Epidemiology, Etiology, and Treatment of Gastroparesis: Real-World Evidence From a Large US National Claims Database.

BACKGROUND & AIMS: Although gastroparesis carries a considerable health care and patient burden, associated epidemiological data are limited. To provide new real-world evidence for gastroparesis, we estimated disease prevalence, and investigated patient demographics and disease etiology in a large US claims database. METHODS: This retrospective, cross-sectional analysis used de-identified, longitudinal patient-level enrollment and billing data for adults from the Optum Clinformatics Data Mart database, a large US national administrative health insurance claims database. Prevalence was age-, sex-, and geographical region-standardized using the 2018 US census. Descriptive analyses of demographic and clinical variables and underlying disease etiologies were performed. RESULTS: The overall standardized prevalence of gastroparesis was 267.7 (95% confidence interval [CI] 264.8-270.7) per 100,000 US adults, whereas prevalence of "definite" gastroparesis (individuals diagnosed within 3 months of gastric emptying scintigraphy testing with persistent symptoms for more than 3 months) was 21.5 (95% CI 20.6-22.4) per 100,000 persons. Patients with gastroparesis had an overall Charlson Comorbidity Index score of 4.2, indicating substantial comorbidity burden. The most frequently documented comorbidities were chronic pulmonary disease (46.4%), diabetes with chronic complication (37.3%), and peripheral vascular disease (30.4%). Patients most commonly had a diabetic etiology (57.4%; type 1, 5.7% and type 2, 51.7%), followed by postsurgical (15.0%), drug-induced (11.8%), and idiopathic (11.3%) etiologies. CONCLUSIONS: New evidence is provided regarding the prevalence, patient demographics, and etiology of gastroparesis in the US general population. Wider availability of reliable objective gastric emptying measures and further education of medical professionals in recognizing and diagnosing gastroparesis would benefit future studies and improve understanding of disease epidemiology.

Pediatric Feeding Disorder: Consensus Definition and Conceptual Framework.

Pediatric feeding disorders (PFDs) lack a universally accepted definition. Feeding disorders require comprehensive assessment and treatment of 4 closely related, complementary domains (medical, psychosocial, and feeding skill-based systems and associated nutritional complications). Previous diagnostic paradigms have, however, typically defined feeding disorders using the lens of a single professional discipline and fail to characterize associated functional limitations that are critical to plan appropriate interventions and improve quality of life. Using the framework of the World Health Organization International Classification of Functioning, Disability, and Health, a unifying diagnostic term is proposed: "Pediatric Feeding Disorder" (PFD), defined as impaired oral intake that is not age-appropriate, and is associated with medical, nutritional, feeding skill, and/or psychosocial dysfunction. By incorporating associated functional limitations, the proposed diagnostic criteria for PFD should enable practitioners and researchers to better characterize the needs of heterogeneous patient populations, facilitate inclusion of all relevant disciplines in treatment planning, and promote the use of common, precise, terminology necessary to advance clinical practice, research, and health-care policy.

Impact of a Standardized Clinical Assessment and Management Plan (SCAMP®) on growth in infants with CHD.

BACKGROUND: Growth failure is prevalent among infants with CHD. A Standardized Clinical Assessment and Management Plan was introduced at Boston Children's Hospital's cardiac medical ward to identify patients with growth failure, evaluate relevant contributing conditions, and recommend a management plan including collaboration with nutrition physicians. OBJECTIVE: The objective of this study was to determine whether enrolled patients had improved growth compared with historical controls. METHODS: A total of 29 patients were enrolled in the period July, 2013-June, 2014. In all, 42 historical controls who met eligibility criteria for enrolment were selected for comparison from patients admitted to the same ward in the period June, 2010-June, 2011. Patients with CHD aged <1 year , with growth failure defined as weight-for-age z-score <-2, or failure to sustain adequate weight gain were eligible for participation. Primary outcome was change in weight-for-age z-score from enrolment to most recent weight measurement among patients with at least 6 months of follow-up. RESULTS: Control patients were older at baseline admission weight (118 versus 95 days, p=0.33), and had a higher weight-for-age z-score, -2.9 (-3.1, -2.6) versus -3.7 (-4.3, -3.0) (p=0.02), compared with enrolled patients. Enrolled patients had greater gain in weight-for-age z-score, 2.7 (2.0, 3.4) versus 1.8 (1.5, 2.2) (p=0.03), from baseline to most recent follow-up. CONCLUSION: Patients enrolled in a nutrition-focused protocol had greater weight improvement than historical controls. Identification of growth failure and collaboration with a nutrition support team was associated with improved weight gain among CHD patients experiencing growth failure. CHD programmes should consider a structural approach, including nutrition expertise to address growth failure.

Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome.

BACKGROUND: Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA yielding the farnesylated aberrant protein progerin. Without progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation. METHODS: Thirty-seven participants with Hutchinson-Gilford progeria syndrome received pravastatin, zoledronic acid, and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial. RESULTS: No participants withdrew because of side effects. Primary outcome success was predefined by improved per-patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded (P<0.0001). Key cardiovascular and skeletal secondary variables were predefined. Secondary improvements included increased areal (P=0.001) and volumetric (P<0.001-0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (P<0.001). Median carotid artery wall echodensity and carotid-femoral pulse wave velocity demonstrated no significant changes. Percentages of participants with carotid (5% to 50%; P=0.001) and femoral (0% to 12%; P=0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%; P=0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial. CONCLUSIONS: Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit but likely no added cardiovascular benefit with the addition of pravastatin and zoledronic acid. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.

Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status.

Survey of nutrition screening practices in pediatric hospitals across the United States.

BACKGROUND: Nutrition screening on admission is critically important to systematically identify patients with undernutrition given the known relationship with deleterious clinical outcomes. Limited data exist regarding optimal processes and criteria for pediatric nutrition screening. Therefore, we sought to characterize nutrition screening practices in pediatric hospitals. METHODS: A total of 365 inpatient pediatric hospitals in the United States were identified, eligible, and contacted. Eligible hospitals included general pediatric hospitals, adult hospitals with pediatric units, and specialty pediatric hospitals. One respondent at each eligible hospital was asked to complete a 33-question survey of admission nutrition screening practices. RESULTS: Of 268 survey respondents, 37% represented pediatric units in adult hospitals, 35% general pediatric hospitals, and 28% pediatric specialty or psychiatric hospitals. A total of 98.5% endorsed the existence of a screening process on admission. Anthropometrics (eg, body mass index z score, 84%) and nutrition status (eg, change in intake, 67%) were the most common screening criteria applied. A nutrition screening instrument was used in 37% of institutions, and only 31% of institutions reported using pediatric-specific screening instruments. Pediatric units within adult hospitals were 1.38 times more likely to use a screening instrument validated in any population. Barriers to nutrition screening included the lack of a standard screening procedure and insufficient staff to conduct screening. Fifty-four percent of respondents reported a desire to change their hospital's nutrition screening process. CONCLUSION: Most pediatric hospitals screen for nutrition risk on admission. However, methods and criteria varied widely across pediatric hospitals, highlighting the importance of standardized best practices.

Improving anthropometric measurements in hospitalized children: A quality-improvement project.

BACKGROUND: The objective of this quality-improvement project was to increase documentation rates of anthropometrics (measured weight, length/height, and body mass index [BMI], which are critical to identify patients at malnutrition (undernutrition) risk) from <50% to 80% within 24 hours of hospital admission for pediatric patients. METHODS: Multidisciplinary champion teams on surgical, cardiac, and intensive care (ICU) pilot units were established to identify and iteratively test interventions addressing barriers to documentation from May 2016 to June 2018. Percentage of patients with documented anthropometrics <24 h of admission was assessed monthly by statistical process control methodology. Percentage of patients at malnutrition (undernutrition) risk by anthropometrics was compared by χ2 for 4 months before and after intervention. RESULTS: Anthropometric documentation rates significantly increased (P < 0.001 for all): BMI, from 11% to 89% (surgical), 33% to 57% (cardiac), and 16% to 51% (ICU); measured weight, from 24% to 88% (surgical), 69% to 83% (cardiac), and 51% to 67% (ICU); and length/height, from 12% to 89% (surgical), 38% to 57% (cardiac), and 26% to 63% (ICU). Improvement hospital-wide was observed (BMI, 42% to 70%, P < 0.001) with formal dissemination tactics. For pilot units, moderate/severe malnutrition (undernutrition) rates tripled (1.2% [24 of 2081] to 3.4% [81 of 2374], P < 0.001). CONCLUSION: Documentation of anthropometrics on admission substantially improved after establishing multidisciplinary champion teams. Goal rate (80%) was achieved within 26 months for all anthropometrics in the surgical unit and for weight in the cardiac unit. Improved documentation rates led to significant increase in identification of patients at malnutrition (undernutrition) risk.

Efficacy and safety of linaclotide in treating functional constipation in paediatric patients: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Linaclotide, a guanylate cyclase C agonist, has been approved in the USA for the treatment of chronic idiopathic constipation and irritable bowel syndrome with predominant constipation in adults. We aimed to assess the efficacy and safety of linaclotide in paediatric patients aged 6-17 years with functional constipation. METHODS: This randomised, double-blind, placebo-controlled, multicentre, phase 3 study was done at 64 clinic or hospital sites in seven countries (USA, Canada, Israel, Italy, the Netherlands, Ukraine, and Estonia). Patients aged 6-17 years who met modified Rome III criteria for functional constipation were randomly assigned (1:1), with a block size of four and stratified by age (6-11 years and 12-17 years), to receive either oral linaclotide 72 µg or placebo once daily for 12 weeks. Participants, investigators, and data assessors were masked to assignment. The primary efficacy endpoint was change from baseline (CFB) in the 12-week frequency rate of spontaneous bowel movements (SBMs; occurring in the absence of rescue medication on the calendar day of or before the bowel movement) per week and the secondary efficacy endpoint was CFB in stool consistency over the 12-week treatment period; efficacy and safety were analysed in all patients in the randomised population who received at least one dose of study intervention (modified intention-to-treat population and safety population, respectively). The study is registered with ClinicalTrials.gov, NCT04026113, and the functional constipation part of the study is complete. FINDINGS: Between Oct 1, 2019, and March 21, 2022, 330 patients were enrolled and randomly assigned to linaclotide (n=166) or placebo (n=164). Two patients in the linaclotide group did not receive any treatment; thus, efficacy and safety endpoints were assessed in 328 patients (164 patients in each group). 293 (89%) patients completed the 12-week treatment period (148 in the linaclotide group and 145 in the placebo group). 181 (55%) of 328 patients were female and 147 (45%) were male. At baseline, the mean frequency rate for SBMs was 1·28 SBMs per week (SD 0·87) for placebo and 1·16 SBMs per week (0·83) for linaclotide, increasing to 2·29 SBMs per week (1·99) for placebo and 3·41 SBMs per week (2·76) for linaclotide during intervention. Compared with placebo (least-squares mean [LSM] CFB 1·05 SBMs per week [SE 0·19]), patients treated with linaclotide showed significant improvement in SBM frequency (LSM CFB 2·22 SBMs per week [0·19]; LSM CFB difference 1·17 SBMs per week [95% CI 0·65-1·69]; p<0·0001). Linaclotide also significantly improved stool consistency over placebo (LSM CFB 1·11 [SE 0·08] vs 0·69 [0·08]; LSM CFB difference 0·42 [95% CI 0·21-0·64]; p=0·0001). The most reported treatment-emergent adverse event (TEAE) by patients treated with linaclotide was diarrhoea (seven [4%] of 164 vs three [2%] of 164 patients in the placebo group) and by patients treated with placebo was COVID-19 (five [3%] vs four [2%] in the linaclotide group). The most frequent treatment-related TEAE was diarrhoea (linaclotide: six [4%] patients; placebo: two [1%] patients). One serious adverse event of special interest (treatment-related severe diarrhoea resulting in dehydration and hospitalisation) occurred in a female patient aged 17 years in the linaclotide group; this case resolved without sequelae after administration of intravenous fluids. No deaths occurred during the study. INTERPRETATION: Linaclotide is an efficacious and well tolerated treatment for functional constipation in paediatric patients and has subsequently been approved by the US Food and Drug Administration for this indication. FUNDING: AbbVie and Ironwood Pharmaceuticals.

Clinical Presentations of Drug-Induced Hyperprolactinaemia: A Literature Review.

Screening for drug-induced hyperprolactinaemia, a condition characterised by higher-than-normal levels of serum prolactin induced by drug treatments, requires a comprehensive understanding of the clinical presentations and long-term complications of the condition. Using two databases, Embase and MEDLINE, we summarised the available evidence on the clinical presentations and long-term complications of drug-induced hyperprolactinaemia. Clinical and observational studies reporting on drug treatments known or suspected to induce hyperprolactinaemia were included. Database searches were limited to the English language; no date or geographic restrictions were applied. Fifty studies were identified for inclusion, comprising a variety of study designs and patient populations. Most data were reported in patients treated with antipsychotics, but symptoms were also described among patients receiving other drugs, such as prokinetic drugs and antidepressants. Notably, the diagnosis of drug-induced hyperprolactinaemia varied across studies since a standard definition of elevated prolactin levels was not consistently applied. Frequent clinical presentations of hyperprolactinaemia were menstrual cycle bleeding, breast or lactation disorders, and sexual dysfunctions, described in 80% (40/50), 74% (37/50), and 42% (21/50) of the included studies, respectively. In the few studies reporting such symptoms, the prevalence of vaginal dryness impacted up to 53% of females, and infertility in both sexes ranged from 15 to 31%. Clinicians should be aware of these symptoms related to drug-induced hyperprolactinaemia when treating patients with drugs that can alter prolactin levels. Future research should explore the long-term complications of drug-induced hyperprolactinaemia and apply accepted thresholds of elevated prolactin levels (i.e., 20 ng/mL for males and 25 ng/mL for females) to diagnose hyperprolactinaemia as a drug-induced adverse event.Trial Registration PROSPERO International Prospective Register Of Systematic Reviews (CRD42021245259).

Risk of Adverse Events Associated with Domperidone and Metoclopramide in Gastroparesis: Systematic Review and Meta-analysis.

BACKGROUND: Dopamine antagonists are the main pharmacological options to treat gastroparesis. The aim of this study was to conduct a systematic literature review (SLR) to evaluate the profile of adverse events (AEs) of dopamine antagonists used in the treatment of children and adults with gastroparesis. METHODS: We searched EMBASE and MEDLINE up to March 25, 2021, for relevant clinical trials and observational studies. We conducted a proportional meta-analysis to estimate the pooled occurrence of AEs (%), with 95% confidence interval (CI), from arm-level data across studies and the comparative occurrence of AEs from placebo-controlled clinical trials (odds ratio [OR] with 95% CI). RESULTS: We identified 28 studies assessing AEs experienced by patients treated for gastroparesis with domperidone and metoclopramide; 22 studies contributed data to the meta-analyses. Cardiovascular, neurological, and endocrine AEs were commonly observed, with point incidences varying from 1 to > 50%. Clinically important AEs, such as QTc prolongation, occurred in 5% of patients treated with domperidone (95% CI: 3.32-8.62). Restlessness, an extrapyramidal AE, occurred in 15% of patients (95% CI: 7.48-26.61) treated with metoclopramide, with a 7-fold increase compared with patients receiving placebo (OR: 7.72; 95% CI: 1.27-47.05). Variation in terminology to describe extrapyramidal events precluded further pooled analyses. Additional meta-analyses were not feasible due to discrepancies in the assessment and reporting of the AEs. CONCLUSIONS: The evidence confirms concerns of cardiovascular, extrapyramidal, and endocrine AEs in patients with gastroparesis treated with domperidone and metoclopramide. Imprecise AE reporting limits firm interpretation and conclusions. REGISTRATION: PROSPERO international prospective register of systematic reviews (registration number: CRD42021248888).

Randomized clinical trial: A phase 2b controlled study of the efficacy and safety of trazpiroben (TAK-906) for idiopathic or diabetic gastroparesis.

BACKGROUND: Previous clinical studies of trazpiroben, a dopamine D2 /D3 receptor antagonist for long-term treatment of moderate-to-severe idiopathic and diabetic gastroparesis, have shown improved symptoms of fullness. This study assessed trazpiroben efficacy, safety, and tolerability in adults with idiopathic and diabetic gastroparesis versus placebo. METHODS: This global, multicenter, double-blind, parallel-group, phase 2b study (NCT03544229) enrolled eligible adults aged 18-85 years with symptomatic idiopathic or diabetic gastroparesis. Randomized participants received either oral placebo or trazpiroben 5, 25, or 50 mg, administered twice daily over 12 weeks, and completed the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary. Change in weekly composite score from baseline to week 12 (primary endpoint) and treatment-emergent adverse events were assessed. Data were summarized descriptively. KEY RESULTS: Overall, 242 participants were enrolled (mean [standard deviation] age 55.7 [14.2] years; 75.6% female); 193 completed the study. No significant differences in change from baseline in weekly average of the daily diary composite score occurred at week 12 between placebo (least-squares mean [standard error] -1.19 [0.12]) and trazpiroben (5, 25, and 50 mg: -1.11 [0.22], -1.17 [0.12], and -1.21 [0.12], respectively). Overall, 41.4% of participants receiving trazpiroben reported treatment-emergent adverse events (placebo, 39.7%). No serious events were considered trazpiroben-related; no life-threatening or fatal events were reported. CONCLUSIONS & INFERENCES: There was no clinically meaningful difference in efficacy between trazpiroben and placebo in treating gastroparesis, based on the primary endpoint analysis. Trazpiroben was well tolerated with no new safety concerns identified, strengthening evidence supporting its favorable safety profile. NCT number: NCT03544229.

Vitamin D deficiency in pregnancy and gestational diabetes mellitus.

OBJECTIVE: We examined the association of second-trimester maternal plasma 25-hydroxyvitamin D (25[OH]D) during pregnancy with gestational diabetes mellitus (GDM). STUDY DESIGN: Among 1314 pregnant women who participated in Project Viva, a birth cohort study, we measured 25(OH)D levels at 26-28 weeks gestation during GDM screening using a 1-hour 50-g glucose challenge test. RESULTS: We found 25(OH)D levels of <25 nmol/L in 44 of 1087 women (4.0%) with normal glucose tolerance, 9 of 159 women (5.7%) with impaired glucose tolerance, and 9 of 68 women (13.2%) with GDM. Analyses that were adjusted for sociodemographics, season, maternal body mass index, gestational weight gain, and dietary factors suggested that women with 25(OH)D levels of <25 vs ≥25 nmol/L may have higher odds of experiencing GDM (odds ratio, 2.2; 95% confidence interval, 0.8-5.5). Glucose levels after the glucose challenge test were associated inversely with 25(OH)D levels (P < .01). CONCLUSION: Second-trimester 25(OH)D levels were associated inversely with glucose levels after 1-hour 50-g glucose challenge test; low 25(OH)D levels may be associated with increased risk of GDM.

Clinical characteristics and MRI-based phenotypes of perianal abscess formation in children with fistulizing Crohn's Disease.

Purpose: The aim of this study was to explore potential correlation of the MR imaging features and clinical characteristics with formation of perianal abscess in children with Crohn's perianal fistulas (CPF). Methods: From 2010 to 2020, pediatric patients with CPF diagnosis on their first pelvic MRI were identified retrospectively. All patients were divided into two groups based on the presence or absence of perianal abscess. Baseline clinical and MRI characteristics were recorded for each patient. All the statistical calculations were performed using R (version 3.6.3). Results: A total of 60 patients [F:M 17:43, median age 14 years (IQR 10-15), ranging 3-18 years] were included in this study. Forty-four abscesses were identified in 36/60 children (mean volume 3 ± 8.6 ml, median 0.3 ml). In 24/60 patients with perianal disease, no abscess was detected on the MRI. Ten patients (28%) showed perianal abscess on pelvic MRI at the initial diagnosis. The rate of active disease on colonoscopy (visible ulcerations/aphthous ulcers) was similar in both groups (95% vs. 94%). With regards to disease location, the majority of patients (40/60, 66.6%) in both groups had ileocolonic CD. All patients without abscess had a single perianal fistula (n = 24; 3 simple and 21 complex fistulae), however, patients with perianal abscess tended to have >1 fistulous tracts (n = 50 fistulas; all complex, 27 single, 10 double and 1 triple). Intersphincteric fistula was the most common fistula type in both groups (79% and 66%, p = 0.1). The total length of fistula (3.8 ± 1.7 vs. 2.8 ± 0.8 cm, p = 0.006) and presence of multiple external openings (n = 25 vs. 7, p = 0.019) were significantly higher in patients with abscesses, and fistula length >3.3 cm showed 80% specificity and 83% PPV for the presence of perianal abscess. Fistulas were symptomatic (pain, bleeding or drainage) at similar rates in both groups (68% and 70%, p = 0.1). Conclusion: Pediatric patients with CPF who develop perianal abscess have a distinct imaging phenotype defined by longer fistula length (>3.3 cm), multiple skin openings and multiple fistulous tracts (≥2) on MRI. Patients who have these features but does not have an abscess on imaging may merit more aggressive treatment (and close monitoring) to prevent the development of an abscess.

The pharmacokinetics of oral trazpiroben (TAK-906) after organic anion transporting polypeptide 1B1/1B3 inhibition: A phase I, randomized study.

Trazpiroben is a dopamine D2 /D3 receptor antagonist under development for the treatment of gastroparesis. This phase I, open-label, randomized, two-way crossover study (NCT04121078) evaluated the effect of single-dose intravenous rifampin, a potent inhibitor of the organic anion transporting polypeptides (OATPs) 1B1 and 1B3, on the pharmacokinetics and safety of trazpiroben in healthy adults. The utility of coproporphyrin (CP) I and CPIII as biomarkers of OATP inhibition was also assessed. Overall, 12 participants were enrolled and randomized (1:1) into one of two treatment sequences (AB and BA). Participants received either a single oral dose of trazpiroben 25 mg (treatment A) or a single oral dose of trazpiroben 25 mg immediately after a single 30-min intravenous infusion of rifampin 600 mg (treatment B). After a washout period of at least 7 days, participants received the other treatment. Geometric mean area under the curve from time 0 extrapolated to infinity (AUC∞ ) and maximum serum concentration (Cmax ) of plasma trazpiroben were higher in participants receiving treatment B than those receiving treatment A (AUC∞ , 168.5 vs. 32.68 ng*h/ml; Cmax , 89.62 vs. 14.37 ng/ml); corresponding geometric mean ratios (90% confidence interval) showed 5.16 (4.25-6.25) and 6.24 (4.62-8.42)-fold increases in these parameters, respectively. In this study, trazpiroben was confirmed as a substrate of OATP1B1/1B3, and therefore co-administration of trazpiroben with moderate to strong inhibitors of OATP1B1/1B3 is not recommended. This is also the first assessment of the utility of CPI and CPIII as endogenous biomarkers of OATP1B1/1B3 inhibition after a single intravenous dose of rifampin.

Health-care resource use and costs associated with diabetic and idiopathic gastroparesis: A claims analysis of the first 3 years following the diagnosis of gastroparesis.

BACKGROUND: Due to limited treatment options, many patients with diabetic gastroparesis (DG) or idiopathic gastroparesis (IG) experience inadequate symptom control resulting in increased health-care resource utilization (HRU) and associated costs. We compared all-cause HRU and health-care costs over the 3 years after patients' first gastroparesis diagnosis with that of matched controls without gastroparesis. METHODS: Newly diagnosed adults with DG or IG were identified in Optum's de-identified Clinformatics® Data Mart Database (Q1-2007 to Q1-2019). Patients with DG/IG were matched 1:1 to controls using a mixed approach of exact matching and propensity score matching. The index date was the first gastroparesis diagnosis for cases or randomly selected for controls. All-cause HRU and direct health-care costs per person-year (PPY) were compared between DG/IG cases and controls in Years 1-3 post-index. KEY RESULTS: Demographics and comorbidities were balanced between patients with gastroparesis (n = 18,015 [DG]; n = 14,305 [IG]) and controls. In each of the Years 1-3 post-index, patients with DG or IG had significantly higher annual HRU and costs versus controls (mean total cost differences PPY: DG Year 1 $34,885, Year 2 $28,071, Year 3 $25,606; IG Year 1 $23,176, Year 2 $16,627, Year 3 $14,396) (all p < 0.05). Across all 3 years, DG/IG cohorts had approximately twice the costs of controls. HRU and costs were highest in Year 1 post-index for both DG and IG. CONCLUSIONS & INFERENCES: The economic burden of gastroparesis remains high several years after diagnosis, emphasizing the need for chronic treatment to effectively manage symptoms and consequently reduce the burden of this disorder.

Delivery by caesarean section and offspring adiposity and cardio-metabolic health at ages 6.5, 11.5 and 16 years: results from the PROBIT cohort in Belarus.

BACKGROUND: Caesarean delivery has been associated with later adiposity, perhaps via early programming or perhaps because of residual confounding by maternal or birth characteristics. OBJECTIVES: Examine associations of caesarean delivery with adiposity and cardio-metabolic biomarkers. METHODS: Observational analysis of 15 069 children in the PROBIT cohort in Belarus. We examined measures of child anthropometry and blood pressure at 6.5, 11.5 and 16 years and fasting blood (11.5 years). RESULTS: Caesarean-delivered children were slightly heavier at 6.5 (mean BMI 15.8 vs. 15.6 kg/m2 ), 11.5 (18.4 vs. 18.2) and 16 years (21.5 vs. 21.3). After adjustment for prenatal characteristics including maternal third trimester BMI, however, we observed no association of caesarean versus vaginal delivery with child BMI (ß 0.05 kg/m2 ; 95%CI: -0.03, 0.14), sum of skinfolds (0.14 mm; -0.13, 0.42), waist circumference (-0.07 cm; -0.23, 0.10), obesity (OR 0.99; 0.76, 1.29), or systolic (-0.20 mmHg; -0.70, 0.30) or diastolic (-0.17 mmHg, -0.60, 0.26) blood pressure at 6.5 years; results were similar at 11.5 and 16 years. At 11.5 years, we observed a modest association of caesarean delivery with fasting insulin (0.33 mU/L; 0.00, 0.65). CONCLUSIONS: Caesarean delivery had little or no association with adiposity or related cardio-metabolic biomarkers in childhood. Adjustment for maternal BMI attenuated all outcome effect estimates.

Macronutrient Analysis of Modified-Fat Breast Milk Produced by 3 Methods of Fat Removal.

BACKGROUND: Infants with chylothorax after congenital heart disease surgery are commonly treated using modified-fat breast milk. The effect of fat removal on breast milk macronutrients remains unclear. We compared macronutrient content of breast milk with breast milk skimmed using 3 methods, including a novel device, a cream separator. METHODS: Thawed frozen breast milk samples from 30 women were defatted using refrigerated centrifuge, cream separator, and manual separation after refrigeration. We used standard assays to measure energy, protein, and fat content of breast milk samples. RESULTS: All fat removal methods yielded skimmed breast milk with substantially lower fat and energy content. Mean energy content in breast milk skimmed by centrifuge (36.7 [SD 3.6] kcal/100 mL) was similar to that from cream separator (38.8 [3.5] kcal/100 mL). Both centrifuge and cream separator methods removed almost all fat and substantially more fat than the manual fat removal method. For unprocessed milk, energy and fat content estimated by creamatocrit was similar to reference method measurements; in skimmed milk, the creamatocrit significantly overestimated fat content. Mean protein content of skimmed breast milk was similar to unprocessed breast milk (mean 1.25 [0.31] g/100 mL). CONCLUSION: Breast milk fat removal did not significantly alter protein levels. In skimmed breast milk, the overestimation of fat content using creamatocrit method suggests a need for more accurate bedside methods to assess macronutrient content. The similar macronutrient composition of breast milk skimmed by cream separator and centrifuge suggests the potential for cream separator use as a new, portable defatting method for hospitals and families.

Maternal Place of Birth, Socioeconomic Characteristics, and Child Health in US-Born Latinx Children in Boston.

OBJECTIVE: Among US-born children of Latina US (USB) and Latina foreign-born mothers (FBM), to determine whether 1) household and child characteristics differ; 2) child health outcomes differ; 3) these differences diminish for children of FBM with longer duration of residence in the United States; and 4) these differences can be explained by food insecurity (FI) or by Supplemental Nutrition Assistance Program (SNAP) participation. METHODS: Cross-sectional survey of 2145 Latina mothers of publicly insured US-born children 0 to 48 months old in a Boston emergency department (ED) 2004 to 2013. Predictors were FBM versus USBM and duration of residence in the United States. Outcomes were mothers' report of child health, history of hospitalization, developmental risk, and hospital admission on the day of ED visit. Multivariable logistic regression adjusted for potential confounders and effect modification. RESULTS: FBM versus USBM households had more household (31% vs 26%) and child (19% vs 11%) FI and lower SNAP participation (44% vs 67%). Children of FBM versus USBM were more likely to be reported in fair/poor versus good/excellent health (adjusted odds ratios 1.9, 95% confidence interval [1.4, 2.6]), with highest odds for children of FBM with shortest duration of residence, and to be admitted to the hospital on the day of the ED visit (adjusted odds ratios 1.7, 95% confidence interval [1.3, 2.2]). SNAP and FI did not fully explain these outcomes. CONCLUSION: When providing care and creating public policies, clinicians and policymakers should consider higher rates of food insecurity, lower SNAP participation, and risk for poor health outcomes in Latinx children of FBM.

Association between umbilical cord glucocorticoids and blood pressure at age 3 years.

BACKGROUND: Animal data show that decreased activity of placental 11-beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which potently inactivates glucocorticoids (e.g. cortisol) to inert forms (cortisone), allows increased access of maternal glucocorticoids to the fetus and 'programs' hypertension. Data in humans are limited. We examined in humans the association between venous umbilical cord blood glucocorticoids, a potential marker for placental 11beta-HSD2 enzyme activity, and blood pressure at age 3 years. METHODS: Among 286 newborns in Project Viva, a prospective pre-birth cohort study based in eastern Massachusetts, we measured cortisol (F) and cortisone (E) in venous cord blood and used the ratio of F/E as a marker for placental 11beta-HSD2 activity. We measured blood pressure (BP) when the offspring reached age 3 years. Using mixed effects regression models to control for BP measurement conditions, maternal and child characteristics, we examined the association between the F/E ratio and child BP. RESULTS: At age 3 years, each unit increase in the F/E ratio was associated with a 1.6 mm Hg increase in systolic BP (95% CI 0.0 to 3.1). The F/E ratio was not associated with diastolic blood pressure or birth weight for gestational age z-score. CONCLUSION: A higher F/E ratio in umbilical venous cord blood, likely reflecting reduced placental 11beta-HSD2 activity, was associated with higher systolic blood pressure at age 3 years. Our data suggest that increased fetal exposure to active maternal glucocorticoids may program later systolic blood pressure.