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Abstract Background High morbidity and mortality rates of trauma injuries make early detection and correct diagnosis crucial for increasing patient’s survival and quality of life after an injury. Improvements in technology have facilitated the rapid detection of injuries, especially with the use of computed tomography (CT). However, the increased use of CT imaging is not universally advocated for. Some advocate for the use of selective CT imaging, especially in cases where the severity of the injury is low. The purpose of this study is to review the CT indications, findings, and complications in patients with low Injury Severity Scores (ISS) to determine the utility of torso CT in this patient cohort. Methods A retrospective review of non-intubated, adult blunt trauma patients with an initial GCS of 14 or 15 evaluated in an ACS verified level 1 trauma center from July 2012 to June 2015 was performed. Data was obtained from the hospital’s trauma registry and chart review, with the following data included: age, sex, injury type, ISS, physical exam findings, all injuries recorded, injuries detected by torso CT, missed injuries, and complications. The statistical tests conducted in the analysis of the collected data were chi-squared, Fischer exact test, and ANOVA analysis. Results There were 2306 patients included in this study, with a mean ISS of 8. For patients with a normal chest exam that had a chest CT, 15% were found to have an occult chest injury. In patients with a negative chest exam and negative chest X-ray, 35% had occult injuries detected on chest CT. For patients with a negative abdominal exam and CT abdomen and pelvis, 16% were found to have an occult injury on CT. Lastly, 25% of patients with normal chest, abdomen, and pelvis exams with chest, abdomen, and pelvis CT scans demonstrated occult injuries. Asymptomatic patients with a negative CT had a length of stay 1 day less than patients without a corresponding CT. No incidents of contrast-induced complications were recorded. Conclusions A negative physical exam combined with a normal chest X-ray does not rule out the presence of occult injuries and the need for torso imaging. In blunt trauma patients with normal sensorium, physical exam and chest X-ray, the practice of obtaining cross-sectional imaging appears beneficial by increasing the accuracy of total injury burden and decreasing the length of stay.

Abstract Background The United Nations’ Millennium Development Goals Report, 2015, documents that, since 1990, the number of stunted children in sub-Saharan Africa has increased by 33% even though it has fallen in all other world regions. Recognizing this, in 2011 the Government of Uganda implemented a 5-year Nutrition Action Plan. One important tenet of the Plan is to lessen malnutrition in young children by discouraging over-consumption of nutritionally deficient, but plentiful, staple foods, which it defines as a type of food insecurity. Methods We use a sample of 6101 observations on 3427 children age five or less compiled from three annual waves of the Uganda National Panel Survey to measure undernourishment. We also use the World Health Organization’s Child Growth Standards to create a binary variable indicating stunting and another indicating wasting for each child in each year. We then use random effects to estimate binary logistic regressions that show that greater staple food concentrations affect the probability of stunting and wasting. Results The estimated coefficients are used to compute adjusted odds ratios (OR) that estimate the effect of greater staple food concentration on the likelihood of stunting and the likelihood of wasting. Controlling for other relevant covariates, these odds ratios show that a greater proportion of staple foods in a child’s diet increases the likelihood of stunting (OR = 1.007, p = 0.005) as well as wasting (OR = 1.011, p = 0.034). Stunting is confirmed with subsamples of males only (OR = 1.006, p = 0.05) and females only (OR = 1.008, p = 0.027), suggesting that the finding is not gender specific. Another subsample of children aged 12 months or less, most of whom do not yet consume solid food, shows no statistically significant relationship, thus supporting the validity of the other findings. Conclusion Diets containing larger proportions of staple foods are associated with greater likelihoods of both stunting and wasting in Ugandan children. Other causes of stunting and wasting identified in past research are also confirmed with the Uganda data. Finally, the analysis provides clues to other possible causes of undernourishment in young children.

Purpose: CTR9 is a subunit of the PAF1 complex (PAF1C) that plays a crucial role in transcription regulation by binding CTR9 to RNA polymerase II. It is involved in transcription-coupled histone modification through promoting H3K4 and H3K36 methylation. We describe the clinical and molecular studies in 13 probands, harboring likely pathogenic CTR9 missense variants, collected through GeneMatcher., Methods: Exome sequencing was performed in all individuals. CTR9 variants were assessed through 3-dimensional modeling of the activated human transcription complex Pol II-DSIF-PAF-SPT6 and the PAF1/CTR9 complex. H3K4/H3K36 methylation analysis, mitophagy assessment based on tetramethylrhodamine ethyl ester perchlorate immunofluorescence, and RNA-sequencing in skin fibroblasts from 4 patients was performed., Results: Common clinical findings were variable degrees of intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. For 11 CTR9 variants, de novo occurrence was shown. Three-dimensional modeling predicted a likely disruptive effect of the variants on local CTR9 structure and protein interaction. Additional studies in fibroblasts did not unveil the downstream functional consequences of the identified variants., Conclusion: We describe a neurodevelopmental disorder caused by (mainly) de novo variants in CTR9, likely affecting PAF1C function., Competing Interests: Conflict of Interest Amber Begtrup is an employee of GeneDx, Inc. Stylianos E. Antonarakis and Emmanuelle Ranza are cofounders of MediGenome. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

In patients with treatment-resistant epilepsy (TRE), cannabidiol (CBD) produces variable improvement in seizure control. Patients in the University of Alabama at Birmingham CBD Expanded Access Program (EAP) were enrolled in the genomic study and genotyped using the Affymetrix Drug Metabolizing Enzymes and Transporters plus array. Associations between variants and CBD response (≥50% seizure reduction) and tolerability (diarrhea, sedation, and abnormal liver function) was evaluated under dominant and recessive models. Expression quantitative trait loci (eQTL) influencing potential CBD targets was evaluated in the UK Brain Expression Consortium data set (Braineac), and genetic co-expression examined. Of 169 EAP patients, 112 (54.5% pediatric and 50.0% female) were included in the genetic analyses. Patients with AOX1 rs6729738 CC (aldehyde oxidase; odds ratio (OR) 6.69, 95% confidence interval (CI) 2.19-20.41, P = 0.001) or ABP1 rs12539 (diamine oxidase; OR 3.96, 95% CI 1.62-9.73, P = 0.002) were more likely to respond. Conversely, patients with SLC15A1 rs1339067 TT had lower odds of response (OR 0.06, 95% CI 0.01-0.56, P = 0.001). ABCC5 rs3749442 was associated with lower likelihood of response and abnormal liver function tests, and higher likelihood of sedation. The eQTL revealed that rs1339067 decreased GPR18 expression (endocannabinoid receptor) in white matter (P = 5.6 × 10 -3 ), and rs3749442 decreased hippocampal HTR3E expression (serotonin 5-HT 3E ; P = 8.5 × 10 -5 ). Furthermore, 75% of genes associated with lower likelihood of response were co-expressed. Pharmacogenetic variation is associated with CBD response and influences expression of CBD targets in TRE. Implicated pathways, including cholesterol metabolism and glutathione conjugation, demonstrate potential interactions between CBD and common medications (e.g., statins and acetaminophen) that may require closer monitoring. These results highlight the role of pharmacogenes in fundamental biologic processes and potential genetic underpinnings of treatment-resistance., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: The desire of parents to obtain a genetic diagnosis for their child with intellectual disability and associated symptoms has long been framed as a diagnostic odyssey, an arduous and sometimes perilous journey focused on the goal of identifying a cause for the child's condition. Methods: Semi-structured interviews (N = 60) were conducted with parents of children (N = 59, aged 2-24 years) with intellectual disability and/or developmental delay (IDD) who underwent genome sequencing at a single pediatric multispecialty clinic. Interviews were conducted after parents received their child's sequencing result (positive findings, negative findings, or variants of unknown significance). Thematic analysis was performed on all interviews. Results: Parents reported that obtaining a genetic diagnosis was one important step in their overall goal of helping their child live their best life possible life. They intended to use the result as a tool to help their child by seeking the correct school placement and obtaining benefits and therapeutic services. Conclusions: For the parents of children with IDD, the search for a genetic diagnosis is best conceptualized as a part of parents' ongoing efforts to leverage various diagnoses to obtain educational and therapeutic services for their children. Cleaving parents' search for a genetic diagnosis from these broader efforts obscures the value that some parents place on a sequencing result in finding and tailoring therapies and services beyond the clinic. Interviews with parents reveal, therefore, that genomic sequencing is best understood as one important stage of an ongoing therapeutic odyssey that largely takes place outside the clinic. Findings suggest the need to expand translational research efforts to contextualize a genetic diagnosis within parents' broader efforts to obtain educational and therapeutic services outside clinical contexts.

Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1I368T and SYT1N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1D304G and SYT1D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals' phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.