Miracle-dz/UniFAR-FTUs huggingface dataset:
GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment

GCN2 is a key driver of Mϕ and MDSC polarization in the tumor microenvironment causing T cell exhaustion. Polarization Player Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) suppress T cell functions in the tumor microenvironment (TME). Halaby et al. examine how the serine-threonine kinase general control nonderepressible 2 (GCN2) is a critical driver of Mϕ and MDSC polarization in the TME. Myeloid-lineage deletion of GCN2 caused a shift in TAM and MDSC phenotypes toward increased antitumor responses within the TME due to proinflammatory responses and increased CD8+ T cell expression of IFN-γ. GCN2 was a critical driver of Mϕ polarization and immunosuppression within the TME by promoting translation of the CREB-2/ATF4 transcription factor. GCN2 activity negatively correlated with antitumor responses and overall survival in human melanoma, suggesting further study into therapeutic targeting of this gene. General control nonderepressible 2 (GCN2) is an environmental sensor controlling transcription and translation in response to nutrient availability. Although GCN2 is a putative therapeutic target for immuno-oncology, its role in shaping the immune response to tumors is poorly understood. Here, we used mass cytometry, transcriptomics, and transcription factor–binding analysis to determine the functional impact of GCN2 on the myeloid phenotype and immune responses in melanoma. We found that myeloid-lineage deletion of GCN2 drives a shift in the phenotype of tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs) that promotes antitumor immunity. Time-of-flight mass cytometry (CyTOF) and single-cell RNA sequencing showed that this was due to changes in the immune microenvironment with increased proinflammatory activation of macrophages and MDSCs and interferon-γ expression in intratumoral CD8+ T cells. Mechanistically, GCN2 altered myeloid function by promoting increased translation of the transcription factor CREB-2/ATF4, which was required for maturation and polarization of macrophages and MDSCs in both mice and humans, whereas targeting Atf4 by small interfering RNA knockdown reduced tumor growth. Last, analysis of patients with cutaneous melanoma showed that GCN2-dependent transcriptional signatures correlated with macrophage polarization, T cell infiltrates, and overall survival. Thus, these data reveal a previously unknown dependence of tumors on myeloid GCN2 signals for protection from immune attack.
DSM-5 Internet gaming disorder among a sample of Mexican first-year college students

Background and aims DSM-5 includes Internet gaming disorder (IGD) as a condition for further study. While online and offline gaming may produce undesired negative effects on players, we know little about the nosology of IGD and its prevalence, especially in countries with emerging economies. Methods A self-administered survey has been employed to estimate prevalence of DSM-5 IGD and study the structure and performance of an instrument in Spanish to measure DSM-5 IGD among 7,022 first-year students in 5 Mexican universities that participated in the University Project for Healthy Students (PUERTAS), part of the World Health Organization’s World Mental Health International College Student Initiative. Results The scale for IGD showed unidimensionality with factor loadings between 0.694 and 0.838 and a Cronbach’s α = . 816. Items derived from gaming and from substance disorders symptoms mixed together. We found a 12-month prevalence of IGD of 5.2% in the total sample; prevalence was different for males (10.2%) and females (1.2%), but similar for ages 18–19 years (5.0%) and age 20+ (5.8%) years. Among gamers, the prevalence was 8.6%. Students with IGD were more likely to report lifetime psychological or medical treatment [OR = 1.8 (1.4–2.4)] and any severe role impairment [OR = 2.4 (1.7–3.3)]. Adding any severe role impairment to the diagnostic criteria decreased the 12-month prevalence of IGD to 0.7%. Discussion and conclusions Prevalence of DSM-5 IGD and the performance of diagnostic criteria in this Mexican sample were within the bounds of what is reported elsewhere. Importantly, about one in every seven students with IGD showed levels of impairment that would qualify them for treatment under DSM-5.
Clinical characteristics of late-life depression predicting mortality

Abstract Objective Depression has been associated with increased mortality rates, and modifying mechanisms have not yet been elucidated. We examined whether specific subtypes or characteristics of late-life depression predict mortality. Methods A cohort study including 378 depressed older patients according to DSM-IV criteria and 132 never depressed comparisons. The predictive value of depression subtypes and characteristics on the six-year mortality rate, as well as their interaction with somatic disease burden and antidepressant drug use, were studied by Cox proportional hazard analysis adjusted for demographic and lifestyle characteristics. Results Depressed persons had a higher mortality risk than non-depressed comparisons (HR = 2.95 [95% CI: 1.41–6.16], p = .004), which lost significance after adjustment for age, sex, education, smoking, alcohol, physical activity, number of prescribed medications and somatic comorbidity. Regarding depression subtypes and characteristics, only minor depression was associated with a higher mortality risk when adjusted for confounders (HR = 6.59 [95% CI: 1.79–24.2], p = .005). Conclusions Increased mortality rates of depressed older persons seem best explained by unhealthy lifestyle characteristics and multiple drug prescriptions. The high mortality rate in minor depression, independent of these factors, might point to another, yet unknown, pathway towards mortality for this depression subtype. An explanation might be that minor depression in later life reflects depressive symptoms due to underlying aging-related processes, such as inflammation-based sickness behavior, frailty, and mild cognitive impairment, which have all been associated with increased mortality.
Amnestic mild cognitive impairment in Parkinson’s disease: White matter structural changes and mechanisms

Mild cognitive impairment (MCI) is a heterogeneous cognitive disorder that is often comorbid with Parkinson’s diseases (PD). The amnestic subtype of PD-MCI (PD-aMCI) has a higher risk to develop dementia. However, there is a lack of studies on the white matter (WM) structural changes of PD-aMCI. We characterized the WM structural changes of PD-aMCI (n = 17) with cognitively normal PD (PD-CN, n = 19) and normal controls (n = 20), using voxel-based and tract-based spatial statistics (TBSS) analyses on fractional anisotropy (FA) axial diffusivity (AD), and radial diffusivity (RD). By excluding and then including the motor performance as a covariate in the comparison analysis between PD-aMCI and PD-CN, we attempted to discern the influences of two neuropathological mechanisms on the WM structural changes of PD-aMCI. The correlation analyses between memory and voxel-based WM measures in all PD patients were also performed (n = 36). The results showed that PD-aMCI had smaller FA values than PD-CN in the diffuse WM areas, and PD-CN had higher AD and RD values than normal controls in the right caudate. Most FA difference between PD-aMCI and PD-CN could be weakened by the motor adjustment. The FA differences between PD-aMCI and PD-CN were largely spatially overlapped with the memory-correlated FA values. Our findings demonstrated that the WM structural differences between PD-aMCI and PD-CN were mainly memory-related, and the influence of motor adjustment might indicate a common mechanism underlying both motor and memory impairment in PD-aMCI, possibly reflecting a predominant influence of dopaminergic neuropathology.
Clinicians’ Perspectives on the Duty to Inform Patients About Medical Aid-in-Dying

Abstract Background: As of 2019, ten jurisdictions in the United States have authorized physicians to prescribe a lethal dose of medication to a terminally ill patient for the purpose of hastening death. Relatively little bioethics scholarship has addressed the question of whether physicians have an obligation to inform qualifying patients about aid-in-dying (AID) in permissive jurisdictions and little is known about providers’ actual communication practices with respect to this issue. Methods: One hundred and forty-four in-depth, semi-structured interviews were conducted and analyzed using an inductive analytic approach as part of the Vermont Study on Aid-in-Dying. Results: Seventeen respondents, 14 physicians and 3 nurse practitioners, met the inclusion criteria for this sub-study. Eleven respondents indicated that they at least sometimes inform patients about AID. Respondents described multiple factors that influence whether or not they might initiate discussions of AID, including the importance of informing patients of their options for end-of-life care, worries about undue influence, and worries about the potential effects on the patient-provider relationship. For those providers who do initiate discussion of AID at least some of the time, attention to the particulars of each individual patient’s situation and the context of the discussion appear to play a role in shaping communication about AID. Conclusions: While initiating a clinical discussion of AID is undoubtedly challenging, our study provides compelling descriptive evidence that some medical providers who support AID do not unilaterally follow the conventional bioethics wisdom holding that they ought to wait for patients to introduce the topic of AID. Future research should investigate how to approach these discussions so as to minimize ethical worries about undue influence or potential negative consequences.
Association of Abnormal P‐Wave Indices With Dementia and Cognitive Decline Over 25 Years: ARIC‐NCS (The Atherosclerosis Risk in Communities Neurocognitive Study)

Background Abnormal P‐wave indices (PWIs)—reflecting underlying left atrial abnormality—are associated with increased risk of stroke independent of atrial fibrillation. We assessed whether abnormal PWIs are associated with incident dementia and greater cognitive decline, independent of atrial fibrillation and ischemic stroke. Methods and Results We included 13 714 participants (mean age, 57±6 years; 56% women; 23% black) who were followed for dementia through the end of 2015. (Abnormal P‐wave terminal force in lead V1, ≥4000 μV×ms), abnormal P‐wave axis (>75° or <0°), prolonged P‐wave duration (>120 ms), and advanced interatrial block were determined from ECGs at visits 2 to 4. Dementia was adjudicated by an expert panel using data from cognitive tests and hospitalization International Classification of Diseases codes. Cognitive function was measured longitudinally using 3 neuropsychological tests. Cox proportional hazards models were used to assess the association between time‐dependent abnormal PWIs with incident dementia. Linear regression models were used to evaluate PWIs with cognitive function over time. At the conclusion of the study, 19%, 16%, 28%, and 1.9% of participants had abnormal P‐wave terminal force in lead V1, abnormal P‐wave axis, prolonged P‐wave duration, and advanced interatrial block, respectively. During mean follow‐up of 18 years, there were 1390 (10%) dementia cases. All abnormal PWIs except advanced interatrial block were associated with an increased risk of dementia even after adjustment for incident atrial fibrillation and stroke: multivariable hazard ratio of abnormal P wave terminal force in lead V1=1.60, 95% CI, 1.41 to 2.83; abnormal P‐wave axis, hazard ratio =1.36, 95% CI, 1.17 to 2.57; prolonged P‐wave duration, hazard ratio=1.60, 95% CI, 1.42 to 1.80. Only abnormal P‐wave terminal force in lead V1 was associated with greater decline in global cognition. Conclusions Abnormal PWIs are independently associated with an increased risk of dementia. This novel finding should be replicated in other cohorts and the underlying mechanisms should be evaluated.
Unravelling the association between accelerometer‐derived physical activity and adiposity among preschool children: A systematic review and meta‐analyses

Evidence on the association between physical activity (PA) and adiposity in young children is inconclusive. A systematic review and meta‐analyses were conducted to examine associations between accelerometer‐derived PA and varying adiposity outcomes in preschool children. Searches were conducted in Embase, MEDLINE and Web of Science to identify studies on the association between total PA, sedentary behaviour or different PA intensities and adiposity in children aged 2 to 7 years. Separate random effects meta‐analyses were performed for varying PA intensities and adiposity outcomes. Fifty‐six articles were included in the review and 48 in the meta‐analyses. There was substantial evidence of an inverse association between moderate‐to‐vigorous‐ or vigorous PA and body fat percentage (stdβ [SE] = −0.162[0.041]; 5 studies), weight status (r = −0.120, P<.001; 11 studies), fat mass (stdβ [SE] = −0.103[0.051]; 5 studies), fat mass index (stdβ [SE] = −0.121[0.036]; 2 studies) and skinfold thickness (stdβ [SE] = −0.145[0.036]; 4 studies). However, total PA, sedentary behaviour, and different PA intensities were not associated with body mass index (BMI) or waist circumference. Adiposity levels were lower among preschool children engaged in more (moderate‐to‐) vigorous PA compared with their peers, but no associations between PA and BMI or waist circumference were found.
Perioperative, short-, and long-term mortality related to fixation in primary total hip arthroplasty: a study on 79,557 patients in the Norwegian Arthroplasty Register

Background and purpose — There are reports on perioperative deaths in cemented total hip arthroplasty (THA), and THA revisions are associated with increased mortality. We compared perioperative (intraoperatively or within 3 days of surgery), short-term and long-term mortality after all-cemented, all-uncemented, reverse hybrid (cemented cup and uncemented stem), and hybrid (uncemented cup and cemented stem) THAs. Patients and methods — We studied THA patients in the Norwegian Arthroplasty Register from 2005 to 2018, and performed Kaplan–Meier and Cox survival analyses with time of death as end-point. Mortality was calculated for all patients, and in 3 defined risk groups: high-risk patients (age ≥ 75 years and ASA > 2), intermediate-risk patients (age ≥ 75 years or ASA > 2), low-risk patients (age < 75 years and ASA ≤ 2). We also calculated mortality in patients with THA due to a hip fracture, and in patients with commonly used, contemporary, well-documented THAs. Adjustement was made for age, sex, ASA class, indication, and year of surgery. Results — Among the 79,557 included primary THA patients, 11,693 (15%) died after 5.8 (0–14) years’ follow-up. Perioperative deaths were rare (30/105) and found in all fixation groups. Perioperative mortality after THA was 4/105 in low-risk patients, 34/105 in intermediate-risk patients, and 190/105 in high-risk patients. High-risk patients had 9 (CI 1.3–58) times adjusted risk of perioperative death compared with low-risk patients. All 4 modes of fixation had similar adjusted 3-day, 30-day, 90-day, 3–30 day, 30–90 day, 90-day–10-year, and 10-year mortality risk. Interpretation — Perioperative, short-term, and long-term mortality after primary THA were similar, regardless of fixation type. Perioperative deaths were rare and associated with age and comorbidity, and not type of fixation.
Dark Triad Traits and Mate Retention Behaviors in Romantic Couples: The Actor–Partner Interdependence Model

By using actor–partner interdependence modeling (APIM), we examined the effects of the Dark Triad traits, psychopathy, narcissism, and Machiavellianism on two mate retention (MR) domains, cost-inflicting (C-I B) and benefit-provisioning behaviors (B-P B) as well as overall mate retention (OMR) on the sample of 100 heterosexual romantic couples. These effects were examined first without and then with the control of the overlap between the traits. The results show that actor effects of the Dark Triad traits on MR were stronger in men, and regarding partner effects, the Dark Triad traits in men exerted more frequent MR in women than women’s Dark Triad traits in men. In line with our prediction, psychopathy had the strongest actor and partner effects on MR behaviors, both in men and women. Considering MR domains, we found actor effects on C-I B only in men, whereas actor effects on B-P B in both men and women. The Dark Triad traits, especially in men, exerted stronger partner effects on C-I B than on B-P B domain. Almost all actor and partner effects of psychopathy and narcissism remained significant after the control for the overlap between the traits, whereas all actor effects of Machiavellianism became nonsignificant. In both sets of analyses, without and with the control for the overlap between these traits, the most frequent plausible dyadic patterns were actor-only and couple pattern.
Designing a New Multi-Epitope Pertussis Vaccine with Highly Population Coverage Based on a Novel Sequence and Structural Filtration Algorithm

Pertussis vaccine is produced from physicochemically inactivated toxin for many years. Recent advancements in immunoinformatics [N. Tomar and R. K. De, “Immunoinformatics: an integrated scenario,” Immunology, vol. 131, no. 2, pp. 153–168, 2010] and structural bioinformatics can provide a new multidisciplinary approach to overcome the concerns including unwanted antibodies and incomplete population coverage. In this study we focused on solving the challenging issues by designing a multi-epitope vaccine (MEV) using rational bioinformatics analyses. The frequencies of All HLA DP, DQ, and DR alleles were evaluated in almost all countries. Strong binder surface epitopes on the pertussis toxin were selected based on our novel filtration strategy. Finally, the population coverage of MEV was determined in the candidate country. Filtration steps yielded 312 strong binder epitopes. Finally, 8 surface strong binder epitopes were selected as candidate epitopes. The population coverage of the MEV in France and the world was 98 and 100 percent, respectively. Our algorithm successfully filtered many unwanted strong binder epitopes. Considering the HLA type of all individuals in a country, we theoretically provided the maximum chance to all humans to be vaccinated efficiently. Application of a MEV would be led to production of highly efficient target specific antibodies, significant reduction of unwanted antibodies, and avoid possible raising of auto-antibodies as well.
Effect of Blood Flow Restricted Resistance Exercise and Remote Ischemic Conditioning on Functional Capacity and Myocellular Adaptations in Patients With Heart Failure.

BACKGROUND Patients with congestive heart failure (CHF) have impaired functional capacity and inferior quality of life. The clinical manifestations are associated with structural and functional impairments in skeletal muscle, emphasizing a need for feasible rehabilitation strategies beyond optimal anticongestive medical treatment. We investigated whether low-load blood flow restricted resistance exercise (BFRRE) or remote ischemic conditioning (RIC) could improve functional capacity and quality of life in patients with CHF and stimulate skeletal muscle myofibrillar and mitochondrial adaptations. METHODS We randomized 36 patients with CHF to BFRRE, RIC, or nontreatment control. BFRRE and RIC were performed 3× per week for 6 weeks. Before and after intervention, muscle biopsies, tests of functional capacity, and quality of life assessments were performed. Deuterium oxide was administered throughout the intervention to measure cumulative RNA and subfraction protein synthesis. Changes in muscle fiber morphology and mitochondrial respiratory function were also assessed. RESULTS BFRRE improved 6-minute walk test by 39.0 m (CI, 7.0-71.1, P=0.019) compared with control. BFRRE increased maximum isometric strength by 29.7 Nm (CI, 10.8-48.6, P=0.003) compared with control. BFRRE improved quality of life by 5.4 points (CI, -0.04 to 10.9; P=0.052) compared with control. BFRRE increased mitochondrial function by 19.1 pmol/s per milligram (CI, 7.3-30.8; P=0.002) compared with control. RIC did not produce similar changes. CONCLUSIONS Our results demonstrate that BFRRE, but not RIC, improves functional capacity, quality of life, and muscle mitochondrial function. Our findings have clinical implications for rehabilitation of patients with CHF and provide new insights on the myopathy accompanying CHF. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials. gov. Unique identifier: NCT03380663.
Web Browsing Habits of Healthcare Professions Students in Gross Anatomy Laboratory

Personal computer use for educational purposes by the healthcare professions students has become ubiquitous. Although the effect of computer‐based dissection instructions has been studied, there is a paucity of information regarding student browsing habits of information available on the Internet. Although current students have favorable attitudes toward accessing anatomical information online, web browsing habits have not yet been investigated specifically in the dissection laboratory setting. The purpose of this study was to describe the browsing habits of the healthcare professions students in the gross anatomy setting using a retrospective analysis. Files containing web browser history were retrieved from desktop computers in the gross anatomy laboratory and custom code was written to parse them into comma separated value files. Each web address was categorized and descriptive statistics was calculated. Browser history for 24 computers was analyzed from June 2013 to January 2015. During this period, students accumulated 100,857 webpage visits. Most often, students performed a Google search for anatomy (22.0% of all visits) and non‐anatomy related (20.6% of all visits) information. Students also used the web browser to access various entertainment (16.4% of all visits) and productivity related services (15.9% of all visits). This analysis revealed a large volume of webpage visits by the healthcare professions students in the gross anatomy laboratory. A wide diversity of anatomy and non‐anatomy related webpages were visited. Future analyses could be directed at examination of when in relation to class time students accessed the information, how browsing habits change over time, and what anatomical structures were most commonly searched for.