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The August 2020 explosion in Lebanon resulted in casualties, injuries, and a great number of internally displaced persons. The blast occurred during an economically and politically complex time in the country. Given multiple and competing post-explosion reconstruction priorities, in ths editorial we briefly examine the requirements for a build back better scenario.

Background Missing data in confounding variables present a frequent challenge in generating evidence using real-world data, including electronic health records (EHR). Our objective was to apply a recently published toolkit for characterizing missing data patterns and based on the toolkit results about likely missingness mechanisms, illustrate the decision-making process for analyses in an empirical case example. Methods We utilized the Structural Missing Data Investigations (SMDI) toolkit to characterize missing data patterns in the context of a pharmacoepidemiology study comparing cardiovascular outcomes of initiating sodium-glucose-cotransporter-2 inhibitors (SGLT2i) and dipeptidyl peptidase‐4 inhibitors (DPP‐4i) among older adults. The study used a linked EHR-Medicare claims dataset from Duke Health patients (2015–2017), focusing on partially observed confounders from EHR data (HbA1c lab and body mass index [BMI] values). Our analysis incorporated SMDI's descriptive functions and diagnostic tests to explore missingness patterns and determine missingness mitigation approaches. We used findings from these investigations to inform estimation of adjusted hazard ratios comparing the two classes of medications. Results High levels of missingness were noted for important confounding variables including HbA1c (63.6%) and BMI (16.5%). Diagnostic tests resulted in output that described: 1) the distributions of patient characteristics, exposure, and outcome between patients with or without an observed value of the partially observed covariate, 2) the ability to predict missingness based on observed covariates, and 3) estimate if the missingness of a partially observed covariate is differential with respect to the outcome. There was evidence that missingness could be sufficiently described using observed data, which allowed multiple imputation by chained equations using random forests to address missing confounder data in estimating treatment effects. Multiple imputation resulted in improved alignment of effect estimates with previous studies. Conclusions We were able to demonstrate the practical application of the SMDI toolkit in a real-world setting. Application of the SMDI toolkit and the resulting insights of potential missingness patterns can inform the choice of appropriate analytic methods and increase transparency of research methods in handling missing data. This type of approach can inform analytic decision making and may increase our ability to generate evidence from real-world data.

Background The electronic health record (EHR) contains a wealth of clinical data that may be used to streamline the identification of potential clinical trial participants. However, there is little empirical information on site-level facilitators of and barriers to optimal use of EHR systems with respect to trial recruitment. Methods We conducted qualitative focus groups and quantitative surveys as part of the EHR Ancillary Study, which is being conducted alongside the multicenter, global, Harmony Outcomes Trial comparing albiglutide to standard care for the prevention of cardiovascular events in type 2 diabetes. Subject matter experts used findings from focus groups to draft a 20-question survey examining the use of the EHR for participant identification, common site recruitment strategies, and variation in perceived barriers to optimal use of the EHR. The final survey was fielded with 446 site investigators actively enrolling participants in the main trial. Results Nearly two-thirds of respondents were study coordinators (63.2%), 23.1% were principal investigators, and 13.7% held other research roles. Approximately half of the respondents reported using the EHR to find potential trial participants. Of these, 79.4% reported using EHR searches in conjunction with other recruitment methods, including reviewing of upcoming clinic schedules (75.3%) and contacting past trial participants (71.2%). Important barriers to optimal use of the EHR included the lack of availability of certain research-focused EHR modules and limitations on the ability to contact patients cared for by other providers. Of survey respondents who did not use the EHR to find potential participants, one-quarter reported that the EHR was not accessible in their country; this finding varied from 2.6% of respondents in North America to 50% of respondents in the Asia Pacific. Conclusions While EHR screening was commonly used for recruitment in a cardiovascular outcomes trial, important technical, governance, and regulatory barriers persist. Multifaceted, scalable, and customizable strategies are needed to support the optimal use of the EHR for trial participant identification. Trial registration ClinicalTrials.gov NCT02465515. Registered on 8 June 2015

Background Despite great promise, trials that ascertain patient clinical data from electronic health records (EHR), referred to here as “EHR-sourced” trials, are limited by uncertainty about how existing trial sites and infrastructure can be best used to operationalize study goals. Evidence is needed to support the practical use of EHRs in contemporary clinical trial settings. Main text We describe a demonstration project that used EHR data to complement data collected for a contemporary multi-center pharmaceutical industry outcomes trial, and how a central coordinating center supported participating sites through the technical, governance, and operational aspects of this type of activity. We discuss operational considerations related to site selection, data extraction, site performance, and data transfer and quality review, and we outline challenges and lessons learned. We surveyed potential sites and used their responses to assess feasibility, determine the potential capabilities of sites and choose an appropriate data extraction strategy. We designed a flexible, multimodal approach for data extraction, enabling each site to either leverage an existing data source, create a new research datamart, or send all data to the central coordinating center to produce the requisite data elements. We evaluated site performance, as reflected by the speed of contracting and IRB approval, total patients enrolled, enrollment yield, data quality, and compared performance by data collection strategy. Conclusion While broadening the type of sites able to participate in EHR-sourced trials may lead to greater generalizability and improved enrollment, sites with fewer technical resources may require additional support to participate. Central coordinating center support is essential to facilitate the execution of operational processes. Future work should focus on sharing lessons learned and creating reusable tools to facilitate participation of heterogeneous trial sites.

Background Ketogenic diets (KDs) or short-term fasting are popular trends amongst supportive approaches for cancer patients. Beta-hydroxybutyrate (3-OHB) is the main physiological ketone body, whose concentration can reach plasma levels of 2–6 mM during KDs or fasting. The impact of 3-OHB on the biology of tumor cells described so far is contradictory. Therefore, we investigated the effect of a physiological concentration of 3 mM 3-OHB on metabolism, proliferation, and viability of breast cancer (BC) cells in vitro. Methods Seven different human BC cell lines (BT20, BT474, HBL100, MCF-7, MDA-MB 231, MDA-MB 468, and T47D) were cultured in medium with 5 mM glucose in the presence of 3 mM 3-OHB at mild hypoxia (5% oxygen) or normoxia (21% oxygen). Metabolic profiling was performed by quantification of the turnover of glucose, lactate, and 3-OHB and by Seahorse metabolic flux analysis. Expression of key enzymes of ketolysis as well as the main monocarboxylic acid transporter MCT2 and the glucose-transporter GLUT1 was analyzed by RT-qPCR and Western blotting. The effect of 3-OHB on short- and long-term cell proliferation as well as chemo- and radiosensitivity were also analyzed. Results 3-OHB significantly changed the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in BT20 cells resulting in a more oxidative energetic phenotype. MCF-7 and MDA-MB 468 cells had increased ECAR only in response to 3-OHB, while the other three cell types remained uninfluenced. All cells expressed MCT2 and GLUT1, thus being able to uptake the metabolites. The consumption of 3-OHB was not strongly linked to mRNA overexpression of key enzymes of ketolysis and did not correlate with lactate production and glucose consumption. Neither 3-OHB nor acetoacetate did interfere with proliferation. Further, 3-OHB incubation did not modify the response of the tested BC cell lines to chemotherapy or radiation. Conclusions We found that a physiological level of 3-OHB can change the energetic profile of some BC cell lines. However, 3-OHB failed to influence different biologic processes in these cells, e.g., cell proliferation and the response to common breast cancer chemotherapy and radiotherapy. Thus, we have no evidence that 3-OHB generally influences the biology of breast cancer cells in vitro.

An amendment to this paper has been published and can be accessed via the original article.

Background Acute care inpatient admissions outside of psychiatric facilities have been increasingly identified as a critical touchpoint for opioid use disorder (OUD) treatment. We sought to describe non-opioid overdose hospitalizations with documented OUD and examine receipt of post-discharge outpatient buprenorphine. Methods We examined acute care hospitalizations with an OUD diagnosis in any position within US commercially-insured adults age 18–64 years (IBM MarketScan claims, 2013–2017), excluding opioid overdose diagnoses. We included individuals with ≥ 6 months of continuous enrollment prior to the index hospitalization and ≥ 10 days following discharge. We described demographic and hospitalization characteristics, including outpatient buprenorphine receipt within 10 days of discharge. Results Most (87%) hospitalizations with documented OUD did not include opioid overdose. Of 56,717 hospitalizations (49,959 individuals), 56.8% had a primary diagnosis other than OUD, 37.0% had documentation of an alcohol-related diagnosis code, and 5.8% end in a self-directed discharge. Where opioid use disorder was not the primary diagnosis, 36.5% were due to other substance use disorders, and 23.1% were due to psychiatric disorders. Of all non-overdose hospitalizations who had prescription medication insurance coverage and who were discharged to an outpatient setting (n = 49, 237), 8.8% filled an outpatient buprenorphine prescription within 10 days of discharge. Conclusions Non-overdose OUD hospitalizations often occur with substance use disorders and psychiatric disorders, and very few are followed by timely outpatient buprenorphine. Addressing the OUD treatment gap during hospitalization may include implementing medication for OUD for inpatients with a broad range of diagnoses.

Objectives Tonsillectomy is a common pediatric surgery, and pain is an important consideration in recovery. Due to the opioid epidemic, individual states, medical societies, and institutions have all taken steps to limit postoperative opioids, yet few studies have examined the effect of these interventions on pediatric otolaryngology practices. The primary aim of this study was to characterize opioid prescribing practices following North Carolina state opioid legislation and targeted institutional changes. Methods This single center retrospective cohort study included 1552 pediatric tonsillectomy patient records from 2014 to 2021. The primary outcome was number of oxycodone doses per prescription. This outcome was assessed over three time periods: (1) Before 2018 North Carolina opioid legislation. (2) Following legislation, before institutional changes. (3) After institutional opioid‐specific protocols. Results The mean (± standard deviation) number of doses per prescription in Periods 1, 2, and 3 was: 58 ± 53, range 4–493; 28 ± 36, range 3–488; and 23 ± 17, range 1–139, respectively. In the adjusted model, Periods 2 and 3 had lower doses by −41% (95% CI −49%, −32%) and −40% (95% CI −55%, −19%) compared to Period 1. After 2018 North Carolina legislation, dosage decreased by −9% (95% CI −13%, −5%) per year. Despite interventions, ongoing variability in prescription regimens remained in all periods. Conclusion Legislative and institution specific opioid interventions was associated with a 40% decrease in oxycodone doses per prescription following pediatric tonsillectomy. While variability in opioid practices decreased post‐interventions, it was not eliminated. Level of evidence 3 Tonsillectomy is a common pediatric surgery, and pain is an important consideration in recovery. Due to the opioid epidemic, individual states, medical societies, and institutions have all taken steps to limit postoperative opioids, yet few studies have examined the effect of these interventions on pediatric otolaryngology practices. The primary aim of this study was to characterize opioid prescribing practices following North Carolina state opioid legislation and targeted institutional changes. We found that these interventions were associated with a 40% decrease in oxycodone doses per prescription following pediatric tonsillectomy. While variability in opioid practices decreased post‐interventions, it was not eliminated.

Background The prevalence of carpal tunnel syndrome (CTS) is not well understood in many Arabian Peninsula countries. The objective of this study was to investigate the prevalence and factors associated with self-reported CTS in Kuwait. Findings A cross-sectional, self-administered survey of CTS-related symptoms was used in this study. Multivariate logistic regression was also used to estimate adjusted odds ratios for factors of interest. Participants in this study were adult office workers in Kuwait (n = 470, 55.6% males), who worked in companies employing more than 50 people. Self-reported CTS was reported in 18.7% of the group (88/470). CTS was significantly associated with the following demographic factors: female gender, obesity and number of comorbid conditions. Self-identification of CTS was also associated with key symptoms and impairment in daily activities (e.g., wrist pain, numbness, weakness, night pain, difficulty carrying bags, difficulty grasping [Chi-Square Test for Association: P  < 0.05 for all symptoms/activities]). However, symptoms such as wrist pain, weakness, and functional disabilities were also frequently reported among those who do not self report CTS (range: 12.1%–38.2%). Conclusions Prevalence of self-reported CTS among office workers in Kuwait is 18.7%, and the risk factors for CTS in this population included female gender, obesity and number of related comorbidities. The frequency of symptoms in the sample who did not self report CTS suggest that CTS may be under-recognized, however further research is required to assess the prevalence of clinically diagnosed CTS.

Some vaccines have a small risk of Guillain-Barré Syndrome (GBS), a rare autoimmune disorder characterized by paralysis if untreated. The CDC’s Advisory Committee on Immunization Practices (ACIP) guidelines do not consider GBS a precaution for future vaccines unless GBS developed within six weeks after a tetanus-toxoid–containing vaccine or influenza vaccine. Our goal was to describe vaccine patterns before and after GBS diagnosis. We matched each of 709 patients diagnosed with GBS from 2002 to 2020 with Medicare supplemental insurance to 10 counterparts without GBS (1:10) on age and sex. Propensity score-based weighting balanced covariates between groups, and we estimated weighted mean cumulative counts (wMCC) of vaccines/person before and after GBS diagnosis. Among patients with GBS, 7% were diagnosed within 42 days after a vaccine. Prior to GBS diagnosis, the wMCC of vaccines per person was similar between GBS cases and matched counterparts, but after two years of follow-up, GBS patients received 21 fewer vaccines/100 people than counterparts (wMCC difference −0.21 vaccines/person, 95% CI −0.24 to −0.18); GBS patients received 16 vaccines/100 people while matched counterparts received 36/100. Vaccine use was reduced following GBS diagnosis despite no ACIP precaution for most (93%) patients in this study. The observed drop in vaccines after GBS diagnosis indicates a disconnect between clinical practice and current recommendations.