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The most common gear strength calculations performed in accordance with ISO/TC 60/SC 2 include surface durability and root bending strength. Typical geared power transmissions are characterized by high Hertzian contact stresses (surface durability) on the flanks – frequently in the order of 103 MPa – versus almost half an order magnitude lower first principal stresses on the tooth root (tooth bending strength). Therefore, the use of high strength special steel alloys is almost mandatory, especially in high-end applications, mainly to withstand the high contact stress values. Ceramic materials are typically characterized by high compressive strength versus very low flexural strength that at first glance makes them inefficient for gear transmissions since they are unlikely to withstand the tensile root stresses. Nevertheless, ceramic materials possess a number of advantages that makes them potential candidates for geared transmissions, such as their exceptional thermal properties, their low density (weight), their excellent wear characteristics and limited lubrication demands. The present work investigates the main challenges of using high-end ceramic gears and attempts to provide an insight on defining the design envelope of such gears to counter the main disadvantages. The increase of the normal pressure angle beyond the 25° limit set by ISO 6336 is primarily investigated, since in minimizes the tensile tooth root stresses, while also increasing the curvature of the contact surfaces without greatly increasing Hertzian stresses. Comparative assessment of the performance of fully ceramic gear designs versus their conventional steel counterparts is performed through quasi-static FEA simulations to set the basic design requirements for such gears and to promote further investigation of the feasibility of their usage in high power density applications. [ABSTRACT FROM AUTHOR]

Resin-impregnated fibres are extensively used in a variety of industrial applications as is demonstrated in the literature. Resin-fibre impregnation techniques are used in order to create homogeneous macro – materials and to take full advantage of the mechanical properties of the fibrous reinforcement (i.e. carbon, glass, organic or ceramic fibres). However, achieving highly impregnated fibres is proven quite challenging especially in continuous production techniques that are required for large production rates. The main challenge lies in achieving complete impregnation of the tightly arranged fibres mainly referring to the formed yarns containing multiple fibres, sometimes even twisted. This results in partially impregnated materials containing cavities that tend to exhibit inferior mechanical properties compared to the theoretical calculations, which assume fully impregnated materials. These cavities often lead to crack generation, acting as stress concentration sites, resulting in complete failure of the material at macro-level. In this paper a novel technique for continuous production of fully impregnated woven fibres is presented using non – meshing, co – rotating rollers. A laboratory-scale apparatus is designed and described thoroughly in the context of this work. The method resembles pultrusion in the sense that a reinforcement plain fibre mesh (glass) is co–processed with the liquid resin through a pair of co–rotating toothed rollers to produce a continuously reinforced 3D tape. The surface of the rollers is produced from a double-sinusoidal toothed surface (rack) using the Theory of Gearing in three-dimensions, which imposes significant differential sliding of the fibres without differential tension and facilitates fibre wetting. The geometry of the rollers is calculated not to damage the unprocessed fibres, while facilitating local widespreading of the stranded fibres in the three – dimensional space leading to the resin being able to fully penetrate the reinforcing fibre material.

Slurry pumps are extensively used in the construction industry while positive displacement screw pumps are used in most mobile concrete pump applications. The aggregate size is known to significantly affect pump performance in terms of clogging. Large aggregates tend to be trapped against the stator-rotor interface, blocking the continuous and smooth operation of the screw pump. In order to avoid the development of excessive stress values able to damage the rotor-stator mechanism of the pump, the typical de-clogging mechanism deployed by most positive displacement screw slurry pumps includes reversing the rotation of the pump driving motor thus allowing the aggregates to be carried away with the mixture, so that the pump can soon resume its operation. This procedure causes frequent start-stops of the pump resulting in dis-continuation of the pumped mixture lasting a few seconds, that while being of little importance in most construction applications, can be of significance in applications requiring higher levels of accuracy and continuous mixture flow. In the context of this work, a novel concept of positive displacement screw slurry pump is presented, including a continuous de-clogging mechanism, without the need to reverse the rotation of the driving motor. This de-clogging operation is achieved through the modification of the geometry of both the rotor and stator introducing a conical form along the axial direction. This configuration of the rotor-stator, allows for small displacements along the axial direction, which in turn increases the size of the cavities facilitating the de-clogging of the pump. Variable pitch is also introduced to both the rotor and stator in order to ensure constant mass flow of the mixture throughout the length of the screw pump covering for the velocity increase as a result of the conical geometry. The axial movement of the rotor in relation to the fixed stator, is achieved through the elastic support of the rotor in the axial direction, that allows for small axial displacements, when stresses induced from trapped aggregates exceed the stiffness of the support. The proposed concept comprises a passive real-time de-clogging mechanism that greatly reduces pump idle time compared to the conventional mechanism described earlier, providing smoother operation and stable mass flow of the mixture.

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.)

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.)