Use of Ondansetron for Nausea and Vomiting During Pregnancy and Adverse Pregnancy Outcomes

Ondansetron, a 5-HT3-receptor antagonist, is commonly used off-label in the United States to treat nausea and vomiting in pregnancy. Previous studies of adverse pregnancy outcomes offer an incomplete picture of the safety of ondansetron because they use methods that increase the potential for unmeasured confounding or fail to appropriately account for events occurring along the gestational age time scale. The objective of this project was to compare the risk of various adverse pregnancy outcomes between women exposed to ondansetron during the first 20 weeks pregnancy and women exposed to alternative antiemetic medications, including promethazine and metoclopramide. Adverse outcomes included miscarriage, stillbirth, preterm birth, gestational hypertensive disorders, small for gestational age, and mean birth weight. A pregnancy cohort was created using electronic health record data from the UNC Health Care system in North Carolina. Women were classified as exposed to either ondansetron or comparator antiemetics (metoclopramide or promethazine) based on the first prescription received in the first 20 weeks of gestation. The cumulative incidence of each outcome was estimated using methods that account for the gestational age of antiemetic exposure and competing events in pregnancy, and risk ratios (RR) and risk differences (RD) were calculated. Measured confounding by was controlled using stabilized inverse probability of treatment weights. We identified 2677 eligible pregnancies with antiemetic orders, 66% of which first received ondansetron. After adjustment for measured covariates, there was no difference in risk of miscarriage (RR 1.23, 95% CI 0.23, 8.51; RD 2.3%, 95% CI -25.4, 24.1). No association was observed between ondansetron and stillbirth (odds ratio=1.32; 95% CI 0.39, 4.53), preterm birth (RR=0.91; 95% CI 0.40, 2.54), or gestational hypertensive disorders (RR=0.90; 95% CI 0.47, 1.89). Similarly, no association was observed for small for gestational age (RR=1.19; 95% CI 0.52, 3.38) and there were no clinically important differences in mean birth weight among term births. Results from sensitivity analyses were imprecise but did not change conclusions. These results do not offer evidence that ondansetron increases risks of adverse pregnancy outcomes compared to alternative and commonly used antiemetic therapies.Doctor of Philosoph

Association Between Method of Prescribing and Primary Nonadherence to Dermatologic Medication in an Urban Hospital Population

Importance Prescription underuse is associated with poorer clinical outcomes. A significant proportion of underuse is owing to primary nonadherence, defined as the rate at which patients fail to fill and pick up new prescriptions. Although electronic prescribing increases coordination of care and decreases errors, its effect on primary nonadherence is less certain. Objectives To analyze factors associated with primary nonadherence to dermatologic medications and study whether electronic prescribing affects rates of primary nonadherence. Design, Setting, and Participants A retrospective review of medical records was conducted from January 1, 2011, to December 31, 2013, among a cohort of new patients prescribed dermatologic medications at a single, urban, safety-net hospital outpatient dermatology clinic. Main Outcomes and Measures The primary outcome was the overall rate of primary nonadherence, defined as filling and picking up all prescribed medications within a 1-year period, and the difference in primary nonadherence between patients who received electronic prescriptions and those who received paper prescriptions. Secondary outcomes included the association of primary nonadherence with sex, age, relationship status, primary language, race/ethnicity, and number of prescriptions. Results A total of 4318 prescriptions were written for 2496 patients (mean [SD] age, 47.7 [13.2] years; 849 men and 1647 women). The overall rate of primary nonadherence was 31.6% (n = 788). Based on multivariable analysis, the risk of primary nonadherence was 16 percentage points lower among patients given an electronic prescription (15.2%) than patients given a paper prescription (31.5%). Primary nonadherence decreased with age (<30 y, 38.9%; 30-49 y, 35.3%; and 50-69 y, 26.3%), and then increased in elderly patients 70 years and older (31.9%). Of patients who were given 1, 2, 3, 4, or 5 prescriptions, rates of primary nonadherence were 33.1%, 28.8%, 26.4%, 39.8%, and 38.1%, respectively. Primary nonadherence decreased with age but then increased in elderly patients. Patients identifying English as their primary language had the highest rate of primary nonadherence (33.9%) compared with Spanish (29%) or other speakers (20.4%). Conclusions and Relevance Compared with paper prescriptions, electronic prescriptions were associated with less primary nonadherence. Number of prescriptions, language, race/ethnicity, and age were associated with increased rates of primary nonadherence. Efforts must be made to understand why primary nonadherence occurs, identify patients prone to primary nonadherence, and simplify medication regimens to maximize adherence and quality of care

Functional plasticity in the type IV secretion system of Helicobacter pylori.

Helicobacter pylori causes clinical disease primarily in those individuals infected with a strain that carries the cytotoxin associated gene pathogenicity island (cagPAI). The cagPAI encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into epithelial cells and is required for induction of the pro-inflammatory cytokine, interleukin-8 (IL-8). CagY is an essential component of the H. pylori T4SS that has an unusual sequence structure, in which an extraordinary number of direct DNA repeats is predicted to cause rearrangements that invariably yield in-frame insertions or deletions. Here we demonstrate in murine and non-human primate models that immune-driven host selection of rearrangements in CagY is sufficient to cause gain or loss of function in the H. pylori T4SS. We propose that CagY functions as a sort of molecular switch or perhaps a rheostat that alters the function of the T4SS and "tunes" the host inflammatory response so as to maximize persistent infection

Effect of inhaled corticosteroid particle size on asthma efficacy and safety outcomes: a systematic literature review and meta-analysis

BACKGROUND: Inhaled corticosteroids (ICS) are the primary treatment for persistent asthma. Currently available ICS have differing particle size due to both formulation and propellant, and it has been postulated that this may impact patient outcomes. This structured literature review and meta-analysis compared the effect of small and standard particle size ICS on lung function, symptoms, rescue use (when available) and safety in patients with asthma as assessed in head-to-head randomized controlled trials (RCTs). METHODS: A systematic literature search of MEDLINE was performed to identify RCTs (1998-2014) evaluating standard size (fluticasone propionate-containing medications) versus small particle size ICS medication in adults and children with asthma. Efficacy outcomes included forced expiratory volume in 1 s (FEV1), morning peak expiratory flow (PEF), symptom scores, % predicted forced expiratory flow between 25 and 75% of forced vital capacity (FEF25-75%), and rescue medication use. Safety outcomes were also evaluated when available. RESULTS: Twenty-three independent trials that met the eligibility criteria were identified. Benefit-risk plots did not demonstrate any clinically meaningful differences across the five efficacy endpoints considered and no appreciable differences were noted for most safety endpoints. Meta-analysis results, using a random-effects model, demonstrated no significant difference between standard and small size particle ICS medications in terms of effects on mean change from baseline FEV1 (L) (-0.011, 95% confidence interval [CI]: -0.037, 0.014 [N = 3524]), morning PEF (L/min) (medium/low doses: -3.874, 95% CI: -10.915, 3.166 [N = 1911]; high/high-medium doses: 5.551, 95% CI: -1.948, 13.049 [N = 749]) and FEF25-75% predicted (-2.418, 95% CI: -6.400; 1.564 [N = 115]). CONCLUSIONS: Based on the available literature, no clinically significant differences in efficacy or safety were observed comparing small and standard particle size ICS medications for the treatment of asthma. TRIAL REGISTRATION: GSK Clinical Study Register No: 202012

Facilitating treatment engagement for early psychosis through peer-delivered decision support : Intervention development and protocol for pilot evaluation

Background: Emerging adults with early psychosis demonstrate high rates of service disengagement from critical early intervention services. Decision support interventions and peer support have both been shown to enhance service engagement but are understudied in this population. The purposes of this article are to describe the development of a novel peer-delivered decision coaching intervention for this population and to report plans for a pilot study designed to gather preliminary data about its feasibility, acceptability, and potential impact. Methods: The intervention was developed based on formative qualitative data and in collaboration with a diverse team of researchers, key stakeholders, and expert consultants. The pilot trial will utilize a single-group (N = 20), pre-post, convergent mixed-methods design to explore whether and how the intervention addresses decision-making needs (the primary intervention target). The impact of the intervention on secondary outcomes (e.g., engagement in the program) will also be assessed. Additionally, through observation and feedback from the peer decision coach and study participants, we will evaluate the feasibility of research and intervention procedures, and the acceptability of information and support from the peer decision coach. Discussion: The peer-delivered decision coaching intervention holds promise for assisting young people with making informed and values-consistent decisions about their care, and potentially enhancing service engagement within this traditionally difficult-to-engage population. If the intervention demonstrates feasibility and acceptability, and pilot data show its potential for improving treatment decision-making, our work will also lay the foundation for a new evidence base regarding roles for peer specialists on early intervention teams

Long-term ocean and resource dynamics in a hotspot of climate change

Unidad de excelencia María de Maeztu CEX2019-000940-MThe abundance, distribution, and size of marine species are linked to temperature and nutrient regimes and are profoundly affected by humans through exploitation and climate change. Yet little is known about long-term historical links between ocean environmental changes and resource abundance to provide context for current and potential future trends and inform conservation and management. We synthesize >4000 years of climate and marine ecosystem dynamics in a Northwest Atlantic region currently undergoing rapid changes, the Gulf of Maine and Scotian Shelf. This period spans the late Holocene cooling and recent warming and includes both Indigenous and European influence. We compare environmental records from instrumental, sedimentary, coral, and mollusk archives with ecological records from fossils, archaeological, historical, and modern data, and integrate future model projections of environmental and ecosystem changes. This multidisciplinary synthesis provides insight into multiple reference points and shifting baselines of environmental and ecosystem conditions, and projects a near-future departure from natural climate variability in 2028 for the Scotian Shelf and 2034 for the Gulf of Maine. Our work helps advancing integrative end-to-end modeling to improve the predictive capacity of ecosystem forecasts with climate change. Our results can be used to adjust marine conservation strategies and network planning and adapt ecosystem-based management with climate change

Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups

Background: Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. Method: Adult subjects (N = 2229; 56.2% male) aged 18–69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age − chronological age) controlling for chronological age, sex, and scan site. Results: BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. Discussion: Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan

The effect of sex and irritable bowel syndrome on HPA axis response and peripheral glucocorticoid receptor expression

Background & Aims: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in irritable bowel syndrome (IBS). Enhanced HPA axis responses have been associated with reduced glucocorticoid receptor (GR) mediated negative feedback inhibition. We aimed to study the effects of IBS status, sex, or presence of early adverse life events (EAL) on the cortisol response to corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), and on GR mRNA expression in peripheral blood mononuclear cells (PBMCs). Methods: Rome III+ IBS patients and healthy controls underwent CRF (1μg/kg ovine) and ACTH (250μg) stimulation tests with serial plasma ACTH and cortisol levels measured (n=116). GR mRNA levels were measured using quantitative PCR (n=143). Area under the curve (AUC) and linear mixed effects models were used to compare ACTH and cortisol response measured across time between groups. Results: There were divergent effects of IBS on the cortisol response to ACTH by sex. In men, IBS was associated with an increased AUC (p= 0.009), but in women AUC was blunted in IBS(p=0.006). Men also had reduced GR mRNA expression (p=0.007). Cumulative exposure to EALs was associated with an increased HPA response. Lower GR mRNA was associated with increased pituitary HPA response and increased severity of overall symptoms and abdominal pain in IBS. Conclusion: This study highlights the importance of considering sex in studies of IBS and the stress response in general. Our findings also provide support for PBMC GR mRNA expression as a peripheral marker of central HPA response

Motivational Interviewing as an intervention to increase adolescent self-efficacy and promote weight loss: Methodology and design

<p>Abstract</p> <p>Background</p> <p>Childhood obesity is associated with serious physiological and psychological consequences including type 2 diabetes, higher rates of depression and low self-esteem. With the population of overweight and obese youth increasing, appropriate interventions are needed that speak to the issue of readiness to change and motivation to maintain adherence to healthy behavior changes. Motivational Interviewing (MI) is a method of therapy found to resolve ambivalence, enhance intrinsic motivation and promote confidence in a person's ability to make behavior changes. While MI has shown promise in the adult obesity literature as effecting positive lifestyle change, little is known about the effectiveness of MI with overweight and obese youth. This study aims to: 1) demonstrate that MI is an effective intervention for increasing a person's self-efficacy; 2) demonstrate that exposure to MI will facilitate healthy behavior changes; 3) explore psychological changes related to participation in MI and 4) compare physiological and anthropometric outcomes before and after intervention.</p> <p>Methods/Design</p> <p>The current investigation is a prospective study conducted with ongoing participants who regularly attend an outpatient pediatric care center for weight-loss. Overweight youth (BMI > 85^th%ile) between the ages of 10 and 18 who meet eligibility criteria will be recruited. Participants will be randomly assigned to a control group (social skills training) or a treatment group (MI). Participants will meet with the therapist for approximately 30 minutes prior to seeing the dietician, over the course of 6 months. Participants will also undergo a full day assessment at the beginning and end of psychology intervention to evaluate body fat, and metabolic risk (screening for diabetes, high cholesterol, high blood pressure and fitness level). The paper and pencil portions of the assessments as well as the clinical testing will occur at baseline and at the conclusion of the intervention (6 months) with a repeat assessment 6 months following the completion of the intervention.</p> <p>Discussion</p> <p>Results from this study are expected to enhance our understanding of the efficacy of MI with children and adolescents who are overweight or obese.</p> <p>Trial registration</p> <p>Current Controlled Trials #<a href="http://www.clinicaltrials.gov/ct2/show/NCT00326404">NCT00326404</a>.</p