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Bile acids regulate gastrointestinal motility by mechanisms that are poorly understood. Standard isolated tissue bath assays might not recapitulate in vivo physiology if contractile responses to certain bile acids require direct application to the intestinal mucosa. We sought to determine the feasibility of quantifying longitudinal smooth muscle contractile responses to bile acids from intact segments of everted mouse ileum. Ileum from adult female C57BL/6J mice was isolated, gently everted over a notched metal rod, and mounted in tissue baths. Individual bile acids and agonists of bile acid receptors were added to the baths, and longitudinal smooth muscle contractile responses were quantified by isometric force transduction. Ursodeoxycholic acid robustly increased contractile responses in a dose‐dependent manner. Deoxycholic acid stimulated contractility at low doses but inhibited contractility at high doses. Chenodeoxycholic acid, glycocholic acid, and lithocholic acid did not alter contractility. The dose‐dependent increase in contractility resulting from the application of ursodeoxycholic acid was recapitulated by INT‐777, an agonist of the Takeda G protein‐coupled receptor 5 (TGR5), and by cevimeline, a muscarinic acetylcholine receptor agonist. Agonists to the nuclear receptors farnesoid X receptor, glucocorticoid receptor, pregnane X receptor, vitamin D receptor, and to the plasma membrane epidermal growth factor receptor did not modify baseline contractile patterns. These results demonstrate that gentle eversion of intact mouse ileum facilitates the quantification of longitudinal smooth muscle contractile responses to individual bile acids. Prokinetic effects of ursodeoxycholic acid and low‐dose deoxycholic acid are replicated by agonists to TGR5 and muscarinic acetylcholine receptors. [ABSTRACT FROM AUTHOR]

Background: Early‐life events impact maturation of the gut microbiome, enteric nervous system, and gastrointestinal motility. We examined three regions of gastric tissue to determine how maternal separation and gut microbes influence the structure and motor function of specific regions of the neonatal mouse stomach. Methods: Germ‐free and conventionally housed C57BL/6J mouse pups underwent timed maternal separation (TmSep) or nursed uninterrupted (controls) until 14 days of life. We assessed gastric emptying by quantifying the progression of gavaged fluorescein isothiocyanate (FITC)‐dextran. With isolated rings of forestomach, corpus, and antrum, we measured tone and contractility by force transduction, gastric wall thickness by light microscopy, and myenteric plexus neurochemistry by whole‐mount immunostaining. Key Results: Regional gastric sampling revealed site‐specific differences in contractile patterns and myenteric plexus structure. In neonatal mice, TmSep prolonged gastric emptying. In the forestomach, TmSep increased contractile responses to carbachol, decreased muscularis externa and mucosa thickness, and increased the relative proportion of myenteric plexus nNOS+ neurons. Germ‐free conditions did not appreciably alter the structure or function of the neonatal mouse stomach and did not impact the changes caused by TmSep. Conclusions and Inferences: A regional sampling approach facilitates site‐specific investigations of murine gastric motor physiology and histology to identify site‐specific alterations that may impact gastrointestinal function. Delayed gastric emptying in TmSep is associated with a thinner muscle wall, exaggerated cholinergic contractile responses, and increased proportions of inhibitory myenteric plexus nNOS+ neurons in the forestomach. Gut microbes do not profoundly affect the development of the neonatal mouse stomach or the gastric pathophysiology that results from TmSep. [ABSTRACT FROM AUTHOR]

Background: Slow gastrointestinal (GI) transit occurs in moderate‐to‐severe malnutrition. Mechanisms underlying malnutrition‐associated dysmotility remain unknown, partially due to lack of animal models. This study sought to characterize GI dysmotility in mouse models of malnutrition. Methods: Neonatal mice were malnourished by timed maternal separation. Alternatively, low‐protein, low‐fat diet was administered to dams, with malnourished neonates tested at two weeks or weaned to the same chow and tested as young adults. We determined total GI transit time by carmine red gavage, colonic motility by rectal bead latency, and both gastric emptying and small bowel motility with fluorescein isothiocyanate‐conjugated dextran. We assessed histology with light microscopy, ex vivo contractility and permeability with force‐transduction and Ussing chamber studies, and gut microbiota composition by 16S rDNA sequencing. Key Results: Both models of neonatal malnutrition and young adult malnourished males but not females exhibited moderate growth faltering, stunting, and grossly abnormal stomachs. Progression of fluorescent dye was impaired in both neonatal models of malnutrition, whereas gastric emptying was delayed only in maternally separated pups and malnourished young adult females. Malnourished young adult males but not females had atrophic GI mucosa, exaggerated intestinal contractile responses, and increased gut barrier permeability. These sex‐specific abnormalities were associated with altered gut microbial communities. Conclusions & Inferences: Multiple models of early‐life malnutrition exhibit delayed upper GI transit. Malnutrition affects young adult males more profoundly than females. These models will facilitate future studies to identify mechanisms underlying malnutrition‐induced pathophysiology and sex‐specific regulatory effects. [ABSTRACT FROM AUTHOR]

Background: Early identification and entry into care is critical to reducing morbidity and mortality in children with HIV. The objective of this report is to describe the impact of the Tingathe programme, which utilizes community health workers (CHWs) to improve identification and enrolment into care of HIV-exposed and -infected infants and children. Methods: Three programme phases are described. During the first phase, Mentorship Only (MO) (March 2007-February 2008) on-site clinical mentorship on paediatric HIV care was provided. In the second phase, Tingathe-Basic (March 2008-February 2009), CHWs provided HIV testing and counselling to improve case finding of HIV-exposed and -infected children. In the final phase, Tingathe-PMTCT (prevention of mother-to-child transmission) (March 2009-February 2011), CHWs were also assigned to HIV-positive pregnant women to improve mother-infant retention in care. We reviewed routinely collected programme data from HIV testing registers, patient mastercards and clinic attendance registers from March 2005 to March 2011. Results: During MO, 42 children (38 HIV-infected and 4 HIV-exposed) were active in care. During Tingathe-Basic, 238 HIV-infected children (HIC) were newly enrolled, a six-fold increase in rate of enrolment from 3.2 to 19.8 per month. The number of HIV-exposed infants (HEI) increased from 4 to 118. During Tingathe-PMTCT, 526 HIC were newly enrolled over 24 months, at a rate of 21.9 patients per month. There was also a seven-fold increase in the average number of exposed infants enrolled per month (9.5-70 patients per month), resulting in 1667 enrolled with a younger median age at enrolment (5.2 vs. 2.5 months; p < 0.001). During the Tingathe-Basic and Tingathe-PMTCT periods, CHWs conducted 44,388 rapid HIV tests, 7658 (17.3%) in children aged 18 months to 15 years; 351 (4.6%) tested HIV-positive. Over this time, 1781 HEI were enrolled, with 102 (5.7%) found HIVinfected by positive PCR. Additional HIC entered care through various mechanisms (including positive linkage by CHWs and transfer-ins) such that by February 2011, a total of 866 HIC were receiving care, a 23-fold increase from 2008. Conclusions: A multipronged approach utilizing CHWs to conduct HIV testing, link HIC into care and provide support to PMTCT mothers can dramatically improve the identification and enrolment into care of HIV-exposed and -infected children. [ABSTRACT FROM AUTHOR]

Objective We aimed to improve paediatric inpatient surveillance at a busy referral hospital in Malawi with two new programmes: (i) the provision of vital sign equipment and implementation of an inpatient triage programme ( ITAT) that includes a simplified paediatric severity-of-illness score, and (ii) task shifting ITAT to a new cadre of healthcare workers called 'vital sign assistants' ( VSAs). Methods This study, conducted on the paediatric inpatient ward of a large referral hospital in Malawi, was divided into three phases, each lasting 4 weeks. In Phase A, we collected baseline data. In Phase B, we provided three new automated vital sign poles and implemented ITAT with current hospital staff. In Phase C, VSAs were introduced and performed ITAT. Our primary outcome measures were the number of vital sign assessments performed and clinician notifications to reassess patients with high ITAT scores. Results We enrolled 3994 patients who received 5155 vital sign assessments. Assessment frequency was equal between Phases A (0.67 assessments/patient) and B (0.61 assessments/patient), but increased 3.6-fold in Phase C (2.44 assessments/patient, P < 0.001). Clinician notifications increased from Phases A (84) and B (113) to Phase C (161, P = 0.002). Inpatient mortality fell from Phase A (9.3%) to Phases B (5.7) and C (6.9%). Conclusion ITAT with VSAs improved vital sign assessments and nearly doubled clinician notifications of patients needing further assessment due to high ITAT scores, while equipment alone made no difference. Task shifting ITAT to VSAs may improve outcomes in paediatric hospitals in the developing world. [ABSTRACT FROM AUTHOR]

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Introduction Loss to follow-up is a major challenge in the prevention of mother to child transmission of HIV (PMTCT) programme in Malawi with reported loss to follow-up of greater than 70%. Tingathe-PMTCT is a pilot intervention that utilizes dedicated community health workers (CHWs) to create a complete continuum of care within the PMTCT cascade, improving service utilization and retention of mothers and infants. We describe the impact of the intervention on longitudinal care starting with diagnosis of the mother at antenatal care (ANC) through final diagnosis of the infant. Methods PMTCT service utilization, programme retention and outcomes were evaluated for pregnant women living with HIV and their exposed infants enrolled in the Tingathe-PMTCT programme between March 2009 and March 2011. Multivariate logistic regression was done to evaluate maternal factors associated with failure to complete the cascade. Results Over 24 months, 1688 pregnant women living with HIV were enrolled. Median maternal age was 27 years (IQR, 23.8 to 30.8); 333 (19.7%) were already on ART. Among the remaining women, 1328/1355 (98%) received a CD4 test, with 1243/1328 (93.6%) receiving results. Of the 499 eligible for ART, 363 (72.8%) were successfully initiated. Prior to, delivery there were 93 (5.7%) maternal/foetal deaths, 137 (8.1%) women transferred/moved, 51 (3.0%) were lost and 58 (3.4%) refused ongoing PMTCT services. Of the 1318 live births to date, 1264 (95.9%) of the mothers and 1285 (97.5%) of the infants received ARV prophylaxis; 1064 (80.7%) infants were tested for HIV by PCR and started on cotrimoxazole. Median age at PCR was 1.7 months (IQR, 1.5 to 2.5). Overall transmission at first PCR was 43/1047 (4.1%). Of the 43 infants with positive PCR results, 36 (83.7%) were enrolled in ART clinic and 33 (76.7%) were initiated on ART. Conclusions Case management and support by dedicated CHWs can create a continuum of longitudinal care in the PMTCT cascade and result in improved outcomes. [ABSTRACT FROM AUTHOR]

Beneficial microbes and probiotics show promise for the treatment of pediatric gastrointestinal diseases. However, basic mechanisms of probiosis are not well understood, and most investigations have been performed in germ-free or microbiome-depleted animals. We sought to functionally characterize probiotichost interactions in the context of normal early development. Outbred CD1 neonatal mice were orally gavaged with one of two strains of human-derived Lactobacillus reuteri or an equal volume of vehicle. Transcriptome analysis was performed on enterocyte RNA isolated by laser-capture microdissection. Enterocyte migration and proliferation were assessed by labeling cells with 5-bromo-2-deoxyuridine, and fecal microbial community composition was determined by 16S metagenomic sequencing. Probiotic ingestion altered gene expression in multiple canonical pathways involving cell motility. L. reuteri strain DSM 17938 dramatically increased enterocyte migration (3-fold), proliferation (34%), and crypt height (29%) compared to vehicle-treated mice, whereas strain ATCC PTA 6475 increased cell migration (2-fold) without affecting crypt proliferative activity. In addition, both probiotic strains increased the phylogenetic diversity and evenness between taxa of the fecal microbiome 24 h after a single probiotic gavage. These experiments identify two targets of probiosis in early development, the intestinal epithelium and the gut microbiome, and suggest novel mechanisms for probiotic strain-specific effects. [ABSTRACT FROM AUTHOR]

Background: An important limitation of gastrointestinal motility testing is high variability. Conditions that could contribute to variability, including the duration of pretest fasting and time of day, are rarely reported and have not been examined systematically. This study aimed to explore whether these conditions, as well as age, sex, and strain of mice, affect the results of a standard laboratory test of upper gastrointestinal motility. Methods: Male and female 8‐week‐old C57BL/6J mice received a gastric gavage of fluorescein isothiocyanate (FITC)‐conjugated dextran. FITC‐dextran distribution was measured 30 minutes later. Mean geometric centers (MGCs) were calculated to determine the effects of short versus prolonged fasting and morning versus afternoon testing. The influence of age was assessed in 2‐ to 10‐week‐old animals, and the influence of strain was determined in C57BL/6J, BALB/c, and CD‐1 mice. Key results: Motility was sexually dimorphic. MGC progressed 19% further in 8‐week‐old C57BL/6J males versus females when tested in the morning after a short fast. Similar patterns were observed in morning or afternoon testing after overnight fasting. In males, motility was unaffected by time of day; however, MGC progressed 31% further in females tested in the afternoon versus morning after a short fast. Sex differences also were present in CD‐1 but not BALB/c mice. Testing in neonates revealed strikingly low variability and no sex differences. Conclusions & inferences: Fasting duration, time of day, age, sex, and strain of mice all influence upper gastrointestinal motility testing. Sex differences are not present in neonatal pups, but develop soon after weaning. [ABSTRACT FROM AUTHOR]