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Objective: To examine patient characteristics and resource utilization of hospitalized children and adolescents with somatic symptom and related disorders (SSRDs)., Patients and Methods: This study included 173 patients who were aged 6 to 18 years and admitted to a single, tertiary academic children's hospital between April 2015 and December 2021 with a diagnosis of an SSRD. Sociodemographic information and clinical features were assessed as outcomes. Resource utilization was compared across diagnostic subgroups. Regression analysis was used to determine whether diagnosis predicted length of stay (LOS)., Results: Of the 173 patients included, presenting symptoms were primarily neurologic (n = 109, 63%); the most common diagnostic subgroup was functional neurologic symptom disorder (n = 65, 38%). Resource utilization was notable; the median laboratory studies ordered was 9 (IQR, 4.5-13), 119 of the 173 patients (69%) had at least 1 imaging study, and 124 (72%) had at least 1 physician consultation. The 14-day all-cause emergency department (ED) return rate was 20% (n = 35), and 14-day related ED return rate was 16% (n = 27). After adjustments, LOS was significantly associated with physician-ordered labs (β = 0.32; P = <.001) and consults (β = 0.41; P = <.001)., Conclusion: The findings of this study revealed significant variability in the management of hospitalized patients diagnosed with SSRDs. Future studies to assess the benefit of clinical pathways for SSRDs to standardize management and potentially reduce health care cost by limiting unnecessary evaluation are needed., (Copyright © 2024 by the American Academy of Pediatrics.)

Background: Data regarding care access and outcomes in Black/Indigenous/People of Color/Hispanic (BIPOC/H) individuals is limited. This study evaluated care barriers, disease status, and outcomes among a diverse population of White/non-Hispanic (W/NH) and BIPOC/H inflammatory bowel disease (IBD) patients at a large U.S. health system., Methods: An anonymous online survey was administered to adult IBD patients at Ochsner Health treated between Aug 2019 and Dec 2021. Collected data included symptoms, the Consumer Assessment of Healthcare Providers and Systems and Barriers to Care surveys, health-related quality of life (HRQOL) via the Short Inflammatory Bowel Disease Questionnaire, the Medication Adherence Rating Scale-4, and the Beliefs about Medicines Questionnaire. Medical record data examined healthcare resource utilization. Analyses compared W/NH and BIPOC/H via chi-square and t tests., Results: Compared with their W/NH counterparts, BIPOC/H patients reported more difficulties accessing IBD specialists (26% vs 11%; P = .03), poor symptom control (35% vs 18%; P = .02), lower mean HRQOL (41 ± 14 vs 49 ± 13; P < .001), more negative impact on employment (50% vs 33%; P = .029), worse financial stability (53% vs 32%; P = .006), and more problems finding social/emotional support for IBD (64% vs 37%; P < .001). BIPOC/H patients utilized emergency department services more often (42% vs 22%; P = .004), reported higher concern scores related to IBD medication (17.1 vs 14.9; P = .001), and worried more about medication harm (19.5% vs 17.7%; P = .002). The survey response rate was 14%., Conclusions: BIPOC/H patients with IBD had worse clinical disease, lower HRQOL scores, had more medication concerns, had less access to specialists, had less social and emotional support, and used emergency department services more often than W/NH patients., (© 2023 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

This study assessed direct-acting oral anticoagulant (DOAC) switching/discontinuation patterns in patients with non-valvular atrial fibrillation (NVAF) in 2019, by quarter (Q1-Q4), and associated socioeconomic risk factors. Adults with NVAF initiating stable DOAC treatment (July 2018-December 2018) were selected from Symphony Health Solutions' Patient Transactional Datasets (April 2017-January 2021). Switching/discontinuation rates were reported in 2019 Q1-Q4, separately. Non-medical switching/discontinuation (NMSD) was defined as the difference between switching/discontinuation rates in Q1 and mean rates across Q2-Q4. The associations of socioeconomic factors with switching/discontinuation were assessed. Of 46,793 patients (78.7% ≥ 65 years; 52.6% male; 7.7% Black), 18.0% switched/discontinued their initial DOAC in Q1 vs. 8.8% on average in Q2-Q4, corresponding to an NMSD of 9.2%. During the quarter following the switch/discontinuation, more patients who switched/discontinued in Q1 remained untreated (Q1: 77.0%; Q2: 74.3%; Q3: 71.2%) and fewer reinitiated initial DOAC (Q1: 17.6%; Q2: 20.8%; Q3: 24.0%). Factors associated with the risk of switching/discontinuation in Q1 were race, age, gender, insurance type, and household income (all p < 0.05). More patients with NVAF switched/discontinued DOACs in Q1 vs. Q2-Q4, and more of them tended to remain untreated relative to those who switched/discontinued later in the year, suggesting a potential long-term impact of NMSD. Findings on factors associated with switching/discontinuation highlight potential socioeconomic discrepancies in treatment continuity., Competing Interests: Conflicts of InterestM.I. is a former employee of Janssen Scientific Affairs, LLC and owns stock and options of Janssen Scientific Affairs, LLC. A.P. and V.A. are employees of Janssen Scientific Affairs, LLC and own stock/stock options. H.R., G.C.-L., A.T.-S., P.L. and M.-H.L. are employees of Analysis Group, Inc., a consulting company that has provided paid consulting services to Janssen Scientific Affairs, LLC, which funded the development and conduct of this study and manuscript. The study sponsor was involved in several aspects of the research, including the study design, analyses, interpretation of data, writing of the manuscript, and decision to publish., (© 2024 by the authors.)

Background Medical trainees must learn how to provide effective feedback as an essential communication skill, yet few models exist for training and assessing these skills. Objective To develop an observed structured feedback examination (OSFE) to provide feedback training to pediatric fellows and assess changes in skills and self-reported confidence. Methods This educational study was conducted from 2019 to 2020 at an academic children's hospital. Our team developed the OSFE and trained standardized feedback recipients and faculty. Fellows completed baseline self-assessments (31 items) on prior exposure to feedback training, application of skills, and confidence. They then participated in the OSFE, giving feedback to a standardized recipient using a standardized scenario, and were scored by faculty and recipients using a 15-item checklist for performance. Next, fellows participated in feedback training and received individualized feedback, after which they repeated the OSFE and confidence self-assessment. Three months later, fellows completed self-assessments on confidence and application of skills and another OSFE to assess retention. Descriptive statistics and signed rank sum test were used for analysis. Results Of 60 eligible fellows, 19 participated (32%), with 100% follow-up. After training and individualized feedback, all fellows improved feedback skills as measured by OSFE performance (mean change +0.89). All items, measured on a 5-point Likert scale, were sustained 3 months later (mean change +0.92). All fellows reported improved confidence in feedback knowledge (mean change +2.07 post, +1.67 3 months post). Conclusions Feedback training using simulation and individualized feedback moderately improved fellows' performance, confidence, and 3-month retention of feedback skills.

Purpose: To identify structural markers of active retinopathy of prematurity (ROP) in foveal and parafoveal retinal layers using hand-held optical coherence tomography., Methods: Hand-held optical coherence tomography images (n = 278) were acquired from a prospective mixed cross-sectional longitudinal observational study of 87 participants (23-36 weeks gestational age; n = 30 with ROP, n = 57 without ROP) between 31 and 44 weeks postmenstrual age excluding treated ROP and features of cystoid macular edema. Six retinal layer thicknesses from the fovea to the parafovea were analyzed at five locations up to 1,000 µ m, temporally and nasally., Results: The mean outer retinal thickness during active ROP increased at the fovea and parafovea from postmenstrual age 33 weeks to 39 weeks ( P < 0.001), whereas the parafoveal inner nuclear layer and retinal nerve fiber layer reduced ( P < 0.001). Outer retinal thickness at the fovea from 33 weeks to 39 weeks postmenstrual age was consistently thicker in infants with ROP across all levels of prematurity (gestational age)., Conclusion: Increased foveal and parafoveal outer retina measured using hand-held optical coherence tomography shows potential as a marker for ROP screening., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Background and Objectives: Patient and Family Centered I-PASS (PFC I-PASS) emphasizes family and nurse engagement, health literacy, and structured communication on family-centered rounds organized around the I-PASS framework (Illness severity-Patient summary-Action items-Situational awareness-Synthesis by receiver). We assessed adherence, safety, and experience after implementing PFC I-PASS using a novel "Mentor-Trio" implementation approach with multidisciplinary parent-nurse-physician teams coaching sites., Methods: Hybrid Type II effectiveness-implementation study from 2/29/19-3/13/22 with ≥3 months of baseline and 12 months of postimplementation data collection/site across 21 US community and tertiary pediatric teaching hospitals. We conducted rounds observations and surveyed nurses, physicians, and Arabic/Chinese/English/Spanish-speaking patients/parents., Results: We conducted 4557 rounds observations and received 2285 patient/family, 1240 resident, 819 nurse, and 378 attending surveys. Adherence to all I-PASS components, bedside rounding, written rounds summaries, family and nurse engagement, and plain language improved post-implementation (13.0%-60.8% absolute increase by item), all P < .05. Except for written summary, improvements sustained 12 months post-implementation. Resident-reported harms/1000-resident-days were unchanged overall but decreased in larger hospitals (116.9 to 86.3 to 72.3 pre versus early- versus late-implementation, P = .006), hospitals with greater nurse engagement on rounds (110.6 to 73.3 to 65.3, P < .001), and greater adherence to I-PASS structure (95.3 to 73.6 to 72.3, P < .05). Twelve of 12 measures of staff safety climate improved (eg, "excellent"/"very good" safety grade improved from 80.4% to 86.3% to 88.0%), all P < .05. Patient/family experience and teaching were unchanged., Conclusions: Hospitals successfully used Mentor-Trios to implement PFC I-PASS. Family/nurse engagement, safety climate, and harms improved in larger hospitals and hospitals with better nurse engagement and intervention adherence. Patient/family experience and teaching were not affected., (Copyright © 2024 by the American Academy of Pediatrics.)

Background and Objectives: Acute gastroenteritis (AGE) is a common health care problem accounting for up to 200 000 pediatric hospitalizations annually. Previous studies show disparities in the management of children from different ethnic backgrounds presenting to the emergency department with AGE. Our aim was to evaluate whether differences in medical management also exist between Hispanic and non-Hispanic children hospitalized with AGE., Methods: We performed a single-center retrospective study of children aged 2 months to 12 years admitted to the pediatric hospital medicine service from January 2016 to December 2020 with a diagnosis of (1) acute gastroenteritis or (2) dehydration with feeding intolerance, vomiting, and/or diarrhea. Differences in clinical pathway use, diagnostic studies performed, and medical interventions ordered were compared between Hispanic and non-Hispanic patients., Results: Of 512 admissions, 54.9% were male, 51.6% were Hispanic, and 59.2% were on Medicaid. There was no difference between Hispanic and non-Hispanic patients in reported nausea or vomiting at admission, pathway use, or laboratory testing including stool studies. However, after adjusting for covariates, Hispanic patients had more ultrasound scans performed (odds ratio 1.65, 95% confidence interval 1.04-2.64) and fewer orders for antiemetics (odds ratio 0.53, 95% CI 0.29-0.95) than non-Hispanic patients., Conclusions: Although there were no differences in many aspects of AGE management between Hispanic and non-Hispanic patients, there was still variability in ultrasound scans performed and antiemetics ordered, despite similarities in reported abdominal pain, nausea, and vomiting. Prospective and/or qualitative studies may be needed to clarify underlying reasons for these differences., (Copyright © 2023 by the American Academy of Pediatrics.)

Background: Copay cards are intended to mitigate patient out-of-pocket (OOP) expenses. This qualitative, exploratory focus group study aimed to capture patient perceptions of copay cards and copay adjustment programs (CAPs; insurers' accumulator and maximizer policies), which redirect the copay card utilization benefits intended for patients' OOP expenses., Methods: Patients with chronic conditions were recruited through Janssen's Patient Engagement Research Council program. They completed a survey and attended a live virtual session to provide feedback on copay cards., Results: Among 33 participants (median age, 49 years [range, 24-78]), the most frequent conditions were cardiovascular-metabolic disease and inflammatory bowel disease. Patients associated copay cards with lessening financial burden, improving general and mental health, and enabling medication adherence. An impact on medication adherence was identified by 10 (63%) White and nine (100%) Black respondents. Some patients were unaware of CAPs despite having encountered them; they recommended greater copay card education and transparency about CAPs., Conclusion: Patients relied on copay cards to help afford their prescribed medication OOP expenses and maintain medication adherence. Use of CAPs may increase patient OOP expenses. Patients would benefit from awareness programs and industry - healthcare provider partnerships that facilitate and ensure access to copay cards., Competing Interests: In accordance with Taylor & Francis policy, authors have the following disclosures: D.C. is an independent consultant and a contract consultant with Janssen Scientific Affairs, LLC, and has been diagnosed with multiple sclerosis; B.D., G.G., A.P., S.Z., and L.S., are employees of Janssen Scientific Affairs, LLC. W.P. is an employee of CorEvitas, LLC, which derives its profits from interactions with pharmaceutical sponsors., (© 2023 Jannsen Scientific Affairs, LLC. Published by Informa UK Limited, trading as Taylor & Francis Group.)

Objective: To identify locations with higher need for acute pediatric mental health (MH) interventions or services and describe these communities' socio-demographic characteristics., Methods: This single-center retrospective study included patients 5 to 18 years old with an emergency department (ED) or hospital admission between 2017 and 2019 for a primary known MH diagnosis or symptoms. We extracted visit data from the electronic medical record, mapped patients to their home census tract, calculated normalized visit rates by census tract, and performed spatial analysis to identify nonrandom geographic clusters and outliers of high utilization. Census tract utilization rates were stratified into quartiles, and socioeconomic and demographic characteristics obtained from the US Census Bureau were compared using analysis of variance, chi-square tests, and multivariable analysis., Results: There were 10,866 qualifying visits across 617 census tracts. ED and hospital admission rates ranged from 2.7 to 428.6 per 1000 children. High utilization clusters localized to neighborhoods with lower socioeconomic status (p < .05). Southern regions with high utilizers were more likely to have fewer children per neighborhood, higher rates of teen births, and lower socioeconomic status. Multivariate analysis showed regions with high utilizers had fewer children per neighborhood, lower median household income, and more families that lacked computer access., Conclusion: ED and hospital utilization for pediatric MH concerns varied significantly by neighborhood and demographics. Divergent social factors map onto these locations and are related to MH utilization. Leveraging geography can be a powerful tool in the development of targeted, culturally tailored interventions to decrease acute pediatric MH utilization and advance child MH equity., (Copyright © 2022 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Objective: Oral feeding by children with bronchiolitis on high-flow nasal cannula (HFNC) is questioned, resulting in high practice variability. Our objective was to determine the incidence of aspiration pneumonia and adverse feeding events in otherwise healthy children with bronchiolitis on HFNC who fed orally from admission., Methods: We conducted a single-center, retrospective chart review, in a tertiary children's hospital, of 876 children who were <24 months old, admitted for bronchiolitis, and treated with HFNC in the pediatric ward from March 2017 to May 2020. Primary outcomes included the incidence of aspiration pneumonia and adverse feeding events. Secondary outcomes included escalation of care, frequency and duration of nil per os status, length of stay, and 7-day readmission., Results: Most patients (77.2%) met inclusion criteria and were fed orally within 2 hours of admission. The average maximum HFNC flow rate was 8 L/min (1 L/kg/min); the average maximum respiratory rate was 62 ± 10. Adverse feeding events occurred in 11 patients (1.6%), of which 3 had a concern for possible microaspiration. None were diagnosed with or treated for aspiration pneumonia. Few patients (8.1%) were made nil per os while on HFNC but returned to oral feeding by discharge., Conclusion: Among those with bronchiolitis on HFNC who received oral nutrition on admission, there were few incidences of adverse feeding events and no diagnoses of aspiration pneumonia, suggesting that oral feeding while on HFNC can be well-tolerated in similar populations. However, this study was limited by its single-center retrospective design, and future prospective studies are needed., (Copyright © 2023 by the American Academy of Pediatrics.)

Background: Friedreich's ataxia (FRDA) is an autosomal recessive disease, whereby homozygous inheritance of an expanded GAA trinucleotide repeat expansion in the first intron of the FXN gene leads to transcriptional repression of the encoded protein frataxin. FRDA is a progressive neurodegenerative disorder, but the primary cause of death is heart disease which occurs in 60% of the patients. Several functions of frataxin have been proposed, but none of them fully explain why its deficiency causes the FRDA phenotypes nor why the most affected cell types are neurons and cardiomyocytes., Methods: To investigate, we generated iPSC-derived neurons (iNs) and cardiomyocytes (iCMs) from an FRDA patient and upregulated FXN expression via lentivirus without altering genomic GAA repeats at the FXN locus., Results: RNA-seq and differential gene expression enrichment analyses demonstrated that frataxin deficiency affected the expression of glycolytic pathway genes in neurons and extracellular matrix pathway genes in cardiomyocytes. Genes in these pathways were differentially expressed when compared to a control and restored to control levels when FRDA cells were supplemented with frataxin., Conclusions: These results offer novel insight into specific roles of frataxin deficiency pathogenesis in neurons and cardiomyocytes., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Traumatic brain injuries (TBIs) affect more than 10 million patients annually worldwide, causing long-term cognitive and psychosocial impairments. Frontal lobe TBIs commonly impair executive function, but laboratory models typically focus primarily on spatial learning and declarative memory. We implemented a multi-modal approach for clinically relevant cognitive-behavioral assessments of frontal lobe function in rats with TBI and assessed treatment benefits of the serotonin-norepinephrine reuptake inhibitor, milnacipran (MLN). Two attentional set-shifting tasks (AST) evaluated cognitive flexibility via the rats' ability to locate food-based rewards by learning, unlearning, and relearning sequential rule sets with shifting salient cues. Adult male rats reached stable pre-injury operant AST (oAST) performance in 3-4 weeks, then were isoflurane-anesthetized, subjected to a unilateral frontal lobe controlled cortical impact (2.4 mm depth, 4 m/sec velocity) or Sham injury, and randomized to treatment conditions. Milnacipran (30 mg/kg/day) or vehicle (VEH; 10% ethanol in saline) was administered intraperitoneally via implanted osmotic minipumps (continuous infusions post-surgery, 60 μL/h). Rats had a 10-day recovery post-TBI/Sham before performing light/location-based oAST for 10 days and, subsequently, odor/media-based digging AST (dAST) on the last test day (26-27 days post-injury) before sacrifice. Both AST tests revealed significant deficits in TBI+VEH rats, seen as elevated total trials and errors ( p  < 0.05), which generally normalized in MLN-treated rats ( p  < 0.05). This first simultaneous dual AST assessment demonstrates oAST and dAST are sufficiently sensitive and robust to detect subtle attentional and cognitive flexibility executive impairments after frontal lobe TBI in rats. Chronic MLN administration shows promise for attenuation of post-TBI executive function deficits, thus meriting further investigation.

Background: COVID-19 vaccine hesitancy in the United States is high, with at least 63 million unvaccinated individuals to date. Socioeconomically disadvantaged populations experience lower COVID-19 vaccination rates despite facing a disproportionate COVID-19 burden., Objective: To assess the factors associated with COVID-19 vaccine acceptance among under-resourced, adult patients., Methods: Participants were patients receiving care at a Federally Qualified Health Center (FQHC) in St. Paul, Minnesota. Data were collected via multiple modes over 2 phases in 2020 (self-administered electronic survey) and 2021 (study team-administered survey by telephone, self-administered written survey) to promote diversity and inclusion for study participation. The primary outcome was COVID-19 vaccine acceptance. Using logistic regression analysis, associations between vaccine acceptance and factors including risk perception, concerns about the COVID-19 vaccine, social determinants of health (SDOH), co-morbidities, pandemic-induced hardships, and stress were assessed by adjusted odds ratios (AORs) and 95% confidence intervals (CI)., Results: One hundred sixty-eight patients (62.5% female; mean age [SD]: 49.9 [17.4] years; 32% <$20 000 annual household income; 69%

Bacterial infections continue to pose serious public health challenges. Though anti-bacterial therapeutics are effective remedies for treating these infections, the emergence of antibiotic resistance has imposed new challenges to treatment. Often, there is a delay in prescribing antibiotics at initial symptom presentation as it can be challenging to clinically differentiate bacterial infections from other organisms (e.g., viruses) causing infection. Moreover, bacterial infections can arise from food, water, or other sources. These challenges have demonstrated the need for rapid identification of bacteria in liquids, food, clinical spaces, and other environments. Conventional methods of bacterial identification rely on culture-based approaches which require long processing times and higher pathogen concentration thresholds. In the past few years, microfluidic devices paired with various bacterial identification methods have garnered attention for addressing the limitations of conventional methods and demonstrating feasibility for rapid bacterial identification with lower biomass thresholds. However, such culture-free methods often require integration of multiple steps from sample preparation to measurement. Research interest in using microfluidic methods for bacterial identification is growing; therefore, this review article is a summary of current advancements in this field with a focus on comparing the efficacy of polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), and emerging spectroscopic methods.

Pediatric palliative home-based care has been shown to improve symptoms, quality of life, and coordination of care. Despite these successes, hospital utilization in our own palliative home-based care population remained high as some caregivers lacked confidence to manage symptoms at home and had difficulty in recalling or accessing "sick care plans." Our team developed the Symptom Management Plan (SMP), a multi-system "sick care plan," as a quality improvement project with the aim of improving caregiver confidence to manage symptoms at home. An Electronic Health Record-based SMP template was created for common symptoms: respiratory distress, seizures, feeding intolerance, and constipation with core subspecialists' input. Individualized SMPs were created and reviewed with caregivers at every subsequent palliative home nursing visit. Caregivers were surveyed on their confidence 3 and 6-months post-implementation. Resource utilization was analyzed throughout implementation. At 6 months, 73% of caregivers reported "better" or "much better" confidence in managing their child's symptoms after using the SMP, and 76% of caregivers perceived the SMP prevented urgent care or emergency department (ED) visits. After the SMP was launched, the rate of ED visits decreased from 0.86 to 0.47 per 100 patient-days, and admissions decreased from 0.56 to 0.39 per 100 patient-days. These rates further decreased to 0.31 ED visits and 0.19 admissions per 100 patient-days within 4 and 6 months. Introducing the SMP for our home-based palliative care patients was associated with improved caregiver confidence in managing acute symptoms at home and a reduction in hospital utilization., (Copyright © 2022 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Effective communication in transitions between healthcare team members is associated with improved patient safety and experience through a clinically meaningful reduction in serious safety events. Family-centered rounds (FCR) can serve a critical role in interprofessional and patient-family communication. Despite widespread support, FCRs are not utilized consistently in many institutions. Structured FCR approaches may prove beneficial in increasing FCR use but should address organizational challenges. The purpose of this study was to identify intervention, individual, and contextual determinants of high adherence to common elements of structured FCR in pediatric inpatient units during the implementation phase of a large multi-site study implementing a structured FCR approach., Methods: We performed an explanatory sequential mixed methods study from September 2019 to October 2020 to evaluate the variation in structured FCR adherence across 21 pediatric inpatient units. We analyzed 24 key informant interviews of supervising physician faculty, physician learners, nurses, site administrators, and project leaders at 3 sites using a qualitative content analysis paradigm to investigate site variation in FCR use. We classified implementation determinants based on the Consolidated Framework for Implementation Research., Results: Provisional measurements of adherence demonstrated considerable variation in structured FCR use across sites at a median time of 5 months into the implementation. Consistent findings across all three sites included generally positive clinician beliefs regarding the use of FCR and structured rounding approaches, benefits to learner self-efficacy, and potential efficiency gains derived through greater rounds standardization, as well as persistent challenges with nurse engagement and interaction on rounds and coordination and use of resources for families with limited English proficiency., Conclusions: Studies during implementation to identify determinants to high adherence can provide generalizable knowledge regarding implementation determinants that may be difficult to predict prior to implementation, guide adaptation during the implementation, and inform sustainment strategies., (© 2022. The Author(s).)

Extracellular vesicles (EVs) are double membrane structures released by all cell types with identified roles in the generation, transportation, and degradation of amyloid-β protein (Aβ) oligomers in Alzheimer's disease (AD). EVs are thus increasingly recognized to play a neuroprotective role in AD, through their ability to counteract the neurotoxic effects of Aβ, possibly through interactions with specific receptors on cell membranes. Our previous studies have identified the amylin receptor (AMY), particularly AMY3 subtype, as a mediator of the deleterious actions of Aβ in vitro and in vivo experimental paradigms. In the present study, we demonstrate that AMY3 enriched EVs can bind soluble oligomers of Aß and protect N2a cells against toxic effects of this peptide. The effect was specific to amylin receptor as it was blocked in the presence of amylin receptor antagonist AC253. This notion was supported by reduced Aβ binding to EVs from AMY depleted mice compared to those from wild type (Wt) mice. Finally, application of AMY3, but not Wt derived, EVs to hippocampal brain slices improved Aβ-induced reduction of long-term potentiation, a cellular surrogate of memory. Collectively, our observations support the role of AMY receptors, particularly AMY3, in EVs as a potential therapeutic target for AD., Competing Interests: The authors have declared that no competing interests exist.

Treatment response to clopidogrel is associated with CYP2C19 activity through the formation of the active H4 metabolite. The aims of this study were to develop a physiologically based pharmacokinetic (PBPK) model of clopidogrel and its metabolites for populations of European ancestry, to predict the pharmacokinetics in the Japanese population by CYP2C19 phenotype, and to investigate the effect of clinical and demographic factors. A PBPK model was developed and verified to describe the two metabolic pathways of clopidogrel (H4 metabolite, acyl glucuronide metabolite) for a population of European ancestry using plasma data from published studies. Subsequently, model predictions in the Japanese population were evaluated. The effects of CYP2C19 activity, fluvoxamine coadministration (CYP2C19 inhibitor), and population-specific factors (age, sex, BMI, body weight, cancer, hepatic, and renal dysfunction) on the pharmacokinetics of clopidogrel and its metabolites were then characterized. The predicted/observed ratios for clopidogrel and metabolite exposure parameters were acceptable (twofold acceptance criteria). For all CYP2C19 phenotypes, steady-state AUC 0-τ of the H4 metabolite was lower for the Japanese (e.g., EM, 7.69 [6.26-9.45] ng·h/ml; geometric mean [95% CI]) than European (EM, 24.8 [20.4-30.1] ng·h/ml, p < .001) population. In addition to CYP2C19-poor metabolizer phenotype, fluvoxamine coadministration, hepatic, and renal dysfunction were found to reduce H4 metabolite but not acyl glucuronide metabolite concentrations. This is the first PBPK model describing the two major metabolic pathways of clopidogrel, which can be applied to populations of European and Japanese ancestry by CYP2C19 phenotype. The differences between the two populations appear to be determined primarily by the effect of varying CYP2C19 liver activity., (© 2022 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Background and Objectives: Physiologically based pharmacokinetic (PBPK) modelling has evolved to accommodate different routes of drug administration and enables prediction of drug concentrations in tissues as well as plasma. The inhalation route of administration has proven successful in treating respiratory diseases but can also be used for rapid systemic delivery, holding great promise for treatment of diseases requiring systemic exposure. The objective of this work was to develop a PBPK model that predicts plasma and tissue concentrations following inhalation administration of the PI3Kδ inhibitor nemiralisib., Methods: A PBPK model was built in GastroPlus ® that includes a complete mechanistic description of pulmonary absorption, systemic distribution and oral absorption following inhalation administration of nemiralisib. The availability of clinical data obtained after intravenous, oral and inhalation administration enabled validation of the model with observed data and accurate assessment of pulmonary drug absorption. The PBPK model described in this study incorporates novel use of key parameters such as lung systemic absorption rate constants derived from human physiological lung blood flows, and implementation of the specific permeability-surface area product per millilitre of tissue cell volume (SpecPStc) to predict tissue distribution., Results: The inhaled PBPK model was verified using plasma and bronchoalveolar lavage fluid concentration data obtained in human subjects. Prediction of tissue concentrations using the permeability-limited systemic disposition tissue model was further validated using tissue concentration data obtained in the rat following intravenous infusion administration to steady state., Conclusions: Fully mechanistic inhaled PBPK models such as the model described herein could be applied for cross molecule assessments with respect to lung retention and systemic exposure, both in terms of pharmacology and toxicology, and may facilitate clinical indication selection., (© 2021. The Author(s).)

Advances in cancer research over the past half-century have clearly determined the molecular origins of the disease. Central to the use of molecular signatures for continued progress, including rapid, reliable, and early diagnosis is the use of biomarkers. Specifically, extracellular vesicles as biomarker cargo holders have generated significant interest. However, the isolation, purification, and subsequent analysis of these extracellular vesicles remain a challenge. Technological advances driven by microfluidics-enabled devices have made the challenges for isolation of extracellular vesicles an emerging area of research with significant possibilities for use in clinical settings enabling point-of-care diagnostics for cancer. In this article, we present a tutorial review of the existing microfluidic technologies for cancer diagnostics with a focus on extracellular vesicle isolation methods.

World Health Organization categorized breast cancer as one of the leading cancer types in females worldwide, and its treatment remains challenging. Accumulated evidence suggested the role of estrogen and its metabolites in pre- and post-menopausal women. Upregulation of estrogen-dependent aromatase is significantly involved in the pathogenesis of breast cancer. Several aromatase inhibitors, such as exemestane, formestane, and letrozole, are being used clinically, owing to their estrogen suppression role. Apart from these drugs, several other molecules, such as natural and synthetic flavonoids, have been reported widely for a similar biological activity. However, some reasonable modifications are required for these structures to achieve desired efficacy and to alleviate toxicity. Designing a novel aromatase inhibitor will be possible if we can establish a rational correlation between the chemistry and biological features of the existing molecules. The benzopyranone- ring system, present in the flavonoid molecules, has been reported as a pharmacophore due to its inhibitory activity on aromatase, which helps repress breast cancer progression. This essential feature has been utilized to modify several natural flavonoids into 5 and 7 hydroxy/methoxy flavone, 4-imidazolyl/triazolyl flavone, 5,4'- diamino flavone, 7,8- benzo-4-imidazolyl flavone, α-naphthoflavone, and 2-azole/thiazolyl isoflavone derivatives. These scaffolds have been considered in this review for meticulous study in aspects of the structure-activity relationship for aromatase inhibitory activity, and it would likely pave the way for designing a potential lead candidate in the future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The US Census confirms a rise in Spanish-speakers, many of whom have limited English proficiency (LEP) and require interpreters. Parent perceptions of interpreter services throughout hospitalization are unknown., Objective: To explore Spanish-speaking LEP parents' views regarding roles of interpreters and providers (attending, resident, or nurse) during a hospital encounter, optimal modalities of interpretation, and barriers to services., Methods: Spanish-speaking LEP parents of children discharged from the hospital medicine service participated in focus groups. Sessions were audio-recorded and transcribed in Spanish, translated into English, and verified for translation accuracy. Qualitative methods were used for thematic analysis., Results: Four sessions (n = 23 participants representing 15 families) were held. Parents felt the interpreter's primary role was to act as a conduit for word-for-word interpretation. They desired kind and trustworthy interpreters with medical knowledge. They saw providers as leaders of the encounter who should allot enough time for interpretation, not use Spanish unless they were fluent, and give frequent medical updates. In-person interpreters were preferred over telephone and video for their ability to convey body language and build relationships. Barriers to requesting interpreters included embarrassment and inability to directly request services, which resulted in using family members as interpreters. On family-centered rounds, parents preferred professional interpreters over bilingual providers., Conclusions: Modifications are required to improve interpreter services to meet the needs of LEP families. Parents emphasized in-person interpreters' social skills, frequent provider updates, and additional navigation support as essential components of effective care. Next steps include implementing guidelines and interventions to optimize interpreter services., (Copyright © 2021 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Cardiovascular diseases including cardiac arrhythmias lead to fatal events in patients with coronary artery disease; however, clinical associations from echocardiography, electrocardiography (ECG), and biomarkers remain unknown. We sought to identify the factors that may be related to elevated QRS intervals in patients with risk for coronary artery disease. In this study, we performed analysis of clinical data from 503 patients divided into two groups, i.e., patients with either <50% coronary artery stenosis or >50% coronary artery stenosis. We further examined patients with elevated ECG parameters such as QRS > 100 ms and QTc > 440 ms. Patients with >50% coronary artery stenosis exhibited significant increases in age, triglycerides, and troponin levels. Further, ECG parameters demonstrated increased QRS and QTc durations, while echocardiographic parameters highlighted a decrease in ejection fraction (EF) and fractional shortening (FS). Patients with QTc > 440 ms exhibited increased brain natriuretic peptide and creatinine levels with a decrease in estimated glomerular filtration rate clearance rates. Patients with QRS > 100 ms had greater left ventricular (LV) mass and LV internal diameter in systole and diastole. Multimodal logistic regression showed significant relation between QTc, age, and creatinine. These findings suggest that patients with significant coronary stenosis may have lower EF and FS with prolonged QRS intervals, demonstrating greater risk for arrhythmic events.

Based upon its interactions with amyloid β peptide (Aβ), the amylin receptor, a class B G protein-coupled receptor (GPCR), is a potential modulator of Alzheimer's disease (AD) pathogenesis. However, past pharmacological approaches have failed to resolve whether activation or blockade of this receptor would have greater therapeutic benefit. To address this issue, we generated compound mice expressing a human amyloid precursor protein gene with familial AD mutations in combination with deficiency of amylin receptors produced by hemizygosity for the critical calcitonin receptor subunit of this heterodimeric GPCR. These compound transgenic AD mice demonstrated attenuated responses to human amylin- and Aβ-induced depression of hippocampal long-term potentiation (LTP) in keeping with the genetic depletion of amylin receptors. Both the LTP responses and spatial memory (as measured with Morris water maze) in these mice were improved compared to AD mouse controls and, importantly, a reduction in both the amyloid plaque burden and markers of neuroinflammation was observed. Our data support the notion of further development of antagonists of the amylin receptor as AD-modifying therapies., (© 2021. The Author(s).)

Introduction: People with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD) have increased morbidity and mortality risk. Angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) are recommended to slow kidney function decline in DKD. This representative, real-world data analysis of patients with T2DM was performed to detect onset of DKD and determine methods and timing of DKD diagnosis and time to initiation of ACEi/ARB therapy., Methods: Patients diagnosed with T2DM before January 1, 2016 who developed DKD between January 1, 2017 and June 30, 2019 were identified from a longitudinal ambulatory electronic health record (EHR) dataset (Veradigm Inc). Each record was analyzed using the CLinical INTelligence engine (CLINT™, HealthPals, Inc.) to identify delays and gaps in diagnosing DKD. DKD was diagnosed through two reduced estimated glomerular filtration rate (eGFR; < 60 mL/min/1.73 m 2 ) measurements at least 90 days apart, a single elevated urine albumin-to-creatinine ratio (UACR; > 30 mg/g) measurement, or ICD-9/10 diagnosis codes for DKD and/or albuminuria. Time to diagnose (TTD), time to treat (TTT), and diagnosis to treatment time were assessed., Results: Of 6,499,409 patients with T2DM before January 2016, 245,978 developed DKD between January 1, 2017 and June 30, 2019. In this DKD cohort, ca. 50% were first identified through EHR diagnosis and ca. 50% by UACR or eGFR lab-based diagnosis. In patients who had UACR/eGFR assessed, more than 90% exhibited DKD-level results on the first diagnostic test. Average TTD after eGFR labs was 2 years; average TTT with ACEi/ARB was 6-9 months after DKD lab evidence. The majority of patients who developed DKD received ACEi/ARB therapy 6-7 months after diagnosis., Conclusion: In a contemporary, large national cohort of patients with T2DM, progression to DKD was common but likely underrepresented. The low rate of DKD-screening labs, along with sizable delays in diagnosis of DKD and initiation of ACEi/ARB therapy, indicates that many patients who progress to DKD are not being properly treated., (© 2021. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Introduction: Discharge communication is critical for the continuity of patient care. However, discharge summaries are often not available in time for follow-up visits, and the content is inconsistent. We aimed to decrease the average time to discharge summary completion by 25%, reduce deficiencies (information errors) by 50%, and increase discharge summary template use to >80% in 6 months., Methods: A pediatric interprofessional team used quality improvement methods to identify barriers and implement interventions, including discharge summary completion time expectation, electronic health record discharge summary template changes addressing gaps, and training. Notable changes to the template included embedded writing tips to guide writers and specific template choices for common diagnoses to standardize content. The primary outcome measure was the mean discharge summary completion time. Secondary measures were the percentage of discharge summaries with deficiencies and the rate of template use., Results: After interventions, the mean discharge summary completion time decreased by 70% (from 71.5 to 21.8 hours). Discharge summary deficiencies decreased 44% (from 4.5% to 2.5%), and template use increased from 62% to 97%., Conclusion: Quality improvement methods and a newly designed electronic health record-discharge summary template were used to dramatically improve discharge summary timeliness and standardize content to streamline continuity of care., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background/Objective : This study evaluated emergency department (ED) visit trends, subsequent inpatient admissions for patients with inflammatory bowel disease (IBD) diagnosis and IBD-related abdominal pain (AP), and hospital-level variation in inpatient admission rates in the USA (US). Methods : This population-based, cross-sectional study included data from Nationwide Emergency Department Sample (NEDS, 2006─2013) database. Patients ≥18 years of age with primary ED diagnosis of IBD/IBD-related AP were included. Variables included demographics, insurance information, household income, Quan-Charlson comorbidity score, ED discharge disposition, and length of hospital stay (2006, 2010, and 2013). Variation between hospitals using risk-adjusted admission ratio was estimated. Results : Annual ED visits for IBD/100,000 US population increased (30 in 2006 vs 42 in 2013, p = 0.09), subsequent admissions remained stable (20 in 2006 vs 23 in 2013, p = 0.52). ED visits for IBD-related AP increased by 71% (7 in 2006 vs 12 in 2013; p = 0.12), subsequent admissions were stable (0.50 in 2006 vs 0.58 in 2013; p = 0.88). Proportion of patients with subsequent hospitalization decreased (IBD: 65.7% to 55.7%; IBD-related AP: 6.9% to 4.9%). Variation in subsequent inpatient admissions was 1.42 (IBD) and 1.96 (IBD-related AP). Conclusions : An increase in annual ED visits was observed for patients with IBD and IBD-related AP; however, subsequent inpatient admission rate remained stable., Competing Interests: ZD, AP, JI, and CDP are employees of Janssen Pharmaceuticals (a Johnson & Johnson company) and hold stock in Johnson & Johnson. JHL is a former employee of Janssen Pharmaceuticals and was employed by Janssen Pharmaceuticals during study design, data interpretation and drafting of the manuscript. CWB has worked as a consultant and advisory board member for Janssen Pharmaceuticals, Salix Pharmaceuticals and Vapotherm; has previously received research funding from Janssen Pharmaceuticals and Boehringer Ingelheim; and has also served as an advisory board member and as a paid speaker for Roche Diagnostics., (© 2021 Informa UK Limited, trading as Taylor & Francis.)

The COVID-19 pandemic has disproportionately affected underserved and minority populations in the United States. This is partially attributable to limited access to diagnostic testing from deeply rooted structural inequities precipitating higher infection and mortality rates. We describe the process of establishing a drive-through collection site by leveraging an academic-community partnership between a medical institution and a federally qualified health center in Minnesota. Over 10 weeks, 2006 COVID-19 tests were provided to a socioeconomically disadvantaged population of racial/ethnic minorities and low-income essential workers.

Molibresib (GSK525762), an orally bioavailable small molecule with 2 major equipotent active metabolites, is being developed for the treatment of cancers. Molibresib is a substrate of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp). To enable administering safe doses of molibresib to healthy volunteers, this 2-part randomized, open-label, crossover drug-drug interaction trial was conducted as an adaptive design study using physiologically based pharmacokinetic (PBPK) modeling and simulation to predict the lowest doses of molibresib that could be safely administered alone (10 mg) or with itraconazole and rifampicin (strong inhibitors and inducers of CYP3A and P-gp, respectively). PBPK simulation guided the molibresib dose (5 mg) to be administered along with itraconazole in part 1. Itraconazole increased total exposure (AUC) of molibresib by 4.15-fold with a 66% increase in C max , whereas the total AUC and C max for the 2 major active metabolites of molibresib decreased by about 70% and 87%, respectively. A second PBPK simulation was conducted with part 1 data to also include the active metabolites to update the recommendation for the molibresib dose (20 mg) with rifampicin. With rifampicin, the AUC and C max of molibresib decreased by approximately 91% and 80%, respectively, whereas the AUC of the 2 active metabolites decreased to a lesser extent (8%), with a 2-fold increase in C max . The results of this study confirmed the in vitro data that molibresib is a substrate for CYP3A4. The adaptive design, including Simcyp simulations, allowed evaluation of 2 drug interactions of an oncology drug in a single trial, thus minimizing time and exposures administered to healthy subjects., (© 2020 Glaxo Group Limited. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlus™ (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project. Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters. On average, PK parameters (Area Under the Concentration-time curve (AUC 0-tlast ), Maximal concentration (C max ), half-life (t 1/2 )) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC 0-tlast and around 90% of the simulations were within 10-fold error for AUC 0-tlast . Oral bioavailability (F oral ) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC 0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC 0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: To investigate dynamic foveal morphology with postmenstrual age, in preterm infants with and without retinopathy of prematurity using hand-held optical coherence tomography, adjusting for gestational age (GA) and birthweight (BW)., Methods: Prospective mixed cross-sectional/longitudinal observational study of 87 participants (23-36 weeks GA; n = 30 with, n = 57 without retinopathy of prematurity) using hand-held optical coherence tomography images (n = 278) acquired between 31 weeks and 44 weeks postmenstrual age excluding treated retinopathy of prematurity. Measurements included foveal width, area, depth, central foveal thickness, maximum slope, and parafoveal retinal thickness at 1,000 µm nasal and temporal to the central fovea., Results: Retinopathy of prematurity was significantly correlated with only foveal width in either GA or BW adjusted statistical models. In contrast, severity of prematurity (GA, BW) correlated with foveal area (P < 0.005), depth (P ≤ 0.001), and slope (P < 0.01), although central foveal thickness (P = 0.007) and parafoveal retinal thickness (P < 0.001) correlated with GA, but not with BW., Conclusion: Foveal width is independent of GA and BW with potential in retinopathy of prematurity screening assessment using hand-held optical coherence tomography. Foveal morphology could be graded in prematurity during development, with possible implications for future management of preterm infants.

Introduction: Hospitalization is the largest component of health care spending in the United States. Most hospitalized patients first visit the emergency department (ED), where hospitalization decisions are made. Optimal utilization of hospital resources is critical for all stakeholders., Methods: We performed a population-based, cross-sectional study evaluating ED visits and subsequent inpatient admissions for patients with coronary artery disease (CAD) and chest pain (CP) suggestive of CAD from 2006 to 2013 using the Nationwide Emergency Department Sample database weighted for national estimates. We analyzed trends using a generalized linear regression model with a Poisson distribution and Wald test., Results: From 2006 to 2013, there was a 15% decrease in ED visits for CAD (p < 0.01), while ED visit rates for CP increased 31% (p < 0.01). Subsequent inpatient admission rates decreased 18% for CAD (p < 0.01) and 33% for CP (p < 0.01). Trends were not modified by patient and hospital strata., Conclusion: ED visits and subsequent inpatient admissions resulting from CAD decreased from 2006 to 2013. Patients with CP had a substantially higher number of ED visits, with a significant decline in inpatient admissions.

In vitro data for low-dose inhaled phosphoinositide 3-kinase delta inhibitor nemiralisib revealed that it was a substrate and a potent metabolism-dependent inhibitor of cytochrome P450 (P450) 3A4 and a P-glycoprotein (P-gp) substrate. An integrated in silico, in vitro, and clinical approach including a clinical drug interaction study as well as a bespoke physiologically based pharmacokinetic (PBPK) model was used to assess the drug-drug interaction (DDI) risk. Inhaled nemiralisib (100 µg, single dose) was coadministered with itraconazole, a potent P4503A4/P-gp inhibitor, following 200 mg daily administrations for 10 days in 20 male healthy subjects. Systemic exposure to nemiralisib (AUC 0-inf ) increased by 2.01-fold versus nemiralisib alone. To extrapolate the clinical data to other P4503A4 inhibitors, an inhaled PBPK model was developed using Simcyp software. Retrospective simulation of the victim risk showed good agreement between simulated and observed data (AUC 0-inf ratio 2.3 vs. 2.01, respectively). Prospective DDI simulations predicted a weak but manageable drug interaction when nemiralisib was coadministered with other P4503A4 inhibitors, such as the macrolides clarithromycin and erythromycin (simulated AUC 0-inf ratio of 1.7), both common comedications in the intended patient populations. PBPK and static mechanistic models were also used to predict a negligible perpetrator DDI effect for nemiralisib on other P4503A4 substrates, including midazolam (a sensitive probe substrate of P4503A4) and theophylline (a narrow therapeutic index drug and another common comedication). In summary, an integrated in silico, in vitro, and clinical approach including an inhalation PBPK model has successfully discharged any potential patient DDI risks in future nemiralisib clinical trials. SIGNIFICANCE STATEMENT: This paper describes the integration of in silico, in vitro, and clinical data to successfully discharge potential drug-drug interaction risks for a low-dose inhaled drug. This work featured assessment of victim and perpetrator risks of drug transporters and cytochrome P450 enzymes, utilizing empirical and mechanistic approaches combined with clinical data (drug interaction and human absorption, metabolism, and pharmacokinetics) and physiologically based pharmacokinetic modeling approaches to facilitate bespoke risk assessment in target patient populations., (Copyright © 2020 The Author(s).)

Background: We compared self-reported domains of health between patients who with vs. without a recent heart failure (HF) hospitalization., Methods: We fielded a 59-item questionnaire that included the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12) to age/sex-matched groups of 2000 HF patients who had and had not had a recent HF hospitalization. We entered questionnaire responses and electronic medical record data into multivariable logistic regression models to identify independent associations with a HF hospitalization., Results: After two mailings, we received 468 completed questionnaires for response rate of 23.4%. Patients with a recent HF hospitalization had significantly lower scores on the KCCQ-12 Quality of Life (52.6 vs. 59.6, p = 0.016) and Social Limitations (48.4 vs. 55.5, p = 0.009) scales as well as the Clinical Summary Scale (50.8 vs. 55.3, p = 0.048) and Total KCCQ-12 score (49.6 vs. 56.8, p = 0.003). In sequential logistic regression models designed to achieve parsimony, Total KCCQ was a strong predictor of being in the recent hospitalization group. When using the KCCQ-12 sub-scales, the Social Limitations scale was a strong predictor of being in the recent hospitalization group., Conclusions: After accounting for comorbidities and other risk factors, a HF hospitalization appears to profoundly limit social activities which can increase the risk of poor outcomes.

Background: Many Americans have limited English proficiency (LEP) and difficulty communicating with health care providers, creating inequitable health care delivery. Despite widespread interpreter availability in hospitals, perceptions of interpreter services in the pediatric inpatient setting are largely unknown., Objective: To investigate staff perspectives regarding: 1) roles of the interpreter and provider (attending, resident, and nurse) during an encounter, 2) modalities of interpretation, and 3) barriers to services., Methods: Focus groups were conducted with: 1) hospital-employed Spanish interpreters, 2) Pediatric Hospital Medicine attendings, 3) pediatric and internal medicine-pediatric residents, and 4) medical unit nurses. Sessions were audio-recorded and transcribed. Using Atlas.ti, 2 investigators created the coding scheme, independently coded the data, and achieved consensus. Qualitative methods were used for thematic analysis., Results: Fourteen groups (n = 59 participants) were held: 3 interpreter groups (n = 10), 3 attending groups (n = 14), 2 resident groups (n = 17), and 6 nurse groups (n = 18). Most believed the interpreter's role was to serve as a conduit (provide word-for-word interpretation), act as a cultural broker, and maintain transparency (not withhold information). All groups felt providers should interact with families as they would with English-speaking families. In-person interpreters were preferred over telephone and video for being more accurate, efficient, and personable. Barriers to accessing services included time needed for interpretation, overconfidence in language skills, variable family dynamics, and identification of LEP families., Conclusions: In-person interpreters are highly valued, fulfilling complex roles. However, operational and human factors limit access to services in the hospital. These findings, along with family perspectives, can be used to optimize interpretation experiences., (Copyright © 2019 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Objectives: Skin and soft tissue infections are common pediatric diagnoses with substantial costs. Recent studies suggest blood cultures are not useful in management of uncomplicated skin and soft tissue infections (uSSTIs). Complete blood cell count, erythrocyte sedimentation rate, and C-reactive protein are also of questionable value. We aimed to decrease these tests by 25% for patients with uSSTIs admitted to the pediatric hospital medicine service within 3 months., Methods: An interdisciplinary team led a quality improvement (QI) project. Baseline assessment included review of the literature and 12 months of medical records. Key stakeholders identified drivers that informed the creation of an electronic order set and development of a pediatric hospital medicine-emergency department collaborative QI project. The primary outcome measure was mean number of tests per patient encounter. Balancing measures included unplanned readmissions and missed diagnoses., Results: Our baseline-year rate was 3.4 tests per patient encounter (573 tests and 169 patient encounters). During the intervention year, the rate decreased by 35% to 2.2 tests per patient encounter (286 tests and 130 patient encounters) and was sustained for 14 months postintervention. There were no unplanned readmissions or missed diagnoses for the study period. Order set adherence was 80% (83 out of 104) during the intervention period and sustained at 87% postintervention., Conclusions: Our interdisciplinary team achieved our aim, reducing unnecessary laboratory testing in patients with an uSSTI without patient harm. Awareness of local culture, creation of an order set, defining appropriate patient selection and testing indications, and implementation of a collaborative QI project helped us achieve our aim., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

The deployment of oral multi-unit pellet formulation has gained significant attention in recent years conferring to numerous applications, especially in achieving modified release and acid resistance property. The fluidized bed coating, specifically Wurster technique is commercially utilized for pellet manufacturing, which is a complex process involving too many variables. Risk assessment tools can be employed to determine the critical variables affecting the pre-defined quality profile and screen out important parameters out of literally hundreds of variables to develop a robust product. The present review aims to describe possibly all the variables involved in Wurster coating process and application of FMEA in pellet manufacturing. A brief case study regarding applicability of FMEA to study the effects of critical factors is outlined. Risk assessment tools assist to reduce number of trials to manageable levels with aid of prior art, literature, and preliminary trials to develop an optimized product.

Background: Optimal timing to initiate anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF) is currently unknown. Compared to other stroke etiologies, AF typically provokes larger infarct volumes and greater concern of hemorrhagic transformation, so seminal randomized trials waited weeks to months to begin anticoagulation after initial stroke. Subsequent data are limited and non-randomized. Guidelines suggest anticoagulation initiation windows between 3 and 14 days post-stroke, with Class IIa recommendations, and level of evidence B in the USA and C in Europe. Aims: This open-label, parallel-group, multi-center, randomized controlled trial AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) is designed to evaluate the safety and efficacy of early anticoagulation, based on stroke size, secondary prevention of ischemic stroke, and risks of subsequent hemorrhagic transformation. Methods: Subjects are randomly assigned in a 1:1 ratio to receive early apixaban at day 0-3 for transient ischemic attack (TIA), 3-5 for small-sized AIS (<1.5 cm), and 7-9 for medium-sized AIS (1.5 cm or greater but less than a full cortical territory), or warfarin at 1 week post-TIA or 2 weeks post-stroke. Large AISs are excluded. Study Outcomes: Primary: recurrent ischemic stroke, TIA, and fatal stroke; secondary: intracranial hemorrhage (ICH); hemorrhagic transformation (HT) of ischemic stroke; cerebral microbleeds (CMBs); neurologic disability [e.g., modified Rankin Scores (mRS), National Institutes of Health Stroke Scale (NIHSS), Stroke Specific Quality of Life scale (SS-QOL)]; and cardiac biomarkers [e.g., AF burden, transthoracic echo (TTE)/transesophageal echo (TEE) abnormalities]. Sample Size Estimates: Enrollment goal was 120 for 80% power (two-sided type I error rate of 0.05) to detect an absolute risk reduction of 16.5% postulated to occur with apixaban in the primary composite outcome of fatal stroke/recurrent ischemic stroke/TIA within 180 days. Enrollment was suspended at 91 subjects in 2019 after a focused guideline update recommended direct oral anticoagulants (DOACs) over warfarin in AF, excepting valvular disease (Class I, level of evidence A). Discussion: AREST will offer randomized controlled trial data about timeliness and safety of anticoagulation in AIS patients with AF. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02283294., (Copyright © 2019 Rose, Meriwether, Fradley, Renati, Martin, Kasprowicz, Patel, Mokin, Murtagh, Kip, Bozeman, McTigue, Hilker, Kirby, Wick, Tran, Burgin and Labovitz.)

Feedback is an integral part of medical education. However, there is great variation of training and effectiveness of feedback delivery, especially in the inpatient setting. The unique learning environment provided in hospital medicine allows teachers the opportunity to provide feedback on learner performance under several longitudinal observations in areas such as direct patient care, procedural tasks, and interdisciplinary team leadership skills. Most important, feedback should occur on more than one occasion to truly empower change in knowledge, attitude, and skills. This article aims to provide the reader with foundational theories on feedback and strategies to use best practices for delivery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Recent evidence supports involvement of amylin and the amylin receptor in the pathogenesis of Alzheimer's disease (AD). We have previously shown that amylin receptor antagonist, AC253, improves spatial memory in AD mouse models. Herein, we generated and screened a peptide library and identified two short sequence amylin peptides (12-14 aa) that are proteolytically stable, brain penetrant when administered intraperitoneally, neuroprotective against Aβ toxicity and restore diminished levels of hippocampal long term potentiation in AD mice. Systemic administration of the peptides for five weeks in aged 5XFAD mice improved spatial memory, reduced amyloid plaque burden, and neuroinflammation. The common residue SQELHRLQTY within the peptides is an essential sequence for preservation of the beneficial effects of the fragments that we report here and constitutes a new pharmacological target. These findings suggest that the amylin receptor antagonism may represent a novel therapy for AD.

The maternal cardiovascular system undergoes profound changes to support the increasing demands of fetal growth during pregnancy. An accumulating body of evidence has shown that common pregnancy complications, including gestational diabetes mellitus, preeclampsia, low birth weight, and preterm delivery, can be associated with future cardiovascular adverse events in mothers. Factors such as glucose metabolism, hyperlipidemia, inflammatory markers, and large- and small-vessel stiffness/functionality have been linked with these pregnancy conditions. Critically, there are no established guidelines to account for these maternal factors when considering future cardiovascular disease risk, one of the leading causes of female mortality. This article reviews the study of cardiovascular disease and pregnancy, and proposes possible connections that should spur future investigation in an area of medicine that requires significant research., (Copyright © 2019. Published by Elsevier Inc.)

This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted., (© 2018, The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Competing Interests: Competing interests: None declared.