Benefits of Prokinetics, Gastroparesis Diet, or Neuromodulators Alone or in Combination for Symptoms of Gastroparesis.

BACKGROUND & AIMS: Prokinetics have limited effectiveness for treating symptoms of gastroparesis. Thus, alternative or adjunct therapies, such as gastroparesis diets or neuromodulators, are often prescribed. Their therapeutic benefits alone or in combination remain unclear. METHODS: One hundred and twenty-nine patients with symptoms of gastroparesis underwent wireless motility capsule gastric emptying time and gastric emptying scintigraphy. Based on test results, changes in therapy were recommended. Changes in Gastroparesis Cardinal Symptom Index (GCSI) and individual symptom scores over 6 months were related to recommendations for prokinetics, gastroparesis diet, or neuromodulators given as solo new therapies or in dual combinations. Multivariate analyses were performed to adjust for gastric emptying and other variables. RESULTS: In the whole group regardless of therapy, GCSI scores decreased by 0.53 points (interquartile range, -1.25 to 0.05; P < .0001) over 6 months. GCSI did not decrease for prokinetics as solo new therapy (P = .95). Conversely, neuromodulators as solo therapy decreased GCSI scores (P = .04) and all individual symptoms except nausea/vomiting (P = .86). Prokinetics combined with gastroparesis diets or neuromodulators improved GCSI scores (P ≤ .04) and most individual symptoms. Adjusting for gastric emptying time on multivariate analyses showed greater GCSI decreases for nondelayed emptying for neuromodulators as solo new therapy (P = .01). Gastric emptying scintigraphy, gender, diabetes, and functional dyspepsia did not influence responses to any treatment. CONCLUSIONS: Initiating prokinetics as solo new therapy had little benefit for patients with symptoms of gastroparesis. Neuromodulators as the only new therapy decreased symptoms other than nausea and vomiting, especially with nondelayed gastric emptying. Adding gastroparesis diets or neuromodulators to prokinetics offered relief, suggesting that combination therapies may be more useful in managing these patients. (ClinicalTrials.gov NCT02022826.).

Astrocytic stress response is induced by exposure to astrocyte-binding antibodies expressed by plasmablasts from pediatric patients with acute transverse myelitis.

BACKGROUND: Pediatric acute transverse myelitis (ATM) accounts for 20-30% of children presenting with a first acquired demyelinating syndrome (ADS) and may be the first clinical presentation of a relapsing ADS such as multiple sclerosis (MS). B cells have been strongly implicated in the pathogenesis of adult MS. However, little is known about B cells in pediatric MS, and even less so in pediatric ATM. Our lab previously showed that plasmablasts (PB), the earliest B cell subtype producing antibody, are expanded in adult ATM, and that these PBs produce self-reactive antibodies that target neurons. The goal of this study was to examine PB frequency and phenotype, immunoglobulin selection, and B cell receptor reactivity in pediatric patients presenting with ATM to gain insight to B cell involvement in disease. METHODS: We compared the PB frequency and phenotype of 5 pediatric ATM patients and 10 pediatric healthy controls (HC) and compared them to previously reported adult ATM patients using cytometric data. We purified bulk IgG from the plasma samples and cloned 20 recombinant human antibodies (rhAbs) from individual PBs isolated from the blood. Plasma-derived IgG and rhAb autoreactivity was measured by mean fluorescence intensity (MFI) in neurons and astrocytes of murine brain or spinal cord and primary human astrocytes. We determined the potential impact of these rhAbs on astrocyte health by measuring stress and apoptotic response. RESULTS: We found that pediatric ATM patients had a reduced frequency of peripheral blood PB. Serum IgG autoreactivity to neurons in EAE spinal cord was similar in the pediatric ATM patients and HC. However, serum IgG autoreactivity to astrocytes in EAE spinal cord was reduced in pediatric ATM patients compared to pediatric HC. Astrocyte-binding strength of rhAbs cloned from PBs was dependent on somatic hypermutation accumulation in the pediatric ATM cohort, but not HC. A similar observation in predilection for astrocyte binding over neuron binding of individual antibodies cloned from PBs was made in EAE brain tissue. Finally, exposure of human primary astrocytes to these astrocyte-binding antibodies increased astrocytic stress but did not lead to apoptosis. CONCLUSIONS: Discordance in humoral immune responses to astrocytes may distinguish pediatric ATM from HC.

Factors associated with pathologic myopia onset and progression: A systematic review and meta-analysis.

PURPOSE: To synthesise evidence across studies on factors associated with pathologic myopia (PM) onset and progression based on the META-analysis for Pathologic Myopia (META-PM) classification framework. METHODS: Findings from six longitudinal studies (5-18 years) were narratively synthesised and meta-analysed, using odds ratio (OR) as the common measure of association. All studies adjusted for baseline myopia, age and sex at a minimum. The quality of evidence was rated using the Grades of Recommendation, Assessment, Development and Evaluation framework. RESULTS: Five out of six studies were conducted in Asia. There was inconclusive evidence of an independent effect (or lack thereof) of ethnicity and sex on PM onset/progression. The odds of PM onset increased with greater axial length (pooled OR: 2.03; 95% CI: 1.71-2.40; p < 0.001), older age (pooled OR: 1.07; 1.05-1.09; p < 0.001) and more negative spherical equivalent refraction, SER (OR: 0.77; 0.68-0.87; p < 0.001), all of which were supported by an acceptable level of evidence. Fundus tessellation was found to independently increase the odds of PM onset in a population-based study (OR: 3.02; 2.58-3.53; p < 0.001), although this was only supported by weak evidence. There was acceptable evidence that greater axial length (pooled OR: 1.23; 1.09-1.39; p < 0.001), more negative SER (pooled OR: 0.87; 0.83-0.92; p < 0.001) and higher education level (pooled OR: 3.17; 1.36-7.35; p < 0.01) increased the odds of PM progression. Other baseline factors found to be associated with PM progression but currently supported by weak evidence included age (pooled OR: 1.01), severity of myopic maculopathy (OR: 3.61), intraocular pressure (OR: 1.62) and hypertension (OR: 0.21). CONCLUSIONS: Most PM risk/prognostic factors are not supported by an adequate evidence base at present (an indication that PM remains understudied). Current factors for which an acceptable level of evidence exists (limited in number) are unmodifiable in adults and lack personalised information. More longitudinal studies focusing on uncovering modifiable factors and imaging biomarkers are warranted.

"Filling in the gap": A qualitative case study about identity construction of siblings of youth with a neurodisability.

INTRODUCTION: In families of children with a neurodisability, siblings have unique experiences that can shape their identity. There is limited information about the developmental process of how siblings form their identity. This study aims to understand the identity construction of young siblings who have a sibling with a neurodisability. METHODS: As part of a patient-oriented research program, we engaged with our Sibling Youth Advisory Council in Canada. In this qualitative case study, data from semi-structured interviews augmented by photo elicitation and graphic elicitation of relational maps were analyzed using reflexive thematic analysis. RESULTS: Nineteen sibling participants (median age = 19 years, range = 14-33 years) reflected on the uniqueness of their role during childhood. During adolescence and emerging adulthood, they became closer with their sibling with a neurodisability and increased communication with their parents about how to care for their sibling with a neurodisability. These experiences influenced how they explored and began to reconcile their sibling identity with their professional and social identities. CONCLUSION: Siblings of youth with a neurodisability discover their unique identity and require support in this developmental process. Future interventions could evaluate how supports for siblings can have an impact on the positive development of their identity.

Implementation frameworks, strategies and outcomes in optimizing central venous access device practice in paediatrics: A scoping review.

Paediatric patients with complex or acute conditions may require a central venous access device, however, almost one-third of these devices have associated complications (e.g. infections). Implementation of evidence-based practices regarding central venous access devices can reduce and potentially prevent complications. AIMS: This scoping review aimed to explore recent interventional research in CVAD management through an implementation lens. DESIGN: This scoping review used the Arksey and O'Malley framework. Studies were included if they were written in English, published in 2012 to July 2023, involved children and were relevant to the study aims. Risk of bias was appraised by the Mixed Methods Appraisal Tool. DATA SOURCES: Searches were undertaken in EMBASE, CINAHL (Ebsco), PubMed, Web of Science and Cochrane Library (CENTRAL). RESULTS: Of the 1769 studies identified in a systematic search, 46 studies were included. Studies mostly focused on health professionals and central venous access device maintenance and had quantitative pre-post study designs. Adherence to implementation frameworks was lacking, with many studies employing quality improvement approaches. Implementation strategies were typically multipronged, using health-professional education, bundles and working groups. Bundle compliance and reductions in central line-associated bloodstream infections were the most featured outcomes, with most studies primarily focusing on effectiveness outcomes. CONCLUSION: Translation of evidence-based practices to the clinical setting is difficult and current adoption of implementation frameworks (apart from 'quality improvement') is limited. Implementation strategies are diverse and dependent on the local context, and study outcomes typically focus on the effectiveness of the physical intervention, rather than measuring the implementation effort itself. IMPLICATIONS FOR PATIENTS: Future intervention research requires a more uniform and deliberate application of implementation frameworks and strategies. IMPACT: Greater exploration of relationships between frameworks and strategies and implementation and service outcomes is required to increase understanding of their role in maximizing resources to improve health care. Adhered to best reporting guidelines as per PRISMA-ScR (Tricco et al., 2018). PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Being a sibling of a youth with a neurodisability: A qualitative study about the roles and responsibilities during the transition to adulthood.

BACKGROUND: During the transition to adulthood, a common challenge that youth with a neurodisability may experience is learning how to navigate services in the adult care system. During this transition youth may rely on their families, including siblings, for support. However, delineation of sibling roles and responsibilities during this transition period are unclear. This study aims to identify the roles and responsibilities that siblings perceive to have with their sibling with a neurodisability during the transition to adulthood, and describe the decision-making process of how siblings chose these roles. METHODS: In this descriptive qualitative case study, siblings were eligible to participate if they were between 14 to 40 years old, had a sibling between 14 to 21 years with a childhood-onset neurodisability and spoke English. Semi-structured interviews augmented by techniques of photo elicitation and relational maps were conducted. Reflexive thematic analysis was applied to identify sibling roles, as well as the emotional and decision-making process associated with these roles. Our team partnered with siblings with lived experience in all study phases. RESULTS: Nineteen participants (median age = 19 years, range = 14 to 33 years) from 16 unique families were interviewed. Six unique roles were described: friend, role model/mentor, protector, advocate, supporter, or caregiver. The emotions that siblings experienced with each role, also known as emotional responsibility, were categorized into levels of low, medium or high. Siblings also described a four-phase decision-making process for their roles: (1) acquiring knowledge; (2) preparing plans; (3) making adjustments; and (4) seeking support. Intrapersonal characteristics, including personal identity, values and experiences, influenced roles assumed by siblings. CONCLUSIONS: Siblings identified needing support as they process their decisions and emotional responsibility in their roles when their sibling with a neurodisability is transitioning to adulthood. Resources should be developed or further enhanced to support siblings.

Environmental Pollutants Are Associated With Irritable Bowel Syndrome in a Commercially Insured Cohort of California Residents.

BACKGROUND AND AIMS: Prior studies have linked environmental pollutants with gastrointestinal (GI) diseases. Here, we quantify the relationships between 7 pollutants and the zip code-level incidence of irritable bowel syndrome (IBS), functional dyspepsia, inflammatory bowel diseases (IBDs), and eosinophilic esophagitis (EoE) in California. METHODS: Claims in Optum's Clinformatics Data Mart were linked with environmental exposures in California, derived from CalEnviroScreen 3.0. We identified adult patients with new diagnoses of each GI disease, and estimated claims-derived, zip code-level disease incidence rates. Two study periods were considered: 2009-2014 (International Classification of Diseases-Ninth Revision era) and 2016-2019 (International Classification of Diseases-Tenth Revision [ICD-10] era). Multivariable negative binomial regression models were used to test associations between 7 pollutants (ozone, particulate matter <2.5 µm [PM2.5], diesel emissions, drinking water contaminants, pesticides, toxic releases from industrial facilities, traffic density) and zip code-level incidence of the GI diseases along with a negative control outcome, adjusting for numerous potential confounders. RESULTS: Zip code-level IBS incidence was associated with PM2.5 (P < .001 in both eras) and airborne toxic releases from facilities (P < .001 in both eras). An increase of 1 µg/m3 in PM2.5 or 1% in toxic releases translates to an increase in the IBS incidence rate of about 0.02 cases per 100 person-years. Traffic density and drinking water contaminant exposures were also associated with increasing IBS incidence, but these associations were not significant in both eras. Similarly, exposure to PM2.5, drinking water contaminants and airborne toxic releases from facilities were associated with functional dyspepsia incidence, though not in both eras. No significant associations were noted between pollutants and IBD or EoE incidence. CONCLUSION: Exposure to PM2.5 and airborne toxic releases from facilities are associated with higher IBS incidence among a cohort of commercially insured Californians. Environmental pollutant exposure was not associated with the incidence of IBDs and EoE in this cohort.

Mertk-expressing microglia influence oligodendrogenesis and myelin modelling in the CNS.

BACKGROUND: Microglia, an immune cell found exclusively within the CNS, initially develop from haematopoietic stem cell precursors in the yolk sac and colonise all regions of the CNS early in development. Microglia have been demonstrated to play an important role in the development of oligodendrocytes, the myelin producing cells in the CNS, as well as in myelination. Mertk is a receptor expressed on microglia that mediates immunoregulatory functions, including myelin efferocytosis. FINDINGS: Here we demonstrate an unexpected role for Mertk-expressing microglia in both oligodendrogenesis and myelination. The selective depletion of Mertk from microglia resulted in reduced oligodendrocyte production in early development and the generation of pathological myelin. During demyelination, mice deficient in microglial Mertk had thinner myelin and showed signs of impaired OPC differentiation. We established that Mertk signalling inhibition impairs oligodendrocyte repopulation in Xenopus tadpoles following demyelination. CONCLUSION: These data highlight the importance of microglia in myelination and are the first to identify Mertk as a regulator of oligodendrogenesis and myelin ultrastructure.

The Effect of Vitamin B12 Supplementation on Leukocyte Telomere Length in Mildly Stunted Nepalese Children: A Secondary Outcome of a Randomized Controlled Trial.

BACKGROUND: Vitamin B12 is essential for deoxyribonucleic acid synthesis and genome stability. A deficiency of vitamin B12 is associated with telomere shortening, genomic aging, and increased risk of chronic disease and mortality. OBJECTIVES: The study aims to determine the effect of vitamin B12 supplementation on leukocyte telomere length (LTL) in infants at risk of vitamin B12 deficiency. METHODS: The study was a predefined secondary analysis of a randomized controlled trial enrolling 600 Nepalese infants aged 6 -11 mo, who were supplemented with 2 µg (2-3 recommended daily allowances) vitamin B12 or placebo daily for 1 y. At the end of the study, LTL was measured in 497 participants. Mean LTL was compared between the treatment arms in the full sample and predefined subgroups based on markers of vitamin B12 status, hemoglobin, sex, and growth indices. RESULTS: LTL at end-study did not differ between the vitamin B12 and placebo arm with a standardized mean difference (95% confidence interval) of 0.04 (-0.14, 0.21). There was no effect of vitamin B12 on LTL in any of the subgroups. CONCLUSIONS: Providing daily vitamin B12 for 1 y during infancy in a population at risk of vitamin B12 deficiency does not affect LTL. This trial was registered at clinicaltrials.gov as NCT02272842.

The Gut-brain Connection and Episodic Migraine: an Update.

PURPOSE OF REVIEW: Historical evidence suggests a shared underlying etiology for migraine and gastrointestinal (GI) disorders that involves the gut-brain axis. Here we provide narrative review of recent literature on the gut-brain connection and migraine to emphasize the importance of tailoring treatment plans for patients with episodic migraine who experience GI comorbidities and symptoms. RECENT FINDINGS: Recent population-based studies report the prevalence of migraine and GI disorders as comorbidities as well as overlapping symptomology. American Headache Society (AHS) guidelines have integrated GI symptoms as part of migraine diagnostic criteria and recommend nonoral therapies for patients with GI symptoms or conditions. Nasal delivery is a recommended nonoral alternative; however, it is important to understand potential adverse events that may cause or worsen GI symptoms in some patients due to the site of drug deposition within the nasal cavity with some nasal therapies. Lastly, clinical perspectives emphasize the importance of identifying GI symptoms and comorbidities in patients with episodic migraine to best individualize migraine management. Support for an association between the gut-brain axis and migraine continues to prevail in recent literature; however, the relationship remains complex and not well elucidated. The presence of GI comorbidities and symptoms must be carefully considered when making treatment decisions for patients with episodic migraine.

Prenatal Substance Exposure and Neonatal Abstinence Syndrome: State Estimates from the 2016-2020 Transformed Medicaid Statistical Information System.

INTRODUCTION: Estimating Neonatal Abstinence Syndrome (NAS) and prenatal substance exposure rates in Medicaid can help target program efforts to improve access to services. METHODS: The data for this study was extracted from the 2016-2020 Transformed Medicaid Statistical Information System (T-MSIS) Analytic Files (TAF) Research Identifiable Files (RIF) and included infants born between January 1, 2016 and December 31, 2020 with a either a NAS diagnosis or prenatal substance exposure. RESULTS: Between 2016 and 2020, the estimated national rate of NAS experienced a 18% decline, while the estimated national rate of prenatal substance exposure experienced a 3.6% increase. At the state level in 2020, the NAS rate ranged from 3.2 per 1000 births (Hawaii) to 68.0 per 1000 births (West Virginia). Between 2016 and 2020, 28 states experienced a decline in NAS births and 20 states had an increase in NAS rates. In 2020, the lowest prenatal substance exposure rate was observed in New Jersey (9.9 per 1000 births) and the highest in West Virginia (88.1 per 1000 births). Between 2016 and 2020, 38 states experienced an increase in the rate of prenatal substance exposure and 10 states experienced a decline. DISCUSSION: Estimated rate of NAS has declined nationally, but rate of prenatal substance exposure has increased, with considerable state-level variation. The reported increase in prenatal substance exposure in the majority of US states (38) suggest that substances other than opioids are influencing this trend. Medicaid-led initiatives can be used to identify women with substance use and connect them to services.

What is already known about the topic? Neonatal Abstinence Syndrome (NAS) and prenatal substance exposure are significant risk factors for poor neurodevelopmental and mental health outcomes in early childhood. NAS birth rates have been increasing in the US since 2000 and the majority of NAS births are covered by Medicaid.What this article adds? This article estimates national and state-level prenatal substance exposure and NAS rates among Medicaid-covered infants born between 2016-2020 using data from the Transformed Medicaid Statistical Information System. This is the first study using post-2017 data to estimate national NAS rates. The findings can inform future federal and state policy efforts to improve access to screening, diagnosis and treatment among pregnant women with substance use disorder and infants with NAS.

Further optimisation of a macromolecular ocular irritation test (OptiSafeTM).

PURPOSE: OptiSafeTM (OS) is a shelf stable, nonanimal test for ocular irritation. A recent database search found that half of the OS false positive (FP) materials were associated with reactive oxygen chemistries but were not eye irritants in vivo (based on historical rabbit studies by other groups). We hypothesized that naturally occurring tear antioxidants protect the eye from reactive chemistries in vivo and that specific tear chemistries might help explain why some materials are FP for nonanimal tests but are reported as nonirritants in the live animal. To test this hypothesis, a prior study evaluated tear antioxidants and found that the tear antioxidant ascorbic acid, added at human physiological tear levels to the OS test, specifically reduced the measured values for these FPs but did not reduce the true-positive rate. Based on these findings, the OS test method was further optimized. The purpose of the current study was to comprehensively evaluate the performance of the further optimized test method for detection of ocular irritants. MATERIALS AND METHODS: The OS test measures chemically induced damage to macromolecules and relates these measured values to ocular irritancy. To improve the performance of OS, we made updates to the material to be tested physiochemical handling procedures, prediction model, and test method to include tear-level concentrations of ascorbic acid. We then retested the 78 chemicals from the prior OS-coded validation study in triplicate and compared the accuracy of the 'nonirritant versus irritant' prediction for the further optimized method with the prior results. RESULTS: We report that for the detection of 'nonirritant' versus 'irritant' (GHS NC versus categories 2B/A and 1) test substances, the further optimized OS test with ascorbic acid compared with the original version has a FP rate that is reduced from 40.0 to 22.2%, the false-negative (FN) rate remains at 0.0%, and the accuracy improved from 80.3% to 89.2%. CONCLUSION: A comparison to OECD-adopted tests demonstrates that the further optimized OS test, like the original method, has a higher accuracy and lower FN rate for the detection of 'nonirritants' versus 'irritants' (GHS Category NC versus 2B/A and 1) than the other eye irritation tests (BCOP, EpiOcularTM Eye Irritation Test, ICE, Ocular Irritection®, and STE).

Baseline Predictors of Longitudinal Changes in Symptom Severity and Quality of Life in Patients With Suspected Gastroparesis.

BACKGROUND & AIMS: Whether gastric emptying tests predict longitudinal outcomes in patients with symptoms of gastroparesis is unclear. We aimed to determine whether baseline gastric emptying tests and gut motility parameters could impact longitudinal symptom(s) and quality of life (QOL) in a prospective, observational cohort study of patients with symptoms of gastroparesis. METHODS: One hundred fifty patients with gastroparesis symptoms underwent simultaneous scintigraphy (GES) and wireless motility capsule (WMC) measurement of gastric emptying and other motility parameters. Patient Assessment of Upper Gastrointestinal Symptoms and Quality of Life were administered at baseline, and 3 and 6 months after testing. Multivariable generalized linear marginal models were fit to determine which baseline parameters predict longitudinal changes in symptoms and QOL. RESULTS: Overall upper GI symptoms and QOL scores were moderate in severity at baseline and significantly improved over 6 months. Clinical variables, including female gender, harder stools by Bristol stool form score, and presence of functional dyspepsia (FD) by Rome III criteria, were predictive of more severe upper GI symptoms. Even after controlling for these clinical factors, delayed gastric emptying by GES or WMC was associated with worse symptom severity and QOL scores. Low gastric and elevated small bowel contractile parameters by WMC were also independently associated with more severe upper GI symptoms and worse QOL scores. CONCLUSIONS: Baseline features, including demographic and clinical variables, delayed gastric emptying and abnormal gastrointestinal contractility, were independent predictors of more severe longitudinal symptoms and worse quality of life outcomes. These factors may help to risk stratify patients and guide treatment decisions. ClinicalTrials.gov no: NCT02022826.

Serotonin Deficiency Is Associated With Delayed Gastric Emptying.

BACKGROUND & AIMS: Gastrointestinal (GI) motility is regulated by serotonin (5-hydroxytryptamine [5-HT]), which is primarily produced by enterochromaffin (EC) cells in the GI tract. However, the precise roles of EC cell-derived 5-HT in regulating gastric motility remain a major point of conjecture. Using a novel transgenic mouse line, we investigated the distribution of EC cells and the pathophysiologic roles of 5-HT deficiency in gastric motility in mice and humans. METHODS: We developed an inducible, EC cell-specific Tph1CreERT2/+ mouse, which was used to generate a reporter mouse line, Tph1-tdTom, and an EC cell-depleted line, Tph1-DTA. We examined EC cell distribution, morphology, and subpopulations in reporter mice. GI motility was measured in vivo and ex vivo in EC cell-depleted mice. Additionally, we evaluated 5-HT content in biopsy and plasma specimens from patients with idiopathic gastroparesis (IG). RESULTS: Tph1-tdTom mice showed EC cells that were heterogeneously distributed throughout the GI tract with the greatest abundance in the antrum and proximal colon. Two subpopulations of EC cells were identified in the gut: self-renewal cells located at the base of the crypt and mature cells observed in the villi. Tph1-DTA mice displayed delayed gastric emptying, total GI transit, and colonic transit. These gut motility alterations were reversed by exogenous provision of 5-HT. Patients with IG had a significant reduction of antral EC cell numbers and 5-HT content, which negatively correlated with gastric emptying rate. CONCLUSIONS: The Tph1CreERT2/+ mouse provides a powerful tool to study the functional roles of EC cells in the GI tract. Our findings suggest a new pathophysiologic mechanism of 5-HT deficiency in IG.

miR-10b-5p Rescues Diabetes and Gastrointestinal Dysmotility.

BACKGROUND & AIMS: Interstitial cells of Cajal (ICCs) and pancreatic ß cells require receptor tyrosine kinase (KIT) to develop and function properly. Degeneration of ICCs is linked to diabetic gastroparesis. The mechanisms linking diabetes and gastroparesis are unclear, but may involve microRNA (miRNA)-mediated post-transcriptional gene silencing in KIT+ cells. METHODS: We performed miRNA-sequencing analysis from isolated ICCs in diabetic mice and plasma from patients with idiopathic and diabetic gastroparesis. miR-10b-5p target genes were identified and validated in mouse and human cell lines. For loss-of-function studies, we used KIT+ cell-restricted mir-10b knockout mice and KIT+ cell depletion mice. For gain-of-function studies, a synthetic miR-10b-5p mimic was injected in multiple diabetic mouse models. We compared the efficacy of miR-10b-5p mimic treatment vs antidiabetic and prokinetic medicines. RESULTS: miR-10b-5p is highly expressed in ICCs from healthy mice, but drastically depleted in ICCs from diabetic mice. A conditional knockout of mir-10b in KIT+ cells or depletion of KIT+ cells in mice leads to degeneration of ß cells and ICCs, resulting in diabetes and gastroparesis. miR-10b-5p targets the transcription factor Krüppel-like factor 11 (KLF11), which negatively regulates KIT expression. The miR-10b-5p mimic or Klf11 small interfering RNAs injected into mir-10b knockout mice, diet-induced diabetic mice, and TALLYHO polygenic diabetic mice rescue the diabetes and gastroparesis phenotype for an extended period of time. Furthermore, the miR-10b-5p mimic is more effective in improving glucose homoeostasis and gastrointestinal motility compared with common antidiabetic and prokinetic medications. CONCLUSIONS: miR-10b-5p is a key regulator in diabetes and gastrointestinal dysmotility via the KLF11-KIT pathway. Restoration of miR-10b-5p may provide therapeutic benefits for these disorders.

ACG Clinical Guideline: Gastroparesis.

Gastroparesis is characterized by symptoms suggesting retention of food in the stomach with objective evidence of delayed gastric emptying in the absence of mechanical obstruction in the gastric outflow. This condition is increasingly encountered in clinical practice. These guidelines summarize perspectives on the risk factors, diagnosis, and management of gastroparesis in adults (including dietary, pharmacological, device, and interventions directed at the pylorus), and they represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation process. When the evidence was not appropriate for Grading of Recommendations, Assessment, Development, and Evaluation, we used expert consensus to develop key concept statements. These guidelines should be considered as preferred but are not the only approaches to these conditions.

Restricted diffusion of the callosal splenium is highly specific for seizures in neonates.

BACKGROUND: To determine whether restricted diffusion of the callosal splenium is specific for seizure activity in neonates. METHODS: We performed a retrospective chart review of 123 neonates who had a diagnosis of hypoxic ischemic encephalopathy (HIE) who underwent therapeutic cooling and had magnetic resonance imaging (MRI) within the first 10 days of life. The regions examined for injury include the callosal splenium, cortex, deep gray matter, and subcortical white matter. Neurodevelopmental outcomes were secondarily assessed using the Bayley Scales of Infant Development at 12 to 18 months of age and > 18 months of age. APGAR scores and pH, two important markers of hypoxia/ischemia and encephalopathy, were also analyzed in relation to these outcomes. RESULTS: Approximately 41% of the neonates had at least one abnormal region on brain MRI, and 21% had abnormal signal in the splenium. Clinical and/or electrographic seizures were documented in 32%. Changes in the splenium had a sensitivity of 54%, specificity of 94%, and positive predictive value of 81% for seizure presence. The presence of seizures and splenium lesion was associated poor developmental outcomes at 12 to 18 months of age. APGAR scores at 10 minutes, but not lowest pH was associated with splenial changes. CONCLUSIONS: Restricted diffusion of the callosal splenium is specific for recent seizures in neonates with HIE. Seizures and splenial lesion represent risk factors for poor neurodevelopmental outcomes. Child neurologists and neonatologists should consider splenial signal abnormality in their assessment of neonates at risk for seizures and counsel families about likely outcomes accordingly.

Anorectal manometry for the diagnosis of pelvic floor disorders in patients with hypermobility spectrum disorders and hypermobile Ehlers-Danlos syndrome.

INTRODUCTION: Functional gastrointestinal disorders (FGID) including impaired rectal evacuation are common in patients with Hypermobility Spectrum Disorder (HSD) or Hypermobile Ehlers-Danlos Syndrome (hEDS). The effect of connective tissue pathologies on pelvic floor function in HSD/hEDS remains unclear. We aimed to compare clinical characteristics and anorectal pressure profile in patients with HSD/hEDS to those of age and sex matched controls. METHODS: We conducted a retrospective review of all FGID patients who underwent high resolution anorectal manometry (HR-ARM) and balloon expulsion test (BET) for evaluation of impaired rectal evacuation. Patients with HSD/hEDS were age and sex matched to a randomly selected cohort of control patients without HSD/hEDS. An abnormal BET was defined as the inability to expel a rectal balloon within 2 minutes. Wilcoxon rank sum test and Fisher's exact test were used to make comparisons and logistic regression model for predictive factors for abnormal evacuation. RESULTS: A total of 144 patients (72 with HSD/hEDS and 72 controls) were analyzed. HSD/hEDS patients were more likely to be Caucasian (p < 0.001) and nulliparous. Concurrent psychiatric disorders; depression, and anxiety (p < 0.05), and somatic syndromes; fibromyalgia, migraine and sleep disorders (p < 0.001) were more common in these patients. Rate of abnormal BET were comparable among the groups. HDS/hEDS patients had significantly less anal relaxation and higher residual anal pressures during simulated defecation, resulting in significantly more negative rectoanal pressure gradient. The remaining anorectal pressure profile and sensory levels were comparable between the groups. While diminished rectoanal pressure gradient was the determinant of abnormal balloon evacuation in non HSD/hEDS patients, increased anal resting tone and maximum volume tolerated were independent factors associated with an abnormal BET in HSD/hEDS patients. Review of defecography data from a subset of patients showed no significant differences in structural pathologies between HSD/hEDS and non HSD/hEDS patients. CONCLUSIONS: These results suggest anorectal pressure profile is not compromised by connective tissue pathologies in HSD patients. Whether concurrent psychosomatic disorders or musculoskeletal involvement impact the pelvic floor function in these patients needs further investigation.

A phase IV clinical trial of gastrointestinal motility in adult patients with migraine before and after initiation of a calcitonin gene-related peptide ligand (galcanezumab) or receptor (erenumab) antagonist.

OBJECTIVE: To compare effects of an initial dose of calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) antagonists on gastrointestinal (GI) motility in patients with migraine and to explore if the mechanistic difference contributes to GI adverse events (AEs). BACKGROUND: Different frequencies of constipation have been observed between CGRP mAbs that target the ligand (galcanezumab [GMB]) or receptor (erenumab [ERE]). METHODS: Patients (n = 65) with migraine without significant GI symptoms were enrolled in a multi-center, single-blind phase IV clinical trial (NCT04294147) and randomized 1:1 to receive GMB (240 mg; n = 33) or ERE (140 mg; n = 32). GI whole and regional transit times were assessed using a wireless motility capsule 1 week before and 2 weeks after mAb administration. The primary endpoint was change from baseline in colonic transit time (CTT) within each treatment group. Other measures included GI Symptom Rating Scale (GSRS), Bristol Stool Form Scale (BSFS), and spontaneous bowel movement (SBM) evaluation. AEs were monitored throughout the study. RESULTS: Baseline characteristics indicated significant GI transit time variability with minimal GI reported symptoms. While not statistically significant, a numerical mean increase in CTT was observed in ERE patients (n = 28, mean [SD] at baseline: 33.8 [29.4] h; least square [LS] mean [SE] change: 5.8 [5.7] h, 95% confidence interval [CI] -5.7 to 17.2, p = 0.320), while GMB decreased CTT (n = 31, mean [SD] at baseline: 29.3 [24.5] h; LS mean [SE] change: -5.4 [5.4] h, 95% CI -16.2 to 5.5, p = 0.328) compared to baseline. No meaningful changes were observed in other regional transit times. ERE significantly reduced BSFS (LS mean [SE] score -0.5 [0.2], p = 0.004) and SBM (LS mean [SE] -1.2 [0.5], p = 0.0120), and increased GSRS-constipation compared to baseline (LS mean [SE] score 0.3 [0.1], p = 0.016). GMB increased GSRS-constipation (LS mean [SE] score 0.4 [0.1], p = 0.002). There were no discontinuations due to or serious AEs. A higher percentage of treatment-emergent AEs were reported with ERE than GMB (ERE: nine of 32 [28.1%] versus GMB: three of 33 [9.1%]), with constipation the most frequently reported (ERE: five of 32 [15.6%] versus GMB one of 33 [3.0%]). CONCLUSION: While the primary endpoint of this study was not met, secondary and tertiary endpoints support a within- and between-treatment change in GI effects suggesting possible mechanistic differences between ligand (GMB) and receptor (ERE) antagonism.

Lung transcriptional unresponsiveness and loss of early influenza virus control in infected neonates is prevented by intranasal Lactobacillus rhamnosus GG.

Respiratory viral infections contribute substantially to global infant losses and disproportionately affect preterm neonates. Using our previously established neonatal murine model of influenza infection, we demonstrate that three-day old mice are exceptionally sensitive to influenza virus infection and exhibit high mortality and viral load. Intranasal pre- and post-treatment of neonatal mice with Lactobacillus rhamnosus GG (LGG), an immune modulator in respiratory viral infection of adult mice and human preterm neonates, considerably improves neonatal mice survival after influenza virus infection. We determine that both live and heat-killed intranasal LGG are equally efficacious in protection of neonates. Early in influenza infection, neonatal transcriptional responses in the lung are delayed compared to adults. These responses increase by 24 hours post-infection, demonstrating a delay in the kinetics of the neonatal anti-viral response. LGG pretreatment improves immune gene transcriptional responses during early infection and specifically upregulates type I IFN pathways. This is critical for protection, as neonatal mice intranasally pre-treated with IFNß before influenza virus infection are also protected. Using transgenic mice, we demonstrate that the protective effect of LGG is mediated through a MyD88-dependent mechanism, specifically via TLR4. LGG can improve both early control of virus and transcriptional responsiveness and could serve as a simple and safe intervention to protect neonates.