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Background Rett syndrome ( RTT) is a neurological disorder characterized by severe cognitive impairment, motor dyspraxia, and seizures. Rett syndrome arises predominantly from mutations in MECP2, the gene coding for methyl-CpG-binding protein 2 (Me CP2). Me CP2 is an important mediator of synaptic development and is essential in regulating homeostatic synaptic plasticity ( HSP) in the brain. In addition to demonstrating central nervous system impairment, RTT patients also suffer from gastrointestinal ( GI) dysmotility. We hypothesize that this is due to a similar impairment of plasticity-dependent synaptic function in the enteric nervous system ( ENS). We recently reported that Me CP2 is expressed in the ENS, providing evidence that neuronal dysfunction may mediate the GI pathology. Methods Baseline measures of Me CP2- KO vs wild-type ( WT) GI neuronal nitric oxide synthase ( nNOS) were assessed in tissue samples and in vitro. Experiments were carried out to measure nNOS in baseline vs activated plasticity states in vitro. Functional in vivo studies were carried out to determine whether Me CP2- KO mice reproduced the RTT GI hypomotility. Key Results Methyl-CpG-binding protein 2- KO mice reproduced the GI hypomotility seen in RTT. Me CP2- KO GI tissue demonstrated elevated nNOS levels. Cultured WT enteric neurons showed upregulation of nNOS following moderate, prolonged stimulation by hyperkalemia; neurons from Me CP2- KO mice failed to show this nNOS upregulation. Conclusions & Inferences Me CP2 is required for proper GI motility and normal nNOS levels. Neuronal nitric oxide synthase imbalances could mediate the GI dysmotility seen in RTT. Disruption of Me CP2-dependent HSP may be the basis for aberrant nNOS levels and hence GI dysmotility in Me CP2- KO and RTT. [ABSTRACT FROM AUTHOR]

Background Rett syndrome ( RTT) is an intellectual deficit and movement disorder that develops during early childhood in girls. Affected children are normal until 6-18 months of age, after which symptoms begin to appear. Most cases of RTT are due to mutations in the Me CP2 gene leading to disruption of neuronal communication in the central nervous system. In addition, RTT patients show peripheral ailments such as gastrointestinal ( GI), respiratory, and cardiac dysfunction. The etiology of intestinal dysfunction in RTT is not well-understood. Reports on the presence of Me CP2 in the peripheral nervous system are scant. As such we examined the levels of Me CP2 in human and murine GI tissue and assessed Me CP2 expression at various developmental stages. Methods Immunohistochemistry for Me CP2, HuC/D, juvenile beta tubulin, and GFAP was performed on human and murine intestine. Western blots of these same tissues were probed with Me CP2, vAChT, nNOS, and beta-actin antibodies. Key Results Me CP2 is expressed throughout the GI tract. Me CP2 is expressed specifically in the enteric nervous system of the GI tract. Me CP2 is expressed in the GI tract throughout development with appearance beginning at or before E11.5 in the murine intestine. Conclusions & Inferences The proof of Me CP2 expression in enteric neurons suggests that the GI dysmotility in Rett may arise from enteric network dysfunction secondary to Me CP2 mutation. [ABSTRACT FROM AUTHOR]

Abstract Background In systems biology, the task of reverse engineering gene pathways from data has been limited not just by the curse of dimensionality (the interaction space is huge) but also by systematic error in the data. The gene expression barcode reduces spurious association driven by batch effects and probe effects. The binary nature of the resulting expression calls lends itself perfectly to modern regularization approaches that thrive in high-dimensional settings. Results The Partitioned LASSO-Patternsearch algorithm is proposed to identify patterns of multiple dichotomous risk factors for outcomes of interest in genomic studies. A partitioning scheme is used to identify promising patterns by solving many LASSO-Patternsearch subproblems in parallel. All variables that survive this stage proceed to an aggregation stage where the most significant patterns are identified by solving a reduced LASSO-Patternsearch problem in just these variables. This approach was applied to genetic data sets with expression levels dichotomized by gene expression bar code. Most of the genes and second-order interactions thus selected and are known to be related to the outcomes. Conclusions We demonstrate with simulations and data analyses that the proposed method not only selects variables and patterns more accurately, but also provides smaller models with better prediction accuracy, in comparison to several alternative methodologies.

Purpose of Review: Multiple endoscopic ultrasound (EUS) guided therapeutic interventions have been developed for the management of benign and malignant pancreaticobiliary and gastrointestinal luminal pathology. Recent high-quality evidence is increasingly validating these interventions and positioning them within evidence-based therapeutic algorithms., Recent Findings: Here we review therapeutic EUS-guided interventions including pancreatic fluid collection drainage, gastroenterostomy, biliary drainage, pancreatic duct drainage and gallbladder drainage. The most up-to-date high-quality evidence supporting these interventions is presented including comparative data with other conventional treatment options. Newer emerging interventions such as tumor ablation are also reviewed. Current controversies and future avenues for research are discussed. The key role of EUS-guided interventions in managing pancreaticobiliary pathology in patients with a surgically altered anatomy is highlighted., Summary: Multiple EUS therapeutic interventions have evolved from experimental or rescue options to now well established first- and second-line interventions over other endoscopic, percutaneous and surgical alternatives with the support of high-quality data. Further research is needed to better optimize patient selection and guide long term postintervention follow-up., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Lidocaine is commonly applied to improve the tolerance of esophageal manometry (EM) and ambulatory pH monitoring (PM). We recently published data suggesting a benefit to this practice and we aimed to confirm these findings in a randomized trial., Methods: We conducted a double-blind, randomized trial of lidocaine nasal spray versus placebo (saline) before EM and PM. Patients referred to our center who met inclusion criteria were enrolled. Patients were asked to fill a questionnaire after their test and patient-reported adverse effects were compared., Key Results: Three hundred and four patients were enrolled in our trial. Lidocaine and placebo groups were demographically similar. The primary outcome, pain during catheter insertion, occurred in 60/148 (40.5%) patients in the lidocaine group versus in 72/152 (47.4%) patients in the placebo group (OR: 0.76 [95% CI: 0.48-1.20]; p = 0.23). Patients receiving lidocaine were less likely to report nausea during test recording (OR: 0.48 [95% CI: 0.24-0.91]; p = 0.02) and reported slightly lower intensity of pain during both catheter insertion and test recording (4.68 ± 2.06 versus 5.41 ± 2.24 on 10; p = 0.048 and 3.71 ± 2.00 versus 4.93 ± 2.55 on 10; p = 0.03, respectively). Furthermore, patients receiving lidocaine were less likely to report their test as globally uncomfortable and painful (57% vs. 75%; p = 0.003 and 14% vs. 21%; p = 0.02, respectively). No events of systemic lidocaine toxicity occurred during the study period., Conclusions: Routine use of lidocaine before esophageal function tests does not reduce pain during catheter insertion but may provide other modest benefits with limited toxicity., (© 2021 John Wiley & Sons Ltd.)

Background: High-resolution anorectal manometry (HRM) is widely used in the evaluation of anal incontinence and constipation, which become increasingly prevalent with age. However, the impact of age and comorbidities on physiological digestive parameters remains poorly understood. In this study, we aimed to evaluate the effect of age on anorectal function., Methods: We conducted a retrospective study on patients at our digestive motility clinic between January 2016 and May 2019. All patients with a normal HRM were included. Clinical data and HRM parameters were collected in a database. Multivariate regression analyses were performed to evaluate the effects of age, sex, medical comorbidities and obstetric history on anorectal HRM parameters., Key Results: One hundred and forty-four patients were included (mean age: 53 ± 16 years, 72% females). The main indications for anorectal HRM were incontinence (44%), constipation (37%) and anorectal pain (9%). Age was significantly associated with higher maximum tolerable volume (β = +0.48 mL year -1 , P = 0.04) and higher rectal compliance (β = +0.04 mL year -1 , P = 0.01). Independently from age and medical comorbidities, female demonstrated significantly lower mean endurance squeeze pressure (β = -44.4 mmHg, P < 0.001), maximal squeeze pressure (β = -62.3 mmHg; P < 0.001), volume at first urge (β = -16.7 mL, P = 0.02) and maximum tolerable volume (β = -16.1 mL, P = 0.046). Vaginal birth was associated with lower tolerable maximum pressure (β = -39.4 mmHg, P = 0.046)., Conclusion: Age and sex are independent factors which influence anorectal HRM parameters. These findings should be taken into consideration when interpreting anorectal HRM., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology.)

Background: Jackhammer esophagus (JE) is a newly described esophageal motility disorder. However, there are limited data on JE and this entity remains misunderstood., Methods: We performed a systematic review of clinical series on JE through MEDLINE, EMBASE, and Web of Science. Data from included studies were then extracted, and random-effects meta-analyses were performed., Results: Thirty-eight studies met inclusion criteria. The pooled prevalence of JE was 1.97% [95% CI: 1.39%-2.78%] among patients referred for high-resolution manometry (HRM). The mean age at diagnosis was 60.8 years [95% CI: 57.1-64.4] and 65% [95% CI: 58%-72%] of patients were female. JE was significantly more prevalent in postlung transplant patients and morbidly obese patients undergoing HRM (23.99% [95% CI: 9.00%-38.97%] and 5.18% [95% CI: 1.76%-14.3%] respectively). Dysphagia was the most common presentation of JE (64% [95% CI: 52%-77%]) followed by gastroesophageal reflux disease (46% [95% CI: 26%-67%]). The pooled mean distal contractile integral (DCI) of all standard HRM swallows was 9249 mm Hg·s·cm [95% CI: 7834-10 663], and the pooled mean integrated relaxation pressure (IRP) was 13.9 mm Hg [95% CI: 8.2-19.7]. Overall, 73.6% [95% CI: 64.0%-83.1%] of JE patients who underwent treatment achieved clinical symptom improvement (79% [95% CI: 74%-85%] for endoscopic treatment and 63% [95% CI: 47%-79%] for medical treatment). The pooled clinical success rate of peroral endoscopic myotomy (POEM) specifically was 82% [95% CI: 75%-90%]., Conclusions: JE is a new motility disorder most commonly presenting with dysphagia. High clinical suspicion is important because the diagnosis can only be made through HRM., (© 2020 John Wiley & Sons Ltd.)

Background: Conventionally, topical anesthesia is applied to improve the tolerance of esophageal manometry (EM) and ambulatory pH monitoring (apH) but there is presently no evidence supporting this practice. We aimed to compare the tolerance of EM and apH with vs without topical lidocaine anesthesia., Methods: A prospective study was conducted at our center between January 2017 and January 2019. All patients who underwent EM or apH and completed a systematically distributed standardized patient survey were included. From January 2017 to June 2018, all patients had a viscous lidocaine solution applied before EM and apH ("lidocaine" group). After June 2018, we ceased applying any topical anesthesia ("no lidocaine" group). Patient-reported adverse effects and satisfaction scores were compared between these two patient groups., Key Results: Two hundred forty-nine patient surveys were included. "Lidocaine" (n = 124) and "no lidocaine" (n = 125) groups were similar in age (56.9 ± 14.0 vs 56.0 ± 13.7; P = .77) and gender distributions (65.9% vs 63.3% female; P = .68). Patients in the "lidocaine" group were less likely to report pain during catheter insertion (33.6% vs 50.8%; P = .007, OR: 0.49 [95% CI 0.29-0.83]) and reported a lower overall pain score (2.82 ± 1.38 vs 3.20 ± 1.42 on 5; P = .04). There was a tendency toward increased global satisfaction with lidocaine application but that was not statistically significant (4.36 ± 1.05 vs 4.11 ± 1.13; P = .08). In subgroup analyses, female patients, younger patients, and patients who underwent EM were more likely to benefit from lidocaine application., Conclusions and Inferences: Application of topical lidocaine before esophageal motility tests reduces pain during catheter insertion and overall pain., (© 2019 John Wiley & Sons Ltd.)

Objective: To present a practical and evidence-based approach for primary care physicians to the diagnosis and initial management of common pediatric hand injuries, and to identify injuries requiring prompt referral., Sources of Information: Clinical evidence and expert recommendations were identified by using MEDLINE and EMBASE for each topic presented., Main Message: Pediatric hand injuries are a common reason for physician consultation. The most common and potentially problematic pediatric hand injuries include fingertip injuries, phalangeal fractures, tendon injuries, and hand burns. Management is limited by difficulties in proper assessment of the hand and the paucity of evidence to guide treatment. Nevertheless, outcomes in children are typically excellent., Conclusion: Appropriate assessment, initial management, and, if necessary, timely referral of pediatric patients with hand injuries are paramount given the importance of the hand in function and child development. While some principles from managing adult hand injuries might apply, children often require special considerations., (Copyright© the College of Family Physicians of Canada.)

When sample sizes are small, the ability to identify weak (but scientifically interesting) associations between a set of predictors and a response may be enhanced by pooling existing datasets. However, variations in acquisition methods and the distribution of participants or observations between datasets, especially due to the distributional shifts in some predictors, may obfuscate real effects when datasets are combined. We present a rigorous statistical treatment of this problem and identify conditions where we can correct the distributional shift. We also provide an algorithm for the situation where the correction is identifiable. We analyze various properties of the framework for testing model fit, constructing confidence intervals, and evaluating consistency characteristics. Our technical development is motivated by Alzheimer's disease (AD) studies, and we present empirical results showing that our framework enables harmonizing of protein biomarkers, even when the assays across sites differ. Our contribution may, in part, mitigate a bottleneck that researchers face in clinical research when pooling smaller sized datasets and may offer benefits when the subjects of interest are difficult to recruit or when resources prohibit large single-site studies., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Objectives: Despite the widespread use of bracing to correct Pectus carinatum (PC) there is no consensus in the number of hours per day patients are instructed to wear the brace. In our practice, we use a less rigorous protocol of 8-12h/day. We sought to evaluate our results and those in the literature to determine whether more intensive usage is necessary., Study Design: We reviewed the outcomes of patients with PC treated at our institution between 2012 and 2015. We searched MEDLINE, EMBASE and Web of Science for studies describing the use of bracing to correct PC., Results: Seventy-five patients presented with PC at our institution. Among those who were offered bracing and had adequate follow-up (n=32), the success rate (full correction or improvement) was 90.6%. The compliance rate was 93.8%. Fifteen studies met our inclusion criteria. Our pooled data combining our results with those of other published data showed that less intensive brace usage (<12h/day), when compared to more intensive usage (≥12h/day), is associated with higher patient compliance (89.6% vs. 81.1%) with a similar time to correction (7.3 vs 7.1months) and success rate (85.3% vs. 83.5%)., Conclusions: Implementing a less intensive bracing protocol for PC is successful, efficient and improves compliance., Type of Study: Clinical Research., Levels of Evidence: Oxford Centre for Evidence-Based Medicine Level-of-Evidence rating: Level IV., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Many studies in biomedical and health sciences involve small sample sizes due to logistic or financial constraints. Often, identifying weak (but scientifically interesting) associations between a set of predictors and a response necessitates pooling datasets from multiple diverse labs or groups. While there is a rich literature in statistical machine learning to address distributional shifts and inference in multi-site datasets, it is less clear when such pooling is guaranteed to help (and when it does not) - independent of the inference algorithms we use. In this paper, we present a hypothesis test to answer this question, both for classical and high dimensional linear regression. We precisely identify regimes where pooling datasets across multiple sites is sensible, and how such policy decisions can be made via simple checks executable on each site before any data transfer ever happens. With a focus on Alzheimer's disease studies, we present empirical results showing that in regimes suggested by our analysis, pooling a local dataset with data from an international study improves power.

Background: The enteric nervous system controls gastrointestinal functions such as secretion and smooth muscle contraction/relaxation. Neuronal enteric dysfunction is a feature of many direct gastrointestinal disorders and can be secondary to central nervous system disorders. Research in this field has been limited and there are few published methods on dissociated enteric cultures., New Method: Here we describe a quick and efficient method for culturing myenteric neurons which optimizes neuronal yield. A simplified technique is presented to easily dissect the myenteric plexus and longitudinal muscle from the outside of the intestinal wall reducing non-neuronal cell and bacterial contamination from the final culture. These segments are subjected to enzymatic dissociation and the resulting neurons are placed into an optimal growth media for long term culture., Results: This protocol produces a high yield of neuronal cells. Multiple neuronal subtypes reflecting the in vivo population are observed. Cultures are optimal at 3 weeks in vitro but can be sustained for at least 5 weeks., Comparison With Existing Methods: Unlike other protocols our method does not require a time consuming challenging dissection, long enzymatic treatment times or the use of specialized equipment. Resulting cultures are of higher quality and can be sustained longer permitting proper neuronal recovery. In addition cell attachment to culture substrates have been optimized., Conclusion: We provide a novel method for researchers to dissociate and grow high quality enteric neuronal cultures. Our method can be used for studies on gastrointestinal diseases caused by enteric neuronal dysfunction and to explore possible pharmacological interventions in vitro., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Consider samples from two different data sources [Formula: see text] and [Formula: see text]. We only observe their transformed versions [Formula: see text] and [Formula: see text], for some known function class h (·) and g (·). Our goal is to perform a statistical test checking if P source = P target while removing the distortions induced by the transformations. This problem is closely related to domain adaptation, and in our case, is motivated by the need to combine clinical and imaging based biomarkers from multiple sites and/or batches - a fairly common impediment in conducting analyses with much larger sample sizes. We address this problem using ideas from hypothesis testing on the transformed measurements, wherein the distortions need to be estimated in tandem with the testing. We derive a simple algorithm and study its convergence and consistency properties in detail, and provide lower-bound strategies based on recent work in continuous optimization. On a dataset of individuals at risk for Alzheimer's disease, our framework is competitive with alternative procedures that are twice as expensive and in some cases operationally infeasible to implement.

The conditional lifetime expectancy function (LEF) is the expected lifetime of a subject given survival past a certain time point and the values of a set of explanatory variables. This function is attractive to researchers because it summarizes the entire residual life distribution and has an easy interpretation compared with the popularly used hazard function. In this paper, we propose a general framework of backward multiple imputation for estimating the conditional LEF and the variance of the estimator in the right-censoring setting. Simulation studies are conducted to investigate the empirical properties of the proposed estimator and the corresponding variance estimator. We demonstrate the method on the Beaver Dam Eye Study data, where the expected human lifetime is modeled with smoothing-spline ANOVA given the covariates information including sex, lifestyle factors, and disease variables.

Variable selection is of increasing importance to address the difficulties of high dimensionality in many scientific areas. In this paper, we demonstrate a property for distance covariance, which is incorporated in a novel feature screening procedure together with the use of distance correlation. The approach makes no distributional assumptions for the variables and does not require the specification of a regression model and hence is especially attractive in variable selection given an enormous number of candidate attributes without much information about the true model with the response. The method is applied to two genetic risk problems, where issues including uncertainty of variable selection via cross validation, subgroup of hard-to-classify cases, and the application of a reject option are discussed., (Copyright © 2015 John Wiley & Sons, Ltd.)