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Objective In contrast to intentionally restricting energy intake, restricting the eating window may be an option for treating obesity. By comparing time‐restricted eating (TRE) with an unrestricted (non‐TRE) control, it was hypothesized that TRE facilitates weight loss, alters body composition, and improves metabolic measures. Methods Participants (17 women and 3 men; mean [SD]: 45.5 [12.1] years; BMI 34.1 [7.5] kg/m 2 ) with a prolonged eating window (15.4 [0.9] hours) were randomized to TRE ( n = 11: 8‐hour window, unrestricted eating within window) versus non‐TRE ( n = 9: unrestricted eating) for 12 weeks. Weight, body composition (dual x‐ray absorptiometry), lipids, blood pressure, 2‐hour oral glucose tolerance, 2‐week continuous glucose monitoring, and 2‐week physical activity (actigraphy assessed) were measured during the pre‐ and end‐intervention periods. Results The TRE group significantly reduced the eating window (end‐intervention window: 9.9 [2.0] hours) compared with the non‐TRE group (end‐intervention window: 15.1 [1.1] hours) ( P < 0.01). Compared with non‐TRE, TRE decreased the number of eating occasions, weight, lean mass, and visceral fat (all P ≤ 0.05). Compared with preintervention measures, the TRE group reduced the number of eating occasions (−21.9% [30.1%]) and reduced weight (−3.7% [1.8%]), fat mass (−4% [2.9%]), lean mass (−3.0% [2.7%]), and visceral fat (−11.1% [13.4%]) (all P ≤ 0.05). Physical activity and metabolic measures remained unchanged. Conclusions In the setting of a randomized trial, TRE presents a simplified view of food intake that reduces weight.

Abstract Background Intrathecal opioids are routinely administered during spinal anesthesia for postcesarean analgesia. The effectiveness of intrathecal morphine for postcesarean analgesia is well established, and the use of intrathecal hydromorphone is growing. No prospective studies have compared the effectiveness of equipotent doses of intrathecal morphine versus intrathecal hydromorphone as part of a multimodal analgesic regimen for postcesarean analgesia. The authors hypothesized that intrathecal morphine would result in superior analgesia compared with intrathecal hydromorphone 24 h after delivery. Methods In this single-center, double-blinded, randomized trial, 138 parturients undergoing scheduled cesarean delivery were randomized to receive 150 µg of intrathecal morphine or 75 µg of intrathecal hydromorphone as part of a primary spinal anesthetic and multimodal analgesic regimen; 134 parturients were included in the analysis. The primary outcome was the numerical rating scale score for pain with movement 24 h after delivery. Static and dynamic pain scores, nausea, pruritus, degree of sedation, and patient satisfaction were assessed every 6 h for 36 h postpartum. Total opioid consumption was recorded. Results There was no significant difference in pain scores with movement at 24 h (intrathecal hydromorphone median [25th, 75th] 4 [3, 5] and intrathecal morphine 3 [2, 4.5]) or at any time point (estimated difference, 0.5; 95% CI, 0 to 1; P = 0.139). Opioid received in the first 24 h did not differ between groups (median [25th, 75th] oral morphine milligram equivalents for intrathecal hydromorphone 30 [7.5, 45.06] vs. intrathecal morphine 22.5 [14.0, 37.5], P = 0.769). From Kaplan–Meier analysis, the median time to first opioid request was 5.4 h for hydromorphone and 12.1 h for morphine (log-rank test P = 0.200). Conclusions Although the hypothesis was that intrathecal morphine would provide superior analgesia to intrathecal hydromorphone, the results did not confirm this. At the doses studied, both intrathecal morphine and intrathecal hydromorphone provide effective postcesarean analgesia when combined with a multimodal analgesia regimen. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

AbstractGlutamic acid decarboxylase 65‐kilodalton isoform (GAD65) antibodies have been associated with multiple nonneurological and neurological syndromes including autoimmune epilepsy (AE). Although immunotherapy remains the cornerstone for the treatment of AE, those with GAD65 Ab‐associated AE (GAD65‐AE) remain refractory to immunotherapy and antiseizure medication (ASM). Outcomes of epilepsy surgery in this patient population have also been unsatisfactory. The role of neuromodulation therapy, particularly direct brain‐responsive neurostimulation therapy, has not been previously examined in GAD65‐AE. Here, we describe four consecutive patients with refractory GAD‐65‐associated temporal lobe epilepsy (GAD65‐TLE) receiving bilateral hippocampal RNS System treatment. The RNS System treatment was well tolerated and effective in this study cohort. Three patients had a >50% clinical seizure reduction, and one patient became clinically seizure‐free following resective surgery informed by the RNS System data with continued RNS System treatment. In all four of our patients, the long‐term ambulatory data provided by the RNS System allowed us to gain objective insights on electrographic seizure lateralization, patterns, and burden as well as guided immunotherapy and ASM optimization. Our results suggest the potential utility of the RNS System in the management of ASM intractable GAD65‐AE.

AbstractThe scope of pharmacy practice in global health has expanded over the past decade creating additional education and training opportunities for students, residents and pharmacists. There has also been a shift from short‐term educational and clinical experiences to more sustainable bidirectional partnerships between high‐income countries (HICs) and low‐ to middle‐income countries (LMICs). As more institutional and individual partnerships between HICs and LMICs begin to form, it is clear that there is a lack of guidance for pharmacists on how to build meaningful, sustainable, and mutually beneficial programs. The aim of this paper is to provide guidance for pharmacists in HICs to make informed decisions on global health partnerships and identify opportunities for engagement in LMICs that yield mutually beneficial collaborations. This paper uses the foundations of global health principles to identify five pillars of global health engagement when developing partnerships: (a) sustainability, (b) shared leadership, (c) mutually beneficial partnerships, (d) local needs‐based care and (e) host‐driven experiential and didactic education. Finally, this paper highlights ways pharmacists can use the pillars as a framework to engage and support health care systems, collaborate with academic institutions, conduct research, and interface with governments to improve health policy.

Abstract Background: The IMpassion130 study demonstrated prolonged overall survival when atezolizumab, a PD-L1 inhibitor, was added to nab-paclitaxel in PD-L1 positive patients with advanced triple negative breast cancer (TNBC). Approximately 40% of tumors were PD-L1 positive, utilizing a cutoff of ≥ 1% immune cell (IC) staining with the Ventana SP142 immunohistochemical (IHC) assay. The Food and Drug Administration (FDA) approved this assay as a companion test to determine patient eligibility for atezolizumab therapy. However, literature in lung cancer shows that pathologists have a high discordance in assessing PD-L1 on IC. The FDA companion test documentation for SP142 shows high inter-laboratory reproducibility with nearly 95% overall percent agreement (OPA) between 2 readers for 2 category scoring of IC (positive versus negative) in TNBC in a central laboratory. PD-L1 testing for breast cancer is now becoming widespread in pathology laboratories. The goal of this study was to assess concordance in PD-L1 scoring between 19 pathologists from 14 institutions examining the same 86 TNBC tissues stained with the SP142 and SP263 antibodies. We also present a new method to determine the minimum number for evaluators needed to estimate concordance between large numbers of readers as occurs in real life setting. Methods: Full tissue sections were stained exactly as prescribed on the label on the Ventana Benchmark with the SP142 and SP263 PD-L1 assays. Sixty-eight and 76 cases were evaluable respectively. Stained slides were scanned and digital files distributed to pathologists who independently scored cases as either negative (&lt; 1% IC staining) or positive (≥ 1% IC staining) and estimated the % of IC staining for positive cases. We applied a method that we call Observers Needed to Evaluate Subjective Tests (ONEST). For any combination of pathologists, we can quantify the degree of overall agreement using the proportion of tissue samples upon which all selected pathologists agreed, which can lead to a plot of non-increasing trajectory of agreement as the number of pathologists increases. We computed and plotted the empirical estimate of the overall agreement with the 95% confidence interval (CI) from 1000 randomly selected permutations of the pathologists. Results: PD-L1 was interpreted as positive with SP263 in an average of 78% of cases compared to 58% with the SP142 assay (p&lt;.0001). IC positive continuous scores ranged from 1-95% (mean=20%) and 1-90% (mean=10%) for SP263 and SP142. Complete 2 category (positive vs negative) scoring concordance across all observers was achieved in 38 cases (50%) with SP263 and 26 cases (38%) with SP142. The intraclass correlation coefficient (ICC) for 2 category scoring of SP263 and SP142 was 0.513 and 0.560 respectively. ONEST plots made for each assay for 19 pathologists showed a decrease in OPA as number of observers increased, reaching a low plateau of approximately 0.46 at 10 observers for SP263 and 0.42 at 8 observers for SP142. Conclusions: Utilizing the FDA approved SP142 assay, we found a higher prevalence of PD-L1 positive tumors than published in the IMpassion130 trial but lower prevalence than seen with the SP263 assay. The different proportion of positive cases seen with two different assays highlights the need to establish cutoffs for each assay to correspond with clinical benefit. The ICC of scoring immune cells with both PD-L1 assays showed poor reproducibility across multiple pathologists. The ONEST analysis finds a plateau with 10 pathologists, only reaching an OPA of 0.4 for immune cell assessment. This suggests that more than half of the pathologists in real world situations may mis-assign patient IC scores. This could lead to a high percentage of patients either receiving atezolizumab, when they are unlikely to benefit or not receiving atezolizumab when they may benefit. Citation Format: Emily Suzanne Reisenbichler, Gang Han, Vasiliki Pelekanou, Vesal Yaghoobi, Fahad S Ahmed, Andrew Bellizzi, Veerle Bossuyt, Jane Brock, Kimberly Cole, Oluwole Fadare, Omar Hameed, Krisztina Hanley, Beth T Harrison, M G Kuba, Amy Ly, Dylan Miller, Mirna Podoll, Anja C Roden, Mary A Sanders, Kamaljeet Singh, Shi Wei, Hannah Wen, Lajos Pusztai, David L Rimm. Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD5-01.

AbstractBackgroundBody mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology.MethodsTo improve statistical power and interpretation for gene‐environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype‐Tissue Expression Project for all genes with heritability ≥1%. We used a mixed‐effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI‐CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2.ResultsAmong 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10−5), PSMC5 (P = 4.51 × 10−4) and CD33 (P = 2.71 × 10−4) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10−5) and SCN1B (P = 2.76 × 10−4) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10−5).ConclusionsAggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.

Abstract Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fractureamong people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, andsubcutaneous pharmacotherapies are efficaciousandcanreduce risk of future fracture.Patientsneededucation,however, about thebenefitsandrisks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive butmay be beneficial for selected patients at high risk.Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the earlypost-fractureperiod,prompt treatment is recommended.Adequate dietary or supplemental vitaminDand calciumintake shouldbe assured. Individuals beingtreatedfor osteoporosis shouldbe reevaluated for fracture risk routinely, includingvia patienteducationabout osteoporosisandfracturesandmonitoringfor adverse treatment effects.Patients shouldbestronglyencouraged to avoid tobacco, consume alcohol inmoderation atmost, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease).©2019American Society for Bone andMineral Research.