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The long-term survival benefits after surgical ablation for atrial fibrillation (AF) during cardiac surgery were not confirmed in previous randomized controlled trials or meta-analyses. This study aimed to investigate the long-term efficacy of surgical ablation in patients with AF. MEDLINE, EMBASE, and CENTRAL were searched to identify studies comparing concomitant surgical AF ablation with no surgical ablation during cardiac surgery. The primary outcome was long-term all-cause mortality. Secondary outcomes were stroke, heart failure rehospitalization, major bleeding, freedom from AF, and permanent pacemaker implantation during follow-up. To minimize confounding, only adjusted outcomes were used from observational studies. A total of 38 studies met the inclusion criteria. Of those, 9 randomized controlled trials and 15 observational studies with 41,678 patients (surgical ablation: n = 19,125; no surgical ablation: n = 22,553) were analyzed for all-cause mortality, with a weighted median follow-up of 62.0 months. Surgical ablation was associated with decreased risks of long-term mortality (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.71 to 0.84), stroke (HR 0.60, 95% CI 0.48 to 0.76), heart failure rehospitalization (HR 0.92, 95% CI 0.87 to 0.96), and more freedom from AF during follow-up (relative risk 1.93, 95% CI 1.50 to 2.49), whereas surgical ablation was associated with a higher risk of permanent pacemaker implantation during follow-up (HR 1.35, 95% CI 1.03 to 1.77). There was no significant difference in major bleeding during follow-up between the 2 groups. In patients with AF who underwent cardiac surgery, surgical ablation was associated with decreased risks of long-term mortality, stroke, and heart failure rehospitalization compared with patients with untreated AF. Given that the survival benefits were predominantly observed in observational studies, further randomized trials are necessary to confirm these findings., Competing Interests: Declaration of competing interest Dr. Kaneko has received consulting fees from Edwards Lifesciences, Medtronic, 4C Medical, CardioMech, Cook Medical; and has been a speaker for Abbott and Baylis. The remaining authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The last few years have seen exponential growth in interest, investment, advocacy, and research into psychedelics as therapeutics. This reflects an optimism about the potential promise of psychedelics as therapeutics. As with all therapeutic interventions, research is needed not only into their benefits but also potential risks. Indeed, when substances with therapeutic potential are scrutinized over time, especially in broad populations with psychiatric and medical comorbidities typically excluded from clinical trials, and applied in less well-regulated or controlled settings, a greater understanding of the cautions emerges. Here, we review the literature on the known and potential harms, including enduring perceptual disturbances; triggering or enhancing the risk for onset of mania or psychosis; overuse, misuse, and dependence; challenging experiences or "bad trips"; risks associated with increased neuroplastic potential; and acute and cumulative cardiovascular effects. Each of these issues is addressed in this review, along with the call for continued research, including recommendations for further research and monitoring., Competing Interests: Dr. Ghaznavi owns stock in Atai Life Sciences. Dr. Haggerty is on the scientific advisory boards of 4M Therapeutics, Alzheimer’s Drug Discovery Foundation, Entheos Labs, Frequency Therapeutics, Ilios Therapeutics, the Kissick Family Foundation FTD Grant Program, Psy Therapeutics, Souvien Theraputics, and Sensorium Therapeutics; he has received consulting fees from Juvenescence Life, and Biohaven Pharmaceuticals RBNC; he has also received research funding from Atai Life Sciences, COMPASS Pathways, Entheos Labs, JW Pharmaceuticals, Lexicon Pharmaceuticals, Stealth Biotherapeutics, and Vesigen Therapeutics. Dr. King owns stock in Apex Labs, COMPASS Pathways, and Cybin; he is on the scientific advisory board of Apex Labs; and has received consulting fees from Cybin. Dr. Rosenbaum owns stock in Atai Life Sciences, Cerebral Inc., Entheos Labs, Psy Therapeutics, Sensorium Therapeutics, TaraMind, and Terran Biosciences; he is a member of the board of directors for Cerebral Inc., Entheos Labs, Psy Therapeutics, and Sensorium Therapeutics; he is an advisor for TaraMind. Dr. Ruskin owns stock in Ablacor, Celero, Element Science, Infobionic, LuxMed, and NewPace; he has received consulting fees and is a member of the scientific advisory board for Acesion Pharma, Advanced Medical Education, InCarda, Janssen, Sanofi, and Vertex; he holds a patent from Celero Systems.

Background: The advent of short-course, curative treatment with direct-acting antivirals (DAA) has given promise for the global elimination of hepatitis C virus (HCV) infections by 2030. Virological failure occurs in 2%-12% of persons receiving curative DAA treatment and may be presaged by pre-existing polymorphisms or result from selection of drug resistant variants during therapy., Methods: We conducted a systematic review to assess the prevalence of HCV resistance associated substitutions (RAS) among individuals with chronic hepatitis C infection who had virological failure following initial or re-treatment with pan-genotypic DAA regimens. We included 34 and 22 studies assessing RAS in people with virological failure published between January 2014 and July 2023. Pooled RAS prevalence was estimated using random-effects meta-analysis., Results: The pooled prevalence of RAS in people with virological failure following initial DAA treatment was 78.0% (95% confidence interval [CI]: 62.0-92.0) for sofosbuvir/velpatasvir, 81.0% (95% CI: 67.0-93.0) for sofosbuvir/daclatasvir, and 79.0% (95% CI: 70.0-87.0) for glecaprevir/pibrentasvir, with a high prevalence of resistance to the NS5A inhibitors. Among those with virological failure following re-treatment regimens, RAS were present in 93.0% (95% CI: 83.0-99.0) for sofosbuvir/velpatasvir/voxilepravir and in 100% (95% CI: 92.0-100) for glecaprevir/pibrentasvir, with resistance driven by RAS to NS5A inhibitors., Discussion: At least 1 RAS is present in a high proportion of the few individuals with virological failure following initial or re-treatment with pan-genotypic DAA regimens. There is a need for ongoing surveillance for DAA-associated resistance, to assess risk factors for their development and clinical impact to inform best practice strategies for re-treatment., Competing Interests: Potential conflicts of interest. W. I. reports personal fees from Roche diagnostics, Gilead Sciences, and Source Bioscience Limited outside of the submitted work and stock or stock options in GlaxoSmithKline. P. C. M. reports funding from Francis Crick Institute and University College London Biomedical Research Centre (BRC) and Wellcome Trust during the submitted work, as well as royalties from Oxford University Press and funding from GlaxoSmithKline outside of the submitted work. S. T. reports funding or personal fees ViiV Healthcare and Gilead Sciences outside of the submitted work. D. A. reports funding from Gilead Sciences and Pfizer outside of the submitted work. R. H. serves as the president of World Hepatitis Alliance. All other authors declare no competing interests. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The difference in survival between sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) remains controversial., Objective: To investigate the comparative survival difference between SG and RYGB in adults with morbid obesity., Setting: A meta-analysis., Methods: MEDLINE, EMBASE, and Cochrane Library Central Register of Controlled Trial were searched through June 30th, 2023 to identify studies comparing SG and RYGB. To minimize confounding, only adjusted outcomes were used from observational studies. The primary outcome was all-cause mortality during follow-up. Secondary outcomes were revision, reoperation, reintervention, hospitalization, endoscopic procedure, and emergency department visit., Results: Twenty-two studies (10 randomized controlled trials [RCTs] and 12 observational studies) met the inclusion criteria. Three RCTs and seven observational studies with 333,713 patients (SG, n = 172,909; RYGB, n = 160,804) were analyzed for all-cause mortality, with a weighted median follow-up of 34.4 months. SG was associated with decreased risks of all-cause mortality during follow-up (hazard ratio [HR]: .85; 95% confidence interval [CI]: .79 to .92), reoperation (HR: .69; 95% CI: .59 to .80), reintervention (HR: .74; 95% CI: .66 to .81), hospitalization (HR: .86; 95% CI: .77 to .97), and endoscopic procedure (HR: .55; 95% CI: 0.40-.76), whereas SG was associated with a higher risk of revision (HR: 2.18, 95% CI: 1.52 to 3.14). Meta-regression suggested consistent survival advantages of SG regardless of the proportion of patients with diabetes or follow-up duration., Conclusion: In adults with morbid obesity undergoing bariatric surgery, SG was associated with a decreased risk of all-cause mortality during follow-up compared with RYGB. A large-scale randomized trial with long-term follow-up is still necessary for validation., Competing Interests: Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article., (Copyright © 2024 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Peripheral and deep en face margin assessment (PDEMA), formerly termed by NCCN as complete circumferential peripheral and deep margin assessment (CCPDMA), has the advantages of histologic visualization of the entire marginal surface, highly accurate resection of involved tissue, and sparing of uninvolved tissue. Owing to its highest reported cure rates, PDEMA is the NCCN-preferred treatment for dermatofibrosarcoma protuberans, high-risk basal cell carcinoma, and very-high-risk cutaneous squamous cell carcinoma. In the United States, Mohs micrographic surgery (Mohs) is the most common method of PDEMA. In Germany and some other countries, non-Mohs methods of PDEMA referred to as the Tubingen torte and muffin techniques are more widely used. The Tubingen methods of PDEMA require close communication between surgeon and pathologist. This article describes the background of both Mohs and Tubingen PDEMA, reviews what constitutes PDEMA, and provides a protocol for Tubingen PDEMA detailing critical components in a stepwise fashion using illustrative photos and diagrams. We hope to broaden understanding of the NCCN Guidelines and their rationale, align practice, and optimize patient outcomes.

Background: Little is known about attitudes towards COVID-19 vaccination in sub-Saharan Africa, where immunisation coverage is the lowest in the world., Aim: The study aimed to identify factors associated with COVID-19 vaccine hesitancy and uptake in Cameroon, and assess changes in these factors over a period of time., Setting: The study was conducted in the ten regions of Cameroon., Methods: The authors conducted a two-phase cross-sectional survey in the 10 regions of Cameroon, from July 2021 to August 2021 (Phase one) and from August 2022 to September 2022 (Phase two). We analysed reasons for vaccine hesitancy descriptively and used logistic regression to assess factors associated with hesitancy., Results: Overall, we enrolled 12 109 participants: 6567 (54.23%) in Phase one and 5542 (45.77%) in Phase two. Of these, 8009 (66.14%) were not interested in receiving the COVID-19 vaccine ( n = 4176 in Phase one, n = 3833 in Phase two). The refusal rate increased significantly in the northern region from 27.00% in Phase 1 to 60.00% in Phase two. The leading contributor to COVID-19 vaccine hesitancy was fear that the vaccine was dangerous, which was significantly associated (95% confidence interval [CI], p < 0.05%) with vaccine refusal in both phases. Overall, 32.90% of participants ( n = 2578) perceived the COVID-19 vaccine to be dangerous. Advanced age, male gender, Muslim religion and low level of education were associated with vaccine acceptance. Participants reported that healthcare workers were the most trusted source of information about the COVID-19 vaccine by 5005 (42.84%) participants., Conclusion: Despite the investment of the Ministry of Health and its partners in community engagement, focussing on communication about the vaccine efficacy, tolerance and potential adverse events, fear of the vaccine remains high, likely leading to vaccine hesitancy in Cameroon between 2021 and 2022., Contribution: The study highlight regional variations in COVID-19 vaccine acceptance in Cameroon, with factors age, gender, religion and education influencing willingness to vaccine. Trust in health workers was high, indicating that, tailored, community-led vaccination strategies are key for improving vaccine uptake, not only for COVID-19 but also for future epidemics., Competing Interests: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article., (© 2024. The Authors.)

Microglia are critical innate immune cells of the brain. In vivo targeting of microglia using gene-delivery systems is crucial for studying brain physiology and developing gene therapies for neurodegenerative diseases and other brain disorders such as NeuroAIDS. Historically, microglia have been extremely resistant to transduction by viral vectors, including adeno-associated virus (AAV) vectors. Recently, there has been some progress demonstrating the feasibility and potential of using AAV to transduce microglia after direct intraparenchymal vector injection. Data suggests that combining specific AAV capsids with microglia-specific gene expression cassettes to reduce neuron off-targeting will be key. However, no groups have developed AAV capsids for microglia transduction after intracerebroventricular (ICV) injection. The ICV route of administration has advantages such as increased brain biodistribution while avoiding issues related to systemic injection. Here, we performed an in vivo selection using an AAV peptide display library that enables recovery of capsids that mediate transgene expression in microglia. Using this approach, we identified a capsid, MC5, which mediated enhanced transduction of microglia after ICV injection compared to AAV9. Furthermore, MC5 enhanced both the efficiency (85%) and specificity (93%) of transduction compared to a recently described evolved AAV9 capsid for microglia targeting after direct injection into the brain parenchyma. Exploration of the use of MC5 in a mouse models of Alzheimer's disease revealed transduced microglia surrounding and within plaques. Overall, our results demonstrate that the MC5 capsid is a useful gene transfer tool to target microglia in vivo by direct and ICV routes of administration., Competing Interests: Competing interests: C.A.M. has a financial interest in Sphere Gene Therapeutics, Inc., Chameleon Biosciences, Inc., and Skylark Bio, Inc., companies developing gene therapy platforms. C.A.M.’s interests were reviewed and are managed by MGH and Mass General Brigham in accordance with their conflict-of-interest policies. C.A.M., M.C.S., K.S.H., and P.E. have filed a patent application with claims involving the MC5 capsid.

In a subset of SARS-CoV-2 infected individuals treated with the oral antiviral nirmatrelvir-ritonavir, the virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used a mathematical model to describe the longitudinal viral load dynamics of 51 individuals treated with nirmatrelvir-ritonavir, 20 of whom rebounded. Target cell preservation, either by a robust innate immune response or initiation of nirmatrelvir-ritonavir near the time of symptom onset, coupled with incomplete viral clearance, appear to be the main factors leading to viral rebound. Moreover, the occurrence of viral rebound is likely influenced by time of treatment initiation relative to the progression of the infection, with earlier treatments leading to a higher chance of rebound. Finally, our model demonstrates that extending the course of nirmatrelvir-ritonavir treatment, in particular to a 10-day regimen, may greatly diminish the risk for rebound in people with mild-to-moderate COVID-19 and who are at high risk of progression to severe disease. Altogether, our results suggest that in some individuals, a standard 5-day course of nirmatrelvir-ritonavir starting around the time of symptom onset may not completely eliminate the virus. Thus, after treatment ends, the virus can rebound if an effective adaptive immune response has not fully developed. These findings on the role of target cell preservation and incomplete viral clearance also offer a possible explanation for viral rebounds following other antiviral treatments for SARS-CoV-2., Competing Interests: Competing interests: ASP owns stock in Pfizer. He was also on a Pfizer advisory committee and received an honorarium. The other authors declare that they have no competing interests.

Competing Interests: Conflicts of interest Dr Lebwohl is an employee of Mount Sinai and is a consultant for Almirall, AltruBio Inc, AnaptysBio, Apogee, Arcutis, Inc, AstraZeneca, Atomwise, Avotres Therapeutics, Brickell Biotech, Boehringer-Ingelheim, Bristol-Myers Squibb, Castle Biosciences, Celltrion, Corevitas, Dermavant Sciences, EPI, Evommune, Inc, Facilitation of International Dermatology Education, Forte biosciences, Foundation for Research and Education in Dermatology, Galderma, Genentech, Incyte, LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer,Sanofi-Regeneron, Seanergy, Strata, Takeda,Trevi, and Verrica. Dr Grimes has served as a consultant and/or investigator for Procter & Gamble, Clinuvel, L'Oreal, Galderma Laboratories, LaserOptek, Versicolor Technologies, Incyte, Pfizer, AbbVie/Allergan, and SkinBetterScience. Dr Desai has served as a consultant and/or investigator for Galderma, Pfizer, Dermavant, Scientis, AbbVie and several other organizations. He also serves in multiple leadership roles with dermatologic organizations. Drs Richard and Buzney have no conflicts of interest to declare.

Background: Physical activity is recommended as part of guideline-based care for managing chronic obstructive pulmonary disease (COPD) at all stages of the disease. However, physical activity interventions are less effective in individuals with co-occurring emotional distress (i.e., depression and/or anxiety symptoms). Interventions that dually promote improved physical and mental health in COPD are needed. The first step for intervention development is understanding individuals' experience of these factors., Purpose: To understand the experience of emotional distress in U.S. Veterans diagnosed with COPD and to explore how emotional distress impacts physical activity engagement., Methods: Structured interviews informed by the cognitive and behavioral models of psychopathology were conducted with 29 United States Veterans with COPD (89.66% male, age 67.72 ± 6.55 years, 93.10% White) at the VA Boston Healthcare System. Interviews were audio recorded, transcribed, and underwent thematic analysis., Results: Three major themes encapsulating 17 codes emerged through thematic analysis: (i) the experience of emotional distress in Veterans with COPD; (ii) the complex relationship between emotional distress, physical activity engagement, and COPD; (iii) contextual and personal factors., Conclusions: Veterans' interpretation of their COPD symptoms as unpredictable and uncontrollable and COPD-related physical limitations influenced their experience of emotional distress, while the experience of emotional distress both promoted and deterred physical activity engagement. Veterans were motivated to engage in physical activity despite experiencing emotional distress when they faced a responsibility in daily life. They identified motivational strategies and self-regulation techniques to manage emotional distress and to foster physical activity., (Published by Oxford University Press on behalf of the Society of Behavioral Medicine 2024.)

Sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli to the central nervous system. Single-cell RNA sequencing has provided insights into the diversity of sensory ganglia cell types in rodents, nonhuman primates, and humans, but it remains difficult to compare cell types across studies and species. We thus constructed harmonized atlases of the DRG and TG that describe and facilitate comparison of 18 neuronal and 11 non-neuronal cell types across six species and 31 datasets. We then performed single-cell/nucleus RNA sequencing of DRG from both human and the highly regenerative axolotl and found that the harmonized atlas also improves cell type annotation, particularly of sparse neuronal subtypes. We observed that the transcriptomes of sensory neuron subtypes are broadly similar across vertebrates, but the expression of functionally important neuropeptides and channels can vary notably. The resources presented here can guide future studies in comparative transcriptomics, simplify cell-type nomenclature differences across studies, and help prioritize targets for future analgesic development.

Orbital inflammatory diseases represent a heterogenous group of idiopathic, autoimmune-related, and sometimes neoplastic conditions with overlapping clinical and histopathologic features, as well as variable levels of IgG4-positive plasma cells detected within tissue biopsies. Some histopathologic features, especially in an appropriate clinical context, may point to a specific diagnosis in a given patient. Diagnoses of non-specific orbital inflammation, orbital inflammation related to autoimmune diseases such as granulomatosis with polyangiitis and IgG4-related disease, lymphoma, and xanthogranulomatous diseases are discussed, contrasted and illustrated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cardiovascular diseases (CVDs) remain the leading cause of death and disability worldwide. Digital health technologies are important public health interventions for addressing the burden of cardiovascular disease. In this article, we discuss the importance of translating digital innovations in research-funded projects to low-resource settings globally to advance global cardiovascular health equity. We also discuss current global cardiovascular health inequities and the digital health divide within and between countries. We present various considerations for translating digital innovations across different settings across the globe, including reciprocal innovation , a "bidirectional, co-constituted, and iterative exchange of ideas, resources, and innovations to address shared health challenges across diverse global settings." In this case, afferent reciprocal innovations may flow from high-income countries toward low- and middle-income countries, and efferent reciprocal innovations may be exported to high-income countries from low- and middle-income countries with adaptation. Finally, we discuss opportunities for bidirectional learning between local and global institutions and highlight examples of projects funded through the American Heart Association Health and Innovation Strategically Funded Research Network that have been adapted to lower-resource settings or have the potential to be adapted to lower-resource settings.

Characterizing human thalamocortical network is fundamental for understanding a vast array of human behaviors since the thalamus plays a central role in cortico-subcortical communication. Over the past few decades, advances in functional magnetic resonance imaging have allowed for spatial mapping of intrinsic resting-state functional connectivity (RSFC) between both cortical regions and in cortico-subcortical networks. Despite these advances, identifying the electrophysiological basis of human thalamocortical network architecture remains challenging. By leveraging stereoelectroencephalography electrodes temporarily implanted into distributed cortical regions and the anterior nucleus of the thalamus (ANT) of 10 patients with refractory focal epilepsy, we tested whether ANT stimulation evoked cortical potentials align with RSFC from the stimulation site, derived from a normative functional connectome (n = 1000). Our study identifies spatial convergence of ANT stimulation evoked cortical potentials and normative RSFC. Other than connections to the Papez circuit, the ANT was found to be closely connected to several distinct higher-order association cortices, including the precuneus, angular gyrus, dorsal lateral prefrontal cortex, and anterior insula. Remarkably, we found that the spatial distribution and magnitude of cortical-evoked responses to single-pulse electrical stimulation of the ANT aligned with the spatial pattern and strength of normative RSFC of the stimulation site. The present study provides electrophysiological evidence that stimulation evoked electrical activity flows along intrinsic brain networks connected on a thalamocortical level., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Peripheral sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli including touch, temperature, and pain to the central nervous system. Recent advances in single-cell RNA-sequencing (scRNA-seq) have provided new insights into the diversity of sensory ganglia cell types in rodents, non-human primates, and humans, but it remains difficult to compare transcriptomically defined cell types across studies and species. Here, we built cross-species harmonized atlases of DRG and TG cell types that describe 18 neuronal and 11 non-neuronal cell types across 6 species and 19 studies. We then demonstrate the utility of this harmonized reference atlas by using it to annotate newly profiled DRG nuclei/cells from both human and the highly regenerative axolotl. We observe that the transcriptomic profiles of sensory neuron subtypes are broadly similar across vertebrates, but the expression of functionally important neuropeptides and channels can vary notably. The new resources and data presented here can guide future studies in comparative transcriptomics, simplify cell type nomenclature differences across studies, and help prioritize targets for future pain therapy development., Competing Interests: W.R. receives research funding from Teva Pharmaceuticals and is on an Abbvie scientific advisory board. C.J.W. is a Scientific Advisory Board member of Lundbeck, QurAlis, Axonis, Tafalgie Therapeutics. R.W.G. serves on the Scientific Advisory Board for Doloromics. T.J.P. is a cofounder of Doloromics and receives research funding from Abbvie and Merck.

Introduction: Successful completion of continuing medical education (CME) activities is often required for ongoing physician board certification, licensure, and hospital privileges. CME activities are designed to address professional knowledge or practice gaps. The authors examined participants' "intent to change" after CME activities to evaluate whether CME activity content was suitably linked with the stated learning objectives., Methods: The authors performed a retrospective mixed-methods thematic content analysis of written and electronic records from American Association of Neurological Surgeons-sponsored CME activities. Data from 2011 through 2016 were analyzed using a quantitative, deductive content analysis approach. Data were examined for each year separately as well as longitudinally over the six consecutive years. Intent-to-change data that did not align with meeting objectives were analyzed inductively using a qualitative content analysis approach to explore potential unintended learning themes., Results: The authors examined 85 American Association of Neurological Surgeons CME activities (424 CME objectives). The objectives were compared with 1950 intent-to-change statements. Thematic patterns of recurrent intent-to-change statements that matched with CME objectives included topics of resident education, complication avoidance, clinical best practices and evidence, new innovations, and novel surgical techniques. Just over a third of intent-to-change statements (37.3%) were not related to any meeting objective. Approximately a quarter of these unmatched statements led to new learning objectives in subsequent years., Conclusions: An examination of CME learning objectives and participant intent-to-change statements provides information for examination of both meeting planner and learner attitudes for future CME activity planning., Competing Interests: R. L. Jensen served on the AANS Joint Sponsorship committee as a member and/or Chair during the years for which data were collected for this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The remaining authors declare no conflict of interest., (Copyright © 2021 The Alliance for Continuing Education in the Health Professions, the Association for Hospital Medical Education, and the Society for Academic Continuing Medical Education.)

Growing number of methods for attenuation-coefficient map estimation from magnetic resonance (MR) images have recently been proposed because of the increasing interest in MR-guided radiotherapy and the introduction of positron emission tomography (PET) MR hybrid systems. We propose a deep-network ensemble incorporating stochastic-binary-anatomical encoders and imaging-modality variational autoencoders, to disentangle image-latent spaces into a space of modality-invariant anatomical features and spaces of modality attributes. The ensemble integrates modality-modulated decoders to normalize features and image intensities based on imaging modality. Besides promoting disentanglement, the architecture fosters uncooperative learning, offering ability to maintain anatomical structure in a cross-modality reconstruction. Introduction of a modality-invariant structural consistency constraint further enforces faithful embedding of anatomy. To improve training stability and fidelity of synthesized modalities, the ensemble is trained in a relativistic generative adversarial framework incorporating multiscale discriminators. Analyses of priors and network architectures as well as performance validation were performed on computed tomography (CT) and MR pelvis datasets. The proposed method demonstrated robustness against intensity inhomogeneity, improved tissue-class differentiation, and offered synthetic CT in Hounsfield units with intensities consistent and smooth across slices compared to the state-of-the-art approaches, offering median normalized mutual information of 1.28, normalized cross correlation of 0.97, and gradient cross correlation of 0.59 over 324 images., Competing Interests: Declaration of Competing Interest There is no known competing financial interests or personal relationships that could affect or influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: Adult-children caring for a parent with cancer comprise a significant segment of caregivers. Yet less is known about adult-child caregivers, their burden, or caregivers' and patients' gender's impact, which may differ from the well-studied spousal caregiver. This knowledge gap may hinder efforts to ameliorate adult-children's caregiver burden., Methods: We analyzed caregiver surveys from the Cancer Care Outcomes Research and Surveillance Consortium, a multi-regional population-based study of patients with colorectal or lung cancer. Using t tests and multivariate regression models, we assessed whether adult-child and spousal caregivers' caregiving responsibilities and social/emotional and financial burdens differed and used structural equation models (SEMs) to examine mediating factors., Results: Compared with spouses/partners (N = 1007), adult-children (N = 227) spent less time caregiving (14 vs 23 hours/week; P < .001), but experienced higher social/ emotional burden (P < .01). In models adjusted for objective caregiving burden measures and demographics, adult-children's social/emotional (P < .05) and financial burdens (P < .01) were greater than spouses'. Poor communication quality was associated with greater social/emotional burden for both groups (P < .05). SEMs indicated that gender concordance between caregivers and patients (eg, daughters caring for mothers) and caregiver employment increased the difference between adult-child and spouses' social/emotional burden, whereas caregiver-patient relationship quality reduced it., Conclusions: Adult-children spend less time caregiving than spouses/partners, but have higher social/emotional and financial caregiving burdens, partially due to adult-children's employment, caregiver-patients' gender concordance, and relationship quality. Gender concordance's contribution to greater social/emotional burden adds important context to prior findings, indicating female caregivers experience the most burden. Interventions that improve caregiver-patient communication may reduce both adult-child and spousal caregiver burden., (© 2022 American Cancer Society.)

Fundus fluorescent angiography is a standard examination in Japan that can directly visualize the circulatory failure in diabetic retinopathy but is not used in Western countries. In this study, we examine the relationship between the non-perfusion area in fundus fluorescent angiography and the progression of diabetic retinopathy. We evaluated 22 eyes between 22 patients who had their first fundus fluorescent angiography during a clinical episode at Keio University Hospital from January 2012 to May 2015, were diagnosed as having preproliferative diabetic retinopathy, and could be followed for at least three years. The non-perfusion area index (%) in nine segmented fundi in the initial fundus fluorescent angiography was calculated, and the progression to proliferative diabetic retinopathy over three years was evaluated. Three out of the 22 eyes (13.6%) developed proliferative diabetic retinopathy over three years. The non-perfusion area index for the initial fundus fluorescent angiography was significantly associated with progression to proliferative diabetic retinopathy. The non-perfusion area index in the posterior pole was most strongly correlated with the progression to proliferative diabetic retinopathy. Thus, the non-perfusion area index in the posterior pole among those with preproliferative diabetic retinopathy may predict the progression to proliferative diabetic retinopathy in the subsequent three years.

Background: Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction., Methods: A candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation., Findings: 15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs., Interpretation: This first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes., Funding: UNITAID, Wellcome, MRC, BMGF., Competing Interests: Conflicts of interest C.U.K. is a consultant Becton Dickinson, the Foundation for Innovative New Diagnostics and the TB Alliance. C.U.K. is collaborating with Janssen, PZA Innovation and Thermo Fisher Scientific. C.U.K. worked as a consultant for QuantuMDx, the Stop TB Partnership, the World Health Organization (WHO) Global TB Programme and the WHO Regional Office for Europe. C.U.K. gave a paid educational talk for Oxford Immunotec. Hain Lifescience covered C.U.K.’s and accommodation to present at a meeting. C.U.K. is an unpaid advisor to BioVersys and GenoScreen. E.R. is employed by Public Health England and holds an honorary contract with Imperial College London. I.F.L. is Director of the Scottish Mycobacteria Reference Laboratory. S.N. receives funding from German Center for Infection Research, Excellenz Cluster Precision Medicine in Chronic Inflammation, Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG)tion EXC 2167. P.S. is a consultant at Genoscreen. T.R. is funded by NIH and DoD and receives salary support from the non-profit organization FIND. T.R. is a co-founder, board member and shareholder of Verus Diagnostics Inc, a company that was founded with the intent of developing diagnostic assays. Verus Diagnostics was not involved in any way with data collection, analysis or publication of the results. T.R. has not received any financial support from Verus Diagnostics. UCSD Conflict of Interest office has reviewed and approved T.R.’s role in Verus Diagnostics Inc. T.R. is a co-inventor of a provisional patent for a TB diagnostic assay (provisional patent #: 63/048.989). T.R. is a co-inventor on a patent associated with the processing of TB sequencing data (European Patent Application No. 14840432.0 & USSN 14/912,918). T.R. has agreed to “donate all present and future interest in and rights to royalties from this patent” to UCSD to ensure that he does not receive any financial benefits from this patent. S.S. is working and holding ESOPs at HaystackAnalytics Pvt. Ltd. (Product: Using whole genome sequencing for drug susceptibility testing for Mycobacterium tuberculosis). G.F.G. is listed as an inventor on patent applications for RBD-dimer-based CoV vaccines. The patents for RBD-dimers as protein subunit vaccines for SARS-CoV-2 have been licensed to Anhui Zhifei Longcom Biopharmaceutical Co. Ltd, China. No other authors declare a conflict of interest. I.C. is a consultant for the Foundation for Innovative New Diagnostics. DAC reports funding from GlaxoSmithKline and consultancy fees from Biobeats, Oxford University Innovation, Sensyne Health.C.C. reports funding from FIND to his institution (Pathology Queensland, Queensland Department of Health) for his laboratory to perform molecular analytic studies (limits of detection) for new molecular platforms manufactured by Cepheid and Bioneer.

Background: health-related quality of life (HRQoL) is an important patient-centred outcome in patients surviving ICU admission for COVID-19. It is currently not clear which domains of the HRQoL are most affected., Objective: to quantify HRQoL in order to identify areas of interventions., Design: prospective observation study., Setting: admissions to European ICUs between March 2020 and February 2021., Subjects: patients aged 70 years or older admitted with COVID-19 disease., Methods: collected determinants include SOFA-score, Clinical Frailty Scale (CFS), number and timing of ICU procedures and limitation of care, Katz Activities of Daily Living (ADL) dependence score. HRQoL was assessed at 3 months after ICU admission with the Euro-QoL-5D-5L questionnaire. An outcome of ≥4 on any of Euro-QoL-5D-5L domains was considered unfavourable., Results: in total 3,140 patients from 14 European countries were included in this study. Three months after inclusion, 1,224 patients (39.0%) were alive and the EQ-5D-5L from was obtained. The CFS was associated with an increased odds ratio for an unfavourable HRQoL outcome after 3 months; OR 1.15 (95% confidence interval (CI): 0.71-1.87) for CFS 2 to OR 4.33 (95% CI: 1.57-11.9) for CFS ≧ 7. The Katz ADL was not statistically significantly associated with HRQoL after 3 months., Conclusions: in critically ill old intensive care patients suffering from COVID-19, the CFS is associated with the subjectively perceived quality of life. The CFS on admission can be used to inform patients and relatives on the risk of an unfavourable qualitative outcome if such patients survive., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Social interaction often occurs in noisy environments with many extraneous sensory stimuli. This is especially relevant for youth with autism spectrum disorders (ASD) who commonly experience sensory over-responsivity (SOR) in addition to social challenges. However, the relationship between SOR and social difficulties is still poorly understood and thus rarely addressed in interventions. This study investigated the effect of auditory sensory distracters on neural processing of emotion identification in youth with ASD and the effects of increasing attention to social cues by priming participants with their own emotional faces., Methods: While undergoing functional magnetic resonance imaging (fMRI), 30 youth with ASD and 24 typically developing (TD) age-matched controls (ages 8-17 years) identified faces as happy or angry with and without simultaneously hearing aversive environmental noises. Halfway through the task, participants also viewed videos of their own emotional faces. The relationship between parent-rated auditory SOR and brain responses during the task was also examined., Results: Despite showing comparable behavioral performance on the task, ASD and TD youth demonstrated distinct patterns of neural activity. Compared to TD, ASD youth showed greater increases in amygdala, insula, and primary sensory regions when identifying emotions with noises compared to no sounds. After viewing videos of their own emotion faces, ASD youth showed greater increases in medial prefrontal cortex activation compared to TD youth. Within ASD youth, lower SOR was associated with reduced increased activity in subcortical regions after the prime and greater increased activity in the ventromedial prefrontal cortex after the prime, particularly in trials with noises., Conclusions: The results suggest that the sensory environment plays an important role in how ASD youth process social information. Additionally, we demonstrated that increasing attention to relevant social cues helps ASD youth engage frontal regions involved in higher-order social cognition, a mechanism that could be targeted in interventions. Importantly, the effect of the intervention may depend on individual differences in SOR, supporting the importance of pre-screening youth for sensory challenges prior to social interventions., (© 2021. The Author(s).)

Gilteritinib is primarily metabolized via cytochrome P450 (CYP). Therefore, concomitant administration of strong CYP3A4 inducers or inhibitors is not recommended. We evaluated the incidence of gilteritinib-related adverse events (AEs) in 47 patients who received gilteritinib with or without antifungal triazoles which are known inhibitors of CYP3A4. Reasons for coadministration were antifungal prophylaxis or treatment of suspected or confirmed fungal diseases. Gilteritinib-related AEs were similar in the gilteritinib-triazole group compared to the gilteritinib without triazole group (75 % vs. 55.5 %, P = 0.23). Additionally, severity of AEs, gilteritinib dose reductions (15 % vs. 14.8 %) or discontinuation due to AEs (10 % vs. 22.2 %), and 90-day mortality (35 % vs. 11.1 %) were similar in both groups. Thus, concomitant gilteritinib and triazole therapy is feasible and is not associated with clinically meaningful increase in gilteritinib-related AEs., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Despite considerable public and scholarly debate about the role of social media in self-injurious thoughts and behaviors (SITBs), no comprehensive, quantitative synthesis of this literature has previously been undertaken. The current systematic review and meta-analysis examines associations between social media use and SITBs, including suicidal ideation, suicide plans, suicide attempts, and nonsuicidal self-injury (NSSI). A range of social media behaviors and experiences were identified, including cybervictimization and perpetration, exposure to and generation of SITB-related content, problematic use, sexting, social media importance, and frequency of use. A systematic search of PsycINFO, Medline, CINAHL, and the references of prior reviews yielded 61 eligible studies. Results largely suggested medium effect sizes for associations between specific social media constructs (cybervictimization, SITB-related social media use, problematic social media use) and SITBs. There was no association between frequency of social media use and SITBs; however, studies on this topic were limited. The majority of studies identified focused on cybervictimization, and results suggested positive associations with all SITBs, with the association between cybervictimization and suicidal ideation stronger for adolescents than adults. Overall, findings highlight the utility of examining specific social media behaviors and experiences, and point to the need for more research in this area., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10 -8 ), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

Objectives: While well-designed clinical decision support (CDS) alerts can improve patient care, utilization management, and population health, excessive alerting may be counterproductive, leading to clinician burden and alert fatigue. We sought to develop machine learning models to predict whether a clinician will accept the advice provided by a CDS alert. Such models could reduce alert burden by targeting CDS alerts to specific cases where they are most likely to be effective., Materials and Methods: We focused on a set of laboratory test ordering alerts, deployed at 8 hospitals within the Partners Healthcare System. The alerts notified clinicians of duplicate laboratory test orders and advised discontinuation. We captured key attributes surrounding 60 399 alert firings, including clinician and patient variables, and whether the clinician complied with the alert. Using these data, we developed logistic regression models to predict alert compliance., Results: We identified key factors that predicted alert compliance; for example, clinicians were less likely to comply with duplicate test alerts triggered in patients with a prior abnormal result for the test or in the context of a nonvisit-based encounter (eg, phone call). Likewise, differences in practice patterns between clinicians appeared to impact alert compliance. Our best-performing predictive model achieved an area under the receiver operating characteristic curve (AUC) of 0.82. Incorporating this model into the alerting logic could have averted more than 1900 alerts at a cost of fewer than 200 additional duplicate tests., Conclusions: Deploying predictive models to target CDS alerts may substantially reduce clinician alert burden while maintaining most or all the CDS benefit., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Catheter/endoscope-based optical coherence tomography (OCT) is a powerful modality that visualizes structural information in luminal organs. Increases in OCT speed have reduced motion artifacts by enabling acquisition faster than or comparable to the time scales of physiological motion. However motion distortion remains a challenge because catheter/endoscope OCT imaging involves both circumferential and longitudinal scanning of tissue. This paper presents a novel image processing method to estimate and correct motion distortion in both the circumferential and longitudinal directions using a single en face image from a volumetric data set. The circumferential motion distortion is estimated and corrected using the en face image. Then longitudinal motion distortion is estimated and corrected using diversity of image features along the catheter pullback direction. Finally, the OCT volume is resampled and motion corrected. Results are presented on synthetic images and clinical OCT images of the human esophagus., Competing Interests: The authors declare no conflicts of interest., (© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Background: This study aimed to investigate prevalence and risk factors for prediabetes, undiagnosed diabetes mellitus, poorly and potentially sub-controlled diabetes in a rural-provincial general adult population in Denmark., Methods: Using cross-sectional data from the Lolland-Falster Health Study, we examined a total of 10,895 individuals aged 20 years and above., Results: Prevalence of prediabetes was 5.8% (men: 6.1%; women: 5.5%); of undiagnosed diabetes 0.8% (men: 1.0%; women: 0.5%); of poorly controlled diabetes 1.2% (men: 1.5%; women: 0.8%); and of potentially sub-controlled diabetes 2% (men: 3.0%; women: 1.3%). In total, 9.8% of all participants had a diabetes-related condition in need of intervention; men at a higher risk than women; RR 1.41 (95% CI 1.26-1.58); person aged + 60 years more than younger; RR 2.66 (95% CI 2.34-3.01); obese more than normal weight person, RR 4.51 (95% CI 3.79-5.38); smokers more than non-smokers, RR 1.38 (95% CI 1.19-1.62); persons with self-reported poor health perception more than those with good, RR 2.59 (95% CI 2.13-3.15); low leisure time physical activity more than those with high, RR 2.64 (95% CI 2.17-3.22); and persons with self-reported hypertension more than those without, RR 3.28 (95% CI 2.93-3.68)., Conclusions: In the Lolland-Falster Health Study, nearly 10% of participants had prediabetes, undiagnosed diabetes, poorly controlled, or potentially sub-controlled diabetes. The risk of these conditions was more than doubled in persons with self-reported poor health perception, self-reported hypertension, low leisure time physical activity, or measured obesity, and a large proportion of people with diabetes-related conditions in need of intervention can therefore be identified relatively easily.

Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. Because insulin release and activity are essential processes for glucose homeostasis, the molecular mechanisms involved in the synthesis and release of insulin, as well as in its detection are tightly regulated. Defects in any of the mechanisms involved in these processes can lead to a metabolic imbalance responsible for the development of the disease. This review analyzes the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism leading to T2DM and insulin resistance. For that purpose, we summarize the data gathered up until now, focusing especially on insulin synthesis, insulin release, insulin sensing and on the downstream effects on individual insulin-sensitive organs. The review also covers the pathological conditions perpetuating T2DM such as nutritional factors, physical activity, gut dysbiosis and metabolic memory. Additionally, because T2DM is associated with accelerated atherosclerosis development, we review here some of the molecular mechanisms that link T2DM and insulin resistance (IR) as well as cardiovascular risk as one of the most important complications in T2DM.

Background: The huntingtin gene ( HTT ) pathogenic cytosine-adenine-guanine (CAG) repeat expansion responsible for Huntington disease (HD) is phased with single nucleotide polymorphisms (SNPs), providing targets for allele-selective treatments., Objective: This prospective observational study defined the frequency at which rs362307 (SNP1) or rs362331 (SNP2) was found on the same allele with pathogenic CAG expansions., Methods: Across 7 US sites, 202 individuals with HD provided blood samples that were processed centrally to determine the number and size of CAG repeats, presence and heterozygosity of SNPs, and whether SNPs were present on the mutant HTT allele using long-read sequencing and phasing., Results: Heterozygosity of SNP1 and/or SNP2 was identified in 146 (72%) individuals. The 2 polymorphisms were associated only with the m HTT allele in 61% (95% high density interval: 55%, 67%) of individuals., Conclusions: These results are consistent with previous reports and demonstrate the feasibility of genotyping, phasing, and targeting of HTT SNPs for personalized treatment of HD., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: To evaluate gender-based patterns of utilization and outcomes of arteriovenous fistulas (AVFs) and grafts (AVGs) in a population-based cohort of hemodialysis (HD) patients., Methods: A retrospective analysis of all patients in the United States Renal Data System who had an AVF or AVG placed for HD access (January 2007 to December 2014). Outcomes were access maturation, conduit patency, infection, and mortality. Chi-square, Student's t, Kaplan-Meier, and multivariable Cox regression analyses were employed accordingly., Results: There were 456,693 (57%) males and 341,571 (43%) females who initiated HD via AVF (16%), AVG (4%) and HD catheter (80%). There was a 30% decrease in odds of initiating HD with AVF in females compared with males (adjusted odds ratio [aOR]: 0.70; 95% confidence interval [CI]: 0.69-0.71, P < 0.001). The use of HD catheter as a bridge to AVF was 36% higher in females compared with males (aOR: 1.36; 95% CI: 1.33-1.39, P < 0.001). Preemptive AVF maturation was 78% for males and 76% for females (P < 0.001). The risk-adjusted analyses showed a 7% decrease in AVF maturation comparing females with males (adjusted hazard ratio [aHR]: 0.93; 95% CI: 0.92-0.95, P < 0.001) but no difference in AVG maturation (aHR: 0.99; 95% CI: 0.97-1.01, P = 0.46) After risk adjustment, primary (AVF: aHR-0.87; AVG: aHR-0.96), primary-assisted (AVF: aHR-0.84; AVG: aHR-0.97), and secondary (AVF: aHR-0.85; AVG: aHR-0.98) patency were lower for females compared with males (all P < 0.05). Initiation of HD with a catheter and conversion to AVF was associated with lower patency in males (aHR: 0.29; 95% CI: 0.28-0.29; P < 0.001) and females (aHR: 0.31; 95% CI: 0.30-0.31; P < 0.001) compared with AVF initiates. Patient survival was higher for females compared with males who received AVF (aHR: 1.08; 95% CI: 1.07-1.09; P < 0.001) and AVG (aHR: 1.13; 95% CI: 1.11-1.15; P < 0.001). Initiation with HD catheter and subsequent conversion to AVF was associated with an increase in mortality for males (aHR: 1.45; 95% CI: 1.43-1.47; P < 0.001) and females (aHR: 1.44; 95% CI: 1.44-1.52; P < 0.001) compared with initiation via AVF. There was no significant difference in severe AVG infection comparing females with males (aHR: 1.05; 95% CI: 0.98-1.13; P = 0.16)., Conclusions: Female gender is associated with a lower prevalence of preemptive AVF's, higher utilization of catheters as a bridge to AVF, and lower patency compared with males. There was no difference in access maturation but patient survival was higher for females compared with males., (Published by Elsevier Inc.)

Purpose: The number of cancer survivors worldwide is growing, with over 15.5 million cancer survivors in the United States alone-a figure expected to double in the coming decades. Cancer survivors face unique health challenges as a result of their cancer diagnosis and the impact of treatments on their physical and mental well-being. For example, cancer survivors often experience declines in physical functioning and quality of life while facing an increased risk of cancer recurrence and all-cause mortality compared with persons without cancer. The 2010 American College of Sports Medicine Roundtable was among the first reports to conclude that cancer survivors could safely engage in enough exercise training to improve physical fitness and restore physical functioning, enhance quality of life, and mitigate cancer-related fatigue., Methods: A second Roundtable was convened in 2018 to advance exercise recommendations beyond public health guidelines and toward prescriptive programs specific to cancer type, treatments, and/or outcomes., Results: Overall findings retained the conclusions that exercise training and testing were generally safe for cancer survivors and that every survivor should "avoid inactivity." Enough evidence was available to conclude that specific doses of aerobic, combined aerobic plus resistance training, and/or resistance training could improve common cancer-related health outcomes, including anxiety, depressive symptoms, fatigue, physical functioning, and health-related quality of life. Implications for other outcomes, such as peripheral neuropathy and cognitive functioning, remain uncertain., Conclusions: The proposed recommendations should serve as a guide for the fitness and health care professional working with cancer survivors. More research is needed to fill remaining gaps in knowledge to better serve cancer survivors, as well as fitness and health care professionals, to improve clinical practice.

Background: In the Denosumab and Teriparatide Administration (DATA) study, we showed that denosumab fully inhibits teriparatide-induced bone resorption while allowing for continued teriparatide-induced bone formation, resulting in larger increases in hip and spine bone mineral density (BMD) than with either drug alone. We aimed to assess whether administration of denosumab with high dose teriparatide would stimulate larger increases in bone mass than those observed in the DATA study., Methods: DATA-HD was an open-label, randomised, controlled phase 4 trial done at Massachusetts General Hospital. Eligible women were postmenopausal women (at least 36 months since last menses or since hysterectomy with a follicle-stimulating hormone concentration of ≥40 U/L) with osteoporosis. Participants were randomly assigned (1:1) to receive teriparatide 20 μg (standard dose) or 40 μg (high dose) daily via subcutaneous injection for 9 months. At 3 months, both groups were started on denosumab 60 mg every 6 months via subcutaneous injection for 12 months. Areal BMD (aBMD) was measured at 0, 3, 9, and 15 months. Treatment was given open label, but outcome assessors were masked. The primary endpoint was percentage change from baseline in spine areal BMD (aBMD) at 15 months. Women who completed at least one study visit after baseline were included in the modified intention-to-treat analysis. Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, number NCT02176382., Findings: Between Oct 15, 2014, and June 10, 2016, 269 women were assessed for eligibility. 76 participants were randomly assigned to 20 μg teriparatide (n=39) or 40 μg teriparatide (n=37), of whom 69 completed at least one post-baseline visit. At 15 months, mean spine aBMD had increased to a significantly greater extent in the 40 μg group (17·5% [SD 6·0] increase) than the 20 μg group (9·5% [3·2]; difference 8·1%, 95% CI 5·5 to 10·6, p<0·0001). Mean femoral neck aBMD had also increased to a greater extent in the 40 μg group (6·8% [SD 4·1] increase) than the 20 μg group (4·3% [3·7]; difference 2·5%, 0·5 to 4·5, p=0·04), as did mean total hip aBMD (40 μg group, 6·1% [3·4] increase; 20 μg group, 3·9% [2·9] increase; difference 2·2%, 0·6 to 3·8, p<0·0001). 30 (77%) of 39 participants in the 20 μg group and 29 (78%) of 37 participants in the 40 μg group had an adverse event, and seven (18%) and two (5%) patients had serious adverse events. The most frequent adverse events were joint pain (15 [38%]), muscle cramp (15 [38%]), and fatigue (12 [31%]) in the 20 μg group group and fatigue (14 [38%]), nausea (16 [43%]), and joint pain (17 [46%]) in the 40 μg group. No deaths were reported., Interpretation: Combined treatment with teriparatide 40 μg and denosumab increases spine and hip BMD more than standard combination therapy. This large and rapid increase in bone mass suggest that this high dose regimen might provide a method of restoring skeletal integrity in patients with osteoporosis., Funding: National Institutes of Health and the Dart Foundation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: To explore (1) the social function of shisha cafes for young people living in the UK and (2) other alternative activities (existing or potential) that do not involve tobacco smoking., Methods: We conducted qualitative interviews with young adults (age 18-30) in Leeds, UK. Snowballing sampling was used in selecting the participants. Interviews were audio-recorded and explored the perspectives and experiences of young people in as well as potential alternative activities. Data were transcribed and analysed thematically., Results: Shisha use plays a central role in social interactions. Youth described using shisha because of emotional and sensory pleasure. Shisha use was implicitly endorsed by respected professionals, such as doctors and university lecturers, who were seen smoking it. Most, but not all, shisha smokers acknowledged that shisha use is harmful. Suggestions for reducing shisha use included use of non- tobacco alternatives, legislation to reduce access and alternative means for socialising, such as sports., Conclusion: For young people in the UK, the known health dangers of shisha are outweighed by its social benefits and shisha is perceived as acceptable. Interventions to reverse the increase in shisha cafes should focus on both individual smoker as well as the community, without sacrificing the importance of social interactions., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background:  Subfascial anterolateral thigh (ALT) flap thickness can be problematic with regards to bulk, oral competence, shoe-fit, or as a potential source of recurrent wound breakdown. We have utilized distinct upper thigh fascial planes to fashion thin (suprafascial) or super-thin (periscarpal) ALT flaps to improve surface topography. We compared outcomes based on ALT flap thickness to determine any significant differences in extremity coverage and reconstruction., Methods:  Analysis was completed on patients who consecutively underwent ALT free tissue transfer at a single institution from May 2012 to January 2017. Patient's operative, and postoperative characteristics were evaluated. Univariate analysis determined differences among matching as well as functional outcomes. A multivariable regression identified independent risk factors associated with patient, donor site, and flap complications., Results:  Fifty-one patients met inclusion criteria. Of these, 16 (31.4%) underwent traditional subfascial ALT flaps, and 35 (68.6%) underwent suprafascial ( N  = 23) or super-thin ( N  = 12) flaps. Thin flap patients were more likely to use tobacco (42.9% versus 6.3%; p  < 0.01), have fewer perforators (1.20 ± 0.41 versus 1.64 ± 0.63; p  < 0.009), and shorter mean operative times (425.9 ± 87.8 versus 511.9 ± 79.9; p  < 0.002), but nearly identical flap sizes (163 cm 2 versus 168 cm 2 ). There were no significant differences in flap complications (18% versus 22%) or donor-site complications (6.3% versus 5.7%) between the thick and thin cohorts, respectively ( p  > 0.05). In subgroup analysis, diabetes mellitus was an independent risk factor for donor site morbidity (odds ratio [OR] = 1.23; p  = 0.027) for all groups, whereas tobacco use and obesity (body mass index [BMI] > 30) failed to significantly alter outcomes independently., Conclusions:  Tailoring ALT thickness can be performed safely without compromising flap outcomes or patient morbidity. Suprafascial and super-thin ALTs allowed for safe, precise solutions for tissue coverage., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Purpose: To assess the safety and effectiveness of the MDT-2113 (IN.PACT Admiral) drug-coated balloon (DCB) for the treatment of de novo and native artery restenotic lesions in the superficial femoral and proximal popliteal arteries vs percutaneous transluminal angioplasty (PTA) with an uncoated balloon in a Japanese cohort., Methods: MDT-2113 SFA Japan ( ClinicalTrials.gov identifier NCT01947478) is an independently adjudicated, prospective, randomized, single-blinded trial that randomized (2:1) 100 patients (mean age 73.6±7.0 years; 76 men) from 11 Japanese centers to treatment with DCB (n=68) or PTA (n=32). Baseline characteristics were similar between the groups, including mean lesion length (9.15±5.85 and 8.89±6.01 cm for the DCB and PTA groups, respectively). The primary effectiveness outcome was primary patency at 12 months, defined as freedom from clinically-driven target lesion revascularization (CD-TLR) and freedom from restenosis as determined by duplex ultrasonography. The safety endpoint was a composite of 30-day device- and procedure-related death and target limb major amputation and clinically-driven target vessel revascularization within 12 months., Results: Patients treated with DCBs exhibited superior 12-month primary patency (89%) compared to patients treated with PTA (48%, p<0.001). The 12-month CD-TLR rate was 3% for DCB vs 19% for PTA (p=0.012). There were no device- or procedure-related deaths, major amputations, or thromboses in either group. Quality-of-life measures showed sustained improvement from baseline to 12 months in both groups., Conclusion: Results from the MDT-2113 SFA Japan trial showed superior treatment effect for DCB vs PTA, with excellent patency and low CD-TLR rates. These results are consistent with other IN.PACT SFA DCB trials and demonstrate the safety and effectiveness of this DCB for the treatment of femoropopliteal lesions in this Japanese cohort.

The effect of enhancing insulin's actions in endothelial cells (ECs) to improve angiogenesis and wound healing was studied in obesity and diabetes. Insulin receptor substrate 1 (IRS1) was overexpressed in ECs using the VE-cadherin promoter to create ECIRS1 TG mice, which elevated pAkt activation and expressions of vascular endothelial growth factor (VEGF), Flk1, and VE-cadherin in ECs and granulation tissues (GTs) of full-thickness wounds. Open wound and epithelialization rates and angiogenesis significantly improved in normal mice and high fat (HF) diet-induced diabetic mice with hyperinsulinemia in ECIRS1 TG versus wild type (WT), but not in insulin-deficient diabetic mice. Increased angioblasts and EC numbers in GT of ECIRS1 mice were due to proliferation in situ rather than uptake. GT in HF-fed diabetic mice exhibited parallel decreases in insulin and VEGF-induced pAkt and EC numbers by >50% without changes in angioblasts versus WT mice, which were improved in ECIRS1 TG mice on normal chow or HF diet. Thus, HF-induced diabetes impaired angiogenesis by inhibiting insulin signaling in GT to decrease the differentiation of angioblasts to EC, which was normalized by enhancing insulin's action targeted to EC, a potential target to improve wound healing in diabetes and obesity., (© 2016 by the American Diabetes Association.)

The heterologous or non-specific effects (NSEs) of vaccines, at times defined as "off-target effects" suggest that they can affect the immune response to organisms other than their pathogen-specific intended purpose. These NSEs have been the subject of clinical, immunological and epidemiological studies and are increasingly recognized as an important biological process by a growing group of immunologists and epidemiologists. Much remain to be learned about the extent and underlying mechanisms for these effects. The conference "Off-target effects of vaccination" held in Annecy-France (June 8-10 2015) intended to take a holistic approach drawing from the fields of immunology, systems biology, epidemiology, bioinformatics, public health and regulatory science to address fundamental questions of immunological mechanisms, as well as translational questions about vaccines NSEs. NSE observations were examined using case-studies on live attenuated vaccines and non-live vaccines followed by discussion of studies of possible biological mechanisms. Some possible pathways forward in the study of vaccines NSE were identified and discussed by the expert group., (Copyright © 2016.)

We systematically study how diverse physiologic systems in the human organism dynamically interact and collectively behave to produce distinct physiologic states and functions. This is a fundamental question in the new interdisciplinary field of Network Physiology, and has not been previously explored. Introducing the novel concept of Time Delay Stability (TDS), we develop a computational approach to identify and quantify networks of physiologic interactions from long-term continuous, multi-channel physiological recordings. We also develop a physiologically-motivated visualization framework to map networks of dynamical organ interactions to graphical objects encoded with information about the coupling strength of network links quantified using the TDS measure. Applying a system-wide integrative approach, we identify distinct patterns in the network structure of organ interactions, as well as the frequency bands through which these interactions are mediated. We establish first maps representing physiologic organ network interactions and discover basic rules underlying the complex hierarchical reorganization in physiologic networks with transitions across physiologic states. Our findings demonstrate a direct association between network topology and physiologic function, and provide new insights into understanding how health and distinct physiologic states emerge from networked interactions among nonlinear multi-component complex systems. The presented here investigations are initial steps in building a first atlas of dynamic interactions among organ systems.

Objective: To identify factors that influence the total and negative lymph node counts in colorectal cancer resection specimens independent of pathologists and surgeons., Design: We used multivariate negative binomial regression. Covariates included age, sex, body mass index, family history of colorectal carcinoma, year of diagnosis, hospital setting, tumor location, resected colorectal length (specimen length), tumor size, circumferential growth, TNM stage, lymphocytic reactions and other pathological features, and tumor molecular features (microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element 1 [LINE-1] methylation, and BRAF, KRAS, and PIK3CA mutations)., Setting: Two US nationwide prospective cohort studies., Patients: Patients with rectal and colon cancer (N=918)., Main Outcome Measures: The negative and total node counts (continuous)., Results: Specimen length, tumor size, ascending colon location, T3N0M0 stage, and year of diagnosis were positively associated with the negative node count (all P.002). Mutation of KRAS might also be positively associated with the negative node count (P=.03; borderline significance considering multiple hypothesis testing). Among node-negative (stages I and II) cases, specimen length, tumor size, and ascending colon location remained significantly associated with the node count (all P.002), and PIK3CA and KRAS mutations might also be positively associated (P=.03 and P=.049, respectively, with borderline significance)., Conclusions: This molecular pathological epidemiology study shows that specimen length, tumor size, tumor location, TNM stage, and year of diagnosis are operator-independent predictors of the lymph node count. These crucial variables should be examined in any future evaluation of the adequacy of lymph node harvest and nodal staging when devising individualized treatment plans for patients with colorectal cancer.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting the joint synovium. The normal synovium consists of a lining layer of fibroblast-like synoviocytes (FLS) and macrophages, one to three cells deep that overlies the loose connective tissue of the synovial sublining. During the course of RA, the synovium is the site of inflammation where immune cells are massively infiltrated, and the lining layer becomes hyperplastic and transforms into a pannus tissue that destroys articular cartilage and bone. FLS play an important role in this RA pathogenesis. In this review, we explain that cadherin-11, an adhesion molecule, is selectively expressed on FLS and required for synovial lining formation. In addition, cadherin-11 on FLS contributes to synovial inflammation and mediates cartilage degradation in a mouse model of inflammatory arthritis. Therefore, we suggest that FLS are critical regulators of synovial inflammation and arthritis pathology via mechanisms that are mediated by cadherin-11.

In the fifth and fourth centuries BC, ancient Greek medical practitioners began to use persuasive rhetoric in their practice of medicine. This paper will explore two areas related to rhetoric and medical instruction in ancient Greece--first, the nature of rhetorical instruction given to--or at least expected of--aspiring physicians and second, the effect of rhetoric on the public authority of the physician, as illuminated by the contrasting image of the physician in the Platonic corpus. The first section will examine the Hippocratic Corpus for basic elements of rhetoric with a view to the question: Did the increasing recognition of these techniques by the public actually harm the doctor's public image by creating 'the rhetoric of anti-rhetoric?' The second section focusing on Plato will serve as a contrast to the Hippocratic physician, since Plato purposefully avoids criticizing the medical use of rhetoric while strongly criticizing other uses of rhetoric.