GP workforce will not necessarily level up healthcare provision. Instead, increasing GP training numbers could worsen health inequity and inequalities. This is especially true if there are fewer opportunities to learn, train, and build confidence in underserved, socioeconomically deprived areas. AIM: To investigate the representation of socioeconomic deprivation in postgraduate GP training practices in Northern Ireland (NI). DESIGN & SETTING: An analysis of socioeconomic deprivation indices and scores of GP practices in NI involved in postgraudate GP training. METHOD: The socioeconomic deprivation indices and scores of GP postgraduate training practices were compared against general practice in NI by examining the representation of practices whose patients live in areas of blanket deprivation, higher deprivation, and higher affluence. RESULTS: Of 319 practices in NI, 195 (61%) were registered as postgraduate training practices and had a statistically significantly lower deprivation score (3.02±0.21) compared with non-training practices (3.2±0.32), t(255) -2.02, P = 0.041. The proportion of training practices with blanket deprivation and higher levels of deprivation was underrepresented, with the current postgraduate GP training practices having more affluent populations. CONCLUSION: Postgraduate training practices had a statistically significant lower deprivation score and did not fully reflect the socioeconomic make-up of wider NI general practice. The results, however, are more favourable than in other areas of the UK and better than undergraduate teaching opportunities in general practice. Health inequalities will worsen if the representation of general practice training in areas of greater socioeconomic deprivation is not increased.

The significance of hindbrain herniation reversal following prenatal repair of neural tube defects.

OBJECTIVE: The aim of this study was to determine whether reversal of hindbrain herniation (HBH) on MRI following prenatal repair of neural tube defects (NTDs) is associated with reduced rates of ventriculoperitoneal (VP) shunt placement or endoscopic third ventriculostomy (ETV) within the 1st year of life. METHODS: This is a secondary analysis of prospectively collected data from all patients who had prenatal open repair of a fetal NTD at a single tertiary care center between 2012 and 2020. Patients were offered surgery according to inclusion criteria from the Management of Myelomeningocele Study (MOMS). Patients were excluded if they were lost to follow-up, did not undergo postnatal MRI, or underwent postnatal MRI without a report assessing hindbrain status. Patients with HBH reversal were compared with those without HBH reversal. The primary outcome assessed was surgical CSF diversion (i.e., VP shunt or ETV) within the first 12 months of life. Secondary outcomes included CSF leakage, repair dehiscence, CSF diversion prior to discharge from the neonatal intensive care unit (NICU), and composite neonatal morbidity. Demographic, prenatal sonographic, and operative characteristics as well as outcomes were assessed using standard univariate statistical methods. Multivariate logistic regression models were fit to assess for independent contributions to the primary and secondary outcomes. RESULTS: Following exclusions, 78 patients were available for analysis. Of these patients, 38 (48.7%) had HBH reversal and 40 (51.3%) had persistent HBH on postnatal MRI. Baseline demographic and preoperative ultrasound characteristics were similar between groups. The primary outcome of CSF diversion within the 1st year of life was similar between the two groups (42.1% vs 57.5%, p = 0.17). All secondary outcomes were also similar between groups. Patients who had occurrence of the primary outcome had greater presurgical lateral ventricle width than those who did not (16.1 vs 12.1 mm, p = 0.02) when HBH was reversed, but not when HBH was persistent (12.5 vs 10.7 mm, p = 0.49). In multivariate analysis, presurgical lateral ventricle width was associated with increased rates of CSF diversion before 12 months of life (adjusted OR 1.18, 95% CI 1.03-1.35) and CSF diversion prior to NICU discharge (adjusted OR 1.18, 95% CI 1.02-1.37). CONCLUSIONS: HBH reversal was not associated with decreased rates of CSF diversion in this cohort. Predictive accuracy of the anticipated benefits of prenatal NTD repair may not be augmented by the observation of HBH reversal on MRI.

Co-occurrence of Proteus syndrome and ventricular tachycardia cardiac arrest in a teenager.

Proteus syndrome is an extremely rare overgrowth condition caused by a somatic variant of the AKT1 gene. It can involve multiple organ systems though rarely is there symptomatic cardiac involvement. Fatty infiltration of the myocardium has been described but has not been reported to cause functional or conduction abnormalities. We present an individual with Proteus syndrome who suffered a sudden cardiac arrest.

IMiDs Augment CD3-Bispecific Antibody-Induced CD8+ T-Cell Cytotoxicity and Expansion by Enhancing IL2 Production.

Although CD3-bispecific antibodies have shown promising activity in the treatment of hematological cancers, insufficient T-cell costimulation may limit long-term responses. Immunomodulatory drugs (IMiDs), routinely used in treating multiple myeloma, possess pleiotropic antimyeloma properties and have been described to enhance T-cell responses similar to costimulatory signaling and may therefore have synergistic effects when combined with T-cell bispecifics. In this report, we demonstrate that IMiDs substantially enhance tumor cell killing induced by CD3 bispecifics and increase CD8+ T-cell proliferation and expansion. We further show that the beneficial effects of IMiDs on T-cell function and expansion are mediated by enhanced IL2 production by CD4+ T cells. Our studies provide mechanistic insight into the costimulatory properties of IMiDs and support combination treatments with T-cell agonist therapies in a broad spectrum of indications.

Sustaining Long-Term Asthma Outcomes at a Community and Tertiary Care Pediatric Hospital.

BACKGROUND AND OBJECTIVES: Implementing asthma Clinical Practice Guidelines (CPG) have been shown to improve length of stay (LOS) and readmission rates on a short-term basis at both tertiary care and community hospital settings. Whether these outcomes are sustained long term is not known. The goal of this study was to measure the long-term impact of CPG implementation at both tertiary and community sites in 1 hospital system. METHODS: A retrospective study was conducted using the Pediatric Health Information System database. LOS and 7- and 14-day emergency department (ED) revisit and readmission rates from 2009 to 2020 were compared pre and post implementation of asthma CPG in 2012 at both sites. Implementation involved electronic order sets, early metered dose inhaler introduction, and empowering respiratory therapists to wean per the bronchodilator weaning protocol. Interrupted time series and statistical process control charts were used to assess CPG impact. RESULTS: Implementation of asthma CPG was associated with significant reductions in the variability of LOS without impacting ED revisit or readmission rates at both the tertiary and community sites. Secular trends in the interrupted time series did not demonstrate significant impact of CPG on LOS. However, the overall trend toward decreased LOS that started before CPG implementation was sustained for 7 years after CPG implementation. CONCLUSIONS: Early metered dose inhaler introduction, respiratory therapist-driven bronchodilator weaning, and electronic order sets at both the community and tertiary care site led to a significant reduction in the variation of LOS, without impacting ED revisit or readmission rate.

Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1-related malignant hyperthermia susceptibility.

The ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel specified the American College of Medical Genetics and Genomics/Association of Molecular Pathologists (ACMG/AMP) criteria for RYR1-related MHS and a pilot analysis of 84 variants was published. We have now classified an additional 251 variants for RYR1-related MHS according to current ClinGen standards and updated the criteria where necessary. Criterion PS4 was modified such that individuals with multiple RYR1 variants classified as pathogenic (P), likely pathogenic (LP), or variant of uncertain significance (VUS) were not considered as providing evidence for pathogenicity. Criteria PS1 and PM5 were revised to consider LP variants at the same amino-acid residue as providing evidence for pathogenicity at reduced strength. Finally, PM1 was revised such that if PS1 or PM5 are used PM1, if applicable, should be downgraded to supporting. Of the 251 RYR1 variants, 42 were classified as P/LP, 16 as B/LB, and 193 as VUS. The primary driver of 175 VUS classifications was insufficient evidence supporting pathogenicity, rather than evidence against pathogenicity. Functional data supporting PS3/BS3 was identified for only 13 variants. Based on the posterior probabilities of pathogenicity and variant frequencies in gnomAD, we estimated the prevalence of individuals with RYR1-related MHS pathogenic variants to be between 1/300 and 1/1075, considerably higher than current estimates. We have updated ACMG/AMP criteria for RYR1-related MHS and classified 251 variants. We suggest that prioritization of functional studies is needed to resolve the large number of VUS classifications and allow for appropriate risk assessment. RYR1-related MHS pathogenic variants are likely to be more common than currently appreciated.