Cardiopulmonary resuscitation employing only abdominal compressions in infants after cardiac surgery: A secondary sub-analysis of the ICU-RESUS study.

Importance: Patients with underlying cardiac disease form a considerable proportion of pediatric patients who experience in-hospital cardiac arrest. In pediatric patients after cardiac surgery, CPR with abdominal compressions alone (AC-CPR) may provide an alternative to standard chest compression CPR (S-CPR) with additional procedural and physiologic advantages. Objective: Quantitatively describe hemodynamics during cardiopulmonary resuscitation (CPR) and outcomes of infants who received only abdominal compressions (AC-CPR). Design: This is a sub-group analysis of the prospective, observational cohort from the ICU-RESUS trial NCT028374497. Setting & Patients: A single site quaternary care pediatric cardiothoracic intensive care unit enrolled in the ICU-RESUS trial. Patients less than 1 year of age with congenital heart disease who required compressions during cardiac arrest. Interventions: Use of AC-CPR during cardiac arrest resuscitation. Measurements and Main Results: Invasive arterial line waveforms during CPR were analyzed for 11 patients (10 surgical cardiac and 1 medical cardiac). Median weight was 3.3 kg [IQR 3.0, 4.0]; and median duration of CPR was 5.0 [3.0, 20.0] minutes. Systolic (median 57 [IQR 48, 65] mmHg) and diastolic (median 32 [IQR 24, 43] mmHg) blood pressures were achieved with a median rate of 114 [IQR 100, 124] compressions per minute. Return of spontaneous circulation was obtained in 9 of 11 (82%) patients; 2 patients (18%) were cannulated for extracorporeal cardiopulmonary resuscitation (ECPR) and 6 (55%) survived to hospital discharge with favorable neurologic outcome. Conclusions: AC-CPR may offer an alternative method to maintain perfusion for infants who experience cardiac arrest. This may have particular benefit in pediatric patients after cardiac surgery for whom external chest compressions may be harmful due to anatomic and physiologic considerations.

Eating egg-rich diets and modeling the addition of one daily egg reduced the risk of nutrient inadequacy among U.S. adolescents with and without food insecurity.

BACKGROUND: Adolescents have the poorest dietary intakes throughout the lifespan. Food insecurity worsens these nutritional risks. Eggs are one nutrient-dense strategy to increase nutrient quality. OBJECTIVE: 1) compare usual nutrient intakes, Dietary Reference Intakes and protein compliance with recommendations, and scores of micronutrient quality; and 2) analyze how adding one egg affects adolescents' nutrient profiles, by food security status and egg-rich diets. METHODS: Dietary data of U.S. adolescents in the 2007-2018 NHANES were analyzed (14-17 years; n=3,633). Egg-rich diet levels were categorized 1) non-eggs, 2) eggs as ingredients in dishes, or 3) primarily egg dishes. Food security status was classified using the U.S. Household Food Security Survey Module. The National Cancer Institute method was used to estimate usual nutrient intake and nutrient exposure scores (i.e., food nutrient index and total nutrient index). Nutrient amounts from one medium egg were modeled on existing intakes. Pairwise t-tests determined significant differences. RESULTS: Over 60% of adolescents risked inadequate intake of calcium, choline, magnesium, and vitamins D and E regardless of food security status. Food secure adolescents consuming primarily egg dishes had higher mean usual intakes of lutein + zeaxanthin (1544.1 mcg), choline (408.4 mg), vitamin B2 (2.3 mg), selenium (128.6 mcg), vitamin D (6 mcg), docosahexaenoic acid (70 mg), and protein (89.1g) than other groups (P<0.0002). Those consuming eggs as ingredients in dishes demonstrated higher nutrient adequacy, for magnesium (scored ∼66 out of 100), potassium (scored 81), and total scores (scored 72 and 69, respectively) for the TNI and FNI; and folate only (scored 92) for the TNI, than those not consuming eggs (P<0.0002). Adding one egg increased choline and vitamin D usual intakes for some groups and nutrient index scores for all groups (P<0.0005). CONCLUSIONS: Adolescents are at substantial nutritional risk that was exacerbated by food insecurity and less egg consumption.

Evaluating remission of type 2 diabetes using a metabolic intervention including fixed-ratio insulin degludec and liraglutide: A randomized controlled trial.

AIM: To evaluate the effect on type 2 diabetes remission of short-term intensive metabolic intervention consisting of frequent dietary, exercise and diabetes management coaching, metformin and fixed-ratio insulin degludec/liraglutide. METHODS: In a multicentre open-label randomized controlled trial, insulin-naïve participants within 5 years of diabetes diagnosis were assigned to a 16-week remission intervention regimen or standard care, and followed for relapse of diabetes and sustained remission for an additional year after stopping glucose-lowering drugs. RESULTS: A total of 159 participants aged 57 ± 10 years, with diabetes duration 2.6 ± 1.5 years, body mass index 33.5 ± 6.5 kg/m2, and glycated haemoglobin (HbA1c) level 53 ± 7 mmol/mol were randomized and analysed (79 intervention, 80 control). At the end of the 16-week intervention period, compared to controls, intervention participants achieved lower HbA1c levels (40 ± 4 vs. 51 ± 7 mmol/mol; p < 0.0001), and lost more weight (3.3 ± 4.4% vs. 1.9 ± 3.0%; p = 0.02). There was a lower hazard of diabetes relapse overall in the intervention group compared to controls (hazard ratio 0.63, 95% confidence interval [CI] 0.45, 0.88; p = 0.007), although this was not sustained over time. Remission rates in the intervention group were not significantly higher than in the control group at 12 weeks (17.7% vs. 12.5%, relative risk [RR] 1.42, 95% CI 0.67, 3.00; p = 0.36) or at 52 weeks (6.3% vs. 3.8%, RR 1.69, 95% CI 0.42, 6.82) following the intervention period. CONCLUSIONS: An intensive remission-induction intervention including fixed-ratio insulin degludec/liraglutide reduced the risk of type 2 diabetes relapse within 1 year without sustained remission.

Trauma exposure proximity associated with eating disorder diagnosis in women with food insecurity.

Trauma exposure is a risk factor for both food insecurity (FI) and increased eating disorder (ED) pathology. The purpose of this study was to explore the relation between trauma and ED diagnosis in a sample of women experiencing FI. A cross-sectional analysis of surveys from 99 women with self-reported FI (54% White; mean [SD] age = 40.26 [14.33] years) in the United States was employed. Participants completed online surveys including the Life Events Checklist (LEC) questionnaire, General Anxiety Disorder-7, Patient Health Questionnaire-9, and an interview comprised of the Household Food Security Survey Module (HFSSM) and Eating Disorder Diagnostic Interview (EDDI). LEC traumatic events were weighted by proximity: events experienced directly were weighted by a factor of 3, witnessed by 2, learned about by 1, and summed to a total weighted score. ED diagnosis in the past 12 months was assessed via the EDDI using DSM-5 diagnostic criteria. A binary logistic regression model tested associations between weighted trauma score, FI, and ED diagnosis. Weighted trauma score significantly predicted any ED diagnosis (OR = 1.039, p = .016), but FI severity did not (OR = .746, p = .101). These results suggest trauma proximity predicts ED diagnosis beyond that of FI severity and may be an important component of the association between FI and ED pathology. Future work may consider evaluating longitudinal symptoms of trauma and trauma severity in relation to FI.

Resuscitation arterial waveform quantification and outcomes in pediatric bidirectional Glenn and Fontan patients.

BACKGROUND: Resuscitation with chest compressions and positive pressure ventilation in Bidirectional Glenn (BDG) or Fontan physiology may compromise passive venous return and accentuate neurologic injury. We hypothesized that arterial pressure and survival would be better in BDG than Fontan patients. METHODS: Secondary analyses of the Pediatric Intensive Care Quality of CPR and Improving Outcomes from Pediatric Cardiac Arrest databases. P-values were considered significant if < 0.05. RESULTS: In total, 64 patients had either BDG (42/64, 66%) or Fontan (22/64, 34%) anatomy. Return of spontaneous circulation was achieved in 76% of BDG patients versus 59% of Fontan patients and survival with favorable neurologic outcome in 22/42 (52%) BDG versus 6/22 (27%) Fontan patients, p = 0.067. Twelve of 24 (50%) BDG and 2/7 (29%) Fontan patients who survived to discharge suffered new morbidity as defined by worsening Functional Status Score. More BDG patients achieved adequate DBP (≥25 mmHg for neonates and infants; ≥ 30 mmHg for children) than Fontan patients (21/23 (91%) vs. 5/11 (46%), p = 0.007). CONCLUSIONS: Only 27% of Fontan patients survived to hospital discharge with favorable neurologic outcome after CPR, likely driven by inadequate diastolic blood pressure during resuscitation. One half of the BDG patients who survived to hospital discharge had new neurologic morbidity. BACKGROUND: Cardiac arrest in patients with congenital heart disease (CHD) may present challenges to resuscitation based on the unique cardiovascular physiology resulting from surgical palliation. Recent resuscitation guidelines for CHD patients highlight the lack of data surrounding these special patient populations.1 Univentricular heart disease is palliated by a series of cardiac surgeries that stepwise result in passive pulmonary perfusion from the systemic venous system directly to the pulmonary vascular bed. The bidirectional Glenn (BDG) palliation directly anastomoses the superior vena cava (SVC) to the pulmonary arterial system and leaves normal inferior vena cava (IVC) venous return to the heart.2 The Fontan palliation baffles IVC flow directly to the pulmonary vascular bed which relieves cyanosis due to right to left shunting, but requires systemic ventricular preload to be directly dependent upon pulmonary vascular resistance and intrathoracic pressures.3 IMPACT STATEMENT: Hemodynamic waveforms from 2 large prospective observational studies now allow for exploration of physiology during cardiopulmonary resuscitation for unique anatomy associated with single ventricle congenital heart disease. Fewer patients with Fontan physiology (46%) achieved an adequate diastolic blood pressure (defined as ≥ 25 mmHg for neonates and infants and ≥ 30 mmHg for children) than bidirectional Glenn patients during cardiopulmonary resuscitation (91%, p = 0.007). Only 27% of Fontan patients survived to hospital discharge with favorable neurologic outcome after cardiopulmonary resuscitation. Of the bidirectional Glenn patients who survived, 50% developed a new morbidity as quantified by the Functional Status Score.

Limosilactobacillus reuteri promotes the expression and secretion of enteroendocrine- and enterocyte-derived hormones.

Observations that intestinal microbes can beneficially impact host physiology have prompted investigations into the therapeutic usage of such microbes in a range of diseases. For example, the human intestinal microbe Limosilactobacillus reuteri strains ATCC PTA 6475 and DSM 17938 are being considered for use for intestinal ailments including colic, infection, and inflammation as well as non-intestinal ailments including osteoporosis, wound healing, and autism spectrum disorder. While many of their beneficial properties are attributed to suppressing inflammatory responses in the gut, we postulated that L. reuteri may also regulate hormones of the gastrointestinal tract to affect physiology within and outside of the gut. To determine if L. reuteri secreted factors impact the secretion of enteric hormones, we treated an engineered jejunal organoid line, NGN3-HIO, which can be induced to be enriched in enteroendocrine cells, with L. reuteri 6475 or 17938 conditioned medium and performed transcriptomics. Our data suggest that these L. reuteri strains affect the transcription of many gut hormones, including vasopressin and luteinizing hormone subunit beta, which have not been previously recognized as being produced in the gut epithelium. Moreover, we find that these hormones appear to be produced in enterocytes, in contrast to canonical gut hormones which are produced in enteroendocrine cells. Finally, we show that L. reuteri conditioned media promotes the secretion of several enteric hormones including serotonin, GIP, PYY, vasopressin, and luteinizing hormone subunit beta. These results support L. reuteri affecting host physiology through intestinal hormone secretion, thereby expanding our understanding of the mechanistic actions of this microbe.

Blood Pressure Control in Pregnant Patients with Chronic Hypertension and Diabetes: Should <130/80 be the Target?

BACKGROUND: The Chronic Hypertension and Pregnancy Study (CHAP) demonstrated that a target blood pressure of <140/90 mm Hg during pregnancy is associated with improved perinatal outcomes. Outside of pregnancy, pharmacologic therapy for patients with diabetes and hypertension is adjusted to a target blood pressure of <130/80 mm Hg. During pregnancy, patients with both diabetes and chronic hypertension may also benefit from tighter control with a target blood pressure (BP) <130/80 mm Hg. OBJECTIVE: We compared perinatal outcomes in patients with hypertension and diabetes who achieved BP <130/80 versus 130-139/80-89 mm Hg. STUDY DESIGN: This was a secondary analysis of a multi-center randomized controlled trial. Participants were included in this secondary analysis if they had diabetes diagnosed prior to pregnancy or at <20 weeks' gestation and at least two recorded BP measurements prior to delivery. Average systolic and diastolic BP were calculated using ambulatory antenatal BPs. The primary composite outcome was preeclampsia with severe features, indicated preterm birth <35 weeks, or placental abruption. Secondary outcomes were components of the primary outcome, cesarean delivery, fetal or neonatal death, neonatal intensive care unit (NICU) admission, and small for gestational age (SGA). Comparisons were made between those with an average systolic BP <130 mm Hg and average diastolic BP <80 mm Hg and those with an average systolic blood pressure 130-139 mm Hg or diastolic blood pressure 80-89 mm Hg using Student's t-test and chi-squared tests. Multivariable log-binomial regression models were used to evaluate risk ratios between blood pressure groups for dichotomous outcomes while accounting for baseline covariates. RESULTS: Of 434 participants included, 150 (34.6%) had an average blood pressure less than 130/80 mm Hg. Participants with an average blood pressure less than 130/80 were more likely to be on antihypertensive medications at the start of pregnancy and more likely to have newly diagnosed DM prior to 20 weeks. Participants with an average blood pressure less than 130/80 mm Hg were less likely to have the primary adverse perinatal outcome (19.3% vs 46.5%, adjusted relative risk (aRR) 0.43, 95% CI 0.30-0.61, p<0.01), with decreased risks specifically of preeclampsia with severe features (aRR 0.35, 95% CI 0.23-0.54) and indicated preterm birth prior to 35 weeks (aRR 0.44, 95% CI 0.24-0.79). The risk of NICU admission was lower in the lower blood pressure group (aRR 0.74, 95% CI 0.59-0.94). No differences were noted in cesarean delivery (aRR 1.04, 95% CI 0.90-1.20), fetal or neonatal death (aRR 0.59, 95% CI 0.12-2.92). SGA less than the 10th percentile was lower in the lower blood pressure group (aRR 0.37, 95% CI 0.14-0.96). CONCLUSION: In those with chronic hypertension and diabetes prior to 20 weeks, achieving an average goal blood pressure of <130/80 mm Hg may be associated with improved perinatal outcomes.

Biphasic response of human iPSC-derived neural network activity following exposure to a sarin-surrogate nerve agent.

Organophosphorus nerve agents (OPNA) are hazardous environmental exposures to the civilian population and have been historically weaponized as chemical warfare agents (CWA). OPNA exposure can lead to several neurological, sensory, and motor symptoms that can manifest into chronic neurological illnesses later in life. There is still a large need for technological advancement to better understand changes in brain function following OPNA exposure. The human-relevant in vitro multi-electrode array (MEA) system, which combines the MEA technology with human stem cell technology, has the potential to monitor the acute, sub-chronic, and chronic consequences of OPNA exposure on brain activity. However, the application of this system to assess OPNA hazards and risks to human brain function remains to be investigated. In a concentration-response study, we have employed a human-relevant MEA system to monitor and detect changes in the electrical activity of engineered neural networks to increasing concentrations of the sarin surrogate 4-nitrophenyl isopropyl methylphosphonate (NIMP). We report a biphasic response in the spiking (but not bursting) activity of neurons exposed to low (i.e., 0.4 and 4 µM) versus high concentrations (i.e., 40 and 100 µM) of NIMP, which was monitored during the exposure period and up to 6 days post-exposure. Regardless of the NIMP concentration, at a network level, communication or coordination of neuronal activity decreased as early as 60 min and persisted at 24 h of NIMP exposure. Once NIMP was removed, coordinated activity was no different than control (0 µM of NIMP). Interestingly, only in the high concentration of NIMP did coordination of activity at a network level begin to decrease again at 2 days post-exposure and persisted on day 6 post-exposure. Notably, cell viability was not affected during or after NIMP exposure. Also, while the catalytic activity of AChE decreased during NIMP exposure, its activity recovered once NIMP was removed. Gene expression analysis suggests that human iPSC-derived neurons and primary human astrocytes resulted in altered genes related to the cell's interaction with the extracellular environment, its intracellular calcium signaling pathways, and inflammation, which could have contributed to how neurons communicated at a network level.

Relational Persistent Homology for Multispecies Data with Application to the Tumor Microenvironment.

Topological data analysis (TDA) is an active field of mathematics for quantifying shape in complex data. Standard methods in TDA such as persistent homology (PH) are typically focused on the analysis of data consisting of a single entity (e.g., cells or molecular species). However, state-of-the-art data collection techniques now generate exquisitely detailed multispecies data, prompting a need for methods that can examine and quantify the relations among them. Such heterogeneous data types arise in many contexts, ranging from biomedical imaging, geospatial analysis, to species ecology. Here, we propose two methods for encoding spatial relations among different data types that are based on Dowker complexes and Witness complexes. We apply the methods to synthetic multispecies data of a tumor microenvironment and analyze topological features that capture relations between different cell types, e.g., blood vessels, macrophages, tumor cells, and necrotic cells. We demonstrate that relational topological features can extract biological insight, including the dominant immune cell phenotype (an important predictor of patient prognosis) and the parameter regimes of a data-generating model. The methods provide a quantitative perspective on the relational analysis of multispecies spatial data, overcome the limits of traditional PH, and are readily computable.

Magnesium-L-threonate improves sleep quality and daytime functioning in adults with self-reported sleep problems: A randomized controlled trial.

Objective/Background: Sleep problems challenge overall wellbeing. Magnesium has been implicated to benefit sleep, although the clinical evidences varied based on the magnesium source used. Magnesium L-threonate (MgT) is a promising intervention due to its brain bioavailability and effects on cognition, memory and mood. We investigated MgT supplementation on sleep quality and daily function. Patients/methods: Eighty 35-55-year-olds with self-assessed sleep problems participated in a randomized, double-blind, placebo-controlled, parallel-arm study, taking 1 g/day of MgT or placebo for 21 days. Sleep and daily behaviors were measured subjectively using standardized questionnaires including the Insomnia Severity Index, Leeds Sleep Evaluation Questionnaire, and Restorative Sleep Questionnaire, and objectively using an Oura ring. The Profile of Mood States questionnaire and a daily diary were used to evaluate mood, energy and productivity, and record any safety concerns. Results: The MgT group maintained good sleep quality and daytime functioning, while placebo declined. From objective Oura ring measurements, MgT significantly (p < 0.05) improved vs placebo deep sleep score, REM sleep score, light sleep time, and activity and readiness parameters activity score, activity daily movement score, readiness score, readiness activity balance, and readiness sleep balance. From subjective questionnaires, MgT significantly (p < 0.05) improved vs placebo behavior upon awakening, energy and daytime productivity, grouchiness, mood and mental alertness. MgT was safe and well tolerated. Conclusions: This showed MgT improved sleep quality, especially deep/REM sleep stages, improved mood, energy, alertness, and daily activity and productivity. These are consistent with how MgT works in neuron cells and animal models, suggesting broader positive impacts on overall brain health.

Consolidation ALK Tyrosine Kinase Inhibitors versus Durvalumab or Observation After Chemoradiation in Unresectable Stage III ALK+ Non-Small Cell Lung Cancer.

INTRODUCTION: Patients with advanced ALK-positive non-small cell lung cancer (NSCLC) typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation (cCRT). METHODS: We conducted a retrospective study using a multi-center study of 17 institutions globally. Patients with unresectable stage III ALK-positive NSCLC treated between 2015-2022 were included. Patients received ALK TKI, durvalumab, or observation after cCRT. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related adverse events (trAE) were classified by Common Terminology Criteria for Adverse Events v5.0. Outcomes were assessed by multivariable Cox regression analysis. RESULTS: Sixty-seven patients were included, of whom 39 (58%) were female. Median age was 57 years (IQR: 49-67). Fifteen received consolidation ALK TKI, 30 received durvalumab, and 22 underwent observation. Baseline characteristics were similar across the 3 groups other than differences in race. After adjusting for stage, age, and nodal status, median rwPFS was significantly longer for ALK TKI (rwPFS not reached [NR], 95% CI 22.7-NR) versus durvalumab (11.3 months, 95% CI 8.9-18.5, hazard ratio [HR]=0.12, 95% CI: 0.026-0.5, p-adjusted=0.006) or observation (7.2 months, 95% CI 3.4-10.6, HR=0.04, 95% CI: 0.009-0.2, p-adjusted<0.0001). Durvalumab significantly improved median rwPFS compared to observation (HR=0.37, 95% CI: 0.19-0.71, p-adj = 0.002, p-adjusted=0.002). Median OS in the ALK TKI and durvalumab cohorts was significantly improved compared to patients on observation (ALK TKI-observation: p=0.04; durvalumab-observation: p=0.03). TrAE of any grade occurred in 8 (53%) and 11 (37%) patients treated with ALK-TKI and durvalumab, respectively. Grade ≥3 trAEs occurred in 27% (n=4) of patients treated with ALK TKI and 6.7% of patients treated with durvalumab. CONCLUSIONS: Patients with ALK-positive NSCLC experience significantly improved rwPFS when treated with consolidation ALK TKI therapy, surpassing outcomes seen with either durvalumab or observation. While both ALK TKI therapy and durvalumab offer an extension in OS compared to observation alone, it appears that ALK TKI therapy is the superior choice, underscoring its pivotal role in enhancing patient survival.

Effects of Antihypertensive Therapy During Pregnancy on Postpartum Blood Pressure Control.

OBJECTIVE: To compare differences in postpartum blood pressure (BP) control (BP below 140/90 mm Hg) for participants with hypertension randomized to receive antihypertensive treatment compared with no treatment during pregnancy. METHODS: This study was a planned secondary analysis of a multicenter, open-label, randomized controlled trial (The CHAP [Chronic Hypertension and Pregnancy] trial). Pregnant participants with mild chronic hypertension (BP below 160/105 mm Hg) were randomized into two groups: active (antihypertensive treatment) or control (no treatment unless severe hypertension, BP 160/105 mm Hg or higher). Study outcomes were BP control below 140/90 mm Hg (primary) and medication nonadherence based on a composite score threshold (secondary) at the 6-week postpartum follow-up visit. Participants without follow-up BP measurements were excluded from analysis of the BP control outcome. Participants without health care professional-prescribed antihypertensives at delivery were excluded from the analysis of the adherence outcome. Multivariable logistic regression was used to adjust for potential confounders. RESULTS: Of 2,408 participants, 1,684 (864 active, 820 control) were included in the analysis. A greater percentage of participants in the active group achieved BP control (56.7% vs 51.5%; adjusted odds ratio [aOR] 1.22, 95% CI, 1.00-1.48) than in the control group. Postpartum antihypertensive prescription was higher in the active group (81.7% vs 58.4%, P<.001), and nonadherence did not differ significantly between groups (aOR 0.81, 95% CI, 0.64-1.03). CONCLUSION: Antihypertensive treatment of mild chronic hypertension during pregnancy was associated with better BP control below 140/90 mm Hg in the immediate postpartum period.

Mice lacking ASIC2 and ßENaC are protected from high-fat-diet-induced metabolic syndrome.

Introduction: Degenerin proteins, such as ßENaC and ASIC2, have been implicated in cardiovascular function. However, their role in metabolic syndrome have not been studied. To begin to assess this interaction, we evaluated the impact of a high fat diet (HFD) on mice lacking normal levels of ASIC2 (ASIC2-/-) and ßENaC (ßENaCm/m). Methods: Twenty-week-old male and female mice were placed on a 60% HFD for 12 weeks. Body weight was measured weekly, and body composition by non-invasive ECHO MRI and fasting blood glucose were measured at 0, 4, 8 and 12 weeks. A glucose tolerance test was administered after 12 weeks. Differences between ASIC2-/-/ßENaCm/m and WT groups were compared using independent t-tests or ANOVA where appropriate within each sex. Data are presented as mean ± SEM and ASIC2-/-/ßENaCm/m vs. WT. Results: At 20 weeks of age, ASIC2-/-/ßENaCm/m mice (n=9F/10M) weighed less and gained less weight than WT (n=12F/16M). Total body fat and lean body masses were reduced in female and male ASIC2-/-/ßENaCm/m mice. Total body fat and lean body masses as % control were identical at the end of 12 weeks. Fasting blood glucoses were lower in female and male ASIC2-/-/ßENaCm/m vs. WT mice after 12 weeks HFD. The area under the curve for the glucose tolerance test was reduced in female and tended (p=.079) to decrease in male ASIC2-/-/ßENaCm/m. Plasma leptin and insulin were reduced in female and male ASIC2-/-/ßENaCm/m vs. WT mice. Plasma insulin in female ASIC2-/-/ßENaCm/m mice remained unchanged throughout the HFD period. Liver and liver fat masses, as well as percent liver fat, were reduced in both female and male ASIC2-/-/ßENaCm/m mice after HFD. Plasma triglycerides, cholesterol, LDL- and HDL-cholesterols were markedly improved in male and/or female ASIC2-/-/ßENaCm/m following the HFD. Discussion: These novel findings suggest that loss of ASIC2 and ßENaC offer a significant protection against HFD-induced metabolic syndrome.

Enteroendocrine cells regulate intestinal homeostasis and epithelial function.

Enteroendocrine cells (EECs) are well-known for their systemic hormonal effects, especially in the regulation of appetite and glycemia. Much less is known about how the products made by EECs regulate their local environment within the intestine. Here, we focus on paracrine interactions between EECs and other intestinal cells as they regulate three essential aspects of intestinal homeostasis and physiology: 1) intestinal stem cell function and proliferation; 2) nutrient absorption; and 3) mucosal barrier function. We also discuss the ability of EECs to express multiple hormones, describe in vitro and in vivo models to study EECs, and consider how EECs are altered in GI disease.

Preanalytical and analytical factors affecting elastase quantitation in stool.

Exocrine pancreatic insufficiency (EPI) is a condition caused by a deficiency of exocrine pancreatic enzymes, resulting in malabsorption of nutrients. Clinical manifestations of EPI may include steatorrhea, weight loss, diarrhea, and abdominal pain. Although direct testing is the most sensitive and specific for EPI, these tests are invasive, time consuming, expensive, and not well standardized. Fecal elastase (FE-1) has been shown to be an indirect marker of the exocrine secretory capacity of the pancreas and has become the most commonly employed indirect test for diagnosis of EPI. Measurement of fecal elastase consists of two main phases, a preanalytical phase and analytical phase. The preanalytical phase involves stool collection, storage and handling. The second phase is the analytical phase, which includes the actual assay processes and products used to produce a result. For FE-1 this includes sample extraction and measurement on an immunoassay. Each step in the process can influence the result and contribute to heterogeneity in FE-1 measurement, potentially impacting clinical diagnosis and management. Thus, this paper provides an overview of the preanalytical and analytical factors that can affect measurement and interpretation of FE-1 results.

Prebiotic Treatment in People With Schizophrenia.

BACKGROUND: Preliminary evidence suggests that people with schizophrenia have decreased relative abundance of butyrate-producing bacteria in the gut microbiota. Butyrate plays a critical role in maintaining the integrity of the gut-blood barrier and has a number of anti-inflammatory effects. This proof-of-concept study was designed to assess whether the addition of the oligofructose-enriched inulin (OEI) prebiotic: Prebiotin could increase the production of butyrate. METHODS: Twenty-seven people who met the criteria for either Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, schizophrenia or schizoaffective disorder were entered into a 10-day, double-blind, placebo-controlled, randomized clinical trial. The study was conducted on an inpatient unit to standardize the participant diet and environment. Participants were randomized to either OEI (4 g, 3 times a day) or a placebo (4 g of maltodextrin, 3 times a day). In order to assess the effect of OEI treatment on butyrate levels, participants underwent pretreatment and posttreatment OEI challenges. The primary outcome measure was relative change in postchallenge plasma butyrate levels after 10 days of OEI treatment. RESULTS: In both the intent-to-treat and completer analyses, OEI treatment was associated with a greater number of participants who met the OEI challenge responder criteria than those treated with placebo. OEI treatment was also associated with an increase in baseline butyrate levels (effect size for the group difference in the change of baseline butyrate levels was 0.58). CONCLUSIONS: We were able to demonstrate that treatment with the prebiotic OEI selectively increased the level of plasma butyrate in people with schizophrenia.Trial registration:ClinicalTrials.gov identifier NCT03617783.

Emerging Clostridioides difficile ribotypes have divergent metabolic phenotypes.

Clostridioides difficile is a gram-positive spore-forming pathogen that commonly causes diarrheal infections in the developed world. Although C. difficile is a genetically diverse species, certain ribotypes are overrepresented in human infections. It is unknown if metabolic adaptations are essential for the emergence of these epidemic ribotypes. Here, we tested carbon substrate utilization by 88 C. difficile isolates and looked for differences in growth between 22 ribotypes. By profiling clinical isolates, we assert that C. difficile is a generalist species capable of growing on a variety of carbon substrates. Further, C. difficile strains clustered by phylogenetic relationship and displayed ribotype-specific and clade-specific metabolic capabilities. Surprisingly, we observed that two emerging lineages, ribotypes 023 and 255, have divergent metabolic phenotypes. In addition, although C. difficile Clade 5 is the most evolutionary distant clade and often detected in animals, it displayed more robust growth on simple dietary sugars than Clades 1-4. Altogether, our results corroborate the generalist metabolic strategy of C. difficile and demonstrate lineage-specific metabolic capabilities. In addition, our approach can be adapted to the study of additional pathogens to ascertain their metabolic niches in the gut. IMPORTANCE: The gut pathogen Clostridioides difficile utilizes a wide range of carbon sources. Microbial communities can be rationally designed to combat C. difficile by depleting its preferred nutrients in the gut. However, C. difficile is genetically diverse with hundreds of identified ribotypes and most of its metabolic studies were performed with lab-adapted strains. Here, we profiled carbon metabolism by a myriad of C. difficile clinical isolates. While the metabolic capabilities of these isolates clustered by their genetic lineage, we observed surprising metabolic divergence between two emerging lineages. We also found that the most genetically distant clade grew robustly on simple dietary sugars, posing intriguing questions about the adaptation of C. difficile to the human gut. Altogether, our results underscore the importance of considering the metabolic diversity of pathogens in the study of their evolution and the rational design of therapeutic interventions.

Drug-induced QT interval prolongation in patients with heart failure with preserved ejection fraction.

Heart failure (HF) with reduced ejection fraction (HFrEF) is a risk factor for drug-induced QT interval prolongation. It is unknown if HF with preserved ejection fraction (HFpEF) is also associated with an increased risk. Dofetilide and sotalol are potent QT interval-prolonging agents that are frequently used in patients with HFpEF, in whom atrial fibrillation is a common comorbidity. We tested the hypothesis that the risk of QT interval prolongation associated with dofetilide and sotalol is increased in patients with HFpEF. We conducted a retrospective cohort study conducted using electronic health records from the Indiana Network for Patient Care (January 31, 2010 -May 3, 2021). After removing patients with overlapping diagnoses of HFpEF and HFrEF, no diagnosis code, and absence of QT interval records, we identified patients taking dofetilide or sotalol among three groups: HFrEF (n = 138), HFpEF (n = 109), and no HF (n = 729). QT prolongation was defined as heart rate-corrected QT (QTc) > 500 ms during dofetilide/sotalol therapy. Unadjusted odds ratios (OR) for QT prolongation were determined by univariate analysis. Adjusted ORs were determined by generalized estimating equations (GEE) with logit link to account for an individual cluster with different times of hospitalization and covariates. QTc prolongation associated with dofetilide or sotalol occurred in 53.2%, 71.7% and 30.0% of patients with HFpEF, HFrEF, and patients with no HF, respectively. After adjusting for age, sex, race, serum potassium and magnesium concentrations, kidney function, concomitant drug therapy, and comorbid conditions, the adjusted odds of QTc prolongation were significantly higher in patients with HFpEF [OR = 1.98 (95% CI 1.17-3.33)], and in those with HFrEF [OR = 5.23, (3.15-8.67)], compared to those with no evidence of HF. The odds of QT prolongation among inpatients receiving dofetilide or sotalol were increased in patients with HFpEF and HFrEF compared to those who did not have HF.