Mutations in SCNM1 cause orofaciodigital syndrome due to minor intron splicing defects affecting primary cilia.

Orofaciodigital syndrome (OFD) is a genetically heterogeneous ciliopathy characterized by anomalies of the oral cavity, face, and digits. We describe individuals with OFD from three unrelated families having bi-allelic loss-of-function variants in SCNM1 as the cause of their condition. SCNM1 encodes a protein recently shown to be a component of the human minor spliceosome. However, so far the effect of loss of SCNM1 function on human cells had not been assessed. Using a comparative transcriptome analysis between fibroblasts derived from an OFD-affected individual harboring SCNM1 mutations and control fibroblasts, we identified a set of genes with defective minor intron (U12) processing in the fibroblasts of the affected subject. These results were reproduced in SCNM1 knockout hTERT RPE-1 (RPE-1) cells engineered by CRISPR-Cas9-mediated editing and in SCNM1 siRNA-treated RPE-1 cultures. Notably, expression of TMEM107 and FAM92A encoding primary cilia and basal body proteins, respectively, and that of DERL2, ZC3H8, and C17orf75, were severely reduced in SCNM1-deficient cells. Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia. Conversely, cilia length and expression of SCNM1-regulated genes were restored in SCNM1-deficient fibroblasts following reintroduction of SCNM1 via retroviral delivery. Additionally, functional analysis in SCNM1-retrotransduced fibroblasts showed that SCNM1 is a positive mediator of Hedgehog (Hh) signaling. Our findings demonstrate that defective U12 intron splicing can lead to a typical ciliopathy such as OFD and reveal that primary cilia length and Hh signaling are regulated by the minor spliceosome through SCNM1 activity.

Genetics of inherited peripheral neuropathies and the next frontier: looking backwards to progress forwards.

Inherited peripheral neuropathies (IPNs) encompass a clinically and genetically heterogeneous group of disorders causing length-dependent degeneration of peripheral autonomic, motor and/or sensory nerves. Despite gold-standard diagnostic testing for pathogenic variants in over 100 known associated genes, many patients with IPN remain genetically unsolved. Providing patients with a diagnosis is critical for reducing their 'diagnostic odyssey', improving clinical care, and for informed genetic counselling. The last decade of massively parallel sequencing technologies has seen a rapid increase in the number of newly described IPN-associated gene variants contributing to IPN pathogenesis. However, the scarcity of additional families and functional data supporting variants in potential novel genes is prolonging patient diagnostic uncertainty and contributing to the missing heritability of IPNs. We review the last decade of IPN disease gene discovery to highlight novel genes, structural variation and short tandem repeat expansions contributing to IPN pathogenesis. From the lessons learnt, we provide our vision for IPN research as we anticipate the future, providing examples of emerging technologies, resources and tools that we propose that will expedite the genetic diagnosis of unsolved IPN families.

An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches.

The hereditary cerebellar ataxias (HCAs) are rare, progressive neurologic disorders caused by variants in many different genes. Inheritance may follow autosomal dominant, autosomal recessive, X-linked or mitochondrial patterns. The list of genes associated with adult-onset cerebellar ataxia is continuously growing, with several new genes discovered in the last few years. This includes short-tandem repeat (STR) expansions in RFC1, causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), FGF14-GAA causing spinocerebellar ataxia type 27B (SCA27B), and THAP11. In addition, the genetic basis for SCA4, has recently been identified as a STR expansion in ZFHX3. Given the large and growing number of genes, and different gene variant types, the approach to diagnostic testing for adult-onset HCA can be complex. Testing methods include targeted evaluation of STR expansions (e.g. SCAs, Friedreich ataxia, fragile X-associated tremor/ataxia syndrome, dentatorubral-pallidoluysian atrophy), next generation sequencing for conventional variants, which may include targeted gene panels, whole exome, or whole genome sequencing, followed by various potential additional tests. This review proposes a diagnostic approach for clinical testing, highlights the challenges with current testing technologies, and discusses future advances which may overcome these limitations. Implementing long-read sequencing has the potential to transform the diagnostic approach in HCA, with the overall aim to improve the diagnostic yield.

Two New Families and a Literature Review of ELOVL4-Associated Spinocerebellar Ataxia Type 34.

Autosomal dominant variants in ELOVL4 cause spinocerebellar ataxia type 34 (SCA34; ATX-ELOVL4), classically associated with a skin condition known as erythrokeratoderma. Here, we report a large Italian-Maltese-Australian family with spinocerebellar ataxia. Notably, while there were dermatological manifestations (eczema), erythrokeratoderma was not present. Using a next-generation sequencing panel, we identified a previously reported ELOVL4 variant, NM_022726.4: c.698C > T p.(Thr233Met). The variant was initially classified as a variant of uncertain significance; however, through segregation studies, we reclassified the variant as likely pathogenic. We next identified an individual from another family (Algerian-Maltese-Australian) with the same ELOVL4 variant with spinocerebellar ataxia but without dermatological manifestations. We subsequently performed the first dedicated literature review of ELOVL4-associated ataxia to gain further insights into genotype-phenotype relationships. We identified a total of 60 reported cases of SCA34 to date. The majority had gait ataxia (88.3%), limb ataxia (76.7%), dysarthria (63.3%), and nystagmus (58.3%). Of note, skin lesions related to erythrokeratoderma were seen in a minority of cases (33.3%). Other extracerebellar manifestations included pyramidal tract signs, autonomic disturbances, retinitis pigmentosa, and cognitive impairment. For brain MRI data, cerebellar atrophy was seen in all cases (100%), whereas the hot cross bun sign (typically associated with multiple system atrophy type C) was seen in 32.4% of cases. Our family study and literature review highlight the variable phenotypic spectrum of SCA34. Importantly, it shows that erythrokeratoderma is not found in most cases and that, while a dermatological assessment may be helpful in these patients, SCA34 diagnosis should be considered irrespective of dermatological manifestations.

A deep intronic variant in MME causes autosomal recessive Charcot-Marie-Tooth neuropathy through aberrant splicing.

BACKGROUND: Loss-of-function variants in MME (membrane metalloendopeptidase) are a known cause of recessive Charcot-Marie-Tooth Neuropathy (CMT). A deep intronic variant, MME c.1188+428A>G (NM_000902.5), was identified through whole genome sequencing (WGS) of two Australian families with recessive inheritance of axonal CMT using the seqr platform. MME c.1188+428A>G was detected in a homozygous state in Family 1, and in a compound heterozygous state with a known pathogenic MME variant (c.467del; p.Pro156Leufs*14) in Family 2. AIMS: We aimed to determine the pathogenicity of the MME c.1188+428A>G variant through segregation and splicing analysis. METHODS: The splicing impact of the deep intronic MME variant c.1188+428A>G was assessed using an in vitro exon-trapping assay. RESULTS: The exon-trapping assay demonstrated that the MME c.1188+428A>G variant created a novel splice donor site resulting in the inclusion of an 83 bp pseudoexon between MME exons 12 and 13. The incorporation of the pseudoexon into MME transcript is predicted to lead to a coding frameshift and premature termination codon (PTC) in MME exon 14 (p.Ala397ProfsTer47). This PTC is likely to result in nonsense mediated decay (NMD) of MME transcript leading to a pathogenic loss-of-function. INTERPRETATION: To our knowledge, this is the first report of a pathogenic deep intronic MME variant causing CMT. This is of significance as deep intronic variants are missed using whole exome sequencing screening methods. Individuals with CMT should be reassessed for deep intronic variants, with splicing impacts being considered in relation to the potential pathogenicity of variants.

Novel gene-intergenic fusion involving ubiquitin E3 ligase UBE3C causes distal hereditary motor neuropathy.

Distal hereditary motor neuropathies (dHMNs) are a group of inherited diseases involving the progressive, length-dependent axonal degeneration of the lower motor neurons. There are currently 29 reported causative genes and four disease loci implicated in dHMN. Despite the high genetic heterogeneity, mutations in the known genes account for less than 20% of dHMN cases, with the mutations identified predominantly being point mutations or indels. We have expanded the spectrum of dHMN mutations with the identification of a 1.35 Mb complex structural variation (SV) causing a form of autosomal dominant dHMN (DHMN1 OMIM %182906). Given the complex nature of SV mutations and the importance of studying pathogenic mechanisms in a neuronal setting, we generated a patient-derived DHMN1 motor neuron model harbouring the 1.35 Mb complex insertion. The DHMN1 complex insertion creates a duplicated copy of the first 10 exons of the ubiquitin-protein E3 ligase gene (UBE3C) and forms a novel gene-intergenic fusion sense transcript by incorporating a terminal pseudo-exon from intergenic sequence within the DHMN1 locus. The UBE3C intergenic fusion (UBE3C-IF) transcript does not undergo nonsense-mediated decay and results in a significant reduction of wild-type full-length UBE3C (UBE3C-WT) protein levels in DHMN1 iPSC-derived motor neurons. An engineered transgenic Caenorhabditis elegans model expressing the UBE3C-IF transcript in GABA-ergic motor neurons shows neuronal synaptic transmission deficits. Furthermore, the transgenic animals are susceptible to heat stress, which may implicate defective protein homeostasis underlying DHMN1 pathogenesis. Identification of the novel UBE3C-IF gene-intergenic fusion transcript in motor neurons highlights a potential new disease mechanism underlying axonal and motor neuron degeneration. These complementary models serve as a powerful paradigm for studying the DHMN1 complex SV and an invaluable tool for defining therapeutic targets for DHMN1.

Detection of Postpartum Hemorrhage Using Compensatory Reserve Index in Patients Undergoing Cesarean Delivery.

BACKGROUND: Postpartum hemorrhage (PPH) is the leading cause of maternal death worldwide. Early recognition and management are imperative for improved outcomes. The compensatory reserve index (CRI) is a novel physiological parameter that trends changes in intravascular volume, by continuously comparing extracted photoplethysmogram waveforms to a reference model that was derived from a human model of acute blood loss. This study sought to determine whether the CRI pattern was differential between those who do and do not experience PPH during cesarean delivery and compare these results to the American Society of Anesthesiologists (ASA) standards for noninvasive monitoring. METHODS: Parturients undergoing cesarean delivery were enrolled between February 2020 and May 2021. A noninvasive CRI monitor was applied to collect continuous CRI values throughout the intraoperative and immediate postpartum periods. Patients were stratified based on blood loss into PPH versus non-PPH groups. PPH was defined as a quantitative blood loss >1000 mL. Function-on-scalar (FoS) regression was used to compare trends in CRI between groups (PPH versus non-PPH) during the 10 to 60-minute window after delivery. Two subanalyses excluding patients who received general anesthesia and preeclamptics were performed. RESULTS: Fifty-one patients were enrolled in the study. Thirteen (25.5%) patients experienced PPH. Pregnant patients who experienced PPH had, on average, lower postdelivery CRI values (-0.13; 95% CI, -0.13 to -0.12; P < .001) than those who did not experience PPH. This persisted even when adjusting for preeclampsia and administration of uterotonics. The average mean arterial pressure (MAP) measurements were not statistically significant (-1.67; 95% CI, -3.57 to 0.22; P = .09). Similar trends were seen when excluding patients who underwent general anesthesia. When excluding preeclamptics, CRI values remained lower in those who hemorrhaged (-0.18; 95% CI, -0.19 to -0.17; P < .001). CONCLUSIONS: CRI detects changes in central volume status not distinguished by MAP. It has the potential to serve as a continuous, informative metric, notifying providers of acute changes in central volume status due to PPH during cesarean delivery.

Role of Mediterranean diet in endocrine diseases: a joint overview by the endocrinologist and the nutritionist.

PURPOSE: The purpose of this review is to examine the current evidence on the potential role of Mediterranean diet (MD) in the prevention and management of endocrine disorders and to highlight the importance of interdisciplinary collaboration between endocrinologists and nutritionists. METHODS: A literature search was conducted using PubMed and Google Scholar databases to identify relevant studies published in English. Studies were selected based on their relevance to the role of MD in the prevention and management of endocrine disorders. The search terms included "Mediterranean diet," "endocrine disorders," "thyroid disorders," "gonadal disorders," and "neuroendocrine tumors". RESULTS: The studies reviewed suggest that MD may have a beneficial effect in the prevention and management of various endocrine disorders, including thyroid disorders, gonadal disorders, and neuroendocrine tumors. MD has been associated with decreased risk of nodular thyroid disease and thyroid cancer, improved male and female reproductive health, and a potential role in the management of neuroendocrine tumors. MD's anti-inflammatory and antioxidant properties, as well as its high levels of phytochemicals, may play a role in its beneficial effects. CONCLUSION: Interdisciplinary collaboration between endocrinologists and nutritionists is essential for the optimal management of endocrine disorders, including the potential role of MD in their prevention and management. While further research is needed, the current evidence suggests that MD may have a protective effect against endocrine disorders, and its incorporation into dietary recommendations may be beneficial.

Facial cues to physical strength are not always associated with facial masculinity: Comparative study of Europeans and Southern Siberians.

OBJECTIVES: The aim of our study was to compare morphometric patterns of facial sexual dimorphism with strength-face relationship in members of two distinct populations of European and Central Asian origin: Russians and Tuvans. METHODS: Handgrip strength (HGS) measures and facial photographs were collected from Russian (n = 233) and Tuvan (n = 187) men and women. We digitized 70 landmarks and semilandmarks on full-face and 54 landmarks and semilandmarks on profile photos. This was done to capture variation in facial morphology. After that, we performed the shape regressions of landmarks' coordinates upon sex and HGS. Results were visualized in forms of thin-plate deformation grids and geometric morphometric morphs. RESULTS: In both populations, HGS was associated significantly with male facial shape only. In Russian men, strength-related changes of facial shape were almost completely in direction of increase in male-typicality. This was especially evident for the relative lower facial width, which was higher in men compared to women, as well as in stronger men compared to weaker ones. On the contrary, in Tuvans the lower face was relatively narrower in men than in women. However, the facial shape of strong Tuvan men was also associated with relatively wider lower face. Our results indicate that the effect of strength on facial shape is relatively independent of facial sexual dimorphism. CONCLUSIONS: Our findings clearly demonstrate that physical strength is associated with the shape of the lower part of male faces even in populations with a mismatched direction of lower face sexual dimorphism.

Effect of Routine Child Physical Abuse Screening Tool on Emergency Department Efficiency.

OBJECTIVES: Physical abuse is a significant cause of morbidity and mortality for children. Routine screening by emergency nurses has been proposed to improve recognition, but the effect on emergency department (ED) workflow has not yet been assessed. We sought to evaluate the feasibility of routine screening and its effect on length of stay in a network of general EDs. METHODS: A 2-question child physical abuse screening tool was deployed for children <6 years old who presented for care in a system of 27 general EDs. Data were compared for the 6 months before and after screening was deployed (4/1/2019-10/2/2019 vs 10/3/2019-3/31/2020). The main outcome was ED length of stay in minutes. RESULTS: There were 14,133 eligible visits in the prescreening period and 16,993 in the screening period. Screening was completed for 13,404 visits (78.9%), with 116 (0.7%) screening positive. The mean ED length of stay was not significantly different in the prescreening (95.9 minutes) and screening periods (95.2 minutes; difference, 0.7 minutes; 95% CI, -1.5, 2.8). Among those who screened positive, 29% were reported to child protective services. On multivariable analysis, implementation of the screening tool did not impact overall ED length of stay. There were no significant differences in resource utilization between the prescreening and screening periods. CONCLUSIONS: Routine screening identifies children at high risk of physical abuse without increasing ED length of stay or resource utilization. Next steps will include determining rates of subsequent serious physical abuse in children with or without routine screening.

Self-Supervised Open-Set Speaker Recognition with Laguerre-Voronoi Descriptors.

Speaker recognition is a challenging problem in behavioral biometrics that has been rigorously investigated over the last decade. Although numerous supervised closed-set systems inherit the power of deep neural networks, limited studies have been made on open-set speaker recognition. This paper proposes a self-supervised open-set speaker recognition that leverages the geometric properties of speaker distribution for accurate and robust speaker verification. The proposed framework consists of a deep neural network incorporating a wider viewpoint of temporal speech features and Laguerre-Voronoi diagram-based speech feature extraction. The deep neural network is trained with a specialized clustering criterion that only requires positive pairs during training. The experiments validated that the proposed system outperformed current state-of-the-art methods in open-set speaker recognition and cluster representation.

Bacterial diversity using metagenomics of 16s rDNA in water kefir, an innovative source of probiotics for bee nutrition.

Water kefir is a sparkling, slightly acidic fermented beverage made from sugar, water, and water kefir grains, which are a mixture of yeast and bacteria. These grains produce a variety of fermentation compounds such as lactic acid, acetaldehyde, acetoin, ethanol and carbon dioxide. In this study, a high-throughput sequencing technique was used to characterize the bacterial composition of the original water kefir from which potential probiotics were obtained. We studied the bacterial diversity of both water kefir grains and beverages. DNA was extracted from three replicate samples of both grains and beverages using the Powerlyzer Microbial Kit. The hypervariable V1-V2 region of the bacterial 16S ribosomal RNA gene was amplified to prepare six DNA libraries. Between 1.4M and 2.4M base-pairs were sequenced for the library. In total, 28721971 raw reads were obtained from all the samples. Estimated species richness was higher in kefir beverage samples compared to grain samples. Moreover, a higher level of microbial alpha diversity was observed in the beverage samples. Particularly, the predominant bacteria in beverages were Anaerocolumna and Ralstonia, while in grains Liquorilactobacillus dominated, with lower levels of Leuconostoc and Oenococcus. Although the bacterial diversity in kefir grains was low because only three genera were the most represented, all of them are LAB bacteria with the potential to serve as probiotics in the artificial feeding of bees.

Analysis of asymptomatic Drosophila models for ALS and SMA reveals convergent impact on functional protein complexes linked to neuro-muscular degeneration.

BACKGROUND: Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) share phenotypic and molecular commonalities, including the fact that they can be caused by mutations in ubiquitous proteins involved in RNA metabolism, namely SMN, TDP-43 and FUS. Although this suggests the existence of common disease mechanisms, there is currently no model to explain the resulting motor neuron dysfunction. In this work we generated a parallel set of Drosophila models for adult-onset RNAi and tagged neuronal expression of the fly orthologues of the three human proteins, named Smn, TBPH and Caz, respectively. We profiled nuclear and cytoplasmic bound mRNAs using a RIP-seq approach and characterized the transcriptome of the RNAi models by RNA-seq. To unravel the mechanisms underlying the common functional impact of these proteins on neuronal cells, we devised a computational approach based on the construction of a tissue-specific library of protein functional modules, selected by an overall impact score measuring the estimated extent of perturbation caused by each gene knockdown. RESULTS: Transcriptome analysis revealed that the three proteins do not bind to the same RNA molecules and that only a limited set of functionally unrelated transcripts is commonly affected by their knock-down. However, through our integrative approach we were able to identify a concerted effect on protein functional modules, albeit acting through distinct targets. Most strikingly, functional annotation revealed that these modules are involved in critical cellular pathways for motor neurons, including neuromuscular junction function. Furthermore, selected modules were found to be significantly enriched in orthologues of human neuronal disease genes. CONCLUSIONS: The results presented here show that SMA and ALS disease-associated genes linked to RNA metabolism functionally converge on neuronal protein complexes, providing a new hypothesis to explain the common motor neuron phenotype. The functional modules identified represent promising biomarkers and therapeutic targets, namely given their alteration in asymptomatic settings.

Charcot-Marie-tooth disease causing mutation (p.R158H) in pyruvate dehydrogenase kinase 3 (PDK3) affects synaptic transmission, ATP production and causes neurodegeneration in a CMTX6 C. elegans model.

Charcot-Marie-Tooth (CMT) is a commonly inherited, non-fatal neurodegenerative disorder that affects sensory and motor neurons in patients. More than 90 genes are known to cause axonal and demyelinating forms of CMT. The p.R158H mutation in the pyruvate dehydrogenase kinase 3 (PDK3) gene is the genetic cause for an X linked form of axonal CMT (CMTX6). In vitro studies using patient fibroblasts and iPSC-derived motor neurons have shown that this mutation causes deficits in energy metabolism and mitochondrial function. Animal models that recapitulate pathogenic in vivo events in patients are crucial for investigating mechanisms of axonal degeneration and developing therapies for CMT. We have developed a C. elegans model of CMTX6 by knocking-in the p.R158H mutation in pdhk-2, the ortholog of PDK3. In addition, we have developed animal models overexpressing the wild type and mutant form of human PDK3 specifically in the GABAergic motor neurons of C. elegans. CMTX6 mutants generated in this study exhibit synaptic transmission deficits, locomotion defects and show signs of progressive neurodegeneration. Furthermore, the CMTX6 in vivo models display energy deficits that recapitulate the phenotype observed in patient fibroblasts and iPSC-derived motor neurons. Our CMTX6 animals represent the first in vivo model for this form of CMT and have provided novel insights into the cellular function and metabolic pathways perturbed by the p.R158H mutation, all the while closely replicating the clinical presentation observed in CMTX6 patients.

Outcomes in Pediatric Trauma Patients Who Receive Blood Transfusion.

INTRODUCTION: Increased blood volumes, due to massive transfusion (MT), are known to be associated with both infectious and noninfectious adverse outcomes. The aim of this study was to assess the association between MT and outcomes in pediatric trauma patients, and, secondarily, determine if these outcomes are differential by age once MT is reached. METHODS: Pediatric patients (ages 1-18 y old) in the ACS pediatric Trauma Quality Improvement Program (TQIP) database (2015-2018) who received blood were included. Patients were stratified by MT status, which was defined as blood product volume of 40 mL/kg within 24 h of admission (MT+) and compared to children who received blood products but did not meet the MT threshold (MT-). Defined MT + patients were matched 1:1 to MT-patients via propensity score matching of characteristics before comparisons. Adjusted logistic regression was performed on univariably significant outcomes of interest. RESULTS: There were 2318 patients in the analytic cohort. Patients who received MT had higher rates of deep venous thrombosis (DVT) (2.5% versus 1.0%, P < 0.001), acute kidney injury (AKI) (1.5% versus 0.0%, P = 0.022), CLABSI (4.0% versus 2.0% P = 0.008), and severe sepsis (2.3% versus. 1.1%, P = 0.02). On logistic regression MT was an independent risk factor for these outcomes. There was no differential effect of MT on these outcomes based on age. CONCLUSIONS: Outcomes associated with blood transfusion in pediatric trauma patients are low overall, but rates of DVT, AKI, CLABSI, and sepsis are higher in those who receive MT+ with no differences based on age.

Using the Social Vulnerability Index to Examine Disparities in Surgical Pediatric Trauma Patients.

INTRODUCTION: The Social Vulnerability Index (SVI) is a composite measure geocoded at the census tract level that has the potential to identify target populations at risk for postoperative surgical morbidity. We applied the SVI to examine demographics and disparities in surgical outcomes in pediatric trauma patients. METHODS: Surgical pediatric trauma patients (≤18-year-old) at our institution from 2010 to 2020 were included. Patients were geocoded to identify their census tract of residence and estimated SVI and were stratified into high (≥70th percentile) and low (<70th percentile) SVI groups. Demographics, clinical data, and outcomes were compared using Kruskal-Wallis and Fisher's exact tests. RESULTS: Of 355 patients included, 21.4% had high SVI percentiles while 78.6% had low SVI percentiles. Patients with high SVI were more likely to have government insurance (73.7% versus 37.2%, P < 0.001), be of minority race (49.8% versus 19.1%, P < 0.001), present with penetrating injuries (32.9% versus 19.7%, P = 0.007), and develop surgical site infections (3.9% versus 0.4%, P = 0.03) compared to the low SVI group. CONCLUSIONS: The SVI has the potential to examine health care disparities in pediatric trauma patients and identify discrete at-risk target populations for preventative resources allocation and intervention. Future studies are necessary to determine the utility of this tool in additional pediatric cohorts.

Pneumatosis Intestinalis in Children With Intestinal Failure: The Result of Intestinal Stress From Enteral Feeding?

OBJECTIVE: The incidence and significance of pneumatosis intestinalis (PI) in children with a diagnosis of intestinal failure is not well understood. The aim of this study was to identify clinical and anatomical factors associated with the imaging findings of PI in patients with intestinal failure. METHODS: We performed a retrospective review of all children with a diagnosis of intestinal failure at Children's Hospital Colorado between January 2019 and April 2022. Patients were stratified and compared based on the incidence of PI on abdominal imaging. Differences were compared using 2-sample Wilcoxon tests, chi-square, or Fisher exact tests. RESULTS: There were 111 patients identified with a diagnosis of intestinal failure and 30.6% (34) developed at least 1 instance of PI. There were no differences in etiology of intestinal failure or anatomy between those who developed PI and those who did not. Patients who developed PI, were less likely to be on total parental nutrition (60.6% vs 98.6%, P < 0.001) and more likely to be receiving any form of enteral feeds (87.9% vs 66.2%, P = 0.035) or tube feeds (75.8% vs 44.2%, P = 0.0045). Of the children with PI, 30.3% (10) were undergoing an enteral feed advancement at time of PI development. Three patients with PI underwent laparotomy for PI treatment, 2 of which were negative laparotomies. CONCLUSIONS: The development of PI in children with intestinal failure is likely a benign finding. It is associated with enteral feeding and may be due to increased intestinal stress.

Effects of very low-calorie ketogenic diet on hypothalamic-pituitary-adrenal axis and renin-angiotensin-aldosterone system.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system involved in controlling stress responses in humans under physiological and pathological conditions; cortisol is the main hormone produced by the HPA axis. It is known that calorie restriction acts as a stressor and can lead to an increase in cortisol production. Renin-angiotensin-aldosterone system (RAAS) is a complex endocrine network regulating blood pressure and hydrosaline metabolism, whose final hormonal effector is aldosterone. RAAS activation is linked to cardiometabolic diseases, such as heart failure and obesity. Obesity has become a leading worldwide pandemic, associated with serious health outcomes. Calorie restriction represents a pivotal strategy to tackle obesity. On the other hand, it is well known that an increased activity of the HPA may favour visceral adipose tissue expansion, which may jeopardize a successful diet-induced weight loss. Very low-calorie ketogenic diet (VLCKD) is a normoprotein diet with a drastic reduction of the carbohydrate content and total calorie intake. Thanks to its sustained protein content, VLCKD is extremely effective to reduce adipose tissue while preserving lean body mass and resting metabolic rate. PURPOSE: The purpose of this narrative review is to gain more insights on the effects of VLCKD on the HPA axis and RAAS, in different phases of weight loss and in different clinical settings.

Use and benefit of information, communication, and assistive technology among community-dwelling older adults - a cross-sectional study.

BACKGROUND: Technology can support healthy aging and empower older adults to live independently. However, technology adoption by older adults, particularly assistive technology (AT), is limited and little is known about the types of AT used among older adults. This study explored the use of key information and communication technologies (ICT) and AT among community-dwelling adults aged ≥ 65. METHODS: A cross-sectional study was conducted among community-dwelling adults aged ≥ 65 in southern Germany using a paper-based questionnaire. The questionnaire included questions on the three domains sociodemographic aspects, health status, and technology use. Technology use was considered separately for key ICT (smartphone, computer/laptop, and tablet) and a range of 31 different AT. Data were analyzed using descriptive statistics, univariate analyses, and Bernoulli Naïve Bayes modelling. RESULTS: The questionnaire was answered by 616 participants (response rate: 24.64%). ICT were used by 497 (80.68%) participants and were associated with lower age, higher level of education, living together with someone, availability of internet connection, higher interest in technology, and better health status (p < .05). No association was found with sex and size of the hometown. The most frequently owned AT were a landline phone, a body scale, and a blood pressure monitor. Several AT related to functionality, (instrumental) activities of daily living- (IADL), and morbidity were used more frequently among non-ICT users compared to ICT-users: senior mobile phone (19.33% vs. 3.22%), in-house emergency call (13.45% vs. 1.01%), hearing aid (26.89% vs. 16.7%), personal lift (7.56% vs. 1.61%), electronic stand-up aid (4.2% vs. 0%). Those with higher interest in technology reported higher levels of benefit from technology use. CONCLUSIONS: Despite the benefits older adults can gain from technology, its use remains low, especially among those with multimorbidity. Particularly newer, more innovative and (I)ADL-related AT appear underutilized. Considering the potential challenges in providing adequate care in the future, it may be crucial to support the use of these specific AT among older and frailer populations. To focus scientific and societal work, AT with a high impact on autonomy ((I)ADL/disease-related) should be distinguished from devices with a low impact on autonomy (household-/ comfort-related).

Irregular ventricular tachycardia originating from the moderator band.

Ventricular tachycardias (VT) may initially show beat to beat oscillations but rapidly stabilize into a regular tachycardia with a stable cycle length. A persistently irregular ventricular tachycardia is a rare phenomenon. We report a rare case of an "irregular" ventricular tachycardia with so pronounced oscillations in cycle length that it was initially misdiagnosed as atrial fibrillation with aberrant conduction. This ventricular tachycardia was incessant and resulted in a tachycardia induced cardiomyopathy refractory to several antiarrhythmic drugs. Mapping of the right ventricle demonstrated that the tachycardia had a focal origin in the moderator band close to its insertion into the anterior papillary muscle. Radiofrequency ablation eliminated the tachycardia with eventual normalization of left ventricular function. The moderator band and anterior papillary muscle of the right ventricle are known to be the source of short-coupled ventricular premature beats and regular ventricular tachycardias. However, an "irregular" ventricular tachycardia has not been previously reported to arise from these structures.