Search

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2)+ AT1 cells via oncogenic KRASG12D. Activation of KRASG12D in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8+ intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2+, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2+ AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Abstract Background In recent studies, receipt of chiropractic care has been associated with lower odds of receiving prescription opioids and, among those already prescribed, reduced doses of opioids among patients with non-cancer spine pain. These findings suggest that access to chiropractic services may reduce reliance on opioids for musculoskeletal pain. Objective To assess the impact of chiropractic care on initiation, or continued use, of prescription opioids among patients with non-cancer spine pain. Methods We will search for eligible randomized controlled trials (RCTs) and observational studies indexed in MEDLINE, Embase, AMED, CINAHL, Web of Science, and the Index to Chiropractic Literature from database inception to June 2024. Article screening, data extraction, and risk-of-bias assessment will be conducted independently by pairs of reviewers. We will conduct separate analyses for RCTs and observational studies and pool binary outcomes (e.g. prescribed opioid receipt, long-term opioid use, and higher versus lower opioid dose) as odds ratios (ORs) with associated 95% confidence intervals (CIs). When studies provide hazard ratios (HRs) or relative risks (RRs) for time-to-event data (e.g. time-to-first opioid prescription) or incidence rates (number of opioid prescriptions over time), we will first convert them to an OR before pooling. Continuous outcomes such as pain intensity, sleep quality, or morphine equivalent dose will be pooled as weighted mean differences with associated 95% CIs. We will conduct meta-analyses using random-effects models and explore sources of heterogeneity using subgroup analyses and meta-regression. We will evaluate the certainty of evidence of all outcomes using the GRADE approach and the credibility of all subgroup effects with ICEMAN criteria. Our systematic review will follow the PRISMA statement and MOOSE guidelines. Discussion Our review will establish the current evidence informing the impact of chiropractic care on new or continued prescription opioid use for non-cancer spine pain. We will disseminate our results through peer-reviewed publication and conference presentations. The findings of our review will be of interest to patients, health care providers, and policy-makers. Trial registration Systematic review registration: PROSPERO CRD42023432277.

Background: Throughout the SARS-CoV-2 pandemic, policymakers have had to navigate between recommending voluntary behaviour change and policy-driven behaviour change to mitigate the impact of the virus. While individuals will voluntarily engage in self-protective behaviour when there is an increasing infectious disease risk, the extent to which this occurs and its impact on an epidemic is not known. Methods: This paper describes a deterministic disease transmission model exploring the impact of individual avoidance behaviour and policy-mediated avoidance behaviour on epidemic outcomes during the second wave of SARS-CoV-2 infections in Ontario, Canada (September 1, 2020 to February 28, 2021). The model incorporates an information feedback function based on empirically derived behaviour data describing the degree to which avoidance behaviour changed in response to the number of new daily cases COVID-19. Results: Voluntary avoidance behaviour alone was estimated to reduce the final attack rate by 23.1%, the total number of hospitalizations by 26.2%, and cumulative deaths by 27.5% over 6 months compared to a counterfactual scenario in which there were no interventions or avoidance behaviour. A provincial shutdown order issued on December 26, 2020 was estimated to reduce the final attack rate by 66.7%, the total number of hospitalizations by 66.8%, and the total number of deaths by 67.2% compared to the counterfactual scenario. Conclusion: Given the dynamics of SARS-CoV-2 in a pre-vaccine era, individual avoidance behaviour in the absence of government action would have resulted in a moderate reduction in disease however, it would not have been sufficient to entirely mitigate transmission and the associated risk to the population in Ontario. Government action during the second wave of the COVID-19 pandemic in Ontario reduced infections, protected hospital capacity, and saved lives.

Background: Frailty, rather than age, is associated with postoperative morbidity and mortality. We sought to determine whether preoperative frailty as defined by a novel scoring system could predict the outcomes among older patients undergoing esophagectomy. Methods: We identified patients 65 years or older who underwent esophagectomy between 2011 and 2021 at our institution. Frailty was assessed using the MSK-FI, which consists of 1 component related to functional status and 10 medical comorbidities. We used a multivariable logistic regression model to test for the associations between frailty and short-term outcomes, with continuous frailty score as the predictor and additionally adjusted for age and Eastern Cooperative Oncology Group performance status. Results: In total, 447 patients were included in the analysis (median age of 71 years [interquartile range, 68–75]). Most of the patients underwent neoadjuvant treatment (81%), an Ivor Lewis esophagectomy (86%), and minimally invasive surgery (55%). A total of 22 patients (4.9%) died within 90 days of surgery, 144 (32%) had a major complication, 81 (19%) were readmitted, and 31 (7.2%) were discharged to a facility. Of the patients who died within 90 days, 19 had a major complication, yielding a failure-to-rescue rate of 13%. The risk of 30-day major complications (OR, 1.24 [95% CI, 1.09–1.41]; p = 0.001), readmissions (OR, 1.31 [95% CI, 1.13–1.52]; p < 0.001), and discharge to a facility (OR, 1.86 [95% CI, 1.49–2.37]; p < 0.001) increased with increasing frailty. Frailty and 90-day mortality were not associated. Conclusions: Frailty assessment during surgery decision-making can identify patients with a high risk of morbidity.

Abstract The Iowa State University Veterinary Diagnostic Laboratory detected nineteen human-to-swine reverse zoonoses of the 2022–2023 human seasonal H3N2 between November 2022 and November 2023. Cases from seven U.S. locations were detected: 3 Colorado, 1 Illinois, 1 Indiana, 2 Missouri, 7 North Carolina, 1 Ohio, and 1 Pennsylvania. One additional case was detected in Mexico and two cases were identified from Chile. Case samples were comprised of 4 nasal swabs and 15 oral fluids. Virus was successfully isolated from two of four nasal swab samples, but isolation from oral fluids was unsuccessful. The swine detections of H3 human viruses were classified to one of two human-seasonal H3 clades, 3C.2a1b.2a.2b and 3C.2a1b.2a.2a.1. Phylogenetic inference indicated at minimum 7 reverse zoonotic events occurred, with possible swine-to-swine transmission following the initial spillover. Twelve neuraminidase genes were sequenced, and nine were classified as human-seasonal H3N2 lineage: the remaining were endemic swine IAV NA genes from the N2.2002B, N2.1998, or the N1.Classical lineage, suggesting reassortment. The two viral isolates obtained from nasal swab samples were sequenced and were entirely human-lineage viruses. Seven swine samples with human seasonal H3 were sequenced and revealed co-detections with H1 1A.3.3.3 (gamma), with internal gene segments from both the triple reassortant internal gene (TRIG) and pandemic 2009 lineages. Serologic investigation of samples from swine production systems provided evidence for infection with human seasonal H3N2. One farm in the United States and four farms in Mexico had concurrent virologic evidence. The swine-isolated 3C.2a1b.2a.2b H3N2 was antigenically distinct from endemic 1990.4.A, 2010.1, and 2010.2 swine H3N2 lineages, but retained antigenic similarity to a recent human seasonal H3N2 (A/Darwin/6/2021). Pigs experimentally inoculated with a representative isolate demonstrated replication in the nose and lungs and minimal to mild macroscopic and microscopic lung lesions, but primary pigs did not transmit the virus to indirect contacts. If sustained in the pig population, this human seasonal H3 would represent the first new lineage detected in pigs the 2020 decade and present an emerging threat to swine health and production.

Abstract Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.

Abstract Artificial intelligence in the workplace is becoming increasingly common. These tools are sometimes used to aid users in performing their task, for example, when an artificial intelligence tool assists a radiologist in their search for abnormalities in radiographic images. The use of artificial intelligence brings a wealth of benefits, such as increasing the efficiency and efficacy of performance. However, little research has been conducted to determine how the use of artificial intelligence assistants might affect the user’s cognitive skills. In this theoretical perspective, we discuss how artificial intelligence assistants might accelerate skill decay among experts and hinder skill acquisition among learners. Further, we discuss how AI assistants might also prevent experts and learners from recognizing these deleterious effects. We then discuss the types of questions: use-inspired basic cognitive researchers, applied researchers, and computer science researchers should seek to answer. We conclude that multidisciplinary research from use-inspired basic cognitive research, domain-specific applied research, and technical research (e.g., human factors research, computer science research) is needed to (a) understand these potential consequences, (b) design artificial intelligence systems to mitigate these impacts, and (c) develop training and use protocols to prevent negative impacts on users’ cognitive skills. Only by answering these questions from multidisciplinary perspectives can we harness the benefits of artificial intelligence in the workplace while preventing negative impacts on users’ cognitive skills.

Patients from historically under-represented racial and ethnic groups are enrolled in cancer clinical trials at disproportionately low rates in the USA1-3. As these patients often have limited English proficiency4-7, we hypothesized that one barrier to their inclusion is the cost to investigators of translating consent documents. To test this hypothesis, we evaluated more than 12,000 consent events at a large cancer centre and assessed whether patients requiring translated consent documents would sign consent documents less frequently in studies lacking industry sponsorship (for which the principal investigator pays the translation costs) than for industry-sponsored studies (for which the translation costs are covered by the sponsor). Here we show that the proportion of consent events for patients with limited English proficiency in studies not sponsored by industry was approximately half of that seen in industry-sponsored studies. We also show that among those signing consent documents, the proportion of consent documents translated into the patient's primary language in studies without industry sponsorship was approximately half of that seen in industry-sponsored studies. The results suggest that the cost of consent document translation in trials not sponsored by industry could be a potentially modifiable barrier to the inclusion of patients with limited English proficiency.

Objective: To assemble and characterize an electronic health record (EHR) dataset for a large cohort of US military Veterans diagnosed with ALS (Amyotrophic Lateral Sclerosis). Methods: An EHR dataset for 19,662 Veterans diagnosed with ALS between January 1, 2000 to December 31, 2020 was compiled from the Veterans Health Administration (VHA) EHR database by a query for ICD9 diagnosis (335.20) or ICD10 diagnosis (G12.21) for Amyotrophic Lateral Sclerosis. Results: The cohort is predominantly male (98.94%) and white (72.37%) with a median age at disease onset of 68 years and median survival from the date of diagnosis of 590 days. With the designation of ALS as a compensable illness in 2009, there was a subsequent increase in the number of Veterans diagnosed per year in the VHA, but no change in median survival. The cohort included a greater-than-expected proportion of individuals whose branch of service at the time of separation was the Army. Conclusions: The composition of the cohort reflects the VHA population who are at greatest risk for ALS. The greater than expected proportion of individuals whose branch of service at the time of separation was the Army suggests the possibility of a branch-specific risk factor for ALS.

Introduction: Pennsylvania opened its first medical marijuana (MMJ) dispensary in 2018. Qualifying conditions include six conditions determined to have no or insufficient evidence to support or refute MMJ effectiveness. We conducted a study to describe MMJ dispensary access in Pennsylvania and to determine whether dispensary proximity was associated with MMJ certifications and community demographics. Methods: Using data from the Pennsylvania Department of Health, we geocoded MMJ dispensary locations and linked them to US Census Bureau data. We created dispensary access measures from the population-weighted centroid of Zip Code Tabulation Areas (ZCTAs): distance to nearest dispensary and density of dispensaries within a 15-min drive. We evaluated associations between dispensary access and the proportion of adults who received MMJ certification and the proportion of certifications for low evidence conditions (amyotrophic lateral sclerosis, epilepsy, glaucoma, Huntington's disease, opioid use disorder, and Parkinson's disease) using negative binomial modeling, adjusting for community features. To evaluate associations racial and ethnic composition of communities and distance to nearest dispensary, we used logistic regression to estimate the odds ratios (OR) and 95% confidence intervals (CI), adjusting for median income. Results: Distance and density of MMJ dispensaries were associated with the proportion of the ZCTA population certified and the proportion of certifications for insufficient evidence conditions. Compared to ZCTAs with no dispensary within 15 min, the proportion of adults certified increased by up to 31% and the proportion of certifications for insufficient evidence decreased by up to 22% for ZCTAs with two dispensaries. From 2018 to 2021, the odds of being within five miles of a dispensary was up to 20 times higher in ZCTAs with the highest proportions of individuals who were not White (2019: OR: 20.14, CI: 10.7-37.8) and more than double in ZCTAs with the highest proportion of Hispanic individuals (2018: OR: 2.81, CI: 1.51-5.24), compared to ZCTAs with the lowest proportions. Conclusions: Greater dispensary access was associated with the proportions of certified residents and certifications for low evidence conditions. Whether these patterns are due to differences in accessibility or demand is unknown. Associations between community demographics and dispensary proximity may indicate MMJ access differences. Keywords: Medical cannabis, Geospatial, Evidence-based medicine, Marijuana, Dispensary, Author(s): Annemarie G. Hirsch; Eric A. Wright; Cara M. Nordberg; Joseph DeWalle; Elena L. Stains; Amy L. Kennalley; Joy Zhang; Lorraine D. Tusing; Brian J. Piper Introduction The legalization of [...]