Search

Psychological trauma has profound effects on brain function and precipitates psychiatric disorders in vulnerable individuals, however, the molecular mechanisms linking trauma with psychiatric risk remain incompletely understood. Using RNA-seq data postmortem brain tissue of a cohort of 304 donors (N=136 with trauma exposure), we investigated transcriptional signatures of trauma exposures in two cortical regions (dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex) and two amygdala regions (medial amygdala and basolateral amygdala) associated with stress processing and regulation. We focused on dissecting heterogeneity of traumatic experiences in these transcriptional signatures by investigating exposure to several trauma types (childhood, adulthood, complex, single acute, combat, and interpersonal traumas) and interactions with sex. Overall, amygdala regions were more vulnerable to childhood traumas, whereas cortical regions were more vulnerable to adulthood trauma (regardless of childhood experience). Using cell-type-specific expression imputation, we identified a strong transcriptional response of medial amygdala excitatory neurons to childhood trauma, which coincided with dysregulation observed in a human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons exposed to hydrocortisone. We resolved multiscale coexpression networks for each brain region and identified modules enriched in trauma signatures and whose connectivity was altered with trauma. Trauma-associated coexpression modules provide insight into coordinated functional dysregulation with different traumas and point to potential gene targets for further dissection. Together, these data provide a characterization of the long-lasting human encoding of traumatic experiences in corticolimbic regions of human brain., Competing Interests: CONFLICT STATEMENT J.H.K. has consulting agreements (less than US$10,000 per year) with the following: Aptinyx, Inc. Biogen, Idec, MA, Bionomics, Limited (Australia), Boehringer Ingelheim International, Epiodyne, Inc., EpiVario, Inc., Janssen Research & Development, Jazz Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc., Spring Care, Inc., Sunovion Pharmaceuticals, Inc.; is the co-founder for Freedom Biosciences, Inc.; serves on the scientific advisory boards of Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), Cerevel Therapeutics, LLC, Delix Therapeutics, Inc., Eisai, Inc., EpiVario, Inc., Jazz Pharmaceuticals, Inc., Neumora Therapeutics, Inc., Neurocrine Biosciences, Inc., Novartis Pharmaceuticals Corporation, PsychoGenics, Inc., Takeda Pharmaceuticals, Tempero Bio, Inc., Terran Biosciences, Inc..; has stock options with Biohaven Pharmaceuticals Medical Sciences, Cartego Therapeutics, Damona Pharmaceuticals, Delix Therapeutics, EpiVario, Inc., Neumora Therapeutics, Inc., Rest Therapeutics, Tempero Bio, Inc., Terran Biosciences, Inc., Tetricus, Inc.; and is editor of Biological Psychiatry with income greater than $10,000.

Background: Black women in academic medicine experience racial and gender discrimination, all while being tasked with improving a flawed system. Representation of Black women in medicine remains low, yet they bear the burden of fostering diversity and mentoring trainees, exacerbating their minority tax and emotional labor, and negatively impacting career progression., Objective: To complement qualitative accounts of Black women authors in the medical education literature with a quantitative account of their representation. We used statistical modeling to estimate the representation of Black women authors in medical education publishing as compared to other groups., Design: An intersectional methodology employing bibliometric analysis and testimonio reflection., Subjects: US-based authors of journal articles published in medical education journals between 2000 and 2020., Main Measures: Author race was determined using a probability-based algorithm incorporating US Census data, and author gender was ascribed using Social Security Administration records. We conducted two negative binomial generalized linear models by first and last author publications. Metadata for each article was retrieved from Web of Science and PubMed to include author names, country of institutional affiliation, and Medical Subject Headings (MeSH). Results were contextualized via the "testimonio" account of a Black woman author., Key Results: Of 21,945 unique authors, Black women (and other racially minoritized groups) published far fewer first and last author papers than white women and men. In addition, major MeSH terms used by Black women authors reveal little overlap with highly ranked medical education topics. The testimonio further narrated struggles with belonging and racial identity., Conclusion: This study revealed that Black women are underrepresented in medical education publishing. We believe that dismantling oppressive structures in the publishing ecosystem and the field is imperative for achieving equity. Additionally, further experiential accounts are needed to contextualize this quantitative account and understand underrepresentation in medical education publishing., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Moral injury has emerged as a construct of interest in healthcare workers' (HCW) occupational stress and health. We conducted one of the first multidisciplinary, longitudinal studies evaluating the relationship between exposure to potentially morally injurious events (PMIEs), burnout, and turnover intentions. HCWs (N = 473) completed surveys in May of 2020 (T1) and again in May of 2021 (T2). Generalized Linear Models (robust Poisson regression) were used to test relative risk of turnover intentions, and burnout at T2 associated with PMIE exposure, controlling for T1 covariates. At T1, 17.67% reported they had participated in a PMIE, 41.44% reported they witnessed a PMIE and 76.61% reported feeling betrayed by healthcare or a public health organization. In models including all T1 PMIE exposures and covariates, T2 turnover intentions were increased for those who witnessed a PMIE at T1 (Relative Risk [RR] = 1.66, 95% Confidence Interval [CI] 1.17-2.34) but not those that participated or felt betrayed. T2 burnout was increased for those who participated in PMIE at T1 (RR = 1.38, 95%CI 1.03-1.85) but not those that witnessed or felt betrayed. PMIE exposure is highly prevalent among HCWs, with specific PMIEs associated with turnover intentions and burnout. Organizational interventions to reduce and facilitate recovery from moral injury should account for differences in the type of PMIE exposures that occur in healthcare work environments., (© 2024. The Author(s).)

Cystic fibrosis (CF) is a multi-organ genetic disorder that affects more than 100,000 individuals worldwide. Chronic respiratory infections are among the hallmark complications associated with CF lung disease, and these infections are often due to polymicrobial communities that colonize the airways of persons with CF (pwCF). Such infections are a significant cause of morbidity and mortality, with studies indicating that pwCF who are co-infected with more than one organism experience more frequent pulmonary exacerbations, leading to a faster decline in lung function. Previous work established an in vitro CF-relevant polymicrobial community model composed of P. aeruginosa , S. aureus , S. sanguinis , and P. melaninogenica . P. melaninogenica cannot survive in monoculture in this model. In this study, we leverage this model to investigate the interactions between P. aeruginosa and P. melaninogenica , allowing us to understand the mechanisms by which the two microbes interact to support the growth of P. melaninogenica specifically in the context of the polymicrobial community. We demonstrate a cross-feeding mechanism whereby P. melaninogenica metabolizes mucin into short-chain fatty acids that are in turn utilized by P. aeruginosa and converted into metabolites (succinate, acetate) that are cross-fed to P. melaninogenica , supporting the survival of this anaerobe in the CF lung-relevant model.

Prior research has rarely examined how people understand or react to the names of psychological treatments. In the case of evidence-based psychotherapies for posttraumatic stress disorder (PTSD), such reactions may be relevant to the low rates of uptake of such treatments. Participants who screened positive for PTSD (n = 887) completed questions assessing their initial reactions to PTSD treatment names as well as how a different name would affect their openness to treatment. In addition, they gave brief responses to open-ended questions about the reason for their initial reactions, and content analysis was used to better understand these reasons. The results indicated that among the treatment name options, cognitive processing therapy (CPT) and present-centered therapy (PCT) were viewed most positively. Approximately 40% of the sample preferred plain language alternatives for treatment names. Content analyses focused on descriptions of the treatments-which could be accurate or inaccurate-as well as whether respondents evaluated a treatment name itself as positive or negative. Some names conveyed treatments more accurately (e.g., CPT and written exposure therapy) than others (e.g., eye movement desensitization and reprocessing and prolonged exposure [PE]). Some names were also evaluated more positively (e.g., PCT) than others (e.g., PE). The general term "trauma-focused therapy" was seen as positive and clear. Addressing the ways patients react to psychological terms and treatment names could help clarify misperceptions about evidence-based psychotherapies and promote more widespread uptake of effective treatments for PTSD., (© 2024 International Society for Traumatic Stress Studies.)

Background: Timely follow-up after an abnormal cancer screening test result is needed to maximize the benefits of screening, but is frequently not achieved. Little is known about patient experiences with the process of following up abnormal screening results., Objective: Assess patient experiences and perceptions regarding the process of a diagnostic workup following abnormal breast, cervical, or colorectal cancer screening results., Design: Survey of participating patients between April 2021 and June 2022 after reaching the primary outcome time point in a randomized controlled trial to improve follow-up of overdue abnormal screening results., Participants: Patients from 44 participating practices in three primary care practice networks., Main Measures: Self-reported ease of scheduling follow-up, perceived barriers or concerns, provider trust, and satisfaction with communication and care received for the follow-up of abnormal screening results., Results: Overall, 241 (25.0%) patients completed the survey including 66 (32.8%) with breast, 79 (25.3%) with cervical, and 96 (21.3%) with colorectal screening test; median age 55 years, 79.7% women, 80.5% non-Hispanic white, and 51.0% did not complete recommended follow-up. Most patients were worried that the test would find cancer (63.1%), but fewer worried about discomfort or side effects (34.4%), and neither were associated with completing follow-up. However, 17% of patients did not think they needed follow-up tests or appointments and were less likely to complete follow-up (10.5% vs. 24.0%, respectively, p-value 0.009). Most patients were very satisfied with their overall care (71.0%), but only 50.2% strongly agreed that they trusted their provider to put their medical needs above all else when making recommendations., Conclusions: Patients with overdue abnormal breast, cervical, and colorectal cancer screening test results reported important deficiencies in the management of recommended follow-up. Addressing patient concerns about fear of cancer and effectively communicating the need for follow-up procedures may improve timely follow-up after an abnormal cancer screening result., Trial Registration: ClinicalTrials.gov NCT03979495., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Epigenetic modifications control gene expression and are essential for turning genes on and off to regulate and maintain differentiated cell types. Epigenetics are also modified by a multitude of environmental exposures, including diet and pollutants, allowing an individual's environment to influence gene expression and resultant phenotypes and clinical outcomes. These epigenetic modifications due to gene-environment interactions can also be transmitted across generations, raising the possibility that environmental influences that occurred in one generation may be transmitted beyond the second generation, exerting a long-lasting effect. In this review, we cover the known mechanisms of epigenetic modification acquisition, reprogramming and persistence, animal models and human studies used to understand multigenerational epigenetic transmission, and examples of environmentally induced epigenetic change and its transmission across generations. We highlight the importance of environmental health not only on the current population but also on future generations that will experience health outcomes transmitted through epigenetic inheritance., (© 2024. The Author(s).)

Purpose: Several lung function endpoints are utilized in clinical trials of inhaled bronchodilators for chronic obstructive pulmonary disease (COPD). Trough forced expiratory volume in 1 second (FEV 1 ) is a commonly reported endpoint in COPD trials and can be complemented by area under the FEV 1 vs time curve (FEV 1 AUC), which provides information on duration and consistency of bronchodilation over a dosing interval. Revefenacin, a once-daily bronchodilator, significantly improved lung function in patients with COPD when measured by trough FEV 1 in two replicate Phase 3 trials. Here, we report an FEV 1 AUC substudy using data from these trials., Patients and Methods: This post hoc analysis examined substudy data from 12-week replicate Phase 3 trials (NCT02459080/NCT02512510); patients with moderate to very severe COPD were randomized 1:1 to revefenacin 175 μg or placebo once daily. The substudy patients had FEV 1 AUC 0-2h assessed on Day 1, and those who continued to Day 84 also underwent 24-hour serial spirometry postdose where FEV 1 AUC 0-2h, AUC 0-12h , AUC 12-24h , and AUC 0-24h were evaluated., Results: Fifty and 47 patients who received revefenacin and placebo underwent 24-hour serial spirometry; most baseline characteristics were aligned between groups. At Day 84 postdose, revefenacin demonstrated sustained improvements in bronchodilation over 24 hours; differences in least squares mean vs placebo were 282, 220, 205, and 212 mL for FEV 1 AUC 0-2h , AUC 0-12h , AUC 12-24h , and AUC 0-24h (all P <0.001), respectively., Conclusion: This substudy analysis supplements previous findings that revefenacin provides sustained bronchodilation over 24 hours. Assessing additional complementary COPD clinical trial endpoints can help clinicians make treatment decisions., Competing Interests: Corey J. Witenko is a current employee of Theravance Biopharma US, Inc. and owns stock. Melinda K. Lacy is a current employee of Theravance Biopharma US, Inc. and owns stock. Ann W. Olmsted is a paid consultant for Theravance Biopharma US, Inc. and owns stock. Edmund J. Moran is a current employee of Theravance Biopharma US, Inc. and owns stock. In addition, Edmund J. Moran has a patent US11484531 licensed to Viatris. Donald A. Mahler serves on the advisory boards of AstraZeneca, Boehringer Ingelheim, Theravance, Verona, and Viatris and receives royalties from pharmaceutical companies (Elpen Pharmaceutical Company and University of Aberdeen) for the use of baseline dyspnea index/transition dyspnea index. The authors report no other conflicts of interest in this work., (© 2024 LeMaster et al.)

Patients with maxillofacial trauma require careful evaluation due to the anatomical proximity of the maxillofacial region to the head and neck. Facial trauma can lead to life-threatening airway compromise or hemorrhage, or permanent facial deformity. Although the Advanced Trauma Life Support guidelines provide a framework for the management of trauma patients, they do not provide a detailed reference for many subtle or complex facial injuries. In addition to an overview of maxillofacial trauma pathophysiology, associated injuries, and physical examination, this review will also discuss relevant imaging, treatment, and disposition plans.

In response to the coronavirus disease 2019 (COVID-19) pandemic, vaccines were quickly and successfully developed and deployed, saving millions of lives globally. While first-generation vaccines are safe and effective in preventing disease caused by SARS-CoV-2, next-generation vaccines have the potential to improve efficacy and safety. Vaccines delivered by a mucosal route may elicit greater protective immunity at respiratory surfaces, thereby reducing transmission. Inclusion of viral antigens in addition to the spike protein may enhance protection against emerging variants of concern. Next-generation vaccine platforms with a new mechanism of action may necessitate efficacy trials to fulfill regulatory requirements. The Biomedical Advanced Research and Development Authority (BARDA) will be supporting Phase 2b clinical trials of candidate next-generation vaccines. The primary endpoint will be improved efficacy in terms of symptomatic disease relative to a currently approved COVID-19 vaccine. In this paper, we discuss the planned endpoints and potential challenges to this complex program., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: Depression substantially contributes to pregnancy-related morbidity, and pregnancy is increasingly recognized as a vulnerable window for exposure effects on maternal mental health. Exposures to organophosphate esters (OPEs) are ubiquitous and may have neurotoxic effects; however, their impacts on prenatal depression remain unknown. We evaluated associations of third trimester OPE metabolites on maternal depressive symptoms during pregnancy., Methods: This study included 422 participants in the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) cohort, a prospective pregnancy cohort of primarily low-income and Hispanic participants residing in Los Angeles, California. We measured concentrations of nine OPEs in third trimester spot urine samples (mean gestational age = 31.5 ± 2.0 weeks). Using the Center for Epidemiologic Studies-Depression (CES-D) scale, we classified participants as having probable depression during pregnancy (N = 137) or not (N = 285) if one or more CES-D scores administered at each trimester met the suggested cutoff score for clinically significant depressive symptoms (≥16). We estimated associations of prenatal OPE metabolite concentrations in tertiles and risk of prenatal depression using modified Log-Poisson regression. We examined associations of the OPE mixture on depression during pregnancy using Bayesian kernel machine regression (BKMR)., Results: Participants with the highest tertiles of DPHP and BDCIPP exposure had a 67% (95% CI: 22%, 128%) and 47% (95% CI: 4%, 108%) increased risk of maternal depressive symptoms during pregnancy, respectively. No associations between other OPE metabolites and maternal depression symptoms were observed. In mixture analyses, we observed a positive and linear association between higher exposure to the OPE metabolite mixture and odds of prenatal maternal depression, primarily driven by DPHP., Conclusions: Our findings provide new evidence of associations between frequently detected OPE metabolites on maternal depression symptoms during pregnancy. Results could inform future intervention efforts aimed at reducing perinatal maternal depression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the leading cause of dementia, significantly impacting cost, mortality, and burden worldwide. The advent of high-throughput omics technologies, such as genomics, transcriptomics, proteomics, and epigenomics, has revolutionized the molecular understanding of AD. Conventional AI approaches typically require the completion of all omics data at the outset to achieve optimal AD diagnosis, which are inefficient and may be unnecessary. To reduce the clinical cost and improve the accuracy of AD diagnosis using multi-omics data, we propose a novel staged graph convolutional network with uncertainty quantification (SGUQ). SGUQ begins with mRNA and progressively incorporates DNA methylation and miRNA data only when necessary, reducing overall costs and exposure to harmful tests. Experimental results indicate that 46.23% of the samples can be reliably predicted using only single-modal omics data (mRNA), while an additional 16.04% of the samples can achieve reliable predictions when combining two omics data types (mRNA + DNA methylation). In addition, the proposed staged SGUQ achieved an accuracy of 0.858 on ROSMAP dataset, which outperformed existing methods significantly. The proposed SGUQ can not only be applied to AD diagnosis using multi-omics data, but also has the potential for clinical decision making using multi-viewed data. Our implementation is publicly available at https://github.com/chenzhao2023/multiomicsuncertainty., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Aging is the major risk factor for Alzheimer's disease (AD). In the aged brain, myelin debris accumulates and is cleared by microglia. Phagocytosed myelin debris increases neutral lipid droplet content in microglia. Neutral lipids include cholesteryl esters (CE) and triacylglycerol (TAG). To examine the effects of myelin debris on neutral lipid content in microglia, we added myelin debris to human HMC3 and mouse N9 cells. The results obtained when using 3 H-oleate as a precursor in intact cells reveal that myelin debris significantly increases the biosynthesis of CE but not TAG. Mass analyses have shown that myelin debris increases both CE and TAG. The increase in CE biosynthesis was abolished using inhibitors of the cholesterol storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1/SOAT1). ACAT1 inhibitors are promising drug candidates for AD treatment. In myelin debris-loaded microglia, treatment with two different ACAT1 inhibitors, K604 and F12511, increased the mRNA and protein content of ATP-binding cassette subfamily A1 (ABCA1), a protein that is located at the plasma membrane and which controls cellular cholesterol disposal. The effect of the ACAT1 inhibitor on ABCA1 was abolished by preincubating cells with the liver X receptor (LXR) antagonist GSK2033. We conclude that ACAT1 inhibitors prevent the accumulation of cholesterol and CE in myelin debris-treated microglia by activating ABCA1 gene expression via the LXR pathway.

Purpose: Mesenchymal neoplasms composed of vascular, smooth muscle, and adipocytic components are uncommon in the nasal cavity. While angioleiomyoma (AL) is a smooth muscle tumor in the Head & Neck WHO classification, it is considered of pericytic origin in the Skin as well as Soft Tissue and Bone classifications. For nasal AL with an adipocytic component, the terms AL with adipocytic differentiation and angiomyolipoma (AML) have been applied, among others. AML is a type of perivascular epithelioid cell tumor (PEComa), most often arising in the kidney, sometimes associated with the tuberous sclerosis complex (TSC). It is uncertain whether nasal cavity AML and AL are best considered hamartomas or neoplasms, as their genetics are largely unexplored., Methods: We performed a multi-institutional retrospective study of nasal cavity mesenchymal lesions. Patient demographics, clinical histories, and histologic and immunohistochemical findings were collected. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue and analyzed by SNP-based chromosomal microarray, targeted RNA fusion sequencing, and whole-exome sequencing., Results: Fifteen lesions (3-42 mm) were identified, predominantly in male (87%) patients with a median age of 60. Patients typically presented with obstructive symptoms, and none had a history of TSC. One AL was a recurrence from six years prior; 11 cases showed no recurrence (median 4.7 years, range: 0.88-12.4). Morphologically, 11 AML contained 30-80% smooth muscle, 10-25% vasculature, and 2-60% adipose tissue, while four AL contained 70-80% smooth muscle and 20-30% vasculature. Other histologic observations included ulceration, thrombosis, inflammation, myxoid change, senescent nuclei, and extramedullary hematopoiesis; no well-developed epithelioid cell morphology was identified. Immunohistochemically, all cases were positive for smooth muscle markers (actin, desmin, and/or caldesmon) and negative for melanocytic markers. Molecular analysis revealed loss of 3p and 11q in a single AML. No other known pathogenic copy number or molecular alterations were seen, including in TSC1/2, TFE3, or NOTCH2., Conclusion: Nasal cavity AML lacks morphologic, immunophenotypic, and genetic features of PEComa family AML. The significant histologic overlap between nasal AML and AL without distinguishing molecular features in either entity suggests "sinonasal angioleiomyoma with adipocytic differentiation" may be the most appropriate terminology for hybrid vascular and smooth muscle lesions containing adipocytic components., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: We examined the relationship between travel burden for surgical cancer care and rurality, geographic bypass of the nearest surgical facility, cancer type, and mortality outcomes., Methods: Using Medicare claims and enrollment data (2016-2018) from beneficiaries with cancer of the colon, rectum, lung, or pancreas, we measured travel times to: the nearest surgical facility and facility used. For those who bypassed the nearest, we examined travel time and rurality in relation to surgical rates. Using multivariable regression modeling, we estimated associations of bypass with 90-day postoperative- and one-year mortality; rurality was examined as an effect modifier., Findings: Among 211,025 beneficiaries with cancer, 25.5% resided in non-metropolitan areas. About 66% of metropolitan/micropolitan, and 78% of small town/rural patients bypassed their closest facility. Increasing rurality was significantly associated with increased likelihood of bypass (Referent = metropolitan, OR; 95%CI: micropolitan 1.10; 1.04-1.16, small town/rural 2.08; 1.96-2.20. Bypassing the nearest facility was associated with decreased likelihood of both 90-day postoperative mortality (OR = 0.79; 95%CI 0.74-0.85) and 1-year mortality (OR = 0.81; 95%CI 0.77-0.86). The greatest decrement in 1-year mortality was for pancreatic cancer across all rural-urban categories (OR; 95%CI: metropolitan 0.63; 0.53-0.76; micropolitan 0.53; 0.29-0.97); small town/rural 0.46; 0.25-0.86)., Conclusions: Most Medicare beneficiaries with lung, colon, rectal, or pancreatic cancer bypassed the closest facility providing surgical cancer care, especially rural patients. Bypassing was associated with a lower likelihood of 90-day postoperative, and 1-year mortality. Understanding determinants of bypassing, particularly among rural patients, may reveal potential mechanisms to improve cancer outcomes and reduce rural cancer disparities., (© 2024 The Author(s). The Journal of Rural Health published by Wiley Periodicals LLC on behalf of National Rural Health Association.)

Importance: How rates of thyroid cancer diagnosis were affected by the emergence of COVID-19 variants during the 2020 to 2021 era of the pandemic has not been described., Objective: To estimate the total number of undiagnosed cases of thyroid cancer, by histologic type, during the first 2 years of the COVID-19 pandemic (2020 and 2021) by comparing observed to expected incidence and to test for changes in size of cancer at incidence during the same period compared to prior years., Design, Setting, and Participants: This longitudinal study analyzed trends in thyroid cancer diagnoses from 2016 to 2021 among US adults using data from the Surveillance, Epidemiology, and End Results 22 (SEER-22) program database. Data analyses were performed in April to May 2024., Main Outcomes and Measures: Age-adjusted incidence rate per 100 000 US adults, changes in incidence, estimated number of undiagnosed cases, and mean cancer size., Results: Absolute rates of overall thyroid cancer incidence in the first quarter of 2016 and of 2019 were 21.0 and 18.8 per 100 000, respectively. From 2020 through 2021, the quarterly rates were 17.3, 11.1, 17.2, 17.9, 17.4, 19.0, 17.1, and 17.3 per 100 000, respectively. The observed incidence of thyroid cancers decreased by 11% for papillary cancers 2 cm or smaller (risk ratio [RR], 0.89; 95% CI, 0.83-0.95), 14% for papillary cancers larger than 2 cm (RR, 0.86; 95% CI, 0.79-0.93), 8% for follicular cancers (RR, 0.92; 95% CI, 0.82-0.92), 10% for medullary cancers (RR, 0.90; 95% CI, 0.78-1.04), and 15% for anaplastic cancers (RR, 0.85; 95% CI, 0.68-1.07) from March 2020 to December 2021. Oncocytic cancers declined in incidence early in the pandemic, but rates returned to baseline or above through 2021 (RR, 1.15; 95% CI, 0.97-1.37). Extrapolated to the general US population, the total estimated number of thyroid cancer cases not diagnosed (expected minus observed) from March 2020 to December 2021 was approximately 10 200: 5400 papillary cancers 2 cm or smaller (95% CI, 2380-8530), 3700 papillary cancers larger than 2 cm (95% CI, 1660-5810), 600 follicular cancers (95% CI, -260 to 1550), 300 medullary cancers (95% CI, -110 to 720), and 190 anaplastic cancers (95% CI, -75 to 530). Mean size at diagnosis did not change significantly between 2016 and 2021 for any histologic type., Conclusions and Relevance: This longitudinal study found that by the end of 2021, many thyroid cancers remained undiagnosed. These were predominantly small papillary cancers but also affected all histologic types except oncocytic. These deficits in diagnosis could produce a temporary increase in the rate of patients presenting with larger or more advanced stage cancers in the future, and consequently, temporary increases in population morbidity and mortality.

This article explores food allergy and the nascent field of nutritional psychiatry. Individuals with food allergy experience lower levels of "food freedom" than their nonallergic counterparts, which can create cognitive, emotional, social, nutritional, and financial burdens. Patterns of food avoidance may influence neuroinflammatory states and the gut microbiome; these changes may be associated with neuropsychiatric symptoms. Food restriction may promote disruption of the microbiome neuroimmune axis, which has been linked to various allergic diseases. Targeted psychological counseling strategies can provide benefit. Food allergy and restricted diets may impact dietary health benefits., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Importance: The Centers for Medicare & Medicaid Services (CMS) implemented advance care planning (ACP) billing codes in 2016 to encourage practitioners to conduct and document ACP conversations, and included ACP as a quality metric in the CMS Bundled Payments for Care Improvement Initiative in 2018. Use of this billing code in the inpatient setting has not been studied., Objective: To determine whether a quality improvement intervention to increase inpatient ACP is effective in increasing ACP billing rates or changing hospital treatment plans or patient outcomes., Design, Settings, and Participants: This nationwide cohort study and difference-in-differences analyses compared changes in ACP billing, treatment, and outcomes in Medicare fee-for-service beneficiaries aged 65 years and older who were hospitalized and cared for by 3 different groups: practitioners employed by a national acute care staffing organization who underwent an ACP quality improvement intervention, nonintervention practitioners at the same hospital, and control group practitioners from other hospitals. Using data from the Master Beneficiary Summary File, acute care hospital stays for nonsurgical conditions were linked to Medicare enrollment, claims, and vital status data from 1-year preadmission to 1-year postadmission from 2015 to 2019. The ACP billing rates for each group were assessed for associations with 6 inpatient treatments and 4 outcomes. Data analyses were performed from January 2022 to December 2024., Main Outcomes and Measures: Billed ACP conversations, receipt of intensive care and life support (intensive care unit admission, gastrostomy tube placement, mechanical ventilation, tracheostomy), treatment limitations (newly initiated do-not-resuscitate orders) and outcomes (discharge to hospice, inpatient death, 30-day postadmission death, and 1-year postadmission death)., Results: The total study sample included 109 intervention hospitals, 1691 control hospitals, nearly 12 million Medicare fee-for-service beneficiaries aged 65 years and older, and 738 309 practitioners associated with admissions from 2016 to 2018. ACP billing rates increased more for the intervention (1.3% in preintervention to 14.0% in postintervention; P < .001) than for the nonintervention (same hospitals) and control groups (odds ratio [OR], 2.6; 95% CI, 1.7-4.1 intervention vs control). Increased ACP billing rates were significantly associated with decreased rates of inpatient death in the intervention group (OR, 0.95; 95% CI, 0.90-1.00) compared to the nonintervention (OR, 1.10; 95% CI, 1.04-1.17) and control groups (reference). All other associations were nonsignificant., Conclusions and Relevance: This nationwide cohort study suggests that while the ACP quality initiative increased ACP billing, changes in clinical outcomes were inconsistent with the hypotheses. Further study is needed to address questions regarding confounding by unobserved measures of care quality.

The PP2A-B55 phosphatase regulates a plethora of signaling pathways throughout eukaryotes. How PP2A-B55 selects its substrates presents a severe knowledge gap. By integrating AlphaFold modeling with comprehensive high-resolution mutational scanning, we show that α helices in substrates bind B55 through an evolutionary conserved mechanism. Despite a large diversity in sequence and composition, these α helices share key amino acid determinants that engage discrete hydrophobic and electrostatic patches. Using deep learning protein design, we generate a specific and potent competitive peptide inhibitor of PP2A-B55 substrate interactions. With this inhibitor, we uncover that PP2A-B55 regulates the nuclear exosome targeting (NEXT) complex by binding to an α-helical recruitment module in the RNA binding protein 7 (RBM7), a component of the NEXT complex. Collectively, our findings provide a framework for the understanding and interrogation of PP2A-B55 function in health and disease.

Introduction: Validity is frequently conceptualized in health professions education (HPE) assessment as an argument that supports the interpretation and uses of data. However, previous work has shown that many validity scholars believe argument and argumentation are relatively lacking in HPE. To better understand HPE's discourse around argument and argumentation with regard to assessment validity, the authors explored the discourses present in published HPE manuscripts., Methods: The authors used a bricolage of critical discourse analysis approaches to understand how the language in influential peer reviewed manuscripts has shaped HPE's understanding of validity arguments and argumentation. The authors used multiple search strategies to develop a final corpus of 39 manuscripts that were seen as influential in how validity arguments are conceptualized within HPE. An analytic framework drawing on prior research on Argumentation Theory was used to code manuscripts before developing themes relevant to the research question., Results: The authors found that the elaboration of argument and argumentation within HPE's validity discourse is scant, with few components of Argumentation Theory (such as intended audience) existing within the discourse. The validity as an argument discourse was legitimized via authorization (reference to authority), rationalization (reference to institutionalized action), and mythopoesis (narrative building). This legitimation has cemented the validity as an argument discourse in HPE despite minimal exploration of what argument and argumentation are., Discussion: This study corroborates previous work showing the dearth of argument and argumentation present within HPE's validity discourse. An opportunity exists to use Argumentation Theory in HPE to better develop validation practices that support use of argument., Competing Interests: Erik Driessen is the Editor-in-Chief for Perspectives on Medical Education. He was removed from all editorial processes relating to the handling of this submission., (Copyright: © 2024 The Author(s).)

Although trauma-focused evidence-based psychotherapy (TF-EBP) is recommended for posttraumatic stress disorder (PTSD), rates of TF-EBP initiation among veterans is very low. Service delivery research has shown that other treatments are commonly provided to veterans diagnosed with PTSD, including stabilization treatments. As little is known about how veterans experience the transition to TF-EBP, we conducted a qualitative examination of veterans' perspectives on transitions in PTSD treatment. We recruited a diverse sample of veterans ( n  = 30) who recently initiated TF-EBP to complete semi-structured qualitative interviews focusing on six domains (PTSD treatment options, cultural sensitivity of treatment, PTSD treatment selection, transition criteria, beliefs about stabilization treatment, treatment needs/preferences). Rapid qualitative analysis procedures were used to identify themes. Themes included: (1) wanting to learn about TF-EBP earlier; (2) perceived risks of transition; (3) relationships with non-TF-EBP providers as transition barriers; (4) high symptoms and poor interpersonal functioning as transition facilitators; (5) benefits of treatment planning and handoffs; (6) prior therapy best when aligned with TF-EBP; (7) socialization as a key benefit of prior therapy; and (8) medications supporting TF-EBP. Results highlight the importance of introducing TF-EBP early to veterans, establishing and communicating a comprehensive care plan, and anchoring stabilization treatment in TF-EBP concepts.

A number of challenges hinder artificial intelligence (AI) models from effective clinical translation. Foremost among these challenges is the lack of generalizability, which is defined as the ability of a model to perform well on datasets that have different characteristics from the training data. We recently investigated the development of an AI pipeline on digital images of the cervix, utilizing a multi-heterogeneous dataset of 9,462 women (17,013 images) and a multi-stage model selection and optimization approach, to generate a diagnostic classifier able to classify images of the cervix into "normal", "indeterminate" and "precancer/cancer" (denoted as "precancer+") categories. In this work, we investigate the performance of this multiclass classifier on external data not utilized in training and internal validation, to assess the generalizability of the classifier when moving to new settings. We assessed both the classification performance and repeatability of our classifier model across the two axes of heterogeneity present in our dataset: image capture device and geography, utilizing both out-of-the-box inference and retraining with external data. Our results demonstrate that device-level heterogeneity affects our model performance more than geography-level heterogeneity. Classification performance of our model is strong on images from a new geography without retraining, while incremental retraining with inclusion of images from a new device progressively improves classification performance on that device up to a point of saturation. Repeatability of our model is relatively unaffected by data heterogeneity and remains strong throughout. Our work supports the need for optimized retraining approaches that address data heterogeneity (e.g., when moving to a new device) to facilitate effective use of AI models in new settings., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Objective: Direct admission (DA) to hospital can reduce emergency department (ED) utilization by bypassing the ED during the admission process. We implemented a DA program across 3 health systems and compared timeliness of care, family experience of care, and post-admission clinical deterioration among children admitted via DA versus the ED after their clinic was randomized to begin the DA program., Methods: Using a stepped-wedge design, 69 primary and urgent care clinics were randomized to 1 of 4 time points to begin a voluntary DA program, February 1, 2020 to April 30, 2023. Outcomes in children <18 years admitted with 7 common medical diagnoses were compared using adjusted logistic or linear regression., Results: A total of 2599 children were admitted with eligible diagnoses during the study period , including 145 children admitted directly and 1852 admitted through EDs after program implementation at their clinic. Median age was 2.8 (interquartile range: 1.1-6.8) years, 994 (49.8%) were female, and 1324 (66.3%) were Medicaid-insured. Adjusted regression analyses showed that if each child was admitted via DA versus the ED, average time to initial clinical assessment was 3.1 minute (95% confidence interval: 1.7-4.5) slower, whereas time to initial therapeutic management was 49.6 minutes faster on average (95% confidence interval: 30.3.2-68.9). There were no significant differences in time to initial diagnostic testing or rates of post-admission clinical deterioration., Conclusions: Compared with ED admission, DA appears equally safe and acceptable to families, and may be associated with a significantly shorter time to initial therapeutic management with modestly longer time to initial clinical assessment.

Competing Interests: Conflicts of Interest: See Disclosures at the end of the article.

Background: False-positive results on screening mammography may affect women's willingness to return for future screening., Objective: To evaluate the association between screening mammography results and the probability of subsequent screening., Design: Cohort study., Setting: 177 facilities participating in the Breast Cancer Surveillance Consortium (BCSC)., Patients: 3 529 825 screening mammograms (3 184 482 true negatives and 345 343 false positives) performed from 2005 to 2017 among 1 053 672 women aged 40 to 73 years without a breast cancer diagnosis., Measurements: Mammography results (true-negative result or false-positive recall with a recommendation for immediate additional imaging only, short-interval follow-up, or biopsy) from 1 or 2 screening mammograms. Absolute differences in the probability of returning for screening within 9 to 30 months of false-positive versus true-negative screening results were estimated, adjusting for race, ethnicity, age, time since last mammogram, BCSC registry, and clustering within women and facilities., Results: Women were more likely to return after a true-negative result (76.9% [95% CI, 75.1% to 78.6%]) than after a false-positive recall for additional imaging only (adjusted absolute difference, -1.9 percentage points [CI, -3.1 to -0.7 percentage points]), short-interval follow-up (-15.9 percentage points [CI, -19.7 to -12.0 percentage points]), or biopsy (-10.0 percentage points [CI, -14.2 to -5.9 percentage points]). Asian and Hispanic/Latinx women had the largest decreases in the probability of returning after a false positive with a recommendation for short-interval follow-up (-20 to -25 percentage points) or biopsy (-13 to -14 percentage points) versus a true negative. Among women with 2 screening mammograms within 5 years, a false-positive result on the second was associated with a decreased probability of returning for a third regardless of the first screening result., Limitation: Women could receive care at non-BCSC facilities., Conclusion: Women were less likely to return to screening after false-positive mammography results, especially with recommendations for short-interval follow-up or biopsy, raising concerns about continued participation in routine screening among these women at increased breast cancer risk., Primary Funding Source: National Cancer Institute., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M24-0123.

Introduction: Most formal continuing professional development (CPD) opportunities were offered in person until March 2020 when the COVID-19 pandemic disrupted traditional structures of CPD offerings. The authors explored the adaptations and innovations in CPD that were strengthened or newly created during the first 16 months of the pandemic., Methods: The objectives of the narrative review were to answer the following questions: (1) what types of adaptations to CPD innovations are described? and (2) what may shape future innovations in CPD? The following databases were searched: Medline, Embase, CINAHL, and ERIC to identify the literature published between March 2020 to July 2021. The authors conducted a comprehensive search by including all study types that described adaptations and/or innovations in CPD during the stated pandemic period., Results: Of the 8295 citations retrieved from databases, 191 satisfied the inclusion criteria. The authors found three categories to describe adaptations to CPD innovations: (1) creation of new online resources, (2) increased use of the existing online platforms/software to deliver CPD, and (3) use of simulation for teaching and learning. Reported advantages and disadvantages associated with these adaptations included logistical, interactional, and capacity building elements. The review identified five potential future CPD innovations: (1) empirical research on the effectiveness of virtual learning; (2) novel roles and ways of thinking; (3) learning from other disciplines beyond medicine; (4) formation of a global perspective; and (5) emerging wellness initiatives., Discussion: This review provided an overview of the adaptations and innovations that may shape the future of CPD beyond the pandemic., Competing Interests: Disclosures: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Alliance for Continuing Education in the Health Professions, the Association for Hospital Medical Education, and the Society for Academic Continuing Medical Education.)

Background: Aedes aegypti, is the primary vector of dengue, Chikungunya, Zika, and yellow fever viruses. Both natural and human-impacted landscapes have selective pressures on Ae. aegypti, resulting in strong genomic structure even within close geographical distances. Materials and Methods: We assess the genetic structure of this medically important mosquito species at the northern leading edge of their distribution in Southwestern USA. Ae. aegypti were collected during 2017 in the urban communities of El Paso and Sparks, Texas (USA) and in the city of Ciudad Juárez, Mexico. Results: Thousands of nuclear loci were sequenced across 260 captured Ae. aegypti. First, we recovered the genetic structure of Ae. aegypti following geography, with all four major collection communities being genetically distinct. Importantly, we found population structure and genetic diversity that suggest rapid expansion through active-short distance dispersals, with Anapra being the likely source for the others. Next, tests of selection recovered eight functional genes across six outliers: calmodulin with olfactory receptor function; the protein superfamily C-type lectin with function in mosquito immune system and development; and TATA box binding protein with function in gene regulation. Conclusion: Despite these populations being documented in the early 2000s, we find that selective pressures on specific genes have already occurred and likely facilitate Ae. aegypti range expansion.

Abstract: The conventional morphological characteristics of Wnt-activated deep penetrating/plexiform melanocytomas/nevi (DPN) are those of large spindled or epithelioid melanocytes with distinctive voluminous amphophilic cytoplasm, fine pigmented granules, and surrounding melanophages. The central molecular hallmark is the activation of the Wnt-pathway predominantly driven by mutations in the beta-catenin ( CTNNB1 ) gene. Although typically lacking a junctional component, a lesser-known superficial variant with a junctional component has been identified, which could potentially lead to diagnostic challenges. This study presents a cohort of 11 such cases displaying a junctional component of DPN from 10 patients (5 women and 5 men; age range: 27-78 years; median age: 51 years). The nevi were distributed as follows: 1 conjunctival, 1 scalp, 2 lower limb, and 6 truncal lesions. Eight cases were combined with a conventional nevus, 2 cases displayed pure DPN cytology exhibiting only a junctional element, and 9 cases exhibited some degree of lentiginous architecture. All cases demonstrated a low mitotic index (<1 mitosis/mm 2 ). Immunohistochemistry revealed positive BRAF V600E staining in 8 cases (8/11), whereas all cases tested (11/11) were PRAME negative. Nuclear beta-catenin and LEF1 staining was consistently strong and diffuse with DPN cytology (11/11), along with robust cyclin D1 staining in all cases tested (11/11). By contrast, all 9 conventional nevi showed an absence of nuclear beta-catenin staining (0/9) and weaker, mosaic-type LEF1 and cyclin D1 staining was observed. This study emphasizes the diagnostic challenge these nevi can pose in the absence of a conventional, deeper DPN component, which can potentially be misdiagnosed as melanoma., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Tea and coffee are the most frequently consumed beverages in the world. Green tea in particular contains compounds with potential anti-cancer effects, but its association with survival after ovarian cancer is uncertain., Methods: We investigated the associations between tea and coffee consumption before diagnosis and survival using data from 10 studies in the Ovarian Cancer Association Consortium. Data on tea (green, black, herbal), coffee and caffeine intake were available for up to 5724 women. We used Cox proportional hazards regression to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI)., Results: Compared with women who did not drink any green tea, consumption of one or more cups/day was associated with better overall survival (aHR = 0.84, 95% CI 0.71-1.00, p-trend = 0.04). A similar association was seen for ovarian cancer-specific survival in five studies with this information (aHR = 0.81, 0.66-0.99, p-trend = 0.045). There was no consistent variation between subgroups defined by clinical or lifestyle characteristics and adjustment for other aspects of lifestyle did not appreciably alter the estimates. We found no evidence of an association between coffee, black or herbal tea, or caffeine intake and survival., Conclusion: The observed association with green tea consumption before diagnosis raises the possibility that consumption after diagnosis might improve patient outcomes., (© 2024. The Author(s).)

Context: Outpatient palliative care (PC) has strong evidence demonstrating impact across serious illnesses, resulting in growing demand for skilled outpatient PC clinicians. However, there is limited literature examining the existing state and quality of outpatient PC education during postgraduate training., Objectives: Characterize the current state of outpatient training in United States (US) Hospice and Palliative Medicine (HPM) physician fellowships and elicit perceptions regarding quality of outpatient PC education., Methods: A cross-sectional survey of US adult HPM fellowship program directors (PDs) or their designee conducted between March and July, 2023., Results: Of 161 programs, 85 participated (53% response rate) with representation across all US regions. HPM fellows spend a median of 4.8 weeks in outpatient PC compared to 24 weeks inpatient PC and 10.5 weeks in hospice settings. Over half (51%) of fellows saw outpatients from primarily one disease type with limited exposure to patients with other serious illnesses. Across programs, fellows' clinic structure, interdisciplinary team composition, and didactic experiences varied. On a 5-point rating scale, PDs reported significantly lower quality outpatient versus inpatient training (mean rating: 3.58 vs. 4.62, P<0.001) and perceived fellows as less prepared for independent outpatient practice upon graduation (mean: 4.06 vs. 4.73, P<0.001)., Conclusion: Our survey of US HPM fellowships identified multiple gaps between outpatient and inpatient PC education and training during fellowship and raises concern about the adequacy of outpatient PC training. To prepare the HPM workforce to meet the diverse needs of seriously ill populations and ensure adequate access, outpatient PC training requires reform., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. All rights reserved.)

GLI1 -altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1 -altered mesenchymal neoplasms to date, including 23 GLI1- amplified and 15 GLI1 -rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1- rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1 -amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1 -amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1- amplified tumors. GLI1 -amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1 -amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1 -rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1 -amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1- rearranged group. Despite comparable progression rates, GLI1 -amplified tumors had a shorter median progression-free survival compared with GLI1 -rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1 -altered mesenchymal tumors., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

When low muscle mass and impaired strength and physical function coexist with excess adiposity, it is termed sarcopenic obesity (SO). Handgrip strength (HGS) is a predictor of disability and mortality. Asymmetry in HGS, particularly ≥ 10% strength differences between hands, may indicate neuromuscular dysfunction observable prior to declines in maximal strength are detectedand therefore could be incorporated to identify those at risk of physical limitations and SO. This study compares HGS values and asymmetry in older adults with excess adiposity and evaluates their relationships with physical function. Baseline data from two previous pilot weight loss studies in 85 older adults with body mass index values ≥ 30 kg m -2 are included with measures of body composition, walking speed, and chair stand ability. Sixty-three participants met the criteria for SO. HGS correlated to gait speed (r = 0.22), distance walked (r = 0.40), chair stand time for 5 repetitions (r = 0.42) and during 30 s (r = 0.31). HGS asymmetry is only correlated to gait speed (r = 0.31) and there are no differences in physical function between those with and without asymmetry. Maximal HGS tests should continue to be used to screen for functional decline and disability., (© 2024 Wiley‐VCH GmbH.)

Competing Interests: Financial/Nonfinancial Disclosures None declared.

Modern consensus panel guidelines recommend restriction from most organized sports for patients with moderate or severe aortic stenosis (AS). However, there is little published data on how frequently physicians deviate from guidelines, how well patients adhere to exercise restrictions, or the effect of restriction on patient-reported quality of life. In this study, we surveyed 93 subjects with AS and their cardiologists regarding participation in organized sports, physical activity, weightlifting, and exercise restriction. Subjects completed the pediatric quality of life inventory (PedsQL) and the pediatric cardiac quality of life inventory (PCQLI). We found that subjects with severe AS (n = 3) were commonly, but not universally, restricted from organized sports (n = 2, 66%). Subjects with moderate AS (n = 40) were rarely restricted from organized sports (n = 6, 17%). No physician-specific characteristics were associated with increased likelihood of recommending exercise restriction. Subjects were more likely to be restricted if they were older (16 years vs. 13 years, p 0.02) and had moderate versus mild AS (p 0.013). PCQLI scores for teens and young adults with AS (age 13-25) were lower than a comparison group of patients with mild congenital heart disease. For all age groups, the PedsQL social functioning score was lower for subjects with exercise restriction (p 0.052). In summary, cardiologists apply consensus guidelines leniently when restricting patients with moderate/severe AS from organized sports and weightlifting. Patients with AS routinely adhere to exercise restriction recommendations. Children and young adults with AS and exercise restriction have lower QOL scores in the social functioning domain., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

For clinicians involved in improving healthcare for patients with allergic and immunologic conditions, advocacy on a broader level through public outreach is key to advancing value-based care. In this article, we provide a toolkit of strategies and resources that can be used to raise public awareness of important issues through various mediums, including podcasts and social media, newspapers, testimonies, presentations, and interviews. A simple approach to effective media interactions is described using the acronym "RATIO," which stands for Research, Audience, Targeted topic, Interview rephrasing, and Optimism. The acronym also reminds the person who is presenting information that only a fraction of what is discussed will be recalled, and an even smaller proportion will be implemented. Key points should be made early. Examples of key talking points are provided for selected topics, including food allergy, anaphylaxis, asthma, rhinitis, and broader healthcare advocacy., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: Within the past decade, Medicare Part B reimbursements for various surgical procedures have been declining, whereas health care expenses continue to increase. As a result, hospitals may increase service charges to offset losses in revenue, which may disproportionately affect underinsured patients. Our analysis aimed to characterize Medicare billing and utilization trends across common vascular surgical procedures., Methods: The 2017 to 2021 Medicare Physician and Other Practitioners by Provider and Service dataset was queried for Current Procedural Terminology (CPT) codes for common vascular surgery procedures. The average charges, reimbursements, charge-to-reimbursement ratios, and service counts were calculated for the most common interventions performed by vascular surgeons. Data was stratified by care setting, facility (inpatient and outpatient hospital) vs non-facility locations. All monetary values were adjusted to the 2021 United States dollars to account for inflation., Results: For facility settings, the mean charge billed to Medicare Part B increased from $3708 to $3952 (6.6%) from 2017 to 2021, with the average charge-to-reimbursement ratio increasing from 7.2 to 8.6. There were 17 of the 19 facility procedures that had a decline in reimbursements, decreasing from an average of $558 to $499 (-10.4%). Stab phlebectomy had the largest individual decrease in facility reimbursement (-53.5%), followed by above-knee amputation (-11.3%) and below-knee amputation (-11.0%). Both non-facility charges (-10.8%) and reimbursements (-12.2%) declined over the study period. Procedural utilization remained stable from 2017 to 2019. Tibial and femoral-popliteal atherectomy had increases of 45.9% and 33.7%, respectively, in overall procedural utilization when performed in non-facility settings from 2017 to 2019., Conclusions: Our analysis of vascular surgery procedures billed to Medicare Part B from 2017 to 2021 demonstrates an increase in charges, a decline in reimbursements, and a resultant increase in charge-to-reimbursement ratios for facility care settings. In contrast, non-facility charges have decreased in the face of declining reimbursements. These markups in submitted charges in facility locations may serve as an additional barrier to accessing care for patients who are underinsured., Competing Interests: Disclosures J.J.S. receives an education grant paid to Boston University from W.L. Gore & Associates, Inc and Becton, Dickinson & Company. A.F. is the primary investigator of the BEST-CLI., (Copyright © 2024 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: We evaluate available evidence for the role of inflammation in depression. We reappraise literature involving systemic inflammation, neuroinflammation and neurotransmission and their association with depression. We review the connection between depression, autoimmunity and infectious diseases. We revise anti-inflammatory treatments used in depression., Recent Findings: Peripheral inflammatory markers are present in a subset of patients with depression and can alter common neurotransmitters in this population but there is no clear causality between depression and systemic inflammation. Infectious conditions and autoimmune illnesses do not have a clear correlation with depression. Certain medications have positive evidence as adjunctive treatments in depression but studies are heterogenic, hence they are sparsely used in clinical settings. The current evidence does not fully support inflammation, infections or autoimmunity as possible etiologies of depression. The available studies have numerous confounders that obscure the findings. Anti-inflammatory agents may have potential for treatment of depression, but further research is needed to clarify their usefulness in routine clinical practice., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Acquired resistance to immune checkpoint blockers (ICBs) is a major barrier in cancer treatment, emphasizing the need for innovative strategies. Dectin-1 (gene Clec7a) is a C-type lectin receptor best known for its ability to recognize β-glucan-rich structures in fungal cell walls. While Dectin-1 is expressed in myeloid cells and tumor cells, its significance in cancer remains the subject of controversy., Methods: Using Celc7a-/- mice and curdlan administration to stimulate Dectin-1 signaling, we explored its impact. VISTA KO mice were employed to assess VISTA's role, and bulk RNAseq analyzed curdlan effects on neutrophils., Results: Our findings reveal myeloid cells as primary Dectin-1 expressing cells in the tumor microenvironment (TME), displaying an activated phenotype. Strong Dectin-1 co-expression/co-localization with VISTA and PD-L1 in TME myeloid cells was observed. While Dectin-1 deletion lacked protective effects, curdlan stimulation significantly curtailed B16-F10 tumor progression. RNAseq and pathway analyses supported curdlan's role in triggering a cascade of events leading to increased production of pro-inflammatory mediators, potentially resulting in the recruitment and activation of immune cells. Moreover, we identified a heterogeneous subset of Dectin-1+ effector T cells in the TME. Similar to mice, human myeloid cells are the prominent cells expressing Dectin-1 in cancer patients., Conclusion: Our study proposes Dectin-1 as a potential adjunctive target with ICBs, orchestrating a comprehensive engagement of innate and adaptive immune responses in melanoma. This innovative approach holds promise for overcoming acquired resistance to ICBs in cancer treatment, offering avenues for further exploration and development., (© 2024. The Author(s).)

Importance: Information on long-term benefits and harms of screening with digital breast tomosynthesis (DBT) with or without supplemental breast magnetic resonance imaging (MRI) is needed for clinical and policy discussions, particularly for patients with dense breasts., Objective: To project long-term population-based outcomes for breast cancer mammography screening strategies (DBT or digital mammography) with or without supplemental MRI by breast density., Design, Setting, and Participants: Collaborative modeling using 3 Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer simulation models informed by US Breast Cancer Surveillance Consortium data. Simulated women born in 1980 with average breast cancer risk were included. Modeling analyses were conducted from January 2020 to December 2023., Intervention: Annual or biennial mammography screening with or without supplemental MRI by breast density starting at ages 40, 45, or 50 years through age 74 years., Main Outcomes and Measures: Lifetime breast cancer deaths averted, false-positive recall and false-positive biopsy recommendations per 1000 simulated women followed-up from age 40 years to death summarized as means and ranges across models., Results: Biennial DBT screening for all simulated women started at age 50 vs 40 years averted 7.4 vs 8.5 breast cancer deaths, respectively, and led to 884 vs 1392 false-positive recalls and 151 vs 221 false-positive biopsy recommendations, respectively. Biennial digital mammography had similar deaths averted and slightly more false-positive test results than DBT screening. Adding MRI for women with extremely dense breasts to biennial DBT screening for women aged 50 to 74 years increased deaths averted (7.6 vs 7.4), false-positive recalls (919 vs 884), and false-positive biopsy recommendations (180 vs 151). Extending supplemental MRI to women with heterogeneously or extremely dense breasts further increased deaths averted (8.0 vs 7.4), false-positive recalls (1088 vs 884), and false-positive biopsy recommendations (343 vs 151). The same strategy for women aged 40 to 74 years averted 9.5 deaths but led to 1850 false-positive recalls and 628 false-positive biopsy recommendations. Annual screening modestly increased estimated deaths averted but markedly increased estimated false-positive results., Conclusions and Relevance: In this model-based comparative effectiveness analysis, supplemental MRI for women with dense breasts added to DBT screening led to greater benefits and increased harms. The balance of this trade-off for supplemental MRI use was more favorable when MRI was targeted to women with extremely dense breasts who comprise approximately 10% of the population.

Objectives: China introduced an innovative Supplementary High-Cost Illness Insurance (SHCII) program to enhance existing social health insurance by providing extra financial support for individuals facing catastrophic illnesses in 2015. The SHCII has notably increased access to healthcare and alleviated financial strain for economically disadvantaged individuals. However, there is a lack of information regarding the program's impact on the mental health of its beneficiaries. This study aims to assess the impact of SHCII on the mental well-being of middle-aged and older individuals., Methods: Using data from the China Health and Retirement Longitudinal Study (2011, 2013, 2015, and 2018), this study examined how SHCII affects mental health among middle-aged and older individuals in China using propensity score matching with the time-varying difference-in-differences method., Results: We found that SHCII implementation can significantly reduce the Center for Epidemiologic Studies-Depression Scale scores of middle-aged and older individuals. This reduction was more pronounced among older individuals with poor self-rated health, chronic disease, and low household wealth when compared to their counterparts., Discussion: The implementation of SHCII has had a significant and positive impact on mental health outcomes. We recommend that governments consider expanding the program to other areas within China, focusing especially on the most economically disadvantaged segments of the population., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Although behavioral interventions have been effective in gastrointestinal (GI) conditions, barriers exist in implementing these interventions into clinical practice. The majority of previously published studies have focused on workforce limitations and have not considered individual and social determinants of health (SDoH) factors that can impact engagement in GI behavioral healthcare., Aims: To characterize barriers to engagement in appointment attendance and health management, explore individual and SDoH factors impacting GI behavioral healthcare engagement, and identify barriers that occur more often for patients with SDoH-related vulnerability (low health literacy and/or financial insecurity)., Methods: A survey was distributed to adult patients who had been seen in Gastroenterology at the Dartmouth-Hitchcock Medical Center from June 2022 to December 2022., Results: One hundred participants [mean age = 58 years, 57.1% women] completed the survey. SDoH vulnerability was present in 32.3% of the population. For the entire sample, 73% reported at least one barrier to accessing care and 75% reported at least one factor which impacted health management. Those with SDoH vulnerability reported significantly more barriers to attending appointments and to managing health. In addition, they were significantly more likely to endorse physical health problems, difficulty affording medical bills, pain, mobility issues, trauma experiences, significant stress, and difficulty with concentration., Conclusions: Patients in a GI clinic reported multiple barriers to accessing care and participating in health management. Innovative, multi-level strategies are needed to address barriers to ensure that all patients are able to obtain quality GI behavioral health services., (© 2024. The Author(s).)

Abstract: COVID-19 unleashed a maelstrom of distress on health care professionals. The pandemic contributed to a host of stressors for workers because of the need for rapid acquisition of new knowledge and skills to provide best treatment while simultaneously dealing with personal safety, limited resources, staffing shortages, and access to care issues. Concurrently, problems with systemic racial inequality and discrimination became more apparent secondary to difficulties with accessing health care for minorities and other marginalized groups. These problems contributed to many health care professionals experiencing severe moral injury and burnout as they struggled to uphold core values and do their jobs professionally. Some left or disengaged. Others died. As continuing professional development leaders focused on all health professionals, we must act deliberately to address health care professionals' distress and mental health. We must incorporate wellness and mental health as organizing principles in all we do. We must adopt a new mental model that recognizes the importance of learners' biopsychosocial functioning and commit to learners' wellness by developing activities that embrace a biopsychosocial point of view. As educators and influencers, we must demonstrate that the Institute for Healthcare Improvement's fourth aim to improve clinician well-being and safety (2014) and fifth aim to address health equity and the social determinants of health (2021) matter. It is crucial that continuing professional development leaders globally use their resources and relationships to accomplish this imperative call for action., Competing Interests: Disclosures: The authors declare no conflict of interest., (Copyright © 2024 The Alliance for Continuing Education in the Health Professions, the Association for Hospital Medical Education, and the Society for Academic Continuing Medical Education.)

Purpose: High consumption of fruits and vegetables decrease the risk of bladder cancer (BC). The evidence of specific fruits and vegetables and the BC risk is still limited., Methods: Fruit and vegetable consumptions in relation to BC risk was examined by pooling individual participant data from case-control studies. Unconditional logistic regression was used to estimate study-specific odds ratio's (ORs) with 95% confidence intervals (CIs) and combined using a random-effects model for intakes of total fruits, total vegetables, and subgroups of fruits and vegetables., Results: A total of 11 case-control studies were included, comprising 5637 BC cases and 10,504 controls. Overall, participants with the highest intakes versus the lowest intakes of fruits in total (OR 0.79; 95% CI 0.68-0.91), citrus fruits (OR 0.81; 95% CI 0.65-0.98), pome fruits (OR 0.76; 95% CI 0.65-0.87), and tropical fruits (OR 0.84; 95% CI 0.73-0.94) reduced the BC risk. Greater consumption of vegetables in total, and specifically shoot vegetables, was associated with decreased BC risk (OR 0.82; 95% CI 0.68-0.96 and OR 0.87; 95% CI 0.78-0.96, respectively). Substantial heterogeneity was observed for the associations between citrus fruits and total vegetables and BC risk., Conclusion: This comprehensive study provides compelling evidence that the consumption of fruits overall, citrus fruits, pome fruits and tropical fruits reduce the BC risk. Besides, evidence was found for an inverse association between total vegetables and shoot vegetables intake., (© 2024. The Author(s).)

Background: Depression is common in Parkinson's disease (PD) but is underrecognized clinically. Although systematic screening is a recommended strategy to improve depression recognition in primary care practice, it has not been widely used in PD care., Methods: The 15-item Geriatric Depression Scale (GDS-15) was implemented at 5 movement disorders clinics to screen PD patients. Sites developed processes suited to their clinical workflow. Qualitative interviews with clinicians and patients provided information on feasibility, acceptability, and perceived utility., Results: Prior to implementation, depression screening was recorded in 12% using a formal instrument; 64% were screened informally by clinical interview, and no screening was recorded in 24%. Of 1406 patients seen for follow-up care during the implementation period, 88% were screened, 59% using the GDS-15 (self-administered in 51% and interviewer administered in 8%), a nearly 5-fold increase in formal screening. Lack of clinician or staff time and inability to provide the GDS-15 to the patient ahead of the visit were the most commonly cited reasons for lack of screening using the GDS-15; 378 (45%) patients completing the GDS-15 screened positive for depression, and 137 were enrolled for a 12-month prospective follow-up. Mean GDS-15 scores improved from 8.8 to 7.0 (P < 0.0001) and the 39-item Parkinson's Disease Questionnaire emotional subscore from 42.2 to 36.7 (P = 0.0007)., Conclusions: Depression screening in PD using a formal instrument can be achieved at much higher levels than is currently practiced, but there are barriers to implementing this in clinical practice. An individual site-specific process is necessary to optimize screening rates., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Purpose of Review: To review the updated 2023 Allergy Immunology Joint Task Force on Practice Parameters (JTFPP) GRADE and Institute of Medicine (IOM) Based Guidelines for the management of atopic dermatitis., Recent Findings: Topical corticosteroids and/or calcineurin inhibitors are recommended in individuals with atopic dermatitis refractory to moisturizer alone and may be used to maintain remission after acute flare control is achieved. Calcineurin inhibitors are a class of immunosuppressants used to effectively manage different autoimmune disorders. Bleach baths and allergen immunotherapy may be beneficial for individuals with moderate-to-severe disease, while elimination diets, azathioprine, methotrexate, mycophenolate, and systemic corticosteroids are not recommended. Dupilumab is strongly recommended for refractory atopic dermatitis. Oral Janus kinase (JAK) inhibitors carry significant risks; however, this class of medicines may be considered in cases of severe or refractory atopic dermatitis with intolerance to dupilumab. Patient preferences regarding cost, availability, feasibility, and tolerability should be integrated into all treatment plans using a shared decision-making approach., Summary: The 2023 JTFPP Atopic Dermatitis Guidelines offer up-to-date guidance for the management of atopic dermatitis of varying severity in infants, children, and adults., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Subtotal cholecystectomy is advocated in patients with severe inflammation and distorted anatomy preventing safe removal of the entire gallbladder. Not well documented in this surgically complex population is the feasibility of intraoperative imaging and management of common bile duct (CBD) stones. We evaluated these operative maneuvers in our subtotal cholecystectomy patients., Methods: We retrospectively reviewed all cholecystectomy cases from 2014 to 2023 at a single Veterans Affairs (VA) Medical Center using VASQIP (VA Surgical Quality Improvement Program), selecting subtotal cholecystectomy cases for detailed analysis. We reviewed operative reports, imaging and laboratory studies, and clinical notes to understand biliary imaging, stone management, complications, and late outcomes including retained stones (within 6 months), and recurrent stones (beyond 6 months)., Results: 419 laparoscopic (n = 406) and open (n = 13) cholecystectomies were performed, including 40 subtotal cholecystectomies (36 laparoscopic, 4 laparoscopic converted to open). Among these 40 patients IOC was attempted in 35 and completed in 26, with successful stone management in 11 (9 common bile duct exploration [CBDE], 2 intraoperative endoscopic retrograde cholangiopancreatography [ERCP]). In follow-up, 3 additional patients had CBD stones managed by ERCP, including 1 with a negative IOC and 2 without IOC. Thus, 14 (35%) of 40 patients had CBD stones. Of note, IOC permitted identification and oversewing or closure of the cystic duct in 32 patients. There were no major bile duct injuries and one cystic duct stump leak (2.5%) that resolved spontaneously., Conclusions: Subtotal cholecystectomy patients had a high incidence of bile duct stones, with most detected and managed intraoperatively with CBDE, making a strong argument for routine IOC and single-stage care. When intraoperative imaging is not possible, postoperative imaging should be considered. Routine imaging, biliary clearance, and cystic duct closure during subtotal cholecystectomy is feasible in most patients with low rates of retained stones and bile leaks., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)