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The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery. We have recruited 209 individuals with a rare EHMT1 variant and performed comprehensive molecular in silico and in vitro testing alongside DNA methylation (DNAm) signature analysis for the identified variants. We (re)classified the variants as likely pathogenic/pathogenic (molecularly confirming Kleefstra syndrome) in 191 individuals. We provide an updated and broader clinical and molecular spectrum of Kleefstra syndrome, including individuals with normal intelligence and familial occurrence. Analysis of the EHMT1 variants reveals a broad range of molecular effects and their associated phenotypes, including distinct genotype-phenotype associations. Notably, we showed that disruption of the "reader" function of the ankyrin repeat domain by a protein altering variant (PAV) results in a KLEFS1-specific DNAm signature and milder phenotype, while disruption of only "writer" methyltransferase activity of the SET domain does not result in KLEFS1 DNAm signature or typical KLEFS1 phenotype. Similarly, N-terminal truncating variants result in a mild phenotype without the DNAm signature. We demonstrate how comprehensive variant analysis can provide insights into pathogenesis of the disorder and DNAm signature. In summary, this study presents a comprehensive overview of KLEFS1 and EHMT1, revealing its broader spectrum and deepening our understanding of its molecular mechanisms, thereby informing accurate variant interpretation, counseling, and clinical management., Competing Interests: Declaration of interests A.M.M. is an employee of GeneDx, LLC. B.S. is a shareholder in EpiSign Inc., a biotechnology company involved in commercialization of EpiSign technology., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)

CTNND2 encodes δ-catenin, a component of an adherens junction complex, and plays an important role in neuronal structure and function. To date, only heterozygous loss-of-function CTNND2 variants have been associated with mild neurodevelopmental delay and behavioral anomalies, a condition, which we named Rauch-Azzarello syndrome. Here, we report three siblings of a consanguineous family of Syrian descent with a homozygous deletion encompassing the last 19 exons of CTNND2 predicted to disrupt the transcript. All presented with severe neurodevelopmental delay with absent speech, profound motor delay, stereotypic behavior, microcephaly, short stature, muscular hypotonia with lower limb hypertonia, and variable eye anomalies. The parents and the fourth sibling were heterozygous carriers of the deletion and exhibited mild neurodevelopmental impairment resembling that of the previously described heterozygous individuals. The present study unveils a severe manifestation of CTNND2-associated Rauch-Azzarello syndrome attributed to biallelic loss-of-function aberrations, clinically distinct from the already described mild presentation of heterozygous individuals. Furthermore, we demonstrate novel clinical features in homozygous individuals that have not been reported in heterozygous cases to date., (© 2024 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

ARID1B is the most frequently mutated gene in Coffin-Siris syndrome (CSS). To date, the vast majority of causative variants reported in ARID1B are truncating, leading to nonsense-mediated mRNA decay. In the absence of experimental data, only few ARID1B amino acid substitutions have been classified as pathogenic, mainly based on clinical data and their de novo occurrence, while most others are currently interpreted as variants of unknown significance. The present study substantiates the pathogenesis of ARID1B non-truncating/NMD-escaping variants located in the SMARCA4-interacting EHD2 and DNA-binding ARID domains. Overexpression assays in cell lines revealed that the majority of EHD2 variants lead to protein misfolding and formation of cytoplasmic aggresomes surrounded by vimentin cage-like structures and co-localizing with the microtubule organisation center. ARID domain variants exhibited not only aggresomes, but also nuclear aggregates, demonstrating robust pathological effects. Protein levels were not compromised, as shown by quantitative western blot analysis. In silico structural analysis predicted the exposure of amylogenic segments in both domains due to the nearby variants, likely causing this aggregation. Genome-wide transcriptome and methylation analysis in affected individuals revealed expression and methylome patterns consistent with those of the pathogenic haploinsufficiency ARID1B alterations in CSS cases. These results further support pathogenicity and indicate two approaches for disambiguation of such variants in everyday practice. The few affected individuals harbouring EHD2 non-truncating variants described to date exhibit mild CSS clinical traits. In summary, this study paves the way for the re-evaluation of previously unclear ARID1B non-truncating variants and opens a new era in CSS genetic diagnosis., (© 2024. The Author(s).)

Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research., (© 2024. The Author(s).)

The association between asymmetric skin folds (ASFs) of the gluteal, groin, or thigh regions and ipsilateral developmental dysplasia of the hip (DDH) has not been elucidated yet. Why are ASFs formed in some infants with DDH? Do DDH-associated ASFs persist during childhood and adulthood? Is it possible for ASFs to emerge without DDH pathology? Three cases of acute and chronic hip pathology in adults are presented in an attempt to explain the formation and the natural history of ASFs in infants with DDH. It is suggested that ASFs are formed when the excess soft tissues of the thigh shrink over a short femur. On the other hand, ASFs disappear after the length of the thigh is restored and the soft tissues of the thigh are re-stretched. This telescoping mechanism of the formation and disappearance of ASFs is applicable regardless of the underlying hip pathology or the age of the patient., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Samelis et al.)

Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders., Competing Interests: Declaration of interests B.S. is a shareholder in EpiSign Inc, involved in commercial uses of EpiSign(TM) technology D.A.C. and K.G.M. are employees of GeneDx, LLC., (Copyright © 2024. Published by Elsevier Inc.)

Background: Trauma outcome prediction models have traditionally relied upon patient injury and physiologic data (eg, Trauma and Injury Severity Score [TRISS]) without accounting for comorbidities. We sought to prospectively evaluate the role of the American Society of Anesthesiologists physical status (ASA-PS) score and the National Surgical Quality Improvement Program Surgical Risk-Calculator (NSQIP-SRC), which are measurements of comorbidities, in the prediction of trauma outcomes, hypothesizing that they will improve the predictive ability for mortality, hospital length of stay (LOS), and complications compared to TRISS alone in trauma patients undergoing surgery within 24 hours., Methods: A prospective, observational multicenter study (9/2018-2/2020) of trauma patients ≥18 years undergoing operation within 24 hours of admission was performed. Multiple logistic regression was used to create models predicting mortality utilizing the variables within TRISS, ASA-PS, and NSQIP-SRC, respectively. Linear regression was used to create models predicting LOS and negative binomial regression to create models predicting complications., Results: From 4 level I trauma centers, 1213 patients were included. The Brier Score for each model predicting mortality was found to improve accuracy in the following order: 0.0370 for ASA-PS, 0.0355 for NSQIP-SRC, 0.0301 for TRISS, 0.0291 for TRISS+ASA-PS, and 0.0234 for TRISS+NSQIP-SRC. However, when comparing TRISS alone to TRISS+ASA-PS ( P = .082) and TRISS+NSQIP-SRC ( P = .394), there was no significant improvement in mortality prediction. NSQIP-SRC more accurately predicted both LOS and complications compared to TRISS and ASA-PS., Conclusions: TRISS predicts mortality better than ASA-PS and NSQIP-SRC in trauma patients undergoing surgery within 24 hours. The TRISS mortality predictive ability is not improved when combined with ASA-PS or NSQIP-SRC. However, NSQIP-SRC was the most accurate predictor of LOS and complications., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

Introduction: Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney disease in children. Although only 20% of cases can be genetically explained, the majority remain without an identified underlying etiology. The neurodevelopmental disorder Chung-Jansen syndrome (CHUJANS) is caused by haploinsufficiency of Pleckstrin homology domain-interacting protein (PHIP) and was previously associated with genital malformations. Anecdotal coincidence of CHUJANS and CAKUT prompted us to investigate whether urorenal malformations are part of the phenotypic spectrum of CHUJANS., Methods: Analysis of existing CHUJANS and CAKUT cohorts, consulting matchmaking platforms, and systematic literature review to look for additional patients with both CHUJANS and CAKUT. Prenatal expression studies in murine and human renal tissues to investigate the role for PHIP in kidney development., Results: We identified 4 novel and 8 published cases, indicating variable expressivity with a urorenogenital trait frequency of 5% to 35%. The prenatal expression studies supported a role for PHIP in normal kidney and urinary tract development., Conclusion: Pathogenic PHIP gene variants should be considered as causative in patients with syndromal CAKUT. Conversely, patients with CHUJANS should be clinically evaluated for urorenogenital manifestations. Because neurodevelopmental disorders are often associated with kidney phenotypes, an interdisciplinary re-evaluation offers promise in identifying incompletely penetrant kidney associations and uncovering novel molecular mechanisms of disturbed nephrogenesis., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Calmodulin-binding transcriptional activator 1 (CAMTA1) is highly expressed in the brain and plays a role in cell cycle regulation, cell differentiation, regulation of long-term memory, and initial development, maturation, and survival of cerebellar neurons. The existence of human neurological phenotypes, including cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA), associated with CAMTA1 variants, has further supported its role in brain functions. In this study, we phenotypically and molecularly characterize the largest cohort of individuals (n = 26) with 23 novel CAMTA1 variants (frameshift-7, nonsense-6, splicing-1, initiation codon-1, missense-5, and intragenic deletions-3) and compare the findings with all previously reported cases (total = 53). We show that the most notable phenotypic findings are developmental delay/intellectual disability, unsteady or uncoordinated gait, hypotonia, behavioral problems, and eye abnormalities. In addition, there is a high incidence of dysarthria, dysgraphia, microcephaly, gastrointestinal abnormalities, sleep difficulties, and nonspecific brain MRI findings; a few of which have been under-reported. More than one third of the variants in this cohort were inherited from an asymptomatic or mildly affected parent suggesting reduced penetrance and variable expressivity. Our cohort provides a comprehensive characterization of the spectrum of phenotypes and genotypes among individuals with CECBA and the large data will facilitate counseling and formulating management plans and surveillance recommendations for these individuals., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

PPFIA3 encodes the protein-tyrosine phosphatase, receptor-type, F-polypeptide-interacting-protein-alpha-3 (PPFIA3), which is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. The protein structure and function are evolutionarily well conserved, but human diseases related to PPFIA3 dysfunction are not yet reported in OMIM. Here, we report 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy with reduced penetrance. Seventeen unique PPFIA3 variants were detected in 18 families. To determine the pathogenicity of PPFIA3 variants in vivo, we generated transgenic fruit flies producing either human wild-type (WT) PPFIA3 or five missense variants using GAL4-UAS targeted gene expression systems. In the fly overexpression assays, we found that the PPFIA3 variants in the region encoding the N-terminal coiled-coil domain exhibited stronger phenotypes compared to those affecting the C-terminal region. In the loss-of-function fly assay, we show that the homozygous loss of fly Liprin-α leads to embryonic lethality. This lethality is partially rescued by the expression of human PPFIA3 WT, suggesting human PPFIA3 function is partially conserved in the fly. However, two of the tested variants failed to rescue the lethality at the larval stage and one variant failed to rescue lethality at the adult stage. Altogether, the human and fruit fly data reveal that the rare PPFIA3 variants are dominant-negative loss-of-function alleles that perturb multiple developmental processes and synapse formation., Competing Interests: Declaration of interests The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the clinical exome sequencing services offered at Baylor Genetics. J.L.M., M.J.G.S., and R.P. are employees of GeneDx, LLC., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Coffin-Siris syndrome (CSS) is a rare multisystemic autosomal dominant disorder. Since 2012, alterations in genes of the SWI/SNF complex were identified as the molecular basis of CSS, studying largely pediatric cohorts. Therefore, there is a lack of information on the phenotype in adulthood, particularly on the clinical outcome in adulthood and associated risks. In an international collaborative effort, data from 35 individuals ≥ 18 years with a molecularly ascertained CSS diagnosis (variants in ARID1B, ARID2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, BICRA) using a comprehensive questionnaire was collected. Our results indicate that overweight and obesity are frequent in adults with CSS. Visual impairment, scoliosis, and behavioral anomalies are more prevalent than in published pediatric or mixed cohorts. Cognitive outcomes range from profound intellectual disability (ID) to low normal IQ, with most individuals having moderate ID. The present study describes the first exclusively adult cohort of CSS individuals. We were able to delineate some features of CSS that develop over time and have therefore been underrepresented in previously reported largely pediatric cohorts, and provide recommendations for follow-up., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Peristaltic pumps are widely used in biomedical applications to ensure the safe flow of sterile or medical fluids. They are commonly employed for drug injections, IV fluids, and blood separation (apheresis). These pumps operate through a progressive contraction or expansion along a flexible tube, enabling fluid flow. They are also utilized in industrial applications for sanitary fluid transport, corrosive fluid handling, and novel pharmacological delivery systems. This research provides valuable insights into the selection and optimal design of the powertrain stages for peristaltic pumps implemented in drug delivery systems. The focus of this paper lies in the simulation and optimization of the performance of a power transmission gearbox by examining the energy consumption, sound levels, reliability, and volume as output metrics. The components of the powertrain consist of a helical gear pair for the first stage, a bevel gear pair for the second one, and finally a planetary transmission. Through extensive simulations, the model exhibits promising results, achieving an efficiency of up to 90%. Furthermore, alternative configurations were investigated to optimize the overall performance of the powertrain. This process has been simulated by employing the KISSsoft/KISSsys software package. The findings of this investigation contribute to advancements in the field of biomedical engineering and hold significant potential for improving the efficiency, reliability, and performance of drug delivery mechanisms.

Purpose: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort., Methods: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays., Results: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD., Conclusion: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated., Competing Interests: Conflict of Interest Renee Bend and Julie Rath are employees of PreventionGenetics, part of Exact Sciences. Michelle M. Morrow and Francisca Millan are employees of GeneDx, LLC. All other authors declare no conflicts of interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The Trauma and Injury Severity Score (TRISS) uses anatomic/physiologic variables to predict outcomes. The National Surgical Quality Improvement Program Surgical Risk Calculator (NSQIP-SRC) includes functional status and comorbidities. It is unclear which of these tools is superior for high-risk trauma patients (American Society of Anesthesiologists Physical Status (ASA-PS) class IV or V). This study compares risk prediction of TRISS and NSQIP-SRC for mortality, length of stay (LOS), and complications for high-risk operative trauma patients., Methods: This is a prospective study of high-risk (ASA-PS IV or V) trauma patients (≥18 years-old) undergoing surgery at 4 trauma centers. We compared TRISS vs NSQIP-SRC vs NSQIP-SRC + TRISS for ability to predict mortality, LOS, and complications using linear, logistic, and negative binomial regression., Results: Of 284 patients, 48 (16.9%) died. The median LOS was 16 days and number of complications was 1. TRISS + NSQIP-SRC best predicted mortality (AUROC: .877 vs .723 vs .843, P = .0018) and number of complications (pseudo-R 2 /median error (ME) 5.26%/1.15 vs 3.39%/1.33 vs 2.07%/1.41, P < .001) compared to NSQIP-SRC or TRISS, but there was no difference between TRISS + NSQIP-SRC and NSQIP-SRC with LOS prediction ( P = .43)., Discussion: For high-risk operative trauma patients, TRISS + NSQIP-SRC performed better at predicting mortality and number of complications compared to NSQIP-SRC or TRISS alone but similar to NSQIP-SRC alone for LOS. Thus, future risk prediction and comparisons across trauma centers for high-risk operative trauma patients should include a combination of anatomic/physiologic data, comorbidities, and functional status., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Short bowel syndrome (SBS) is a debilitating condition associated with significant morbidity and mortality. Historically, SBS patients require indefinite parenteral nutrition (PN) and endure lifelong nutritional challenges. The purpose of this study was to review the outcomes, specifically nutritional independence, of a multidisciplinary nutrition service., Methods: A retrospective analysis of SBS patients followed by our surgical nutrition service was performed. Patients without 1-year follow-up were excluded. Demographics and nutritional parameters were collected at 4 intervals: initial presentation, 1-year, 2-year, and 5-year follow-up. Short bowel syndrome anatomical subtypes identified through operative reports were characterized as end jejunostomy, jejunocolonic, or jejuno-ileocolonic with ileo-cecal valve intact. Intestinal failure was defined by the requirement of PN, while intestinal insufficiency was defined by enteral support requirement. Clinical outcomes examined included mortality, fistula closure, and nutritional independence., Results: The study cohort comprised 89 patients, 50 of whom had ≤ 100 cm intestinal length. Mean age was 57 ± 17y, 55 (62%) were female, and median initial intestinal length was 77 [60-120] cm. Short bowel syndrome was complicated by fistulas in 47 (53%) of patients. Overall mortality was 13%, and 67 (75%) were liberated from PN. A total of 58 (65%) underwent operative intervention and fistula closure was achieved in 37 of 47 (79%) patients., Conclusions: Short bowel syndrome patients can experience significant benefit under treatment by a multidisciplinary nutrition service. By incorporating surgical intervention, the majority of patients previously relegated to lifelong PN have the opportunity to become nutritionally independent within 5 years.

Purpose: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10., Methods: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis., Results: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length., Conclusion: These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis., Competing Interests: Conflict of Interest Several authors included on the manuscript are employees of GeneDx in Gaithursburg, MD (E.T., D.A.C., K.W., J.J., F.M., R.P., M.J.G.S., Y.S., and I.M.W.). B.K.B has received consulting fees and/or honoraria from Biomarin; Takeda; Alexion; Aeglea; Applied Therapeutics; Moderna, Inc; Denali, JCR Pharmaceuticals Co, Ltd; Horizon; SIO; Synlogic; and Ultragenyx and have conducted clinical trials funded by Biomarin; Takeda; Ultragenyx; Homology Medicines, Inc; and Sangamo. B.A.R. received royalties from UpToDate, Inc and is on the advisory boards for Teva Pharmaceuticals and Sanofi Genzyme. All other authors report no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Enterocutaneous fistula (ECF) is a complication of surgery or inflammatory bowel disease associated with disproportionately high healthcare costs, morbidity, and mortality. We performed this proof-of-concept, feasibility, open-label, pilot randomized, crossover study to assess the efficacy and safety of the use of teduglutide (TED) to treat ECF., Methods: Adults (age >18) with low-output (<200 mL/d) ECF were randomized to 2 months of continuing standard-of-care (SOC) followed by crossover to 2 months of SOC + TED or the reverse order. The primary efficacy endpoint was decrease in fistula volume by 20% of baseline 3-day average. Secondary efficacy endpoints were: fistula resolution and health-related quality of life questionnaire scores., Results: Six out of 10 planned subjects were randomized and completed the study, which was terminated early due to slow enrollment during the Covid-19 pandemic. Overall subject compliance with daily TED injections was high (98%). Five of six enrolled subjects met the definition for the primary efficacy endpoint; these clinical responses were not observed during the SOC arm in these subjects. One subject experienced complete fistula closure during TED treatment. Adverse events during treatment were uncommon, minor, and usually resolved despite ongoing treatment. Quality of life survey responses were highly variable and did not correlate with fistula changes., Conclusions: Two months of teduglutide treatment was feasible, well-tolerated, and resulted in observable decreases in ECF drainage in the majority of subjects, including spontaneous closure in one subject. This therapy shows promise, but larger, multicenter confirmatory trials are required., Clinicaltrials: GOV: (NCT02889393)., Competing Interests: Declaration of competing interest Yeh – Takeda Pharmaceuticals – consulting fees paid to author for participating as a participant and moderator for virtual advisory board, unrestricted educational grant for fellowship training program; Baxter - consulting fees paid to author for participating as a participant for virtual advisory board; Fresenius Kabi - consulting fees paid to author for participating as a participant for virtual advisory board; TrueLearn - consulting fees paid to author for participating as a participant for virtual advisory board; UpToDate – author royalties for review articles. Vasileiou – none. Abdul Jawad – none. Pust – none. Byers – Takeda Pharmaceuticals – unrestricted educational grant for fellowship training program., (Copyright © 2022 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Purpose: SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease., Methods: Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher., Results: Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present., Conclusion: We established SRRM2 as a gene responsible for a rare neurodevelopmental disease., Competing Interests: Conflict of Interest This work was carried out within the framework of Nantes University Medical Center activity without additional funding. One patient was diagnosed in the context of work in a private company (AiLife Diagnostics, Pearland, Texas). The other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: Controversy exists about the preferred initial treatment of appendicitis. We sought to compare the two treatments for initial management of simple appendicitis., Methods: In this post hoc analysis of the Multicenter Study for the Treatment of Appendicitis in America: Acute, Perforated, and Gangrenous database, subjects were divided into appendectomy or nonoperative management (NOM; antibiotics only or percutaneous drainage) cohorts. A novel topic-specific hierarchical ordinal scale was created with eight mutually exclusive categories: mortality, reoperation, other secondary interventions, readmission, emergency department visit, wound complication, surgical site infection, and no complication. Pairwise comparisons of American Association for the Surgery of Trauma Imaging Severity Grade 1 (simple appendicitis) patients were compared using win-lose-tie scoring and the sums of appendectomy/NOM groups were compared., Results: A total 3,591 subjects were included: 3,262 appendectomy and 329 NOM, with significant differences in baseline characteristics between groups. Across 28 sites, the rate of NOM ranged from 0% to 48%, and the loss to follow-up rate was significantly higher for NOM compared with appendectomy (16.5% vs. 8.7%, p = 0.024). In the simple appendicitis hierarchical ordinal scale analysis, 2,319 subjects resulted in 8,714,304 pairwise comparisons; 75% of comparisons resulted in ties. The median (interquartile range) sums for the two groups are as follows: surgical, 400 (400-400), and NOM, 400 (-2,427 to 400) (p < 0.001). A larger proportion of appendectomy subjects (88.1%) had an outcome that was equivalent (or better) than at least half of the subjects compared with NOM subjects (NOM, 70.5%; OR [95% confidence interval], 0.3 [0.2-0.4])., Conclusion: In contemporary American practice, appendectomy (compared with NOM) for simple appendicitis is associated with lower odds of developing clinically important unfavorable outcomes in the first year after illness., Level of Evidence: Therapeutic/Care Management; Level III., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Classic experiments demonstrating hypermetabolism after major trauma were performed in a different era of critical care. We aim to describe the modern posttraumatic metabolic response in the trauma intensive care unit (TICU)., Methods: This prospective observational study enrolled TICU mechanically ventilated adults (aged ≥18) from 3/2018-2/2019. Multiple, daily resting energy expenditure (REE) measurements were recorded. Basal energy expenditure (BEE) was calculated by the Harris-Benedict equation. Hypometabolism was defined as average daily REE < 0.85*BEE and hypermetabolism defined as average daily REE > 1.15*BEE. Demographics, interventions, and clinical outcomes were abstracted. Descriptive statistics and multivariable logistical regression models evaluating demographics with the outcome variable of hypermetabolism for the first 3 days ("sustained hypermetabolism") were performed, along with group-based trajectory modeling (GBTM)., Results: Fifty-five patients were analyzed: median age was 38 (28-56) years; 38 (69%) were male; body mass index (kg/m 2 ) was 28 (26-32); and Injury Severity Score was 27 (19-34), with (38 [71%] blunt, 8 [15%] penetrating, 7 [13%] burn) injury mechanism. Overall, 19 (35%) had hypermetabolism on day 1 ("immediate hypermetabolism"), and 11 (21%) had sustained hypermetabolism for the first 3 days. Logistic regression analysis identified penetrating mechanism (adjusted odds ratio [AOR], 16.4; 95% CI, 1.9-199.6; p = .015), burn mechanism (AOR, 11.1; 95% CI, 1.3-116.8; p =.029), and maximum temperature (AOR, 4.2; 95% CI, 1.3-20.3; p= .041) as independent predictors of sustained hypermetabolism. GBTM identified 4 nutrition phenotypes, with 2 hyperconsumptive phenotypes associated with increased risk of malnutrition at discharge., Conclusion: Only a minority of injured patients is hypermetabolic in the first week after injury. Elevated temperature, penetrating mechanism, and burn mechanism are independently associated with sustained hypermetabolism. Hyperconsumptive phenotype patients are more likely to develop malnutrition during hospitalization., (© 2020 American Society for Parenteral and Enteral Nutrition.)

Background: The American Association for the Surgery of Trauma (AAST) has developed a grading system for emergency general surgery (EGS) conditions. We sought to validate the AAST EGS grades for patients undergoing urgent/emergent colorectal resection., Methods: Patients enrolled in the "Eastern Association for the Surgery of Trauma Multicenter Colorectal Resection in EGS-to anastomose or not to anastomose" study undergoing urgent/emergent surgery for obstruction, ischemia, or diverticulitis were included. Baseline demographics, comorbidity severity as defined by Charlson comorbidity index (CCI), procedure type, and AAST grade were prospectively collected. Outcomes included length of stay (LOS) in-hospital mortality, and surgical complications (superficial/deep/organ-space surgical site infection, anastomotic leak, stoma complication, fascial dehiscence, and need for further intervention). Multivariable logistic regression models were used to describe outcomes and risk factors for surgical complication or mortality., Results: There were 367 patients, with a mean (± SD) age of 62 ± 15 years. 39% were women. The median interquartile range (IQR) CCI was 4 (2-6). Overall, the pathologies encompassed the following AAST EGS grades: I (17, 5%), II (54, 15%), III (115, 31%), IV (95, 26%), and V (86, 23%). Management included laparoscopic (24, 7%), open (319, 87%), and laparoscopy converted to laparotomy (24, 6%). Higher AAST grade was associated with laparotomy ( P = .01). The median LOS was 13 days (8-22). At least 1 surgical complication occurred in 33% of patients and the mortality rate was 14%. Development of at least 1 surgical complication, need for unplanned intervention, mortality, and increased LOS were associated with increasing AAST severity grade. On multivariable analysis, factors predictive of in-hospital mortality included AAST organ grade, CCI, and preoperative vasopressor use (odds ratio (OR) 1.9, 1.6, 3.1, respectively). The American Association for the Surgery of Trauma emergency general surgery grade was also associated with the development of at least 1 surgical complication (OR 2.5), while CCI, preoperative vasopressor use, respiratory failure, and pneumoperitoneum were not., Conclusion: The American Association for the Surgery of Trauma emergency general surgery grading systems display construct validity for mortality and surgical complications after urgent/emergent colorectal resection. These results support incorporation of AAST EGS grades for quality benchmarking and surgical outcomes research.

Background: The Trauma and Injury Severity Score (TRISS) uses anatomical and physiologic variables to predict mortality. Elderly (65 years or older) trauma patients have increased mortality and morbidity for a given TRISS, in part because of functional status and comorbidities. These factors are incorporated into the American Society of Anesthesiologists Physical Status (ASA-PS) and National Surgical Quality Improvement Program Surgical Risk Calculator (NSQIP-SRC). We hypothesized scoring tools using comorbidities and functional status to be superior at predicting mortality, hospital length of stay (LOS), and complications in elderly trauma patients undergoing operation., Methods: Four level I trauma centers prospectively collected data on elderly trauma patients undergoing surgery within 24 hours of admission. Using logistic regression, five scoring models were compared: ASA-PS, NSQIP-SRC, TRISS, TRISS-ASA-PS, and TRISS-NSQIP-SRC.Brier scores and area under the receiver operator characteristics curve were calculated to compare mortality prediction. Adjusted R2 and root mean squared error were used to compare LOS and predictive ability for number of complications., Results: From 122 subjects, 9 (7.4%) died, and the average LOS was 12.9 days (range, 1-110 days). National Surgical Quality Improvement Program Surgical Risk Calculator was superior to ASA-PS and TRISS at predicting mortality (area under the receiver operator characteristics curve, 0.978 vs. 0.768 vs. 0.903; p = 0.007). Furthermore, NSQIP-SRC was more accurate predicting LOS (R2, 25.9% vs. 13.3% vs. 20.5%) and complications (R2, 34.0% vs. 22.6% vs. 29.4%) compared with TRISS and ASA-PS. Adding TRISS to NSQIP-SRC improved predictive ability compared with NSQIP-SRC alone for complications (R2, 35.5% vs. 34.0%; p = 0.046). However, adding ASA-PS or TRISS to NSQIP-SRC did not improve the predictive ability for mortality or LOS., Conclusion: The NSQIP-SRC, which includes comorbidities and functional status, had superior ability to predict mortality, LOS, and complications compared with TRISS alone in elderly trauma patients undergoing surgery., Level of Evidence: Prognostic and Epidemiologic; Level III., (Copyright © 2021 American Association for the Surgery of Trauma.)

Recently, others and we identified de novo FBXO11 (F-Box only protein 11) variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data, our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs., (© The Author(s) 2021. Published by Oxford University Press.)

Background: There are significant practice variations in antibiotic treatment for appendicitis, ranging from short-course narrow spectrum to long-course broad-spectrum. We sought to describe the modern microbial epidemiology of acute and perforated appendicitis in adults to help inform appropriate empiric coverage and support antibiotic stewardship initiatives., Methods: This is a post-hoc secondary analysis of the Multicenter Study of the Treatment of Appendicitis in America: Acute, Perforated, and Gangrenous (MUSTANG) which prospectively enrolled adult patients (age ≥ 18 years) diagnosed with appendicitis between January 2017 and June 2018 across 28 centers in the United States. We included all subjects with positive microbiologic cultures during primary or secondary (rescue after medical failure) appendectomy or percutaneous drainage. Culture yield was compared between low- and high-grade appendicitis as per the AAST classification., Results: A total of 3,471 patients were included: 230 (7%) had cultures performed, and 179/230 (78%) had positive results. Cultures were less likely to be positive in grade 1 compared to grades 3, 4, or 5 appendicitis with 2/18 (11%) vs 61/70 (87%) (p < .001). Only 1 subject had grade 2 appendicitis and culture results were negative. E. coli was the most common pathogen and cultured in 29 (46%) of primary appendectomy samples, 16 (50%) of secondary, and 44 (52%) of percutaneous drainage samples., Conclusion: Culturing low-grade appendicitis is low yield. E. coli is the most commonly cultured microbe in acute and perforated appendicitis. This data helps inform empiric coverage for both antibiotics alone and as an adjunct to operative or percutaneous intervention., (Copyright © 2021. Published by Elsevier Inc.)

Context: CPE encodes carboxypeptidase E, an enzyme that converts proneuropeptides and propeptide hormones to bioactive forms. It is widely expressed in the endocrine and central nervous system. To date, 4 individuals from 2 families with core clinical features including morbid obesity, neurodevelopmental delay, and hypogonadotropic hypogonadism, harboring biallelic loss-of-function (LoF) CPE variants, have been reported., Objective: We describe 4 affected individuals from 3 unrelated consanguineous families, 2 siblings of Syrian, 1 of Egyptian, and 1 of Pakistani descent, all harboring novel homozygous CPE LoF variants., Methods: After excluding Prader-Willi syndrome (PWS), exome sequencing was performed in both Syrian siblings. The variants identified in the other 2 individuals were reported as research variants in a large-scale exome study and in the ClinVar database. Computational modeling of all possible missense alterations allowed assessing CPE tolerance to missense variants., Results: All affected individuals were severely obese with neurodevelopmental delay and other endocrine anomalies. Three individuals from 2 families shared the same CPE homozygous truncating variant c.361C > T, p.(Arg121*), while the fourth carried the c.994del, p.(Ser333Alafs*22) variant. Comparison of clinical features with previously described cases and standardization according to the Human Phenotype Ontology terms indicated a recognizable clinical phenotype, which we termed Blakemore-Durmaz-Vasileiou (BDV) syndrome. Computational analysis indicated high conservation of CPE domains and intolerance to missense changes., Conclusion: Biallelic truncating CPE variants are associated with BDV syndrome, a clinically recognizable monogenic recessive syndrome with childhood-onset obesity, neurodevelopmental delay, hypogonadotropic hypogonadism, and hypothyroidism. BDV syndrome resembles PWS. Our findings suggest missense variants may also be clinically relevant., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

ZMYND11 is the critical gene in chromosome 10p15.3 microdeletion syndrome, a syndromic cause of intellectual disability. The phenotype of ZMYND11 variants has recently been extended to autism and seizures. We expand on the epilepsy phenotype of 20 individuals with pathogenic variants in ZMYND11. We obtained clinical descriptions of 16 new and nine published individuals, plus detailed case history of two children. New individuals were identified through GeneMatcher, ClinVar and the European Network for Therapies in Rare Epilepsy (NETRE). Genetic evaluation was performed using gene panels or exome sequencing; variants were classified using American College of Medical Genetics (ACMG) criteria. Individuals with ZMYND11 associated epilepsy fell into three groups: (i) atypical benign partial epilepsy or idiopathic focal epilepsy (n = 8); (ii) generalised epilepsies/infantile epileptic encephalopathy (n = 4); (iii) unclassified (n = 8). Seizure prognosis ranged from spontaneous remission to drug resistant. Neurodevelopmental deficits were invariable. Dysmorphic features were variable. Variants were distributed across the gene and mostly de novo with no precise genotype-phenotype correlation. ZMYND11 is one of a small group of chromatin reader genes associated in the pathogenesis of epilepsy, and specifically ABPE. More detailed epilepsy descriptions of larger cohorts and functional studies might reveal genotype-phenotype correlation. The epileptogenic mechanism may be linked to interaction with histone H3.3., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Background: We sought to assess the efficacy of prophylactic abdominal drainage to prevent complications after appendectomy for perforated appendicitis. Methods: In this post hoc analysis of a prospective multi-center study of appendicitis in adults (≥ 18 years), we included patients with perforated appendicitis diagnosed intra-operatively. The 634 subjects were divided into groups on the basis of receipt of prophylactic drains. The demographics and outcomes analyzed were surgical site infection (SSI), intra-abdominal abscess (IAA), Clavien-Dindo complications, secondary interventions, and hospital length of stay (LOS). Multivariable logistic regression for the cumulative 30-day incidence of IAA was performed controlling for age, Charlson Comorbidity Index (CCI), antibiotic duration, presence of drains, and Operative American Association for the Surgery of Trauma (AAST) Grade. Results: In comparing the Drain (n = 159) versus No-Drain (n = 475) groups, there was no difference in the frequency of male gender (61% versus 55%; p = 0.168), weight (87.9 ± 27.9 versus 83.8 ± 23.4 kg; p = 0.071), Alvarado score (7 [6-8] versus 7 [6-8]; p = 0.591), white blood cell (WBC) count (14.8 ± 4.8 versus 14.9 ± 4.5; p = 0.867), or CCI (1 [0-3] versus 1 [0-2]; p = 0.113). The Drain group was significantly older (51 ± 16 versus 48 ± 17 years; p = 0.017). Drain use increased as AAST EGS Appendicitis Operative Severity Grade increased: Grade 3 (62/311; 20%), Grade 4 (46/168; 27%), and Grade 5 (51/155; 33%); p = 0.007. For index hospitalization, the Drain group had a higher complication rate (43% versus 28%; p = 0.001) and longer LOS (4 [3-7] versus 3 [1-5] days; p < 0.001). We could not detect a difference between the groups in the incidence of SSI, IAA, or secondary interventions. There was no difference in 30-day emergency department visits, re-admissions, or secondary interventions. Multi-variable logistic regression showed that only AAST Grade (odds ratio 2.7; 95% confidence interval7 1.5-4.7; p = 0.001) was predictive of the cumulative 30-day incidence of IAA. Conclusions: Prophylactic drainage after appendectomy for perforated appendicitis in adults is not associated with fewer intra-abdominal abscesses but is associated with longer hospital LOS. Increasing AAST EGS Appendicitis Operative Grade is a strong predictor of intra-abdominal abscess.

Background: The post-operative management of simple (acute) appendicitis differs throughout the United States. Guidelines regarding post-operative antibiotic usage remain unclear, and treatment generally is dictated by surgeon preference. We hypothesize that post-operative antibiotic use for simple appendicitis is not associated with lower post-operative complication rates. Methods: In a post-hoc analysis in a large multi-center observational study, only patients with an intra-operative diagnosis of AAST EGS Grade I were included. Subjects were classified into those receiving post-operative antibiotics (POST) and those given pre-operative antibiotics only (NONE). Clinical outcomes examined were length of stay (LOS), 30-day emergency department (ED) visits and hospital re-admissions, secondary interventions, surgical site infection (SSI), and intra-abdominal abscess (IAA). Results: A total of 2,191 subjects were included, of whom 612 (28%) received post-operative antibiotics. Compared with the NONE group, POST patients were older (age 37 [range 26-50] versus 33 [26-46] years; p < 0.001), weighed more (82 [70-96] versus 79 [68-93] kg (p = 0.038), and had higher white blood cell counts (13.5 ± 4.2 versus 13.1 ± 4.4/10 3 /mcL (p = 0.046), Alvarado Scores (6 [5-7] versus 6 [5-7]; p < 0.001), and Charlson Comorbidity Indices (median score 0 in both cohorts; p < 0.001). The POST patients had a longer LOS (1 [1-2] versus 1 [1-1] days; p < 0.001). There were no differences in the number who had ED visits within 30 days (9% versus 8%; p = 0.435), hospital re-admission (4% versus 2%; p = 0.165), an index hospitalization SSI (0.2% for both cohorts; p = 0.69), an SSI within 30 days (4% versus 2%; p = 0.165), index hospitalization IAA rate (0.3% versus 0.1%; p = 0.190), 30-day IAA (2% versus 1%; p = 0.71), index hospitalization interventions (0.5% versus 0.1%; p = 0.137) or 30-day secondary interventions (2% versus 1%; p = 0.155). Conclusions: Post-operative antibiotic use after appendectomy for simple appendicitis is not associated with better post-operative clinical outcomes at index hospitalization or at 30 days after discharge.

Introduction: We sought to evaluate whether the Emergency Surgery Score (ESS) can accurately predict outcomes in elderly patients undergoing emergent laparotomy (EL)., Methods: This is a post-hoc analysis of an EAST multicenter study. Between April 2018 and June 2019, all adult patients undergoing EL in 19 participating hospitals were prospectively enrolled, and ESS was calculated for each patient. Using the c-statistic, the correlation between ESS and mortality, morbidity, and need for ICU admission was assessed in three patient age cohorts (65-74, 75-84, ≥85 years old)., Results: 715 patients were included, of which 52% were 65-74, 34% were 75-84, and 14% were ≥85 years old; 51% were female, and 77% were white. ESS strongly correlated with postoperative mortality (c-statistic:0.81). Mortality gradually increased from 0% to 20%-60% at ESS of 2, 10 and 16 points, respectively. ESS predicted mortality, morbidity, and need for ICU best in patients 65-74 years old (c-statistic:0.81, 0.75, 0.83 respectively), but its performance significantly decreased in patients ≥85 years (c-statistic:0.72, 0.64, 0.67 respectively)., Conclusion: ESS is an accurate predictor of outcome in the elderly EL patient 65-85 years old, but its performance decreases for patients ≥85. Consideration should be given to modify ESS to better predict outcomes in the very elderly patient population., (Copyright © 2020. Published by Elsevier Inc.)

Background: The Emergency Surgery Score (ESS) was recently validated as an accurate mortality risk calculator for emergency general surgery. We sought to prospectively evaluate whether ESS can predict the need for respiratory and/or renal support (RRS) at discharge after emergent laparotomies (EL)., Methods: This is a post hoc analysis of a 19-center prospective observational study. Between April 2018 and June 2019, all adult patients undergoing EL were enrolled. Preoperative, intraoperative, and postoperative variables were systematically collected. In this analysis, patients were excluded if they died during the index hospitalization, were discharged to hospice, or transferred to other hospitals. A composite variable, the need for RRS, was defined as the need for one or more of the following at hospital discharge: tracheostomy, ventilator dependence, or dialysis. Emergency Surgery Score was calculated for all patients, and the correlation between ESS and RRS was examined using the c-statistics method., Results: From a total of 1,649 patients, 1,347 were included. Median age was 60 years, 49.4% were men, and 70.9% were White. The most common diagnoses were hollow viscus organ perforation (28.1%) and small bowel obstruction (24.5%); 87 patients (6.5%) had a need for RRS (4.7% tracheostomy, 2.7% dialysis, and 1.3% ventilator dependence). Emergency Surgery Score predicted the need for RRS in a stepwise fashion; for example, 0.7%, 26.2%, and 85.7% of patients required RRS at an ESS of 2, 12, and 16, respectively. The c-statistics for the need for RRS, the need for tracheostomy, ventilator dependence, or dialysis at discharge were 0.84, 0.82, 0.79, and 0.88, respectively., Conclusion: Emergency Surgery Score accurately predicts the need for RRS at discharge in EL patients and could be used for preoperative patient counseling and for quality of care benchmarking., Level of Evidence: Prognostic and epidemiological, level III., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Evidence comparing stoma creation (STM) versus anastomosis after urgent or emergent colorectal resection is limited. This study examined outcomes after colorectal resection in emergency general surgery patients., Methods: This was an Eastern Association for the Surgery of Trauma-sponsored prospective observational multicenter study of patients undergoing urgent/emergent colorectal resection. Twenty-one centers enrolled patients for 11 months. Preoperative, intraoperative, and postoperative variables were recorded. χ, Mann-Whitney U test, and multivariable logistic regression models were used to describe outcomes and risk factors for surgical complication/mortality., Results: A total of 439 patients were enrolled (ANST, 184; STM, 255). The median (interquartile range) age was 62 (53-71) years, and the median Charlson Comorbidity Index (CCI) was 4 (1-6). The most common indication for surgery was diverticulitis (28%). Stoma group was older (64 vs. 58 years, p < 0.001), had a higher CCI, and were more likely to be immunosuppressed. Preoperatively, STM patients were more likely to be intubated (57 vs. 15, p < 0.001), on vasopressors (61 vs. 13, p < 0.001), have pneumoperitoneum (131 vs. 41, p < 0.001) or fecal contamination (114 vs. 33, p < 0.001), and had a higher incidence of elevated lactate (149 vs. 67, p < 0.001). Overall mortality was 13%, which was higher in STM patients (18% vs. 8%, p = 0.02). Surgical complications were more common in STM patients (35% vs. 25%, p = 0.02). On multivariable analysis, management with an open abdomen, intraoperative blood transfusion, and larger hospital size were associated with development of a surgical complication, while CCI, preoperative vasopressor use, steroid use, open abdomen, and intraoperative blood transfusion were independently associated with mortality., Conclusion: This study highlights a tendency to perform fecal diversion in patients who are acutely ill at presentation. There is a higher morbidity and mortality rate in STM patients. Independent predictors of mortality include CCI, preoperative vasopressor use, steroid use, open abdomen, and intraoperative blood transfusion. Following adjustment by clinical factors, method of colon management was not associated with surgical complications or mortality., Level of Evidence: Therapeutic study, level IV.

Uterine leiomyomas (ULs) constitute a considerable health burden in the general female population. The fumarate hydratase (FH) deficient subtype is found in up to 1.6% and can occur in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. We sequenced 13 FH deficient ULs from a previous immunohistochemical screen using a targeted panel and identified biallelic FH variants in all. In eight, we found an FH point mutation (two truncating, six missense) with evidence for loss of the second allele. Variant allele-frequencies in all cases with a point mutation pointed to somatic variants. Spatial clustering of the identified missense variants in the lyase domain indicated altered fumarase oligomerization with subsequent degradation as explanation for the observed FH deficiency. Biallelic FH deletions in five tumors confirm the importance of copy number loss as mutational mechanism. By curating all pathogenic FH variants and calculating their population frequency, we estimate a carrier frequency of up to 1/2,563. Comparing with the prevalence of FH deficient ULs, we conclude that most are sporadic and estimate 2.7-13.9% of females with an FH deficient UL to carry a germline FH variant. Further prospective tumor/normal sequencing studies are needed to develop a reliable screening strategy for HLRCC in women with ULs.

Background: Overfeeding and underfeeding are associated with poor clinical outcomes. In the absence of indirect calorimetry (IC), the Society of Critical Care Medicine/ASPEN recommend prescribing 25-30 kcal/kg. The Harris-Benedict equation (HBE) multiplied by a stress factor is commonly applied in critically ill patients. We describe the difference between estimated and actual energy needs in critically injured patients., Methods: From March to November 2018, we collected demographics and energy needs determined by continuous IC (started within 4 days) in intubated adults. Ideal or adjusted body weight was used for 25-30 kcal/kg, and HBE was multiplied by a 1.3 stress factor (1.3HBE). Daily requirements up to 14 days, extubation, or death were calculated using all 3 methods and compared with IC., Results: Fifty-five subjects were included. Median age was 38 [27-58] years, 38 (69%) were male, body mass index was 28 [25-33] kg/m 2 , and Acute Physiology and Chronic Health Evaluation II score was 17 [14-24] Mechanism of injury was blunt (38, 69%), penetrating (9, 16%), and burn (8, 15%). By day 14, compared with measured energy requirements by IC, the other methods could result in a cumulative 1827-kcal (+7%) surplus (1.3HBE), a 1313-kcal (-5%) deficit (25 kcal/kg), or a 3950-kcal (+14%) surplus (30 kcal/kg) per patient over a median 9 days., Conclusion: In critically injured patients, predictive equations for energy needs do not account for dynamic metabolic changes over time and could result in underfeeding or overfeeding. Adjusting daily prescription based on continuous IC may result in better individualized treatment., (© 2019 American Society for Parenteral and Enteral Nutrition.)

Background: We sought to compare the effectiveness of narrow- versus broad-spectrum antibiotics (abx) in preventing infectious complications in adults with acute appendicitis treated with appendectomy., Methods: In this post hoc analysis of a prospective multicenter observational study of appendicitis in adults (≥18 y) conducted from January 2017 to June 2018, we included only patients with simple appendicitis. Subjects were grouped based on receipt of broad-spectrum or narrow-spectrum abx before and/or after appendectomy. Outcomes compared were surgical site infection, intra-abdominal abscess, secondary interventions (percutaneous drainage or operation), emergency department (ED) visits, 30-d readmission, and hospital length of stay., Results: A total of 2336 subjects were analyzed. In comparing narrow (n = 778) versus broad (n = 1558) groups, there were no differences in male sex (53% versus 54%, P = 0.704), white blood cell (13.0 ± 3.9 versus 13.4 ± 4.5, P = 0.05), Alvarado score (6 [5-7] versus 6 [5-7], P = 0.25), or Charlson comorbidity index (0 [0-1] versus 0 [0-1], P = 0.09). A total of 688 (29%) received postoperative abx, [184 (24%) narrow and 504 (32%) broad, P < 0.001] for a median 5 [2-7] d [42 (23%) narrow and 235 (47%) broad, P < 0.001]. There were no significant differences between narrow and broad groups in surgical site infection, intra-abdominal abscess, secondary interventions, ED visits, or hospital readmissions., Conclusions: Significant practice variation in duration and spectrum of antibiotic adjunct for surgical treatment of simple acute appendicitis treatment is evident, and broad-spectrum abx did not offer clinical advantages over narrow-spectrum abx. Restriction of antibiotic spectrum should be considered, although randomized trials are required to overcome selection bias., (Copyright © 2019. Published by Elsevier Inc.)

Background: The incidence of underlying malignancy in appendicitis ranges between 0.5% and 1.7%. We sought to identify the subset of patients with appendicitis who are at increased risk of appendiceal malignancy., Methods: Using the Eastern Association for the Surgery of Trauma Multicenter Study of the Treatment of Appendicitis in America: Acute, Perforated, and Gangrenous database, we included all patients from 28 centers undergoing immediate, delayed, or interval appendectomy between 2017 and 2018. Univariate then multivariable analyses were performed to compare patients with and without malignancy and to identify independent demographic, clinical, laboratory, and/or radiological predictors of malignancy. Akaike information criteria for regression models were used to evaluate goodness of fit., Results: A total of 3,293 patients were included. The median age was 38 (27-53) years, and 46.5% were female patients. On pathology, 48 (1.5%) had an underlying malignancy (adenocarcinoma [60.4%], neuroendocrine [37.5%], and lymphoma [2.1%]). Patients with malignancy were older (56 [34.5-67] vs 37 [27-52] years, P < .001), had longer duration of symptoms before presentation (36-41 vs 18-23 hours, P = .03), and were more likely to have a phlegmon on imaging (6.3% vs 1.3%, P = .03). Multivariable analyses showed that an enlarged appendiceal diameter was independently associated with malignancy (odds ratio = 1.06, 95% confidence interval = 1.01-1.12; P = .01). The incidence of malignancy in patients >40 years with an appendiceal diameter >10 mm on computed tomography was 2.95% compared with 0.97% in patients ≤40 years old with appendiceal diameter ≤10 mm. The corresponding risk ratio for that population was 3.03 (95% confidence interval: 1.24-7.42; P = .02)., Conclusion: The combination of age >40 and an appendiceal diameter >10 mm is associated with a greater than 3-fold increased risk of malignancy in patients presenting with appendicitis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: BRCA1/2 deleterious variants account for most of the hereditary breast and ovarian cancer cases. Prediction models and guidelines for the assessment of genetic risk rely heavily on criteria with high variability such as family cancer history. Here we investigated the efficacy of MRI (magnetic resonance imaging) texture features as a predictor for BRCA mutation status., Methods: A total of 41 female breast cancer individuals at high genetic risk, sixteen with a BRCA1/2 pathogenic variant and twenty five controls were included. From each MRI 4225 computer-extracted voxels were analyzed. Non-imaging features including clinical, family cancer history variables and triple negative receptor status (TNBC) were complementarily used. Lasso-principal component regression (L-PCR) analysis was implemented to compare the predictive performance, assessed as area under the curve (AUC), when imaging features were used, and lasso logistic regression or conventional logistic regression for the remaining analyses., Results: Lasso-selected imaging principal components showed the highest predictive value (AUC 0.86), surpassing family cancer history. Clinical variables comprising age at disease onset and bilateral breast cancer yielded a relatively poor AUC (~ 0.56). Combination of imaging with the non-imaging variables led to an improvement of predictive performance in all analyses, with TNBC along with the imaging components yielding the highest AUC (0.94). Replacing family history variables with imaging components yielded an improvement of classification performance of ~ 4%, suggesting that imaging compensates the predictive information arising from family cancer structure., Conclusions: The L-PCR model uncovered evidence for the utility of MRI texture features in distinguishing between BRCA1/2 positive and negative high-risk breast cancer individuals, which may suggest value to diagnostic routine. Integration of computer-extracted texture analysis from MRI modalities in prediction models and inclusion criteria might play a role in reducing false positives or missed cases especially when established risk variables such as family history are missing.

Background: The Emergency Surgery Score (ESS) was recently developed and retrospectively validated as an accurate mortality risk calculator for emergency general surgery. We sought to prospectively validate ESS, specifically in the high-risk nontrauma emergency laparotomy (EL) patient., Methods: This is an Eastern Association for the Surgery of Trauma multicenter prospective observational study. Between April 2018 and June 2019, 19 centers enrolled all adults (aged >18 years) undergoing EL. Preoperative, intraoperative, and postoperative variables were prospectively and systematically collected. Emergency Surgery Score was calculated for each patient and validated using c-statistic methodology by correlating it with three postoperative outcomes: (1) 30-day mortality, (2) 30-day complications (e.g., respiratory/renal failure, infection), and (3) postoperative intensive care unit (ICU) admission., Results: A total of 1,649 patients were included. The mean age was 60.5 years, 50.3% were female, and 71.4% were white. The mean ESS was 6, and the most common indication for EL was hollow viscus perforation. The 30-day mortality and complication rates were 14.8% and 53.3%; 57.0% of patients required ICU admission. Emergency Surgery Score gradually and accurately predicted 30-day mortality; 3.5%, 50.0%, and 85.7% of patients with ESS of 3, 12, and 17 died after surgery, respectively, with a c-statistic of 0.84. Similarly, ESS gradually and accurately predicted complications; 21.0%, 57.1%, and 88.9% of patients with ESS of 1, 6, and 13 developed postoperative complications, with a c-statistic of 0.74. Emergency Surgery Score also accurately predicted which patients required intensive care unit admission (c-statistic, 0.80)., Conclusion: This is the first prospective multicenter study to validate ESS as an accurate predictor of outcome in the EL patient. Emergency Surgery Score can prove useful for (1) perioperative patient and family counseling, (2) triaging patients to the intensive care unit, and (3) benchmarking the quality of emergency general surgery care., Level of Evidence: Prognostic study, level III.

Background: Previous studies have used using Indirect Calorimetry (IC) with solitary or sparse measurements of resting energy expenditure (REE). This "snapshot" may not capture the dynamic nature of metabolic requirements. Using continuous IC, we describe the variation of REE during the first days in the intensive care unit., Methods: Injured adults (≥18 years) requiring mechanical ventilation from March 2018 to September 2018 were enrolled. IC was initiated within 4 days of admission and continuous REE recorded until 14 days, extubation, or death. Multiple 10-minute periods collected during steady state were used to calculate daily REE maximum, minimum, average, and variability [(REEmax - REEmin/2)/average REE]., Results: We included 55 patients. Median age was 38 [27-58] years, 38 (69%) were male, body mass index was 28 [25-33] kg/m 2 , and Acute Physiology and Chronic Health Evaluation II was 17 [14-24]. Mechanism of injury was: blunt (n = 38, 69%), penetrating (n = 9, 16%), and burn (n = 8, 15%). Average REE increased gradually from 1,663 kcal [1,435-2,143] to a maximum of 2,080 [1,701-2,336] on day 7, a relative 25% increase, which was sustained through day 14. REE variability ranged 8%-13% and was not reliably predicted by fever, tachycardia, elevated intracranial pressures, hypertension, or hypotension., Conclusion: In critically injured patients, steady-state REE measurements display fluctuations over a 24-hour period and demonstrate a gradual rise over the first few days after injury. Continuous REE, if available, is recommended for more precise matching of energy delivery to metabolic requirements., (© 2019 American Society for Parenteral and Enteral Nutrition.)

Objective: To compare the presentation, management, and outcomes of appendicitis in pregnant and non-pregnant females of childbearing age (18-45 years). Methods: This was a post-hoc analysis of a prospectively collected database (January 2017-June 2018) from 28 centers in America. We compared pregnant and non-pregnant females' demographics, clinical presentation, laboratory data, imaging findings, management, and clinical outcomes. Results: Of the 3,597 subjects, 1,010 (28%) were of childbearing age, and 41 were pregnant: The mean age of the pregnant subjects was 30 ± 8 years at a median gestational age of 15 (range 10-23) weeks. The two groups had similar demographics and clinical presentation, but there were differences in management and outcomes. For example, in pregnant subjects, abdominal ultrasound scans (US) plus magnetic resonance imaging (MRI) was the most frequently used imaging method (41%) followed by MRI alone (29%), US alone (22%), computed tomography (CT) (5%), and no imaging (2%). Despite similar American Association for the Surgery of Trauma Emergency General Surgery Clinical and Imaging Grade at presentation, pregnant subjects were more likely to be treated with antibiotics alone (15% versus 4%; p = 0.008). Pregnant subjects were less likely to have simple appendicitis and were more likely to have complicated (perforated or gangrenous) appendicitis or a normal appendix. With the exception of index hospital length of stay, there were no significant differences between the groups in clinical outcomes at index hospitalization or at 30 days. Conclusion: Almost 1 in 20 women of childbearing age presenting with appendicitis is pregnant. Appendicitis most commonly affects women in early to mid-pregnancy. Compared with non-pregnant women of childbearing age, pregnant women presenting with appendicitis undergo non-operative management more often and are less likely to have simple appendicitis. Compared with non-pregnant patients, they have similar clinical outcomes at both index hospitalization and 30 days after discharge.

Background: The Advanced Trauma Life Support (ATLS) shock classification has been accepted as the conceptual framework for clinicians caring for trauma patients. We sought to validate its ability to predict mortality, blood transfusion, and urgent intervention., Materials and Methods: We performed a retrospective review of trauma patients using the 2014 National Trauma Data Bank. Using initial vital signs data, patients were categorized into shock class based on the ATLS program. Rates for urgent blood transfusion, urgent operative intervention, and mortality were compared between classes., Results: 630,635 subjects were included for analysis. Classes 1, 2, 3, and 4 included 312,404, 17,133, 31, and 43 patients, respectively. 300,754 patients did not meet criteria for any ATLS shock class. Of the patients in class 1 shock, 2653 died (0.9%), 3123 (1.0%) were transfused blood products, and 7115 (2.3%) underwent an urgent procedure. In class 2, 219 (1.3%) died, 387 (2.3%) were transfused, and 1575 (9.2%) underwent intervention. In class 3, 7 (22.6%) died, 10 (32.3%) were transfused, and 13 (41.9%) underwent intervention. In class 4, 15 (34.9%) died, 19 (44.2%) were transfused, and 23 (53.5%) underwent intervention. For uncategorized patients, 21,356 (7.1%) died, 15,168 (5.0%) were transfused, and 23,844 (7.9%) underwent intervention., Conclusions: Almost half of trauma patients do not meet criteria for any ATLS shock class. Uncategorized patients had a higher mortality (7.1%) than patients in classes 1 and 2 (0.9% and 1.3%, respectively). Classes 3 and 4 only accounted for 0.005% and 0.007%, respectively, of patients. The ATLS classification system does not help identify many patients in severe shock., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD)., Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function., Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits., Conclusion: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

Background: It is commonly taught that a widened mediastinum (WM) on chest X-ray (CXR) is a marker for aortic injury (AI). We sought to describe the epidemiology of injuries for all patients with WM and compare their CXR to those of patients with confirmed AI., Methods: Adults (age ≥ 18) sustaining blunt traumatic injuries from January 2017 to June 2017 with both CXR (supine, anterior-posterior) and chest CT were included. We excluded those whose CT preceded CXR and those with missing data. Basic demographics, injury characteristics, mediastinal width (MW), mediastinal-to-thoracic width ratio (MTR), and all thoracic imaging findings were analyzed. MW > 8 cm was considered WM. We also queried our registry for all AI patients over a 4-year period. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of WM on CXR for AI were calculated. Multivariate logistic regression was performed to identify factors associated with positive traumatic findings, controlling for body mass index (BMI), sex, high-energy mechanism, MTR, and mediastinal width., Results: Of 749 included subjects, 502 (67%) had an MW > 8 cm: mean age was 48 ± 20 y, 381 (76%) were men, and BMI was 28 ± 5 kg/m 2 . Mechanism of injury was motor vehicle crash in 335 (67%); fall in 113 (23%); assault in 31 (6%); other (jet-ski accidents, etc.) in 17 (3%), and unknown in 6 (1%). Only 128 (26%) of patients with WM had positive findings on CT, with the most common [80 (16%)] being nontraumatic findings (pericardial infusion, lymph nodes, etc.), followed by hemomediastinum/pneumomediastinum [32 (6%)], sternal fractures [18 (4%)], multiple findings [15 (3%)], and vertebral fractures [6 (1%)]. Only 2 (1%) had AI. The sensitivity was 100%, specificity was 33%, PPV was 0.4%, NPV was 100%, and accuracy was 33%. From 2013 to 2017, 38 patients had AI: mean age was 46 ± 19 y, 26 (68%) were men, and BMI was 28 ± 4 kg/m 2 . Motor vehicle crash was the most common mechanism (89%), followed by "other" trauma mechanism (5%), fall (3%), and assault (3%). On univariate analysis, compared with all patients with WM, patients with AI had significantly greater MW (9.5 [8.8-10.4] versus 10.2 [9.1-11.1]; P = 0.042) and MTR (0.31 [0.28-0.34] versus 0.32 [0.31-0.37]; P = 0.001), although the actual differences were not clinically significant. The regression analysis did not identify any factors associated with traumatic CXR findings., Conclusions: Most bluntly injured adults have a WM, and the majority have either no findings or nontraumatic findings. The PPV of a WM for AI is <1%. WM on supine CXR is nonspecific and inaccurate for diagnosing traumatic injuries, especially AI., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: 17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies., Methods: Prenatal sequencing and postnatal chromosomal microarray analysis were performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants., Results: In a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA-binding domain, a mutational hot spot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions. Literature screening revealed variable reporting of HNF1B-associated clinical traits. Overall, both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum., Conclusions: We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants are necessary for a more accurate risk quantification of prenatal and postnatal clinical features, improving genetic counseling and prenatal decision making., (© 2019 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Two percent of patients with Wilms tumors have a positive family history. In many of these cases the genetic cause remains unresolved. By applying germline exome sequencing in two families with two affected individuals with Wilms tumors, we identified truncating mutations in TRIM28. Subsequent mutational screening of germline and tumor DNA of 269 children affected by Wilms tumor was performed, and revealed seven additional individuals with germline truncating mutations, and one individual with a somatic truncating mutation in TRIM28. TRIM28 encodes a complex scaffold protein involved in many different processes, including gene silencing, DNA repair and maintenance of genomic integrity. Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss-of-function effect of the mutations identified. The tumors showed an epithelial-type histology that stained negative for TRIM28 by immunohistochemistry. The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests. Exome sequencing on eight tumor DNA samples from six individuals showed loss-of-heterozygosity (LOH) of the TRIM28-locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development. Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis. In conclusion, we identified heterozygous germline truncating mutations in TRIM28 in 11 children with mainly epithelial-type Wilms tumors, which become homozygous in tumor tissue. These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH., (© 2019 UICC.)

Background: The American Association for the Surgery of Trauma (AAST) has proposed a grading system for anatomic severity of 16 Emergency General Surgery conditions, including appendicitis. This is the first prospective, multicenter clinical study evaluating the AAST Appendicitis grading scale., Methods: The EAST Appendicitis study utilized data collected prospectively from 27 centers, between January 2017 to June 2018. An overall grade was assigned as the highest grade of the subscales: clinical, radiographic, operative, and pathologic. Grade 1-3 of the clinical subscale was assigned as Grade 1. Patients with a final diagnosis other than appendicitis were excluded. The cohort was divided into two groups: simple appendicitis (Grades 1 and 2), and complicated appendicitis (Grades 3, 4, and 5).Fisher's exact and Kruskal-Wallis tests were used to determine association between the overall AAST grade and the following outcomes: infectious complications, Clavien-Dindo complications, hospital length of stay (LOS), 30-day emergency department visits, readmissions, and secondary interventions., Results: A total of 2,909 cases were analyzed: 1,656 (57%) were Grade 1; 181 (6%), Grade 2; 399 (14%) Grade 4; and 549 (19%) Grade 5; 94% of patients underwent appendectomy. Index hospitalization LOS increased significantly with increasing grade: 1, [1,1], 1 [1,2], 1 [1,2], 2 [1,3], and 32,5 (p < 0.001). Infectious complications, Clavien-Dindo complications, hospital LOS, and secondary interventions were significantly associated with increasing AAST severity grade during index hospitalization. For 30-day outcomes, similar trends were noted for readmission, 30-day infections complications, 30-day cumulative infectious complications, 30-day Clavien-Dindo complications, 30-day cumulative Clavien-Dindo complications, 30-day secondary interventions, and 30-day cumulative secondary interventions., Conclusion: The AAST emergency general surgery grade for appendicitis is a valid predictor of clinical outcomes such as infectious complications, overall complications, and the need for secondary intervention., Level of Evidence: Prognostic, level III.