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Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Eosinophils play a key role in allergic diseases such as insect bite hypersensitivity (IBH). Together with Th2 cells, they shape the course of inflammation in associated type I/IVb allergies. Therefore, a virus-like particle (VLP)-based vaccine targeting equine interleukin-5 (eIL-5), eIL-5-CuMV-TT, was developed to interfere with the IL-5 dependency of eosinophils by inducing the production of anti-self-IL-5 antibodies and alleviating clinical signs in IBH-affected horses. A previous study highlighted the presence of two eosinophil subsets, steady-state resident eosinophils (rEos) and inflammatory eosinophils (iEos), circulating in the blood of healthy and IBH-affected horses, distinguishable by the expression of integrin CD49f. Furthermore, eIL-5-CuMV-TT 1st year vaccination showed a significant decrease of total eosinophils and, in particular, iEos. Nevertheless, the very few remaining eosinophils still shared an iEos phenotype, reflected by bigger size and higher granularity. The aim of this study was to follow up on the phenotype of eosinophils in the 2nd year of vaccination of IBH-affected horses with eIL-5-CuMV-TT. Using flow cytometry analysis of the blood of healthy, IBH, IBH-placebo, and IBH-vaccinated horses, the percentage and count of cells were compared between groups with a focus on pair analysis of eosinophils in 1st and 2nd year vaccinated horses. Our data showed comparably low levels of iEos and a significant increase of rEos in 2nd year compared to 1st year vaccinated horses, suggesting a phenotypic shift toward a resident-like eosinophil population, primarily associated with the phenotype of healthy horses. The reduction of size, granularity, and expression of integrin CD49f in the 2nd year suggests a benefit of long-term treatment with the eIL-5-CuMV-TT vaccine.

Rheumatoid arthritis (RA) is characterized by erosive pathology associated with joint inflammation and a sexual dimorphism with increased prevalence in females. Here, we aim to determine whether androgen is protective against inflammatory-erosive disease in TNF-transgenic (TNF-Tg) mice. Wild-type (WT) and TNF-Tg male mice underwent sham (WT, n = 3; TNF-Tg, n = 7) or orchiectomy (WT, n = 3; TNF-Tg, n = 7) surgery at 1 month old to remove androgen production confirmed by serum testosterone concentration. Cohorts of orchiectomized TNF-Tg males were treated with either 5ɑ-dihydrotestosterone (.025 mg/day) (n = 3) or placebo (n = 3) via subcutaneous pellet insertion. Weekly clinical measures, along with mid-hindpaw bone volumes and ankle histology at 3 months old were evaluated for all groups. Orchiectomies in TNF-Tg males significantly decreased serum testosterone ( P < .05), weight gain ( P < .001), and mid-hindpaw bone volumes ( P < .05) in comparison to sham TNF-Tg mice. The cuboid bone also had increased synovitis by histology with the loss of androgen ( P < .05). Treatment of orchiectomized TNF-Tg males with 5ɑ-dihydrotestosterone protected against the changes in weight gain ( P < .01) and bone erosion ( P < .05) associated with decreased osteoclast number in the cuboid ( P < .01). In the TNF-Tg model of chronic inflammatory arthritis, androgen is protective in erosive disease. The loss of endogenous androgen significantly accelerated the progression of inflammatory-erosive arthritis in male TNF-Tg mice to a similar severity as age-matched female mice. In addition, treatment with exogenous androgen prevented this observed bone loss in orchiectomized TNF-Tg males. Overall, androgen delays and limits bone erosion even in the presence of active inflammation and future studies are warranted to elucidate the associated mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Understanding the relationship between psychopathology and major domains of human neurobehavioral functioning may identify new transdiagnostic treatment targets. However, studies examining the interrelationship between psychopathological symptoms, sensorimotor, cognitive, and global functioning in a transdiagnostic sample are lacking. We hypothesized a close relationship between sensorimotor and cognitive functioning in a transdiagnostic patient sample., Methods: We applied network analysis and community detection methods to examine the interplay and centrality [expected influence (EI) and strength] between psychopathological symptoms, sensorimotor, cognitive, and global functioning in a transdiagnostic sample consisting of 174 schizophrenia spectrum (SSD) and 38 mood disorder (MOD) patients. All patients (n = 212) were examined with the Positive and Negative Syndrome Scale (PANSS), the Heidelberg Neurological Soft Signs Scale (NSS), the Global Assessment of Functioning (GAF), and the Brief Cognitive Assessment Tool for Schizophrenia consisted of trail making test B (TMT-B), category fluency (CF) and digit symbol substitution test (DSST)., Results: NSS showed closer connections with TMT-B, CF, and DSST than with GAF and PANSS. DSST, PANSS general, and NSS motor coordination scores showed the highest EI. Sensory integration, DSST, and CF showed the highest strength., Conclusions: The close connection between sensorimotor and cognitive impairment as well as the high centrality of sensorimotor symptoms suggests that both domains share aspects of SSD and MOD pathophysiology. But, because the majority of the study population was diagnosed with SSD, the question as to whether sensorimotor symptoms are really a transdiagnostic therapeutic target needs to be examined in future studies including more balanced diagnostic groups., (© 2024. The Author(s).)

We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though the mechanism remained to be elucidated. Here we report trabectedin disrupts the intrinsic cellular antiviral response which increases viral transcript presence in the human tumor cells. We also extended our synergy findings to syngeneic murine sarcoma models, which are poorly susceptible to virus infection. In the absence of robust virus replication, we found trabectedin enhanced viroimmunotherapy efficacy by reducing infiltrating immunosuppressive CD4 T and myeloid cells and stimulating granzyme expression in infiltrating T and natural killer cells to cause immune-mediated tumor regressions. Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients., Competing Interests: L.B. is an employee of JJP Biologics. T.P.C. is a member of the Molecular Therapy editorial board and the editor-in-chief of Molecular Therapy Oncology. D.A.L. and P.R. are associate editors for Molecular Therapy Oncology., (© 2024 The Author(s).)

Introduction: The growth of surgeon burnout is of significant concern. As we work to reimagine the practice of surgery, an accurate understanding of the extent of surgeon burnout is essential. Our goal was to define the current prevalence of burnout and quality of life (QOL) among SAGES surgeons., Methodology: An electronic survey was administered to SAGES members to establish a current baseline for QOL, burnout, depression, and career satisfaction. To assess outcomes, we utilized the validated Maslach Burnout Inventory for Medical Personnel, the Medical Outcomes Study Short Form, and the Primary Care Evaluation of Mental Disorders. All scoring followed validated norm-based methods., Results: Of 4194 active members, 604 responded (14.40%). 69% met burnout threshold, with high levels of emotional exhaustion and depersonalization, and low personal accomplishment. 81% reported "being at the end of their rope", 74% felt emotionally drained, and 65% felt used up daily. Nearly all maintained caring about what happened to their patients (96%), easily understanding how their patients feel (84.3%) and being capable of dealing effectively with their patient's problems (87.6%). However, respondents never, rarely, or occasionally felt energetic (77.5%) or experienced a sense of professional accomplishment (57.8%). The overall QOL score was 69/100, with lower Mental than Physical scores (62.69 (SD 10.20) vs.77.27 (SD 22.24)). More than half of respondents met depression criteria. While 77% supported they would become a physician again, less than half would choose surgery again or recommend surgery to their children. Furthermore, less than a third felt work allowed sufficient time for their personal lives., Conclusions: Participating SAGES surgeons reported alarmingly high rates of burnout and depression. Despite experiencing emotional exhaustion and depersonalization, they maintained a strong commitment to patient care. These findings likely reflect the broader state of surgeons, underscoring the urgent need for action to address this critical issue., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The ability of Large Language Models (LLMs) to analyze and respond to freely written text is causing increasing excitement in the field of psychiatry; the application of such models presents unique opportunities and challenges for psychiatric applications. This review article seeks to offer a comprehensive overview of LLMs in psychiatry, their model architecture, potential use cases, and clinical considerations. LLM frameworks such as ChatGPT/GPT-4 are trained on huge amounts of text data that are sometimes fine-tuned for specific tasks. This opens up a wide range of possible psychiatric applications, such as accurately predicting individual patient risk factors for specific disorders, engaging in therapeutic intervention, and analyzing therapeutic material, to name a few. However, adoption in the psychiatric setting presents many challenges, including inherent limitations and biases in LLMs, concerns about explainability and privacy, and the potential damage resulting from produced misinformation. This review covers potential opportunities and limitations and highlights potential considerations when these models are applied in a real-world psychiatric context., Competing Interests: Declaration of competing interest AM-L has received consultant fees from: Agence Nationale de la Recherche, Brain Mind Institute, Brainsway, CISSN (Catania International Summer School of Neuroscience), Daimler und Benz Stiftung, Fondation FondaMental, Hector Stiftung II, Janssen-Cilag GmbH, Lundbeck A/S, Lundbeckfonden, Lundbeck Int. Neuroscience Foundation, MedinCell, Sage Therapeutics, Techspert.io, The LOOP Zürich, University Medical Center Utrecht, von Behring Röntgen Stiftung. AM-L has received speaker fees from: Arztekammer Nordrhein, BAG Psychiatrie Oberbayern, Biotest¨ AG, Forum Werkstatt Karlsruhe, International Society of Psychiatric Genetics, Brentwood, Klinik für Psychiatrie und Psychotherapie Ingolstadt, Lundbeck SAS France, med Update GmbH, Merz-Stiftung, Siemens Healthineers, Society of Biological Psychiatry. AM-L has received editorial fees from: American Association for the Advancement of Science, Elsevier, Thieme Verlag. ES received speaker fees from bfd buchholz-fachingormationsdienst GmbH and editorial fees from Lundbeckfonden. SV has no conflicts of interest to report., (Copyright © 2024. Published by Elsevier B.V.)

Background: Understanding the biological processes that underlie individual differences in emotion regulation and stress responsivity is a key challenge for translational neuroscience. The gene FKBP5 is a core regulator in molecular stress signaling that is implicated in the development of psychiatric disorders. However, it remains unclear how FKBP5 DNA methylation in peripheral blood is related to individual differences in measures of neural structure and function and their relevance to daily-life stress responsivity., Methods: Here, we characterized multimodal correlates of FKBP5 DNA methylation by combining epigenetic data with neuroimaging and ambulatory assessment in a sample of 395 healthy individuals., Results: First, we showed that FKBP5 demethylation as a psychiatric risk factor was related to an anxiety-associated reduction of gray matter volume in the ventromedial prefrontal cortex, a brain area that is involved in emotion regulation and mental health risk and resilience. This effect of epigenetic upregulation of FKBP5 on neuronal structure is more pronounced where FKBP5 is epigenetically downregulated at baseline. Leveraging 208 functional magnetic resonance imaging scans during a well-established emotion-processing task, we found that FKBP5 DNA methylation in peripheral blood was associated with functional differences in prefrontal-limbic circuits that modulate affective responsivity to daily stressors, which we measured using ecological momentary assessment in daily life., Conclusions: Overall, we demonstrated how FKBP5 contributes to interindividual differences in neural and real-life affect regulation via structural and functional changes in prefrontal-limbic brain circuits., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Psychiatric disorders have a complex biological underpinning likely involving an interplay of genetic and environmental risk contributions. Substantial efforts are being made to use artificial intelligence approaches to integrate features within and across data types to increase our etiological understanding and advance personalized psychiatry. Network science offers a conceptual framework for exploring the often complex relationships across different levels of biological organization, from cellular mechanistic to brain-functional and phenotypic networks. Utilizing such network information effectively as part of artificial intelligence approaches is a promising route toward a more in-depth understanding of illness biology, the deciphering of patient heterogeneity, and the identification of signatures that may be sufficiently predictive to be clinically useful. Here, we present examples of how network information has been used as part of artificial intelligence within psychiatry and beyond and outline future perspectives on how personalized psychiatry approaches may profit from a closer integration of psychiatric research, artificial intelligence development, and network science., (© 2024 The Author(s). American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Introduction: The increasing interest in teledentistry since the COVID-19 pandemic warrants an evaluation of dentists' willingness to adopt it. This study aimed to develop a questionnaire to assess dentist's intention to use teledentistry and the associated factors., Methods: A literature search was used to identify items for the questionnaire. The Unified Theory of Acceptance and Use of Technology (UTAUT2) was adopted as framework. A Delphi panel was constituted of researchers with relevant publications and the International Association of Dental Research e-Oral Health Network members. Three Delphi consultations were conducted to establish consensus on items. Consensus was set at 80% agreement and content validity ratio (CVR), reaffirmed iteratively., Results: Nineteen out of 25 (76%) invited experts participated in the first round, 17 in the second and 15 in the third. The preliminary questionnaire had 81 items in three sections, reduced to 66, 45 and 33 items in the first, second and third rounds. After revision, the final version comprised eight items assessing dentists' backgrounds in Sect. 1, seven items identifying teledentistry uses in Sect. 2, and 17 items assessing intention to use teledentistry and its determinants in seven dimensions in Sect. 3. The initial CVR was 0.45, which increased to 0.80 at the end of the third round., Conclusion: A survey tool was developed to assess the acceptance of teledentistry, and its determinants based on the UTAUT2 framework through consensus among teledentistry experts. The tool had excellent validity and needs further evaluation of its psychometric properties., (© 2024. The Author(s).)

Titanium and titanium alloys remain the gold standard for dental and orthopedic implants. These materials are heavily used because of their bioinert nature, robust mechanical properties, and seamless integration with bone. However, implant-associated infections (IAIs) remain one of the leading causes of implant failure. Eradicating an IAI can be difficult since bacteria can form biofilms on the medical implant, protecting the bacterial cells against systemic antibiotics and the host's immune system. If the infection is not treated promptly and aggressively, device failure is inevitable, leading to costly multi-step revision surgeries. To circumvent this dire situation, scientists and engineers continue to develop novel strategies to protect the surface of medical implants from bacteria. In this review, details on emerging strategies to prevent infection in titanium implants are reported. These strategies include anti-adhesion properties provided by polymers, superhydrophobic, superhydrophilic, and liquid-infused surface coatings, as well as strategies and coatings employed to lyse the bacteria. Additionally, commercially available technologies and those under preclinical trials are examined while discussing current and future trends., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Background: United States drug overdose deaths are being driven by the increasing prevalence of fentanyl, but whether patients are knowingly using fentanyl is unclear. We examined the analytical confirmation of fentanyl in emergency department (ED) patients with documented heroin overdose., Hypothesis: We hypothesized that the proportion of fentanyl and fentanyl analogs would be higher than that of confirmed heroin., Methods: This is a subgroup analysis from a prospective multicenter consecutive cohort of ED patients age 18+ with opioid overdose presenting to 10 US sites within the Toxicology Investigators Consortium from 2020 to 2021. Toxicology analysis was performed using liquid chromatography quadrupole time-of-flight mass spectrometry. De-identified toxicology results were paired with the clinical database. The primary outcome was the proportion of patients with fentanyl analytes detected in their serum., Results: Of 1006 patients screened, 406 were eligible, and of 168 patients who reported that they had taken heroin or had a documented heroin overdose, 88% ( n  = 147) were in fact found to have fentanyl and/or a fentanyl analog present on serum analysis ( p  < 0.0001). In contrast, only 46 of the 168 patients with reported or documented heroin overdose (27%) were found to have heroin biomarkers present., Conclusion: The prevalence of confirmed fentanyl in ED patients with suspected heroin overdose was extremely high, while the prevalence of heroin was very low. There was a high degree of mismatch between the opioids believed to be the overdose agent versus the actual opioids identified on serum toxicology. Clinicians in the United States should presume that fentanyl is involved in all illicit opioid overdoses and should counsel patients on harm reduction measures., Competing Interests: The authors declare no commercial conflicts of interest., (© 2024 The Author(s). Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. We performed GWAS meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and, for the first time, the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signalling and brain ageing-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and ADHD. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases., Competing Interests: IA received speaker’s honorarium Lundbeck; OAA is a consultant to Cortechs.ai and Precision Health, speaker’s honorarium from Lundbeck, Janssen, Otsuka, Sunovion; HB is an Advisory Board Member or Consultant to Biogen, Eisai, Eli Lilly, Roche, Skin2Neuron, Cranbrook Care and Montefiore Homes; CRKC has received past partial research support from Biogen, Inc. (Boston, USA) for work unrelated to the topic of this manuscript; AMD is the Principal Investigator of a research agreement between General Electric Healthcare and the University of California, San Diego (UCSD); he is a Founder of and hold equity in CorTechs Labs, Inc. I am a member of the Scientific Advisory Board of Human Longevity, Inc., and the Mohn Medical Imaging and Visualization Center in Bergen, Norway. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict-of-interest policies; BF has received educational speaking fees from Medice; HJG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care; DPH is a full time employee of Genentech, Inc; NH is a shareholder various manufacturers of medical technology; AM-L has received consultant fees from Daimler und Benz Stiftung, EPFL Brain Mind Institute, Fondation FondaMental, Hector Stiftung II, Invisio, Janssen-Cilag GmbH, Lundbeck A/S, Lundbeckfonden, Lundbeck Int. Neuroscience Foundation, Neurotorium, MedinCell, The LOOP Zürich, University Medical Center Utrecht, University of Washington, Verein für Mentales Wohlbefinden, von Behring-Röntgen-Stiftung; speaker fees from Ärztekammer Nordrhein, Caritas, Clarivate, Dt. Gesellschaft für Neurowissenschaftliche Begutachtung, Gentner Verlag, Landesärztekammer Baden-Württemberg, LWL Bochum, Northwell Health, Ruhr University Bochum, Penn State University, Society of Biological Psychiatry, University Prague, Vitos Klinik Rheingau and editorial and/or author fees fromAmerican Association for the Advancement of Science, ECNP, Servier Int., Thieme Verlag; WN is founder of Quantib BV and was scientific lead of Quantib BV until Jan 31, 2023; MMN has received fees for membership in an advisory board from HMG Systems Engineering GmbH (Fürth, Germany), for membership in the Medical-Scientific Editorial Office of the Deutsches Ärzteblatt, and for serving as a consultant for EVERIS Belgique SPRL in a project of the European Commission (REFORM/SC2020/029). MMN receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All these concerned activities outside the submitted work; BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; AJS receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U19 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, U01 AG072177, and U19 AG074879). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions USA, Inc. (Dementia Advisory Board); NIH NHLBI (MESA Observational Study Monitoring Board); Springer-Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging and Behavior); MSreceived funding from Pfizer Inc. for a project not related to this research; ES received speaker fees from bfd buchholz fachinformationsdienst gmbh; PMT receives partial research support from Biogen, Inc., for research unrelated to this manuscript; MWW serves on Editorial Boards for Alzheimer’s & Dementia, and the Journal for Prevention of Alzheimer’s disease. He has served on Advisory Boards for Acumen Pharmaceutical, Alzheon, Inc., Cerecin, Merck Sharp & Dohme Corp., and NC Registry for Brain Health. He also serves on the USC ACTC grant which receives funding from Eisai for the AHEAD study. MWW has provided consulting to Boxer Capital, LLC, Cerecin, Inc., Clario, Dementia Society of Japan, Eisai, Guidepoint, Health and Wellness Partners, Indiana University, LCN Consulting, Merck Sharp & Dohme Corp., NC Registry for Brain Health, Prova Education, T3D Therapeutics, University of Southern California (USC), and WebMD. MWW has acted as a speaker/lecturer for China Association for Alzheimer’s Disease (CAAD) and Taipei Medical University, as well as a speaker/lecturer with academic travel funding provided by: AD/PD Congress, Cleveland Clinic, CTAD Congress, Foundation of Learning; Health Society (Japan), INSPIRE Project; U. Toulouse, Japan Society for Dementia Research, and Korean Dementia Society, Merck Sharp & Dohme Corp., National Center for Geriatrics and Gerontology (NCGG; Japan), University of Southern California (USC). MWW holds stock options with Alzeca, Alzheon, Inc., ALZPath, Inc., and Anven. MWW received support for his research from the following funding sources: National Institutes of Health (NIH)/NINDS/National Institute on Aging (NIA), Department of Defense (DOD), California Department of Public Health (CDPH), University of Michigan, Siemens, Biogen, Hillblom Foundation, Alzheimer’s Association, Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (HBI-BHR), The Stroke Foundation, and the Veterans Administration; AIC is currently employed by the Regeneron Genetics Center, a wholly-owned subsidiary of Regeneron Pharmaceuticals, Inc., and may hold Regeneron stock or stock options. All other authors declare no competing interests.

Background: Caustic ingestions are relatively uncommon, but remain a significant source of morbidity. Patients with caustic injury often undergo an urgent EGD, although it is not clear if an EGD is routinely needed in an asymptomatic patient. The study has two primary objectives; 1) to determine the utility of routine EGD in asymptomatic suicidal caustic ingestions; 2) to determine if asymptomatic unintentional acidic ingestions can be managed with observation alone, similar to basic ingestions., Methods: This retrospective study, which took place at 14 hospitals in three countries evaluated all patients who presented with a caustic ingestion between 2014-2020. The presence of symptoms and esophageal injury, demographic information, pH of ingested substance, reason for the ingestion, and outcome were recorded., Results: 409 patients were identified; 203 (46.9%) were male. The median (IQR) age was 18 (4-31) years; overall range 10 months to 78 years. Suicidal ingestions accounted for 155 (37.9%) of cases. Dysphagia or dysphonia were more likely in those with significant esophageal injury compared to those without (59.3% vs. 12.6% respectively; OR 10.1; 95% CI 4.43-23.1). Among 27 patients with significant esophageal injury, 48% were found in suicidal patients, compared with 51.9% in non-suicidal patients (p = NS). On multivariate regression, there was no difference in the rate of significant esophageal injury among suicidal vs. non suicidal patients (aOR 1.55; p = 0.45, 95% CI 0.45-5.33). Most ingestions involved basic substances (332/409; 81.2%). Unknown or mixed ingestions accounted for 25 (6.11%) of the ingestions. Significant esophageal burns were found in 6/52 (11.5%) of acid ingestions, compared with 21/332 (6.3%) of basic ingestions. Of the 42 cases of acidic ingestions without dysphagia or odynophagia, 2 (4.8%; 0.58-16.1%) had significant esophageal burns, compared with 9 (3.2%; 95% CI 1.4-5.9%) of the 284 basic ingestions; p = 0.64). On multivariate logistic regression, patients with acidic ingestions were not more likely to experience a significant burn (aOR 1.7; p = 0.11, 95% CI 0.9-3.1) compared to those with basic ingestions. No patient with significant esophageal burns was asymptomatic., Conclusion: In this study, there was no statistical differences in the rates of significant burns between acidic and basic caustic ingestions. There were no significant esophageal injuries noted among asymptomatic patients., (© 2024. American College of Medical Toxicology.)

Navigating the complex landscape of high-dimensional omics data with machine learning models presents a significant challenge. The integration of biological domain knowledge into these models has shown promise in creating more meaningful stratifications of predictor variables, leading to algorithms that are both more accurate and generalizable. However, the wider availability of machine learning tools capable of incorporating such biological knowledge remains limited. Addressing this gap, we introduce BioM2, a novel R package designed for biologically informed multistage machine learning. BioM2 uniquely leverages biological information to effectively stratify and aggregate high-dimensional biological data in the context of machine learning. Demonstrating its utility with genome-wide DNA methylation and transcriptome-wide gene expression data, BioM2 has shown to enhance predictive performance, surpassing traditional machine learning models that operate without the integration of biological knowledge. A key feature of BioM2 is its ability to rank predictor variables within biological categories, specifically Gene Ontology pathways. This functionality not only aids in the interpretability of the results but also enables a subsequent modular network analysis of these variables, shedding light on the intricate systems-level biology underpinning the predictive outcome. We have proposed a biologically informed multistage machine learning framework termed BioM2 for phenotype prediction based on omics data. BioM2 has been incorporated into the BioM2 CRAN package (https://cran.r-project.org/web/packages/BioM2/index.html)., (© The Author(s) 2024. Published by Oxford University Press.)

Both mental health and mental illness unfold in complex and unpredictable ways. Novel artificial intelligence approaches from the area of dynamical systems reconstruction can characterize such dynamics and help understand the underlying brain mechanisms, which can also be used as potential biomarkers. However, applying deep learning to model dynamical systems at the individual level must overcome numerous computational challenges to be reproducible and clinically useful. In this study, we performed an extensive analysis of these challenges using generative modeling of brain dynamics from fMRI data as an example and demonstrated their impact on classifying patients with schizophrenia and major depression. This study highlights the tendency of deep learning models to identify functionally unique solutions during parameter optimization, which severely impacts the reproducibility of downstream predictions. We hope this study guides the future development of individual-level generative models and similar machine learning approaches aimed at identifying reproducible biomarkers of mental illness., Competing Interests: A.M.-L. has received consultant fees from Agence Nationale de la Recherche, Brain Mind Institute, Brainsway, CISSN (Catania International Summer School of Neuroscience), Daimler und Benz Stiftung, Fondation FondaMental, Hector Stiftung II, Janssen-Cilag GmbH, Lundbeck A/S, Lundbeckfonden, Lundbeck Int. Neuroscience Foundation, MedinCell, Sage Therapeutics, Techspert.io, The LOOP Zürich, University Medical Center Utrecht, von Behring Röntgen Stiftung. A.M.-L. has received speaker fees from Arztekammer Nordrhein, BAG Psychiatrie Oberbayern, Biotest AG, Forum Werkstatt Karlsruhe, International Society of Psychiatric Genetics, Brentwood, Klinik für Psychiatrie und Psychotherapie Ingolstadt, Lundbeck SAS France, med Update GmbH, Merz-Stiftung, Siemens Healthineers, Society of Biological Psychiatry. A.M.-L. has received editorial fees from American Association for the Advancement of Science, Elsevier, Thieme Verlag. E.S. received speaker fees from bfd buchholz-fachingormationsdienst GmbH and editorial fees from Lundbeckfonden., (© 2024 The Author(s).)

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy., (© 2024 The Author(s). Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: The carbonic anhydrase inhibitor acetazolamide stimulates ventilation through metabolic acidosis mediated by renal bicarbonate excretion. In animal models, acetazolamide attenuates acute hypoxia-induced pulmonary hypertension (PH), but its efficacy in treating patients with PH due to pulmonary vascular disease (PVD) is unknown., Methods: 28 PVD patients (15 pulmonary arterial hypertension, 13 distal chronic thromboembolic PH), 13 women, mean±SD age 61.6±15.0 years stable on PVD medications, were randomised in a double-blind crossover protocol to 5 weeks acetazolamide (250mg b.i.d) or placebo separated by a ≥2 week washout period. Primary endpoint was the change in 6-minute walk distance (6MWD) at 5 weeks. Additional endpoints included safety, tolerability, WHO functional class, quality of life, arterial blood gases, and hemodynamics (by echocardiography)., Results: Acetazolamide had no effect on 6MWD compared to placebo (treatment effect: mean change [95%CI] -18 [-40 to 4]m, p=0.102) but increased arterial blood oxygenation through hyperventilation induced by metabolic acidosis. Other measures including pulmonary hemodynamics were unchanged. No severe adverse effects occurred, side effects that occurred significantly more frequently with acetazolamide vs. placebo were change in taste (22/0%), paraesthesia (37/4%) and mild dyspnea (26/4%)., Conclusions: In patients with PVD, acetazolamide did not change 6MWD compared to placebo despite improved blood oxygenation. Some patients reported a tolerable increase in dyspnoea during acetazolamide treatment, related to hyperventilation, induced by the mild drug-induced metabolic acidosis. Our findings do not support the use of acetazolamide to improve exercise in patients with PVD at this dosing., Gov Identifier: NCT02755298., Competing Interests: Conflicts of interest None of the authors report any conflict of interest in direct relation to this manuscript. Prof. Dr. med. S. Ulrich reports grants from Johnson and Johnson SA, Switzerland, during the conduct of the study; grants from Zurich Lung, grants from Orpha Swiss, personal fees from Actelion SA, Switzerland, personal fees from MSD Switzerland, outside the submitted work. Dr. Swenson reports that he has a patent: METHODS OF TREATING PULMONARY DISEASE USING ACETAZOLAMIDE AND STRUCTURALLY RELATED DERIVATIVES issued by the US government with the the patent designation US Patent No. 8,614,236, (Copyright © 2022 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Knowledge graphs (KGs) remain an underutilized tool in the field of psychiatric research. In the broader biomedical field KGs are already a significant tool mainly used as knowledge database or for novel relation detection between biomedical entities. This review aims to outline how KGs would further research in the field of psychiatry in the age of Artificial Intelligence (AI) and Large Language Models (LLMs)., Methods: We conducted a thorough literature review across a spectrum of scientific fields ranging from computer science and knowledge engineering to bioinformatics. The literature reviewed was taken from PubMed, Semantic Scholar and Google Scholar searches including terms such as "Psychiatric Knowledge Graphs", "Biomedical Knowledge Graphs", "Knowledge Graph Machine Learning Applications", "Knowledge Graph Applications for Biomedical Sciences". The resulting publications were then assessed and accumulated in this review regarding their possible relevance to future psychiatric applications., Results: A multitude of papers and applications of KGs in associated research fields that are yet to be utilized in psychiatric research was found and outlined in this review. We create a thorough recommendation for other computational researchers regarding use-cases of these KG applications in psychiatry., Conclusion: This review illustrates use-cases of KG-based research applications in biomedicine and beyond that may aid in elucidating the complex biology of psychiatric illness and open new routes for developing innovative interventions. We conclude that there is a wealth of opportunities for KG utilization in psychiatric research across a variety of application areas including biomarker discovery, patient stratification and personalized medicine approaches., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Introduction: Distinct, disease-associated intracellular miRNA (miR) expression profiles have been observed in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematous (SLE) patients. Additionally, we have identified novel estrogenic responses in PBMCs from SLE patients and demonstrated that estrogen upregulates toll-like receptor (TLR)7 and TLR8 expression. TLR7 and TLR8 bind viral-derived single-stranded RNA to stimulate innate inflammatory responses, but recent studies have shown that miR-21, mir-29a, and miR-29b can also bind and activate these receptors when packaged and secreted in extracellular vesicles (EVs). The objective of this study was to evaluate the association of EV-encapsulated small RNA species in SLE and examine the therapeutic approach of miR inhibition in humanized mice., Methods: Plasma-derived EVs were isolated from SLE patients and quantified. RNA was then isolated and bulk RNA-sequencing reads were analyzed. Also, PBMCs from active SLE patients were injected into immunodeficient mice to produce chimeras. Prior to transfer, the PBMCs were incubated with liposomal EVs containing locked nucleic acid (LNA) antagonists to miR-21, mir-29a, and miR-29b. After three weeks, blood was collected for both immunophenotyping and cytokine analysis; tissue was harvested for histopathological examination., Results: EVs were significantly increased in the plasma of SLE patients and differentially expressed EV-derived small RNA profiles were detected compared to healthy controls, including miR-21, mir-29a, and miR-29b. LNA antagonists significantly reduced proinflammatory cytokines and histopathological infiltrates in the small intestine, liver, and kidney, as demonstrated by H&E-stained tissue sections and immunohistochemistry measuring human CD3., Discussion: These data demonstrate distinct EV-derived small RNA signatures representing SLE-associated biomarkers. Moreover, targeting upregulated EV-encapsulated miR signaling by antagonizing miRs that may bind to TLR7 and TLR8 reveals a novel therapeutic opportunity to suppress autoimmune-mediated inflammation and pathogenesis in SLE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Young, Schwarz, Zeno, Bruckner, Mesa, Jablonski, Wu, Roberson and Jarjour.)

Background and Hypothesis: Parkinsonism, psychomotor slowing, negative and depressive symptoms show evident phenomenological similarities across different mental disorders. However, the extent to which they interact with each other is currently unclear. Here, we hypothesized that parkinsonism is an independent motor abnormality showing limited associations with psychomotor slowing, negative and depressive symptoms in schizophrenia spectrum (SSD), and mood disorders (MOD)., Study Design: We applied network analysis and community detection methods to examine the interplay and centrality (expected influence [EI] and strength) between parkinsonism, psychomotor slowing, negative and depressive symptoms in 245 SSD and 99 MOD patients. Parkinsonism was assessed with the Simpson-Angus Scale (SAS). We used the Positive and Negative Syndrome Scale (PANSS) to examine psychomotor slowing (item #G7), negative symptoms (PANSS-N), and depressive symptoms (item #G6)., Study Results: In SSD and MOD, PANSS item #G7 and PANSS-N showed the largest EI and strength as measures of centrality. Parkinsonism had small or no influence on psychomotor slowing, negative and depressive symptoms in SSD and MOD. In SSD and MOD, exploratory graph analysis identified one community, but parkinsonism showed a small influence on its occurrence. Network Comparison Test yielded no significant differences between the SSD and MOD networks (global strength p value: .396 and omnibus tests p value: .574)., Conclusions: The relationships between the individual domains followed a similar pattern in both SSD and MOD highlighting their transdiagnostic relevance. Despite evident phenomenological similarities, our results suggested that parkinsonism is more independent of negative and depressive symptoms than psychomotor slowing in both SSD and MOD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. 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.)

The response variability to repetitive transcranial magnetic stimulation (rTMS) challenges the effective use of this treatment option in patients with schizophrenia. This variability may be deciphered by leveraging predictive information in structural MRI, clinical, sociodemographic, and genetic data using artificial intelligence. We developed and cross-validated rTMS response prediction models in patients with schizophrenia drawn from the multisite RESIS trial. The models incorporated pre-treatment sMRI, clinical, sociodemographic, and polygenic risk score (PRS) data. Patients were randomly assigned to receive active (N = 45) or sham (N = 47) rTMS treatment. The prediction target was individual response, defined as ≥20% reduction in pre-treatment negative symptom sum scores of the Positive and Negative Syndrome Scale. Our multimodal sequential prediction workflow achieved a balanced accuracy (BAC) of 94% (non-responders: 92%, responders: 95%) in the active-treated group and 50% in the sham-treated group. The clinical, clinical + PRS, and sMRI-based classifiers yielded BACs of 65%, 76%, and 80%, respectively. Apparent sadness, inability to feel, educational attainment PRS, and unemployment were most predictive of non-response in the clinical + PRS model, while grey matter density reductions in the default mode, limbic networks, and the cerebellum were most predictive in the sMRI model. Our sequential modelling approach provided superior predictive performance while minimising the diagnostic burden in the clinical setting. Predictive patterns suggest that rTMS responders may have higher levels of brain grey matter in the default mode and salience networks which increases their likelihood of profiting from plasticity-inducing brain stimulation methods, such as rTMS. The future clinical implementation of our models requires findings to be replicated at the international scale using stratified clinical trial designs., (© 2024. The Author(s).)

Oxytocin is a neuropeptide associated with both psychological and somatic processes like parturition and social bonding. Although oxytocin homologs have been identified in many species, the evolutionary timeline of the entire oxytocin signaling gene pathway has yet to be described. Using protein sequence similarity searches, microsynteny, and phylostratigraphy, we assigned the genes supporting the oxytocin pathway to different phylostrata based on when we found they likely arose in evolution. We show that the majority (64%) of genes in the pathway are 'modern'. Most of the modern genes evolved around the emergence of vertebrates or jawed vertebrates (540 - 530 million years ago, 'mya'), including OXTR, OXT and CD38. Of those, 45% were under positive selection at some point during vertebrate evolution. We also found that 18% of the genes in the oxytocin pathway are 'ancient', meaning their emergence dates back to cellular organisms and opisthokonta (3500-1100 mya). The remaining genes (18%) that evolved after ancient and before modern genes were classified as 'medium-aged'. Functional analyses revealed that, in humans, medium-aged oxytocin pathway genes are highly expressed in contractile organs, while modern genes in the oxytocin pathway are primarily expressed in the brain and muscle tissue., (© 2024. The Author(s).)

Background: Enteral nutrition (EN) therapy is a multistep process including evaluation, prescription, procurement, dispensing, labeling, administration, and monitoring. EN therapy is prone to human errors, but these are poorly defined in the literature. The purpose of this study was to audit EN administration practices to quantify errors of execution and identify which components of the EN order were labeled, administered, or documented incorrectly., Methods: On 2 nonconsecutive days, we identified all hospitalized patients with active EN orders and prospectively collected the following information: EN formula hanging/documented, formula hang time, infusion rate/documented rate (continuous EN), infused volume and documented schedule (intermittent EN), and EN modular documentation. Mismatches to the EN order were considered errors. We reviewed 1 month of hospital EN-related safety events for comparison., Results: Of 1045 data points collected from 160 patients, we identified 275 errors of execution: 135 labeling errors and 140 administration errors. The most common were hang time >48 h (85%), wrong number of modulars documented (48%), and wrong infusion rate (19%). We found one reported safety event (wrong formula delivered but not infused)., Conclusion: We identified a 15.9% error rate in EN order execution/documentation and 14% compliance with documentation of 48-h hang time. Errors (safety events) were grossly underreported. This highlighted several areas of opportunity to improve current EN use process, consistent with previous research on EN and oral nutrition supplement administration. Based on our findings, we plan to recommend implementation of EN barcoding at our institution, to model the familiar medication administration record., (© 2023 American Society for Parenteral and Enteral Nutrition.)

Background: Promoting active modes of transportation such as cycling may generate important public health, economic, and climate mitigation benefits. We aim to assess the mortality and morbidity impacts of cycling in a country with relatively low levels of cycling, France, along with associated monetary benefits. We further assess the potential additional benefits of shifting a portion of short trips from cars to bikes, including projected greenhouse gas emissions savings., Methods: Using individual data from a nationally representative mobility survey, we described the French 2019 cycling levels by age and sex. We conducted a burden of disease analysis to assess the incidence of five chronic diseases (breast cancer, colon cancer, cardiovascular diseases, dementia, and type-2 diabetes) and the number of deaths prevented by cycling, based on national incidence and mortality data and dose-response relationships from meta-analyses. We assessed the corresponding direct medical cost savings and the intangible costs prevented based on the value of a statistical life year. Lastly, based on individual simulations, we assessed the likely additional benefits of shifting 25% of short (<5 km) car trips to cycling., Findings: The French adult (20-89 years) population was estimated to cycle on average 1 min 17 sec pers -1 day -1 in 2019, with important heterogeneity across sex and age. This yielded benefits of 1,919 (uncertainty interval, UI: 1,101-2,736) premature deaths and 5,963 (UI: 3,178-8,749) chronic disease cases prevented, with males reaping nearly 75% of these benefits. Direct medical costs prevented were estimated at €191 million (UI: 98-285) annually, while the corresponding intangible costs were nearly 25 times higher (€4.8 billion, UI: 3.0-6.5). We estimated that on average, €1.02 (UI: 0.59-1.62) of intangible costs were prevented for every km cycled. Shifting 25% of short car trips to cycling would yield approximatively a 2-fold increase in deaths prevented, while also generating important CO 2 emissions reductions (0.257 MtCO2e, UI: 0.231-0.288)., Interpretation: In a country with a low- to moderate-cycling culture, cycling already generates important public health and health-related economic benefits. Further development of active transportation would increase these benefits while also contributing to climate change mitigation targets., Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Authors.)

Myeloid-derived suppressor cell (MDSC) levels are elevated in patients with cancer and contribute to reduced efficacy of immune checkpoint therapy. MDSC express Bruton's tyrosine kinase (BTK) and BTK inhibition with ibrutinib, an FDA-approved irreversible inhibitor of BTK, leads to reduced MDSC expansion/function in mice and significantly improves the antitumor activity of anti-PD-1 antibody treatments. Single-cell RNA sequencing (scRNA-seq) was used to characterize the effect of ibrutinib on gene expression of fluorescence-activated cell sorting-enriched MDSC from patients with different cancer types [breast, melanoma, head and neck squamous cell cancer (HNSCC)]. Melanoma patient MDSC were treated in vitro for 4 hours with 5 μmol/L ibrutinib or DMSO, processed for scRNA-seq using the Chromium 10× Genomics platform, and analyzed via the Seurat v4 standard integrative workflow. Baseline gene expression of MDSC from patients with breast, melanoma, and HNSCC cancer revealed similarities among the top expressed genes. In vitro ibrutinib treatment of MDSC from patients with melanoma resulted in significant changes in gene expression. GBP1, IL-1β, and CXCL8 were among the top downregulated genes whereas RGS2 and ABHD5 were among the top upregulated genes (P < 0.001). Double positive CD14+CD15+ MDSC and PMN-MDSC responded similarly to BTK inhibition and exhibited more pronounced gene changes compared with early MDSC and M-MDSC. Pathway analysis revealed significantly downregulated pathways including TREM1, nitric oxide signaling, and IL-6 signaling (P < 0.004)., Implications: scRNA-seq revealed characteristic gene expression patterns for MDSC from different patients with cancer and BTK inhibition led to the downregulation of multiple genes and pathways important to MDSC function and migration., (©2023 American Association for Cancer Research.)

Applications of machine learning in the biomedical sciences are growing rapidly. This growth has been spurred by diverse cross-institutional and interdisciplinary collaborations, public availability of large datasets, an increase in the accessibility of analytic routines, and the availability of powerful computing resources. With this increased access and exposure to machine learning comes a responsibility for education and a deeper understanding of its bases and bounds, borne equally by data scientists seeking to ply their analytic wares in medical research and by biomedical scientists seeking to harness such methods to glean knowledge from data. This article provides an accessible and critical review of machine learning for a biomedically informed audience, as well as its applications in psychiatry. The review covers definitions and expositions of commonly used machine learning methods, and historical trends of their use in psychiatry. We also provide a set of standards, namely Guidelines for REporting Machine Learning Investigations in Neuropsychiatry (GREMLIN), for designing and reporting studies that use machine learning as a primary data-analysis approach. Lastly, we propose the establishment of the Machine Learning in Psychiatry (MLPsych) Consortium, enumerate its objectives, and identify areas of opportunity for future applications of machine learning in biological psychiatry. This review serves as a cautiously optimistic primer on machine learning for those on the precipice as they prepare to dive into the field, either as methodological practitioners or well-informed consumers., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The ability of IL12 to stimulate natural killer (NK) cell and T-cell antitumor activity makes it an attractive candidate for the immune therapy of cancer. Our group has demonstrated that IL12 enhances the NK cell response to antibody-coated tumor cells and conducted three clinical trials utilizing IL12 with mAbs (OSU-9968, OSU-0167, and OSU-11010). To better characterize IL12-induced immunity, plasma cytokine levels were measured in 21 patients from these trials with favorable and unfavorable responses. t-statistics and linear modeling were used to test for differences within and between response groups by examining levels at baseline and post-IL12 administration. Patients exhibited significant increases in 11 cytokines post-IL12 administration when analyzed collectively. However, several cytokines were differentially induced by IL12 depending on response. GMCSF was significantly increased in complete/partially responding patients, while stable disease patients had significant increases in IL10 and decreases in VEGF-C. Patients who experienced progressive disease had significant increases in CCL3, CCL4, IL18, TNFα, CXCL10, CCL8, CCL2, IL6, and IFNγ. The increases in CCL3, CCL4, and IL6 in progressive disease patients were significantly higher than in clinically benefitting patients and most prominent within the first two cycles of IL12 therapy. This correlative pilot study has identified changes that occur in levels of circulating cytokines following IL12 administration to patients with cancer, but this report must be viewed as exploratory in nature. It is meant to spark further inquiry into the topic via the analysis of additional cohorts of patients with similar characteristics who have received IL12 in a uniform fashion., Significance: IL12 activates immune cells and is used to treat cancer. The profile of circulating cytokines was measured in an exploratory fashion in patients with cancer that received IL12 in combination with mAbs. This correlative pilot study could serve as the basis for additional studies of IL12 effects on the production of immune cytokines., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Background: People with type 1 diabetes generally view it easier to exercise when having continuous information of the glucose levels. We evaluated whether patients with type 1 diabetes managed with multiple daily insulin injections (MDI) exercised more after initiating continuous glucose monitoring (CGM) and whether the improved glycemic control and well-being associated with CGM translates into improved blood lipids and markers of inflammation., Method: The GOLD trial was a randomized cross-over trial over 16 months where patients used either CGM or capillary self-monitoring of blood glucose (SMBG) over six months, with a four-month wash-out period between the two treatment periods. We compared grade of physical activity, blood lipids, apolipoproteins, and high-sensitivity C-reactive protein (hsCRP) levels during CGM and SMBG., Results: There were 116 patients with information of physical activity estimated by the International Physical Activity Questionnaire (IPAQ) during both CGM and SMBG. No changes were found during CGM or SMBG, IPAQ scores 3305 versus 3878 ( P = .16). In 136 participants with information of blood lipid levels with no change in lipid-lowering medication during the two treatment periods, HbA1c differed by 4.2 mmol/mol (NGSP 0.39%) between SMBG and CGM treatment ( P < .001). No significant changes existed in low-density lipoprotein, high-density lipoprotein, triglycerides, total cholesterol, apolipoprotein A1, apolipoprotein B1, or hsCRP, during CGM and SMBG., Conclusion: Although many patients experience it easier to perform physical activity when monitoring glucose levels with CGM, it does not influence the amount of physical activity in persons with type 1 diabetes. Blood lipids, apolipoprotein, and hsCRP levels were similar during CGM and SMBG., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TN has received unrestricted grants from AstraZeneca and NovoNordisk and has served on national advisory boards of Abbot, Amgen, Novo Nordisk, Sanofi-Aventis, Eli Lilly, MSD, and Boehringer Ingelheim. ML has received research grants from Eli Lilly and Novo Nordisk and been consultant or received honoraria from Astra Zeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. JH has served on advisory boards or lectured for Novo Nordisk, Sanofi, Lilly, Abbot, Rubin Medical, MSD, and Boehringer Ingelheim. MW has served on advisory boards or lectured for MSD, Lilly, Novo Nordisk, and Sanofi and has organized a professional regional meeting sponsored by Lilly, Rubin Medical, Sanofi, Novartis, and Novo Nordisk. JB has received honoraria for consulting and/or lecture fees from Abbott Diabetes Care, Novo Nordisk, and Sanofi.

Background: The Acquisition of Data for Outcomes and Procedure Transfer (ADOPT) program was established by SAGES to develop and expand individual surgeon's comfort with specific, complex operations using hands-on teaching and longitudinal mentoring. The 2022-2023 Foregut (Dominating the Hiatus) section of the course focused on hiatal hernia dissection and gastric fundoplication techniques. Our aim was to describe the experience of surgeons who participated in the course., Methods: The hands-on component occurred in March 2022 at the SAGES annual meeting. Each expert mentor was matched to two participants. The mentors guided the surgeons through steps of a laparoscopic paraesophageal (PEH) hernia repair and fundoplication using a cadaveric model. Afterwards, monthly group webinars occurred and participants could receive individual coaching from their assigned mentor for a year. Each participant was given a pre-course survey with 3 and 12-month follow-up questionnaires., Results: The majority of the 16 participants were employed in non-academic settings (87.5%). Years in practice ranged from 1 to 26, and 69% completed a fellowship. 100% completed the pre-course survey, and 53.8% responded to the 12-month post-course survey. Participant-reported effectiveness in performing a PEH hernia repair with fundoplication increased from 37.5% pre-course to 85.7% by the conclusion of the course. Confidence levels for the six core steps of the operation also increased: pre-course only 56-75% were confident with each step, this improved to 100% in four out of six steps. 85.7% said the course has changed their practice., Discussion: Since inception, the ADOPT program has aimed to provide expert instruction for practicing surgeons to learn new techniques or improve their confidence in performing operations. The data for the 2022 ADOPT Foregut course shows that 1 year of participation made a positive impact on these surgeons' practices. This helps to fill in the learning gap that occurs after formal surgical training ends., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objectives: CpG ODN is a Toll-like receptor 9 agonist with immunotherapeutic potential for many cancer types, including aggressive breast cancers. There is strong interest in utilizing CpG ODN as an adjuvant to improve clinical efficacy of current treatments and immunogenicity of breast cancers not traditionally responsive to active immunotherapy, such as those that are human epidermal growth factor receptor 2 (HER2)-positive. This study aimed to study the efficacy and safety of combination CpG ODN plus anti-HER2 antibody trastuzumab treatment in patients with advanced/metastatic breast cancer., Methods: This single-arm, open-label phase II clinical trial treated patients (n = 6) with advanced/metastatic HER2-positive breast cancer with weekly subcutaneous CpG ODN and trastuzumab. Patients may have received any number of prior therapies to be enrolled (most enrolled at median 1 prior line of chemotherapy). Peripheral blood was collected at baseline and weeks 2, 6, 12, and 18 for immune analyses. Six patients were enrolled and 50% achieved stable disease (SD) response., Results: Median PFS was 8.3 months. Three of the six patients enrolled opted to stop treatment due to tolerability issues. Multiplex assay for cytokine measurements revealed significantly higher VEGF-D levels at week 2 compared to baseline. Peripheral blood mononuclear cells analyzed by flow cytometry showed a significant increase in monocytic MDSC between weeks 6 and 12. Patients with progressive disease tended to have higher levels of week 6 monocytic MDSC and PD-1+ T cells than patients with SD. NK cell populations did not significantly change throughout treatment., Conclusions: CpG ODN and trastuzumab treatment of metastatic HER2 + breast cancer was safe but was not tolerable for all patients. This combination did induce potentially predictive immune profile changes in treated patients with metastatic HER2 + breast cancer, the significance of which needs to be further explored., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Psychomotor slowing (PS) is characterized by slowed movements and lower activity levels. PS is frequently observed in schizophrenia (SZ) and distressing because it impairs performance of everyday tasks and social activities. Studying brain topography contributing to PS in SZ can help to understand the underlying neurobiological mechanisms as well as help to develop more effective treatments that specifically target affected brain areas. Here, we conducted structural magnetic resonance imaging (sMRI) of three independent cohorts of right-handed SZ patients (SZ#1: n = 72, SZ#2: n = 37, SZ#3: n = 25) and age, gender and education matched healthy controls (HC) (HC#1: n = 40, HC#2: n = 37, HC#3: n = 38). PS severity in the three SZ cohorts was determined using the Positive and Negative Syndrome Scale (PANSS) item #G7 (motor retardation) and Trail-Making-Test B (TMT-B). FreeSurfer v7.2 was used for automated parcellation and segmentation of cortical and subcortical regions. SZ#1 patients showed reduced cortical thickness in right precentral gyrus (M1; p = 0.04; Benjamini-Hochberg [BH] corr.). In SZ#1, cortical thinning in right M1 was associated with PANSS item #G7 (p = 0.04; BH corr.) and TMT-B performance (p = 0.002; BH corr.). In SZ#1, we found a significant correlation between PANSS item #G7 and TMT-B (p = 0.005, ρ=0.326). In conclusion, PANSS G#7 and TMT-B might have a surrogate value for predicting PS in SZ. Cortical thinning of M1 rather than alterations of subcortical structures may point towards cortical pathomechanism underlying PS in SZ., Competing Interests: Conflict of interest The authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)

Importance: Dental caries and periodontal disease are common adult oral health conditions and potentially amenable to primary care screening and prevention., Objective: To systematically review the evidence on primary care screening and prevention of dental caries and periodontal disease in adults to inform the US Preventive Services Task Force., Data Sources: MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews (to October 3, 2022); surveillance through July 21, 2023., Study Selection: Diagnostic accuracy studies of primary care screening instruments and oral examination; randomized and nonrandomized trials of screening and preventive interventions; cohort studies on primary care oral health screening and preventive intervention harms., Data Extraction and Synthesis: One investigator abstracted data; a second checked accuracy. Two investigators independently rated study quality. Diagnostic accuracy data were pooled using a bivariate mixed-effects binary regression model., Main Outcomes and Measures: Dental caries, periodontal disease, morbidity, quality of life, harms; and diagnostic test accuracy., Results: Five randomized clinical trials, 5 nonrandomized trials, and 6 observational studies (total 3300 participants) were included. One poor-quality trial (n = 477) found no difference between oral health screening during pregnancy vs no screening in caries, periodontal disease, or birth outcomes. One study (n = 86) found oral health examination by 2 primary care clinicians associated with low sensitivity (0.42 and 0.56) and high specificity (0.84 and 0.87) for periodontal disease and with variable sensitivity (0.33 and 0.83) and high specificity (0.80 and 0.93) for dental caries. Four studies (n = 965) found screening questionnaires associated with a pooled sensitivity of 0.72 (95% CI, 0.57-0.83) and specificity of 0.74 (95% CI, 0.66-0.82) for periodontal disease. For preventive interventions no study evaluated primary care counseling or dental referral, and evidence from 2 poor-quality trials (n = 178) of sealants, and 1 fair-quality and 4 poor-quality trials (n = 971) of topical fluorides, was insufficient. Three fair-quality trials (n = 590) of persons with mean age 72 to 80 years found silver diamine fluoride solution associated with fewer new root caries lesions or fillings vs placebo (mean reduction, -0.33 to -1.3) and decreased likelihood of new root caries lesion (2 trials; adjusted odds ratio, 0.4 [95% CI, 0.3-0.7]). No trial evaluated primary care-administered preventive interventions., Conclusions and Relevance: Screening questionnaires were associated with moderate diagnostic accuracy for periodontal disease. Research is needed to determine benefits and harms of oral health primary care screening and preventive interventions.

Importance: Dental caries is common in children and adolescents aged 5 to 17 years and potentially amenable to primary care screening and prevention., Objective: To systematically review the evidence on primary care screening and prevention of dental caries in children and adolescents aged 5 to 17 years to inform the US Preventive Services Task Force., Data Sources: MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews (to October 3, 2022); surveillance through July 21, 2023., Study Selection: Diagnostic accuracy of primary care screening instruments and oral examination; randomized and nonrandomized trials of screening and preventive interventions and systematic reviews of such studies; cohort studies on primary care oral health screening and preventive intervention harms., Data Extraction and Synthesis: One investigator abstracted data; a second checked accuracy. Two investigators independently rated study quality. Random-effects meta-analysis was performed for fluoride supplements and xylitol; for other preventive interventions, pooled estimates were used from good-quality systematic reviews., Main Outcomes and Measures: Dental caries, morbidity, functional status, quality of life, harms; diagnostic test accuracy., Results: Three systematic reviews (total 20 684 participants) and 19 randomized clinical trials, 3 nonrandomized trials, and 1 observational study (total 15 026 participants) were included. No study compared screening vs no screening. When administered by dental professionals or in school settings, fluoride supplements compared with placebo or no intervention were associated with decreased change from baseline in the number of decayed, missing, or filled permanent teeth (DMFT index) or decayed or filled permanent teeth (DFT index) (mean difference, -0.73 [95% CI, -1.30 to -0.19]) at 1.5 to 3 years (6 trials; n = 1395). Fluoride gels were associated with a DMFT- or DFT-prevented fraction of 0.18 (95% CI, 0.09-0.27) at outcomes closest to 3 years (4 trials; n = 1525), fluoride varnish was associated with a DMFT- or DFT-prevented fraction of 0.44 (95% CI, 0.11-0.76) at 1 to 4.5 years (5 trials; n = 3902), and resin-based sealants were associated with decreased risk of carious first molars (odds ratio, 0.21 [95% CI, 0.16-0.28]) at 48 to 54 months (4 trials; n = 440). No trial evaluated primary care counseling or dental referral. Evidence on screening accuracy, silver diamine fluoride, xylitol, and harms was very limited, although serious harms were not reported., Conclusions and Relevance: Administration of fluoride supplements, fluoride gels, varnish, and sealants in dental or school settings improved caries outcomes. Research is needed on the effectiveness of oral health preventive interventions in primary care settings and to determine the benefits and harms of screening.

Background: Stem cell transplantation is an emerging therapy for severe cardiomyopathy, proffering stem cell recruitment, anti-apoptosis, and proangiogenic capabilities. Angiogenic cell precursors (ACP-01) are autologous, lineage-specific, cells derived from a multipotent progenitor cell population, with strong potential to effectively engraft, form blood vessels, and support tissue survival and regeneration., Methods: This IRB approved outcome analysis reports upon 74 consecutive patients who failed medical management for severe cardiomyopathy, and were selected to undergo transcatheter intramyocardial or intracoronary implantation of ACP-01. Serious adverse events (SAEs) were reported. Cell analysis was conducted for each treatment. The left ventricular ejection fraction (LVEF) was measured by multi-gated acquisition scan (MUGA) or echocardiogram at 4 months ± 1.9 months and 12 months ± 5.5 months. Patients reported quality of life statements at 6 months (± 5.6 months)., Results: Fifty-four of 74 patients met requirements for inclusion (48 males and five females; age 68.1 ± 11.3 years). The mean treatment cell number of 57 × 10 6 ACP-01 included 7.7 × 10 6 CD34 + and 21 × 10 6 CD31 + cells with 97.6% viability. SAEs included one death (previously unrecognized silent MI), ventricular tachycardia (n = 2) requiring cardioversion, and respiratory infection (n = 2). LVEF in the ischemic subgroup (n = 41) improved by 4.7% ± 9.7 from pre-procedure to the first follow-up (4 months ± 1.9 months) (p < 0.004) and by 7.2% ± 10.9 at final follow-up (n = 25) at average 12 months (p < 0.004). The non-ischemic dilated cardiomyopathy subgroup (n = 8) improved by 7.5% ± 6.0 at the first follow-up (p < 0.017) and by 12.2% ± 6.4 at final follow-up (p < 0.003, n = 6). Overall improvement in LVEF from pre-procedure to post-procedure was significant (Fisher's exact test p < 0.004). LVEF improvement was most marked in the patients with the most severe cardiomyopathy (LVEF < 20%) improving from a mean 14.6% ± 3.4% pre-procedurally to 28.4% ± 8% at final follow-up. Quality of life statements reflected improvement in 33/50 (66%), no change in 14/50 (28%), and worse in 3/50 (6%)., Conclusion: Transcatheter implantation of ACP-01 for cardiomyopathy is safe and improves LVEF in the setting of ischemic and non-ischemic cardiomyopathy. The results warrant further investigation in a prospective, blinded, and controlled clinical study., Trial Registration: IRB from Genetic Alliance #APC01-001, approval date July 25, 2022. Cardiomyopathy is common and associated with high mortality. Stem cell transplantation is an emerging therapy. Angiogenic cell precursors (ACP-01) are lineage-specific endothelial progenitors, with strong potential for migration, engraftment, angiogenesis, and support of tissue survival and regeneration. A retrospective outcomes analysis of 53 patients with ischemic and non-ischemic dilated cardiomyopathy undergoing transcatheter implantation of ACP-01 demonstrated improvements in the left ventricular ejection fraction of 7.2% ± 10.9 (p < 0.004) and 12.2% ± 6.4, respectively, at 12 months (± 5) follow-up. Quality of life statements reflected improvement in 33/50 (66%) patients., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: After completion of training, practicing surgeons rely on hands-on courses to expand their procedure armamentarium and improve their surgical technique. However, such courses vary in standardized teaching methods. SAGES developed the Acquisition of Data for Outcomes and Procedure Transfer (ADOPT) program as a method of longitudinal instruction utilizing standardized teaching techniques, mentorship, and webinars to cover additional techniques. This study examines the adoption of learned techniques and participant confidence before and after an ADOPT course focused on extended-view totally extraperitoneal (eTEP) hernia repair., Methods: A hands-on course focused on eTEP hernia repair was conducted with enrollment capped at 10 participants. Pre-course and post-course surveys at 3, 6, and 12 months determined implementation of the learned procedure, case volume, and confidence with eTEP skills. A 5-point Likert scale (1 = not confident at all to 5 = completely confident) assessed confidence levels. Survey responses were summarized using descriptive statistics., Results: Of the 10 participants, 10 (100%) completed the pre-course survey, and 7 (70%) completed at least one post-course survey. Median age was 48.5 years (36,56) with a median of 16 years (2,23) in practice, mostly in the community setting (70%). After the course, 50% had performed an eTEP procedure, and 100% reported considering this technique during surgical planning. Participants reported higher confidence in eTEP-specific skills at three months post-course from pre-course levels. The highest change in confidence was seen for the following skills: accessing the retromuscular/extraperitoneal space for ventral hernia and recognizing when the linea alba has been violated, p < 0.05., Conclusion: This study shows that rapid incorporation of learned techniques can be achieved through the ADOPT format. Furthermore, through longitudinal mentorship and a structured hands-on course, the ADOPT course supports practicing surgeons to attain autonomy and confidence even when teaching a relatively technically challenging procedure, such as eTEP., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Angiotensin converting enzyme inhibitors (ACEI) are a common class of medications prescribed to patients for hypertension. Anti-hypertensive use is not normally considered an important factor when treating patients with crotalid envenomations; however, in combination with the venom in this patient, it may have resulted in angioedema., Case Report: A 65-year-old male on ACEI presented to his community emergency department following a snake envenomation to his thumb. Six vials of Crotalidae polyvalent immune fab were administered, and he was transferred to a referral center. Approximately 18 hours after the envenomation, the patient complained of tongue swelling and difficulty speaking. There was evidence of angioedema, with the right side of the tongue significantly enlarged compared to the left. He was intubated for airway protection and remained on a ventilator for three days., Conclusion: Angiotensin converting enzyme inhibitors may potentiate the effects of exogenous bradykinin as some snake venom has naturally occurring bradykinin, which may further amplify its effects. Extra vigilance may be warranted for the development of angioedema in patients receiving ACEI.

Background: Despite conflicting data, intravenous lipid emulsion has emerged as a potential antidote. The "lipid sink" theory suggests that following intravenous administration of lipid, lipophilic drugs are sequestered in the vascular compartment, thereby reducing their tissue concentrations. This study sought to determine if survival is associated with the intoxicant's degree of lipophilicity., Methods: We reviewed all cases in the Toxicology Investigators Consortium's lipid sub-registry between May 2012 through December 2018. Information collected included demographics, exposure circumstances, clinical course, management, disposition, and outcome. The primary outcome was survival after lipid emulsion therapy. Survival was stratified by the log of the intoxicant's octanol-water partition coefficient. We also assessed the association between intoxicant lipophilicity and an increase in systolic blood pressure after lipid emulsion administration., Results: We identified 134 patients, including 81 (60.4%) females. The median age was 40 years (interquartile range 21-75). One hundred and eight (80.6%) patients survived, including 45 (33.6%) with cardiac arrest during their intoxication. Eighty-two (61.2%) were hypotensive, and 98 (73.1%) received mechanical ventilation. There was no relationship between survival and the log of the partition coefficient of the intoxicant on linear analysis ( P  = 0.89) or polynomial model ( P  = 0.10). Systolic blood pressure increased in both groups. The median (interquartile range) systolic blood pressure before lipid administration was 68 (60-78) mmHg for those intoxicants with a log partition coefficient < 3.6 compared with 89 (76-104) mmHg after lipid administration. Among those drugs with a log partition coefficient > 3.6, the median (interquartile range) was 69 (60-84) mmHg before lipid and 89 (80-96) mmHg after lipid administration., Conclusion: Most patients in this cohort survived. Lipophilicity was not correlated with survival or the observed changes in blood pressure. The study did not address the efficacy of lipid emulsion.

Women's health care has evolved significantly since it was first acknowledged as an integral part of internal medicine training more than two decades ago. To update and clarify core competencies in sex- and gender-based women's health for general internists, the Society of General Internal Medicine (SGIM) Women and Medicine Commission prepared the following Position Paper, approved by the SGIM council in 2023. Competencies were developed using several sources, including the 2021 Accreditation Council for Graduate Medical Education Program Requirements for Internal Medicine and the 2023 American Board of Internal Medicine Certification Examination Blueprint. These competencies are relevant to the care of patients who identify as women, as well as gender-diverse individuals to whom these principles apply. They align with pivotal advances in women's health and acknowledge the changing context of patients' lives, reaffirming the role of general internal medicine physicians in providing comprehensive care to women., (© 2023. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Background: The GOLD trial demonstrated that continuous glucose monitoring (CGM) in people with type 1 diabetes (T1D) managed with multiple daily insulin injections (MDI) improved not only glucose control but also overall well-being and treatment satisfaction. This analysis investigated which factors contributed to improved well-being and treatment satisfaction with CGM., Methods: The GOLD trial was a randomized crossover trial comparing CGM versus self-monitored blood glucose (SMBG) over 16 months. Endpoints included well-being measured by the World Health Organization-Five Well-Being Index (WHO-5) and treatment satisfaction by the Diabetes Treatment Satisfaction Questionnaire (DTSQ) as well as glucose metrics. Multivariable R 2 -decomposition was used to understand which variables contributed most to treatment satisfaction., Results: A total of 139 participants were included. Multivariable analyses revealed that increased convenience and flexibility contributed to 60% (95% confidence interval [CI] = 50%-69%) of the improvement in treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire change version [DTSQ c ]) observed with CGM, whereas perceived effects on hypoglycemia and hyperglycemia only contributed to 6% (95% CI = 2%-11%) of improvements. Significant improvements in well-being (WHO-5) by CGM were observed for the following: feeling cheerful ( P = .025), calm and relaxed ( P = .024), being active ( P = .046), and waking up fresh and rested ( P = .044). HbA1c reductions and increased time in range (TIR) were associated with increased treatment satisfaction, whereas glycemic variability was not. HbA1c reduction showed also an association with increased well-being and increased TIR with less diabetes-related distress., Conclusions: While CGM improves glucose control in people with T1D on MDI, increased convenience and flexibility through CGM is of even greater importance for treatment satisfaction and patient well-being. These CGM-mediated effects should be taken into account when considering CGM initiation., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.P. has no conflict of interest to declare. W.P. has served as a consultant for Dexcom and Abbott Diabetes Care. H.I. has no conflict of interest to declare. H.H. has no conflict of interest to declare. J.H. has served on advisory boards or lectured for Abbot, AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Nordic Infucare, Novo Nordisk, Rubin Medical, and Sanofi. M.W. has served on advisory boards or lectured for MSD, Lilly, Novo Nordisk, and Sanofi, and has organized a professional regional meeting sponsored by Lilly, Rubin Medical, Sanofi, Novartis, and Novo Nordisk. J.B. has received honoraria for consulting and/or lecture fees from Abbott Diabetes Care, MannKind Corp, Nordic Infucare, NovoNordisk and Sanofi. T.H. has received research funds from Adocia, AstraZeneca, BD, Biocon, Boehringer Ingelheim, Dance Pharmaceuticals, Grünenthal, Eli Lilly, Medtronic, Novo Nordisk, Novartis, Sanofi, and Senseonics. T.H. has participated in advisory panels for Novo Nordisk and received speaker honoraria and travel grants from Eli Lilly, Mylan, and Novo Nordisk. S.D. has no conflict of interest to declare. T.N. has received honoraria on expert group participation from AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, Eli Lilly and Company, Boehringer Ingelheim, Abbot and Amgen. E.S. has no conflict of interest to declare. I.H. has received research funding from Dexcom and Insulet. M.L. has received research grants from Eli Lilly and Novo Nordisk and served as a consultant or received honoraria from AstraZeneca, Eli Lilly, and Novo Nordisk.

Background: Financial relationships with industry may bias educational content delivered by physicians. SAGES strives to mitigate potential bias, relying on physician self-reporting. Retrospective review of relationships is possible using the Open Payments Database (OPD), a public record of industry-reported payments to US physicians. We aimed to evaluate the effectiveness of the SAGES disclosure process by comparing faculty disclosures to SAGES, faculty disclosures within presentations, and OPD records among speakers at the 2018-2020 SAGES meetings., Methods: We reviewed all presentations from the SAGES 2018-2020 Annual Meetings. For each invited presentation, all slide-disclosed relationships were recorded. For US physicians, we queried the OPD and recorded relationships ≥ $500 USD in the calendar year prior to presentation. We compared the slide-disclosed relationships with OPD-reported relationships and with those provided to SAGES during the faculty disclosure process. We surveyed a sample of the 2020 annual meeting speakers to analyze potential reasons for discordance., Results: From 2018 to 2020, there were 1,355 invited presentations, of which 1,234 (91%) were available for review. Disclosure slides were present in 1,098 (89%), increasing from 86% in 2018 to 93% in 2020. The proportion of speakers with OPD-reported relationships ≥ $500 increased from 54% in 2018 to 66% in 2020. The total value of OPD relationships decreased from $5.9 million (2018) to $3.3 million (2020) with a concomitant decrease in the proportion with high discordance from 9% in 2018 to 5% in 2020. Among the 2020 speakers with high discordance, the most common explanations for discordance were being unaware of payment or payment outside the 12-month timeframe (55%)., Conclusions: Discordance between financial disclosures reported to SAGES and OPD highlight the need for improvements in the faculty disclosure process. SAGES will continue to streamline this process by incorporating faculty review of their OPD disclosures to ensure all educational programs remain free of commercial bias., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Policies to restrict population mobility are a commonly used strategy to limit the transmission of contagious diseases. Among measures implemented during the COVID-19 pandemic were dynamic stay-at-home orders informed by real-time, regional-level data. California was the first state in the U.S. to implement this novel approach; however, the effectiveness of California's four-tier system on population mobility has not been quantified., Methods: Utilizing data from mobile devices and county-level demographic data, we evaluated the impact of policy changes on population mobility and explored whether demographic characteristics explained variability in responsiveness to policy changes. For each California county, we calculated the proportion of people staying home and the average number of daily trips taken per 100 persons, across different trip distances and compared this to pre-COVID-19 levels., Results: We found that overall mobility decreased when counties moved to a more restrictive tier and increased when moving to a less restrictive tier, as the policy intended. When placed in a more restrictive tier, the greatest decrease in mobility was observed for shorter and medium-range trips, while there was an unexpected increase in the longer trips. The mobility response varied by geographic region, as well as county-level median income, gross domestic product, economic, social, and educational contexts, the prevalence of farms, and recent election results., Conclusions: This analysis provides evidence of the effectiveness of the tier-based system in decreasing overall population mobility to ultimately reduce COVID-19 transmission. Results demonstrate that socio-political demographic indicators drive important variability in such patterns across counties., (© 2023. The Author(s).)

Ulcerated cutaneous melanoma carries a poor prognosis, and the underlying biology driving its aggressive behavior is largely unexplored. MicroRNAs (miRs) are small, noncoding RNAs that inhibit the expression of specific genes and exhibit dysregulated expression patterns in cancer. We hypothesized that a unique miR profile exists in ulcerated relative to nonulcerated melanoma and that miR expression inversely correlates with target genes of biologic importance. Expression of miRs and mRNAs was assessed in ulcerated and nonulcerated cutaneous melanomas using the NanoString Human miRNA and Tumor Signaling 360 mRNA assays and validated in an independent cohort. Pathway enrichment and functional annotations for differentially expressed miRs and mRNAs were determined using publicly available databases. Pearson correlations were employed to predict potential miR‒mRNA binding pairs. Ulcerated melanoma tissue showed at least 1.5-fold change in relative expression of 24 miRs, including miR-206, miR-1-3p, and miR-4286 (>2.25-fold decrease, P < 0.048) and miR-146a-5p, miR-196b-5p, and miR-363-3p (>2.5-fold increase, P < 0.014). Ulcerated melanomas also had 21 differentially expressed mRNAs relative to nonulcerated tumors (P < 0.01), among which two had an inverse correlation in expression with regulatory miRs (SOCS3 and miR-218-5p and IL7R and miR-376c-5p). This miR expression profile adds to the molecular characterization of the poorly understood histopathologic phenotype of ulcerated melanoma., (Copyright © 2022. Published by Elsevier Inc.)

Background: The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) uses the Laparoscopic colectomy Train the Trainer (Lapco TT) framework for standardization of instructor training for Hands-On surgical skills courses. The curriculum focuses on teaching structure, skills deconstruction, trainer intervention framework, and performance enhancing feedback. A halt in the in-person Lapco TT courses due to the Coronavirus Disease 2019 (COVID-19) pandemic necessitated creation of a virtual alternative. We investigated the effectiveness of this virtual course., Methods: Adaptation of the in-person Lapco TT course to the virtual format retained the majority of content as well as the 4:6 instructor-to-participant ratio. The virtual platform and simulators chosen allowed maximal interactivity and ease of use. After participating in the day and one half course, participants completed an 8-item post-course survey using a 5-point Likert scale related to the training experience. In addition, they had the opportunity to provide answers to several open-ended questions regarding the course. For the survey, frequency counts provided an assessment of each item. For the open questions, qualitative analysis included determination of themes for each question. Frequency counts of each theme provided quantitative analysis., Results: Thirty-six total participants completed a Lapco TT virtual course (six sessions of six participants). Of this number, 32 participants completed post-course surveys and questions. All the participants completing the survey would very likely or definitely (Likert scale 4, 5) recommend the course to a colleague and incorporate the teaching in their practice. The majority of participants completing open-ended questions felt the virtual course format was effective; half thought that post-course follow-up would be useful. Technical concerns were an issue using the virtual format., Conclusion: A virtual Lapco TT course is feasible and well received by participants. It presents a potentially more cost effective option to faculty development., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Professional medical associations (PMAs) have an essential role in advancing medical care and health. PMAs promote skills training, clinical standards, and other important educational activities. Most often, PMAs are not-for-profit entities that rely upon funding from industry to help cover the costs of these valuable activities. Equally important, innovation and progress in surgery require physician collaboration with industry throughout the product development process. SAGES has opined that, with appropriate Conflict of Interest (COI) disclosure and management processes, PMA educational activities can be both scientifically and ethically sound., Methods: SAGES has developed and implemented comprehensive and stringent processes for managing potential COI within the organization, at the annual meeting, and in developing educational offerings. This document reviews the SAGES COI processes and results 2009-2021., Results: Implementation of the SAGES COI disclosure and management processes reduced the reported perceived incidence of bias at the annual meeting from 4.4-6.2% (2008-2010) to 1.2-2.2% (2011-2013). Recent comparison of reported disclosures revealed a rise in number of speakers with financial relationships and an increase in reporting of disclosures in presentations without an associated increase in need for conflict resolution by the COI committee. Despite good overall adherence to COI policies, SAGES was recently cited for non-compliance with ACCME standards related to inclusion of faculty with ownership interest. This experience highlighted the potential for discordance in the interpretation of whether disclosures relate to specific CME content. SAGES COI processes have since been updated to reflect the more stringent 2020 ACCME Standards that exclude speakers and planners with ownership interest from any CME activity., Conclusions: The SAGES experience with disclosure and mitigation of financial relationships highlights the challenges of validating the accuracy of physician disclosures and establishing the relevance of financial relationships to the content of accredited educational activities. SAGES will continue to streamline its COI disclosure process with specific focus on aligning all financial disclosures among the various reporting platforms., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Cognitive dysfunction is common in mental disorders and represents a potential risk factor in childhood. The nature and extent of associations between childhood cognitive function and polygenic risk for mental disorders is unclear. We applied computational modeling to gain insight into mechanistic processes underlying decision making and working memory in childhood and their associations with polygenic risk scores (PRSs) for mental disorders and comorbid cardiometabolic diseases., Methods: We used the drift diffusion model to infer latent computational processes underlying decision making and working memory during the n-back task in 3707 children ages 9 to 10 years from the Adolescent Brain Cognitive Development (ABCD) Study. Single nucleotide polymorphism-based heritability was estimated for cognitive phenotypes, including computational parameters, aggregated n-back task performance, and neurocognitive assessments. PRSs were calculated for Alzheimer's disease, bipolar disorder, coronary artery disease (CAD), major depressive disorder, obsessive-compulsive disorder, schizophrenia, and type 2 diabetes., Results: Heritability estimates of cognitive phenotypes ranged from 12% to 38%. Bayesian mixed models revealed that slower accumulation of evidence was associated with higher PRSs for CAD and schizophrenia. Longer nondecision time was associated with higher PRSs for Alzheimer's disease and lower PRSs for CAD. Narrower decision threshold was associated with higher PRSs for CAD. Load-dependent effects on nondecision time and decision threshold were associated with PRSs for Alzheimer's disease and CAD, respectively. Aggregated neurocognitive test scores were not associated with PRSs for any of the mental or cardiometabolic phenotypes., Conclusions: We identified distinct associations between computational cognitive processes and genetic risk for mental illness and cardiometabolic disease, which could represent childhood cognitive risk factors., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)