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Stress-related psychiatric disorders and the stress system show prominent differences between males and females, as well as strongly divergent transcriptional changes. Despite several proposed mechanisms, we still lack the understanding of the molecular processes at play. Here, we explore the contribution of cell types to transcriptional sex dimorphism using single-cell RNA sequencing. We identify cell-type-specific signatures of acute restraint stress in the paraventricular nucleus of the hypothalamus, a central hub of the stress response, in male and female mice. Further, we show that a history of chronic mild stress alters these signatures in a sex-specific way, and we identify oligodendrocytes as a major target for these sex-specific effects. This dataset, which we provide as an online interactive app, offers the transcriptomes of thousands of individual cells as a molecular resource for an in-depth dissection of the interplay between cell types and sex on the mechanisms of the stress response., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Background: Exercise is a proven therapy for managing cardiometabolic risk factors in type 2 diabetes (T2D). However, its effects on patient-reported outcome measures such as quality of life (QoL) in people with T2D remain unclear. Consequently, the primary aim of this study was to determine the effect of regular exercise on QoL in adults with T2D. A secondary aim was to determine the effect of different exercise modalities on QoL. The third aim was to determine whether improvements in QoL were associated with improvements in gly'cated hemoglobin (A1C)., Methods: Relevant databases were searched to May 2022. Eligible studies included randomized trials involving ≥2 wk of aerobic and/or resistance exercise and assessed QoL using a purpose-specific tool. Mean differences and 95% confidence intervals (CI) were calculated as standardized mean difference (SMD) or weighted mean difference. A regression analysis was undertaken to examine the interaction between change in QoL with change in A1C., Results: Of the 12,642 studies retrieved, 29 were included involving 2354 participants. Exercise improved QoL when compared with control (SMD, 0.384; 95% CI, 0.257 to 0.512; P < 0.001). Aerobic exercise, alone (SMD, 0.475; 95% CI, 0.295 to 0.655; P < 0.001) or in combination with resistance training (SMD, 0.363; 95% CI, 0.179 to 0.548; P < 0.001) improved QoL, whereas resistance training alone did not. Physical components of health-related QoL (HRQoL) improved with all exercise modalities, but mental components of HRQoL remained unchanged. Exercise improved A1C (mean difference, -0.509%; 95% CI, -0.806% to -0.212%; P = 0.001), and this change was associated with improvements in HRQoL ( β = -0.305, SE = 0.140, Z = -2.18, P = 0.030)., Conclusions: These results provide robust evidence that regular aerobic exercise alone or in combination with resistance training is effective for improving QoL in adults with T2D. Such improvements seem to be mediated by improvements in physical components of HRQoL and are associated with improved blood glucose control. Further studies should be undertaken to determine the relative importance of exercise duration, intensity, and frequency on patient-reported outcomes such as QoL., (Copyright © 2023 by the American College of Sports Medicine.)

Pharmacotherapies for the treatment of major depressive disorder were serendipitously discovered almost seven decades ago. From this discovery, scientists pinpointed the monoaminergic system as the primary target associated with symptom alleviation. As a result, most antidepressants have been engineered to act on the monoaminergic system more selectively, primarily on serotonin, in an effort to increase treatment response and reduce unfavorable side effects. However, slow and inconsistent clinical responses continue to be observed with these available treatments. Recent findings point to the glutamatergic system as a target for rapid acting antidepressants. Investigating different cohorts of depressed individuals treated with serotonergic and other monoaminergic antidepressants, we found that the expression of a small nucleolar RNA, SNORD90 , was elevated following treatment response. When we increased Snord90 levels in the mouse anterior cingulate cortex (ACC), a brain region regulating mood responses, we observed antidepressive-like behaviors. We identified neuregulin 3 ( NRG3 ) as one of the targets of SNORD90 , which we show is regulated through the accumulation of N 6 -methyladenosine modifications leading to YTHDF2-mediated RNA decay. We further demonstrate that a decrease in NRG3 expression resulted in increased glutamatergic release in the mouse ACC. These findings support a molecular link between monoaminergic antidepressant treatment and glutamatergic neurotransmission., Competing Interests: RL, AK, JL, JD, LF, JY, YB, ZA, PI, HM, TW, EI, CB, PB, FF, BF, RM, DM, SP, CS, RU, CN, NM, SK, AC, GT No competing interests declared, RL RM has received consulting and speaking honoraria from AbbVie, Allergan, Eisai, Janssen, KYE, Lallemand, Lundbeck, Neomind, Otsuka, and Sunovion, and research grants from CAN-BIND, CIHR, Janssen, Lallemand, Lundbeck, Nubiyota, OBI and OMHF, JF JAF has received consulting and speaking fees from Takeda and RBH, and research funding from NSERC, CIHR, and OBI, (© 2023, Lin, Kos et al.)

The consumption of artificially sweetened beverages (ASBs) is increasing in some countries. However, some meta-analyses have found that habitual consumers of ASBs (compared with low or no consumption) had an increased risk on some health outcomes. We performed an umbrella review of meta-analyses to grade the credibility of the evidence of claimed observational associations between ASBs and health outcomes. Data were searched in Web of Science, Embase, and PubMed for systematic reviews published up to 25 May 2022, examining association between ASBs and any health outcomes. Certainty of the evidence for each health outcome was obtained based on statistical results of tests used in umbrella reviews. The AMSTAR-2 tool (16 items) was used to identify high-quality systematic reviews. Answers of each item were rated as yes, no, or partial yes (for a partial adherence to the standard). We included data from 11 meta-analyses with unique population, exposure, comparison group, outcome obtained from 7 systematic reviews (51 cohort studies and 4 case-control studies). ASBs were associated with higher risk of obesity, type 2 diabetes, all-cause mortality, hypertension, and cardiovascular disease incidence (supported by highly suggestive evidence). Evidence for other outcomes (colorectal cancer, pancreatic cancer, gastrointestinal cancer, cancer mortality, cardiovascular mortality, chronic kidney disease, coronary artery disease, and stroke) was weak. Results of the quality assessment of systematic reviews using AMSTAR-2 showed some notable deficiencies: unclear sources of funding of eligible studies and lack of predefined study protocols to guide authors. The consumption of ASBs was associated with a higher risk of obesity, type 2 diabetes, all-cause mortality, hypertension, and cardiovascular disease incidence. However, further cohort studies and clinical trials in humans are still needed to understand the impact of ASBs on health outcomes., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Mental health disorders often arise as a combination of environmental and genetic factors. The FKBP5 gene, encoding the GR co-chaperone FKBP51, has been uncovered as a key genetic risk factor for stress-related illness. However, the exact cell type and region-specific mechanisms by which FKBP51 contributes to stress resilience or susceptibility processes remain to be unravelled. FKBP51 functionality is known to interact with the environmental risk factors age and sex, but so far data on behavioral, structural, and molecular consequences of these interactions are still largely unknown. Here we report the cell type- and sex-specific contribution of FKBP51 to stress susceptibility and resilience mechanisms under the high-risk environmental conditions of an older age, by using two conditional knockout models within glutamatergic ( Fkbp5 Nex ) and GABAergic ( Fkbp5 Dlx ) neurons of the forebrain. Specific manipulation of Fkbp51 in these two cell types led to opposing effects on behavior, brain structure and gene expression profiles in a highly sex-dependent fashion. The results emphasize the role of FKBP51 as a key player in stress-related illness and the need for more targeted and sex-specific treatment strategies.

Cardiovascular diseases (CVDs) remain the leading cause of worldwide death, accounting for significant morbidity, mortality, disability, and reduced quality of life. The global prevalence of cardiovascular (CV) risk factors, such as type 2 diabetes mellitus, hypertension, dyslipidemia, and obesity, has grown exponentially in the last decades, particularly in low-medium income countries, and it's projected to increase rapidly in the coming years as the population progressively ages, leading to increased cardiovascular disease (CVD) and associated mortality. In fact, data from the global burden of disease study shows that CV mortality, associated disability-adjusted life years (DALYs), and years of life lost (YLL) have increased steadily, nearly doubling from 1990 to 2019. Recent evidence proves the existence of an inverse association between hand grip strength (HGS), as a proxy for global muscle strength, with all-cause mortality, CV mortality, and the development of several chronic diseases. These associations have been demonstrated recurringly across the entire lifespan, beginning in childhood, and carrying on throughout adult life. Mounting evidence strongly indicates that HGS is an early predictor of chronic disease in premorbid populations and a therapeutic target for CVD prevention. Recent clinical trials have consistently shown that resistance exercise, which increases strength and potentially muscle mass, significantly improves the control of known CVD risk factors, reduces the risk of all-cause death and cardiovascular mortality. In this review, we explore the latest evidence regarding the association between low muscle strength and diverse metabolic alterations, along with the interventions that could improve cardiometabolic risk factors, while simultaneously increasing muscle fitness., (Copyright © 2022 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.)

Isometric handgrip or (wall) squat exercise performed three times per week produces reductions in systolic blood pressure (SBP) in adults with hypertension. We aimed to compare these interventions and the potential to retain benefits with one exercise session per week. We compared blood pressure changes following handgrip and squat isometric training interventions with controls in a randomized controlled multicentre trial in 77 unmedicated hypertensive (SBP ≥ 130 mmHg) adults. Exercise sessions were performed in the workplace and consisted of four repetitions-three sessions per week for the first 12 weeks (phase 1), and one session per week for the subsequent 12 weeks (phase 2). Office blood pressure (BP) was measured at baseline, post-phase 1 and post-phase 2. Post-phase 1, mean reductions in SBP were significantly greater in handgrip (-11.2 mmHg, n = 28) and squat (-12.9 mmHg, n = 27) groups than in controls (-.4 mmHg; n = 22) but changes in DBP were not. There were no significant within-group changes during phase 2 but SBP was 3.8 mmHg lower in the wall squat than the handgrip group-a small magnitude but clinically important difference. While both interventions produced significant SBP reductions, the wall squat appears to be more effective in maintaining benefits with a minimal training dose. The low time investment to achieve and retain clinically significant SBP reductions-42 and 12 min, respectively-and minimal cost, particularly of the wall squat, make it a promising intervention for delivery in public health settings., (© 2023 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Diabetic nephropathy is the primary cause of morbidity in type 2 diabetes mellitus (T2DM) patients. New data indicate that hypertension, a common comorbidity in T2DM, can worsen outcomes of diabetic nephropathy. While metformin is a commonly prescribed drug for treating type 2 diabetes, its blood pressure regulating ability is not well documented. The aim of this study was to investigate the effect of metformin on normalizing blood pressure in salt-loaded hypertensive diabetic db/db mice. Sixteen-week-old male and female diabetic db/db mice were individually placed in metabolic cages and then randomized to a control vehicle (saline) or metformin treatment group. We evaluated the blood pressure reducing ability of metformin in salt-induced hypertension and progression of nephropathy in db/db mice. We observed that metformin- normalized systolic blood pressure in hypertensive diabetic mice. Mechanistically, metformin treatment reduced renal cathepsin B expression. Low cathepsin B expression was associated with reduced expression and activity of the epithelial sodium channel (ENaC), sodium retention, and thus control of hypertension. In addition, we identified that urinary extracellular vesicles (EVs) from the diabetic mice are enriched in cathepsin B. Compared to treatment with urinary EVs of vehicle-treated hypertensive diabetic mice, the amiloride-sensitive transepithelial current was significantly attenuated upon exposure of renal collecting duct cells to urinary EVs isolated from metformin-treated db/db mice or cathepsin B knockout mice. Collectively, our study identifies a novel blood pressure reducing role of metformin in diabetic nephropathy by regulating the cathepsin B-ENaC axis.

Stress can have severe psychological and physiological consequences. Thus, inappropriate regulation of the stress response is linked to the etiology of mood and anxiety disorders. The generation and implementation of preclinical animal models represent valuable tools to explore and characterize the mechanisms underlying the pathophysiology of stress-related psychiatric disorders and the development of novel pharmacological strategies. In this commentary, we discuss the strengths and limitations of state-of-the-art molecular and computational advances employed in stress neurobiology research, with a focus on the ever-increasing spatiotemporal resolution in cell biology and behavioral science. Finally, we share our perspective on future directions in the fields of preclinical and human stress research.

Background: The calcium-sensing receptor (CaSR) in the distal convoluted tubule (DCT) activates the NaCl cotransporter (NCC). Glucose acts as a positive allosteric modulator of the CaSR. Under physiologic conditions, no glucose is delivered to the DCT, and fructose delivery depends on consumption. We hypothesized that glucose/fructose delivery to the DCT modulates the CaSR in a positive allosteric way, activating the WNK4-SPAK-NCC pathway and thus increasing salt retention., Methods: We evaluated the effect of glucose/fructose arrival to the distal nephron on the CaSR-WNK4-SPAK-NCC pathway using HEK-293 cells, C57BL/6 and WNK4-knockout mice, ex vivo perfused kidneys, and healthy humans., Results: HEK-293 cells exposed to glucose/fructose increased SPAK phosphorylation in a WNK4- and CaSR-dependent manner. C57BL/6 mice exposed to fructose or a single dose of dapagliflozin to induce transient glycosuria showed increased activity of the WNK4-SPAK-NCC pathway. The calcilytic NPS2143 ameliorated this effect, which was not observed in WNK4-KO mice. C57BL/6 mice treated with fructose or dapagliflozin showed markedly increased natriuresis after thiazide challenge. Ex vivo rat kidney perfused with glucose above the physiologic threshold levels for proximal reabsorption showed increased NCC and SPAK phosphorylation. NPS2143 prevented this effect. In healthy volunteers, cinacalcet administration, fructose intake, or a single dose of dapagliflozin increased SPAK and NCC phosphorylation in urinary extracellular vesicles., Conclusions: Glycosuria or fructosuria was associated with increased NCC, SPAK, and WNK4 phosphorylation in a CaSR-dependent manner., (Copyright © 2022 by the American Society of Nephrology.)

Hypertension remains a major problem, especially in the elderly, as it increases the risk for cardiovascular, coronary artery, cerebrovascular, and kidney diseases. Extracellular vesicles (EVs) play a role in the aging process and contribute to pathophysiology. Our goal was to examine differences in lipid profiles of urinary EVs (uEVs) collected during the inactive and active phases of aged mice and investigate whether these EVs regulate the density of lipid rafts in mouse cortical collecting duct (mpkCCD) principal cells. Here, we demonstrate the epithelial sodium channel (ENaC) inhibitor benzyl amiloride reduced systolic blood pressure in aged male mice during the inactive and active phases. Lipidomics data demonstrate differential enrichment of lipids between the two groups. For example, there are more phosphatidylethanolamine plasmalogens, particularly in the form of alkyl phosphatidylethanolamines, that are enriched in active phase uEVs compared to inactive phase uEVs from the same mice. Amiloride-sensitive transepithelial current increased more in mpkCCD cells challenged with uEVs from the active phase group. Moreover, more ENaC alpha protein was distributed to lipid raft fractions of mpkCCD cells challenged with active phase uEVs. Taken together, the identification of bioactive lipids associated with lipid rafts that are enriched in EVs released during the active phase of aged mice may offer clues to help understand lipid raft organization in recipient principal cells after EV uptake and increased renal ENaC activity, leading to a time-of-day dependent regulation of blood pressure in an aging model.

Purpose of Review: The aim of this manuscript was to review recent evidence uncovering the roles of the With No lysine (K) kinase 1 (WNK1) in the kidney., Recent Findings: Analyses of microdissected mouse nephron segments have revealed the abundance of long-WNK1 and kidney-specific-WNK1 transcripts in different segments. The low levels of L-WNK1 transcripts in the distal convoluted tubule (DCT) stand out and support functional evidence on the lack of L-WNK1 activity in this segment. The recent description of familial hyperkalaemic hypertension (FHHt)-causative mutations affecting the acidic domain of WNK1 supports the notion that KS-WNK1 activates the Na+:Cl- cotransporter NCC. The high sensitivity of KS-WNK1 to KLHL3-targeted degradation and the low levels of L-WNK1 in the DCT, led to propose that this type of FHHt is mainly due to increased KS-WNK1 protein in the DCT. The observation that KS-WNK1 renal protein expression is induced by low K+ diet and recent reassessment of the phenotype of KS-WNK1-/- mice suggested that KS-WNK1 may be necessary to achieve maximal NCC activation under this condition. Evidences on the regulation of other renal transport proteins by WNK1 are also summarized., Summary: The diversity of WNK1 transcripts in the kidney has complicated the interpretation of experimental data. Integration of experimental data with the knowledge of isoform abundance in renal cell types is necessary in future studies about WNK1 function in the kidney., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The 2018 physical activity guidelines for Americans recommend a minimum of 150 to 300 min/wk of moderate physical activity (MPA), 75 to 150 min/wk of vigorous physical activity (VPA), or an equivalent combination of both. However, it remains unclear whether higher levels of long-term VPA and MPA are, independently and jointly, associated with lower mortality., Methods: A total of 116 221 adults from 2 large prospective US cohorts (Nurses' Health Study and Health Professionals Follow-up Study, 1988-2018) were analyzed. Detailed self-reported leisure-time physical activity was assessed with a validated questionnaire, repeated up to 15 times during the follow-up. Cox regression was used to estimate the hazard ratio and 95% CI of the association between long-term leisure-time physical activity intensity and all-cause and cause-specific mortality., Results: During 30 years of follow-up, we identified 47 596 deaths. In analyses mutually adjusted for MPA and VPA, hazard ratios comparing individuals meeting the long-term leisure-time VPA guideline (75-149 min/wk) versus no VPA were 0.81 (95% CI, 0.76-0.87) for all-cause mortality, 0.69 (95% CI, 0.60-0.78) for cardiovascular disease (CVD) mortality, and 0.85 (95% CI, 0.79-0.92) for non-CVD mortality. Meeting the long-term leisure-time MPA guideline (150-299 min/wk) was similarly associated with lower mortality: 19% to 25% lower risk of all-cause, CVD, and non-CVD mortality. Compared with those meeting the long-term leisure-time physical activity guidelines, participants who reported 2 to 4 times above the recommended minimum of long-term leisure-time VPA (150-299 min/wk) or MPA (300-599 min/wk) showed 2% to 4% and 3% to 13% lower mortality, respectively. Higher levels of either long-term leisure-time VPA (≥300 min/wk) or MPA (≥600 min/wk) did not clearly show further lower all-cause, CVD, and non-CVD mortality or harm. In joint analyses, for individuals who reported <300 min/wk of long-term leisure-time MPA, additional leisure-time VPA was associated with lower mortality; however, among those who reported ≥300 min/wk of long-term leisure-time MPA, additional leisure-time VPA did not appear to be associated with lower mortality beyond MPA., Conclusions: The nearly maximum association with lower mortality was achieved by performing ≈150 to 300 min/wk of long-term leisure-time VPA, 300 to 600 min/wk of long-term leisure-time MPA, or an equivalent combination of both.

Aims: In a multinational South American cohort, we examined variations in CVD incidence and mortality rates between subpopulations stratified by country, by sex and by urban or rural location. We also examined the contributions of 12 modifiable risk factors to CVD development and to death., Methods and Results: This prospective cohort study included 24 718 participants from 51 urban and 49 rural communities in Argentina, Brazil, Chile, and Colombia. The mean follow-up was 10.3 years. The incidence of CVD and mortality rates were calculated for the overall cohort and in subpopulations. Hazard ratios and population attributable fractions (PAFs) for CVD and for death were examined for 12 common modifiable risk factors, grouped as metabolic (hypertension, diabetes, abdominal obesity, and high non-HDL cholesterol), behavioural (tobacco, alcohol, diet quality, and physical activity), and others (education, household air pollution, strength, and depression). Leading causes of death were CVD (31.1%), cancer (30.6%), and respiratory diseases (8.6%). The incidence of CVD (per 1000 person-years) only modestly varied between countries, with the highest incidence in Brazil (3.86) and the lowest in Argentina (3.07). There was a greater variation in mortality rates (per 1000 person-years) between countries, with the highest in Argentina (5.98) and the lowest in Chile (4.07). Men had a higher incidence of CVD (4.48 vs. 2.60 per 1000 person-years) and a higher mortality rate (6.33 vs. 3.96 per 1000 person-years) compared with women. Deaths were higher in rural compared to urban areas. Approximately 72% of the PAF for CVD and 69% of the PAF for deaths were attributable to 12 modifiable risk factors. For CVD, largest PAFs were due to hypertension (18.7%), abdominal obesity (15.4%), tobacco use (13.5%), low strength (5.6%), and diabetes (5.3%). For death, the largest PAFs were from tobacco use (14.4%), hypertension (12.0%), low education (10.5%), abdominal obesity (9.7%), and diabetes (5.5%)., Conclusions: Cardiovascular disease, cancer, and respiratory diseases account for over two-thirds of deaths in South America. Men have consistently higher CVD and mortality rates than women. A large proportion of CVD and premature deaths could be averted by controlling metabolic risk factors and tobacco use, which are common leading risk factors for both outcomes in the region., Competing Interests: Conflict of interest: The authors report research funding related to the PURE study, which is summarized in the Funding section. A.A. reports speaking fees and is an advisory board member for Novartis pharmaceuticals. No additional disclosures are reported by the authors., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Nonalcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver disease and is closely associated with cardiometabolic disorders, being insulin resistance (IR) the common pathogenic mechanism. The triglycerides/glucose (TyG) index and triglycerides/HDL-c (TG/HDL) ratio are markers correlated with IR. We compared the capacity of these two indexes, alongside IR, to detect NAFLD., Methods: In a cross-sectional cohort study, we examined 263 active military personnel from the Colombian Air Force, aged between 29 and 54 years. Anthropometric measurements and biochemical determinations (glycemia, lipid profile, and insulin) were obtained, and ultrasound studies were performed to evaluate the presence of NAFLD. HOMA-IR index was calculated as (fasting insulin ( µ IU/mL) × fasting glucose (mmol/L)/22.5), the TyG index as Ln (triglycerides (mg/dL) × fasting glucose (mg/dL)/2), and the TG/HDL ratio as (triglycerides (mg/dL)/HDL-c (mg/dL))., Results: NAFLD ultrasound criteria were met in 70 individuals (26.6%). Subjects with NAFLD had significantly higher values of HOMA-IR (2.55 ± 1.36 vs. 1.51 ± 0.91), TyG (9.17 ± 0.53 vs. 8.7 ± 0.51), and TG/HDL (6.6 ± 4.54 vs. 3.52 ± 2.32) compared to those without NAFLD ( p < 0.001). A TyG cutoff point of 8.92 showed an AUC of 0.731, while cutoff points of 3.83 for TG/HDL and 1.68 for HOMA-IR showed an AUC of 0.766 and 0.781, respectively., Conclusion: Our study shows that novel and lower-cost markers of IR are useful for detecting NALFD, with a performance comparable to the HOMA-IR index. These markers should be used as the first step when screening patients for NAFLD., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Maritza Pérez-Mayorga et al.)

Cardiovascular disease is the leading cause of death globally, accounting for approximately 32% of all deaths in 2019. There has been increasing interest in understanding the role of low muscular strength as a risk factor for cardiovascular disease, given its association with other cardiovascular risk factors such as hypertension, diabetes mellitus, and metabolic syndrome. An inverse association between muscle strength, chronic disease, all-cause mortality, and cardiovascular-related death has been reported. Recent clinical trials have consistently shown that resistance exercise, which increases strength, and potentially muscle mass, significantly improves the control of known cardiovascular disease risk factors and reduces the risk of all-cause death and cardiovascular mortality. In the present article, we review the growing body of evidence that supports the need for future research to evaluate the potential of handgrip strength as a screening tool for cardiovascular disease and its risk factors in the clinical medical setting, as part of routine care using an affordable handgrip strength device. Moreover, it is crucial to devise largescale interventions driven by governmental health policies to educate the general population and healthcare professionals about the importance of muscular strengthening activities and to promote access to these activities to improve cardiometabolic health and reduce incidence of cardiovascular disease and mortality.

A single sub-anesthetic dose of ketamine produces a rapid and sustained antidepressant response, yet the molecular mechanisms responsible for this remain unclear. Here, we identified cell-type-specific transcriptional signatures associated with a sustained ketamine response in mice. Most interestingly, we identified the Kcnq2 gene as an important downstream regulator of ketamine action in glutamatergic neurons of the ventral hippocampus. We validated these findings through a series of complementary molecular, electrophysiological, cellular, pharmacological, behavioral, and functional experiments. We demonstrated that adjunctive treatment with retigabine, a KCNQ activator, augments ketamine's antidepressant-like effects in mice. Intriguingly, these effects are ketamine specific, as they do not modulate a response to classical antidepressants, such as escitalopram. These findings significantly advance our understanding of the mechanisms underlying the sustained antidepressant effects of ketamine, with important clinical implications., Competing Interests: Declaration of interests A.C. and J.P.L. are named on a patent pending for the combined use of retigabine (ezogabine) and ketamine to amplify antidepressant effects to treat depression and related conditions. F.J.T. reports receiving consulting fees from Roche Diagnostics GmbH and Cellarity Inc. and ownership interest in Cellarity, Inc. and Dermagnostix. All other authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: A higher prevalence of hypertension is reported among Afro-descendants compared with other ethnic groups in high-income countries; however, there is a paucity of information in low- and medium-income countries., Methods: We evaluated 3,745 adults from 3 ethnic groups (552 White, 2,746 Mestizos, 447 Afro-descendants) enrolled in the prospective population-based cohort study (PURE)-Colombia. We assessed associations between anthropometric, socioeconomic, behavioral factors, and hypertension., Results: The overall prevalence of hypertension was 39.2% and was higher in Afro-descendants (46.3%) than in Mestizos (37.6%) and Whites (41.5%), differences that were due to the higher prevalence in Afro-descendant women. Hypertension was associated with older age, increased body mass index, waist circumference and waist-to-hip ratio, independent of ethnicity. Low education was associated with hypertension in all ethnic groups, and particularly in Afro-descendants, for whom it was the factor with the strongest association with prevalence. Notably, 70% of Afro-descendants had a low level of education, compared with 52% of Whites-26% of Whites were university graduates while only 7% of Afro-descendants were. We did not find that education level alone had a mediator effect, suggesting that it is not a causal risk factor for hypertension but is an indicator of socioeconomic status, itself an important determinant of hypertension prevalence., Conclusions: We found that a higher prevalence of hypertension in Colombian Afro-descendants than other ethnic groups. This was principally associated with their lower mean educational level, an indicator of lower socioeconomic status., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Plastic surgeons are often asked for intraoperative assistance by other surgical services. Improvement of a plastic surgery service has been shown to improve patient outcomes, decrease length of stay, and increase hospital revenue, yet plastic surgery's contribution to a hospital tends to be undervalued. The purpose of this study was to quantify the multidisciplinary role the plastic surgery service plays within a single, large pediatric institution., Methods: Surgical cases involving both plastic surgery and at least one other team were identified from 2016 to 2019. Each case was categorized as either "combined" or "collaborative" based on whether the two teams worked separately on separate problems or together on the same problem, respectively. Data points collected included combined and collaborative cases, operating room hours, and total hospital charges billed., Results: Of the 7564 total plastic surgery cases performed, multidisciplinary cases made up a minority of total cases (16 percent) but required 32 percent of the operating room hours and provided 49 percent of the total charges billed. Collaborative cases alone accounted for 20 percent of the service's operating room hours and 39 percent of total charges billed, while making up only 8 percent of total cases., Conclusions: Relative to cases where plastic surgery operates alone, combined and collaborative cases account for a disproportionately high number of operating room hours and provide a disproportionately high amount of charges billed., Competing Interests: Disclosure:The authors have no financial conflicts of interest to disclose., (Copyright © 2022 by the American Society of Plastic Surgeons.)

The prevalence of excess body weight (overweight plus obesity) in children has risen during the last decades in many countries, but it is unclear whether it has reached a plateau in Spanish children. We performed an updated systematic review and meta-analysis for the prevalence of excess body weight in children from Spain, comparing the trends between 1999 and 2010 and 2011 and 2021. Data were reported in a prior meta-analysis, plus an updated search using the Web of Science, MEDLINE (via PubMed) and EMBASE databases for data from January 2018 until December 2021. Thirteen representative studies were identified (34,813 children aged 2 to 13 years), with sample sizes averaging 2678 (range: 396-16,665). The prevalence of excess body weight in Spanish children aged 2 to 6 years increased from 23.3% (95% CI, 18.5% to 25.5%) during the period 1999-2010 to 39.9% (95% CI, 35.4% to 44.7%) during 2011-2021. In children aged 7 to 13 years, the prevalence of excess body weight increased from 32.3% (95% CI, 29.1-35.6%) during the period 1999-2010 to 35.3% (95% CI, 32.9-37.7%) during 2011-2021. The prevalence of childhood overweight and obesity in Spain has substantially increased in the last decade. New food policies to address the childhood obesity epidemic are urgently required to reverse current trends.

A comprehensive evaluation of the clear cell renal cell carcinoma (ccRCC) immune landscape was found using 584 RNA-sequencing datasets from The Cancer Genome Atlas (TCGA), we identified 17 key dysregulated immune-associated genes in ccRCC based on association with clinical variables and important immune pathways. Of the numerous findings from our analyses, we found that several of the 17 key dysregulated genes are heavily involved in interleukin and NF-kB signaling and that somatic copy number alteration (SCNA) hotspots may be causally associated with gene dysregulation. More importantly, we also found that key immune-associated genes and pathways are strongly upregulated in ccRCC. Our study may lend novel insights into the clinical implications of immune dysregulation in ccRCC and suggests potential immunotherapeutic targets for further evaluation., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Gene expression dysregulation in the brain has been associated with bipolar disorder, but little is known about the role of non-coding RNAs. Circular RNAs are a novel class of long noncoding RNAs that have recently been shown to be important in brain development and function. However, their potential role in psychiatric disorders, including bipolar disorder, has not been well investigated. In this study, we profiled circular RNAs in the brain tissue of individuals with bipolar disorder. Total RNA sequencing was initially performed in samples from the anterior cingulate cortex of a cohort comprised of individuals with bipolar disorder (N = 13) and neurotypical controls (N = 13) and circular RNAs were identified and analyzed using "circtools". Significant circular RNAs were validated by RT-qPCR and replicated in the anterior cingulate cortex in an independent cohort (24 bipolar disorder cases and 27 controls). In addition, we conducted in vitro studies using B-lymphoblastoid cells collected from bipolar cases (N = 19) and healthy controls (N = 12) to investigate how circular RNAs respond following lithium treatment. In the discovery RNA sequencing analysis, 26 circular RNAs were significantly differentially expressed between bipolar disorder cases and controls (FDR < 0.1). Of these, circCCNT2 was RT-qPCR validated showing significant upregulation in bipolar disorder (p = 0.03). This upregulation in bipolar disorder was replicated in an independent post-mortem human anterior cingulate cortex cohort and in B-lymphoblastoid cell culture. Furthermore, circCCNT2 expression was reduced in response to lithium treatment in vitro. Together, our study is the first to associate circCCNT2 to bipolar disorder and lithium treatment., (© 2021. The Author(s).)

Introduction: To present our novel low submuscular (LSM) pressure regulating balloon (PRB) placement for artificial urinary sphincter (AUS) technique as an alternative to standard approaches with patient-reported satisfaction outcomes., Material and Methods: A retrospective review was conducted on patients who underwent an AUS implantation using the LSM PRB placement with transfascial fixation technique from July 2019 to August 2020. Preoperative characteristics were collected. Patients then conducted a postoperative phone interview using an adapted questionnaire to assess satisfaction of device and PRB concealment., Results: During the study period, nine patients had undergone AUS placement using the LSM technique by a single surgeon at our private institution. Eight of the nine patients had undergone a radical prostatectomy while the ninth patient developed stress urinary incontinence after radiation treatment for prostate cancer. All patients were 'very satisfied' with PRB placement and concealment with no patients endorsing PRB complications. The majority of patients (78%) were satisfied with the device. One patient was able to palpate the PRB while another patient endorsed mild soreness around the PRB. No surgical revisions were required and there were no surgical complications such as bowel obstruction, herniations, bladder erosions, or vascular injuries., Conclusion: LSM placement of AUS PRB with transfascial fixation offers an improved technique for balloon placement with decreased risk for complications. This can be performed as a safe, alternative approach to current standard techniques with a high degree of patient satisfaction.

Hypertension (HT) is one of the main risk factors for cardiovascular disease (CVD). Although it is a global problem, independently of economic situation, region, race or culture, the data available on Latin America are limited. Clinical guidelines emphasise the importance of obtaining reliable blood pressure readings. For this reason, the use of ambulatory blood pressure monitoring (ABPM) is recommended. This improves precision and reproducibility, resulting in better diagnosing and therapeutic decision-making, and constitutes a better estimation of prognosis than office measurements. Unfortunately, there is no global prospective ABPM registry for all of Latin America that analyses HT prevalence, the level of knowledge about it, treatment percentage and the degree of control. Consequently, the authors of this article consider its implementation a priority., (Copyright © 2021 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.)

Lévy flight superdiffusion consists of random walks characterized by very long jumps that dominate the transport. However, the finite size of real samples introduces truncation of long jumps and modifies the transport properties. We measure typical Levy flight parameters for photon diffusion in atomic vapor characterized by a Voigt absorption profile. We observe the change of Lévy parameter as a function of truncation length. We associate this variation with size-dependent contributions from different spectral regions of the emission profile with the Doppler core dominating the transport for thin samples and Lorentz wings for thick samples. Monte Carlo simulations are implemented to support the interpretation of results.

Background: Diabetes accounted for approximately 10% of all-cause mortality among those 20-79 years of age worldwide in 2019. In 1986-1989, Hispanics in the United States of America (USA) represented 6.9% of the national population with diabetes, and this proportion increased to 15.1% in 2010-2014. Recently published findings demonstrated the impact of attained education on amenable mortality attributable to diabetes among Non-Hispanic Whites (NHWs) and Non-Hispanic Blacks (HNBs). Previous cohort studies have shown that low education is also a detrimental factor for diabetes mortality among the Hispanic population in the USA. However, the long-term impact of low education on diabetes mortality among Hispanics in the USA is yet to be determined., Aims and Methods: The aim of this study was to measure the impact of achieving a 12th-grade education on amenable mortality due to diabetes among Hispanics in the USA from 1989 to 2018. We used a time-series designed to analyze death certificate data of Hispanic-classified men and women, aged 25 to 74 years, whose underlying cause of death was diabetes, between 1989 and 2018. Death certificate data from the USA National Center for Health Statistics was downloaded, as well as USA population estimates by age, sex, and ethnicity from the USA Census Bureau. The analyses were undertaken using JointPoint software and the Age-Period-Cohort Web Tool, both developed by the USA National Cancer Institute., Results: The analyses showed that between 1989 to 2018, age- and sex-standardized diabetes mortality rates among the least educated individuals were higher than those among the most educated individuals (both sexes together, p = 0.036; males, p = 0.053; females, p = 0.036). The difference between the least and most educated individuals became more pronounced in recent years, as shown by independent confidence intervals across the study period. Sex-based analyses revealed that the age-adjUSAted diabetes mortality rate had increased to a greater extent among the least educated males and females, respectively, than among the most educated., Conclusions: The results of the analyses demonstrated a powerful effect of low education on amenable mortality attributable to diabetes among the Hispanic population in the USA. As an increasing prevalence of diabetes among the least educated Hispanics has been reported, there is a great need to identify and implement effective preventive services, self-management, and quality care practices, that may assist in reducing the growing disparity among those most vulnerable, such as minority populations.

Major depressive disorder (MDD) is a complex and debilitating illness whose etiology remains unclear. Small RNA molecules, such as micro RNAs (miRNAs) have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified miRNA expression by small RNA sequencing in the anterior cingulate cortex and habenula of individuals with MDD and psychiatrically-healthy controls. Thirty-two miRNAs showed significantly correlated expression between the two regions (False Discovery Rate < 0.05), of which four, miR-204-5p, miR-320b, miR-323a-3p, and miR-331-3p, displayed upregulated expression in MDD. We assessed the expression of predicted target genes of differentially expressed miRNAs in the brain, and found that the expression of erb-b2 receptor tyrosine kinase 4 (ERBB4), a gene encoding a neuregulin receptor, was downregulated in both regions, and was influenced by miR-323a-3p in vitro. Finally, we assessed the effects of manipulating miRNA expression in the mouse ACC on anxiety- and depressive-like behaviors. Mice in which miR-323-3p was overexpressed or knocked-down displayed increased and decreased emotionality, respectively. Additionally, these mice displayed significantly downregulated and upregulated expression of Erbb4, respectively. Overall, our findings indicate the importance of brain miRNAs in the pathology of MDD, and emphasize the involvement of miR-323a-3p and ERBB4 in this phenotype. Future studies further characterizing miR-323a-3p and neuregulin signaling in depression are warranted., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

High impulsive and aggressive traits associate with poor behavioural self-control. Despite their importance in predicting behavioural negative outcomes including suicide, the molecular mechanisms underlying the expression of impulsive and aggressive traits remain poorly understood. Here, we identified and characterized a novel long noncoding RNA (lncRNA), acting as a regulator of the monoamine oxidase A (MAOA) gene in the brain, and named it MAOA-associated lncRNA (MAALIN). Our results show that in the brain of suicide completers, MAALIN is regulated by a combination of epigenetic mechanisms including DNA methylation and chromatin modifications. Elevated MAALIN in the dentate gyrus of impulsive-aggressive suicides was associated with lower MAOA expression. Viral overexpression of MAALIN in neuroprogenitor cells decreased MAOA expression while CRISPR-mediated knock out resulted in elevated MAOA expression. Using viral-mediated gene transfer, we confirmed that MAALIN in the hippocampus significantly decreases MAOA expression and exacerbates the expression of impulsive-aggressive behavioural traits in CD1 aggressive mice. Overall, our findings suggest that variations in DNA methylation mediate the differential expression of a novel lncRNA that acts on MAOA expression to regulate impulsive-aggressive behaviours., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic, and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), the main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. We here demonstrate that the deletion of Fkbp5 in Sim1 + neurons dampens the acute stress response and increases GR sensitivity. In contrast, Fkbp5 overexpression in the PVN results in a chronic HPA axis over-activation, and a PVN-specific rescue of Fkbp5 expression in full Fkbp5 KO mice normalizes the HPA axis phenotype. Single-cell RNA sequencing revealed the cell-type-specific expression pattern of Fkbp5 in the PVN and showed that Fkbp5 expression is specifically upregulated in Crh + neurons after stress. Finally, Crh-specific Fkbp5 overexpression alters Crh neuron activity, but only partially recapitulates the PVN-specific Fkbp5 overexpression phenotype. Together, the data establish the central and cell-type-specific importance of Fkbp5 in the PVN in shaping HPA axis regulation and the acute stress response., (© 2021. The Author(s).)

Background: Physical activity has been associated with reduced risk of seven types of cancer. It remains unclear, however, whether muscle-strengthening activities also reduce cancer incidence and mortality., Methods: PubMed, Embase, Web of Science and Scopus were searched from inception to March 2020. Summary hazard ratio (HR) and 95% confidence intervals (CI) were estimated using random-effects models., Results: Twelve studies (11 cohorts; 1 case-control), 6 to 25 years of follow-up, including 1,297,620 participants, 32,196 cases and 31,939 deaths, met inclusion criteria. Muscle-strengthening activities were associated with a 26% lower incidence of kidney cancer (HR for high vs low levels of muscle-strengthening activities: 0.74; 95% CI 0.56 to 0.98; I 2 0%; 2 studies), but not with incidence of other 12 types of cancer. Muscle-strengthening activities were associated with lower total cancer mortality: HRs for high vs low levels of muscle-strengthening activities was 0.87 (95% CI 0.73 to 1.02; I 2 58%; 6 studies); and HR for ≥2 times/week vs < 2 times/week of muscle-strengthening activities was 0.81 (95% CI 0.74 to 0.87; I 2 0%; 4 studies). Regarding the weekly duration of muscle-strengthening activities, HR for total cancer mortality were 0.91 (95% CI 0.82 to 1.01; I 2 0%; 2 studies) for 1-59 min/week and 0.98 (95% CI 0.89 to 1.07; I 2 0%) for ≥60 min/week vs none. Combined muscle-strengthening and aerobic activities (vs none) were associated with a 28% lower total cancer mortality (HR 0.72; 95% CI 0.53 to 0.98; I 2 85%; 3 studies)., Conclusions: Muscle-strengthening activities were associated with reduced incidence of kidney cancer and total cancer mortality. Combined muscle-strengthening and aerobic activities may provide a greater reduction in total cancer mortality.

Hypertension awareness and control is poor in low- and middle-income countries. Thus, implementing strategies to increase hypertension detection is needed. Colombia participated as one of the 92 countries involved in the third campaign of the May Measurement Month in 2019. Blood pressure (BP) was measured in 48 324 volunteers from 13 departments in Colombia. In total, 27.9% individuals were identified with hypertension. Of those with hypertension, 63.7% were aware of their condition, 60.0% were on antihypertensive medication, and 38.4% had controlled BP. These results showed low levels of awareness, treatment, and control of hypertension in this sample of subjects volunteered to participate, suggest the urgent necessity of implementing programmes to improve the diagnosis and management of hypertension in Colombia., (Published on behalf of the European Society of Cardiology. © The Author(s) 2021.)

As one of the neglected diseases, rabies is as a highly fatal viral infection, most prevalent in low- and middle-income regions, which produces a substantial health and economic burden. It mainly affects the central nervous system causing encephalitis, however extraneuronal involvement has been documented. Cardiac structures may be involved and can play a role in the severity of the disease. Most of the existing literature comes from case reports and case series where cardiac involvement results in myocarditis and cardiac arrhythmias. As part of the "Neglected Tropical Diseases and Other Infectious Diseases Involving the Heart" (NET-HEART Project), the objective of this article is to review all the information available on the cardiac involvement of this disease., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright 2021, Alexander et al.)

Background: Adiposity is a major component of the metabolic syndrome (MetS), low muscle strength has also been identified as a risk factor for MetS and for cardiovascular disease. We describe the prevalence of MetS and evaluate the relationship between muscle strength, anthropometric measures of adiposity, and associations with the cluster of the components of MetS, in a middle-income country., Methods: MetS was defined by the International Diabetes Federation criteria. To assess the association between anthropometric variables (waist circumference (WC), waist-to-hip ratio (W/H), body mass index (BMI)), strength (handgrip/kg bodyweight (HGS/BW)) and the cluster of MetS, we created a MetS score. For each alteration (high triglycerides, low HDLc, dysglycemia, or high blood pressure) one point was conferred. To evaluate the association an index of fat:muscle and MetS score, participants were divided into 9 groups based on combinations of sex-specific tertiles of WC and HGS/BW., Results: The overall prevalence of MetS in the 5,026 participants (64% women; mean age 51.2 years) was 42%. Lower HGS/BW, and higher WC, BMI, and W/H were associated with a higher MetS score. Amongst the 9 HGS/BW:WC groups, participants in the lowest tertile of HGS/BW and the highest tertile of WC had a higher MetS score (OR = 4.69 in women and OR = 8.25 in men;p < 0.01) compared to those in the highest tertile of HGS/BW and in the lowest tertile of WC., Conclusion: WC was the principal risk factor for a high MetS score and an inverse association between HGS/BW and MetS score was found. Combining these anthropometric measures improved the prediction of metabolic alterations over either alone.

Importance: It is unclear whether, for the same amount of total physical activity, a higher proportion of vigorous physical activity (VPA) to total physical activity is associated with a greater reduction in mortality., Objective: To examine the association of the proportion of VPA to total physical activity (defined as moderate to vigorous physical activity [MVPA]) with all-cause mortality, cardiovascular disease mortality, and cancer mortality., Design, Setting, and Participants: This cohort study included 403 681 adults from the National Health Interview Survey 1997-2013 who provided data on self-reported physical activity and were linked to the National Death Index records through December 31, 2015. Statistical analysis was performed from May 15, 2018, to August 15, 2020., Exposures: Proportion of VPA to total physical activity among participants performing any MVPA., Main Outcomes and Measures: All-cause mortality, cardiovascular disease mortality, and cancer mortality. Cox proportional hazards regression models were performed to estimate hazard ratios (HRs) and 95% CIs, adjusted for sociodemographic characteristics, lifestyle risk factors, and total physical activity., Result: Among the 403 681 individuals (225 569 women [51.7%]; mean [SD] age, 42.8 [16.3] years) in the study, during a median 10.1 years (interquartile range, 5.4-14.6 years) of follow-up (407.3 million person-years), 36 861 deaths occurred. Mutually adjusted models considering the recommendations of moderate physical activity (MPA; 150-299 vs 0 minutes per week) and VPA (≥75-149 vs 0 minutes per week) showed similar associations for all-cause mortality (MPA: HR, 0.83; 95% CI, 0.80-0.87; and VPA: HR, 0.80; 95% CI, 0.76-0.84) and cardiovascular disease mortality (MPA: HR, 0.75; 95% CI, 0.68-0.83; and VPA: HR, 0.79; 95% CI, 0.70-0.91). For the same contrasts, VPA (HR, 0.89; 95% CI, 0.80-0.99) showed a stronger inverse association with cancer mortality compared with MPA (HR, 0.94; 95% CI, 0.86-1.02). Among participants performing any MVPA, a higher proportion of VPA to total physical activity was associated with lower all-cause mortality but not with cardiovascular disease and cancer mortality. For instance, compared with participants with 0% of VPA (no vigorous activity), participants performing greater than 50% to 75% of VPA to total physical activity had a 17% lower all-cause mortality (hazard ratio, 0.83; 95% CI, 0.78-0.88), independent of total MVPA. The inverse association between proportion of VPA to total physical activity and all-cause mortality was consistent across sociodemographic characteristics, lifestyle risk factors, and chronic conditions at baseline., Conclusions and Relevance: This study suggests that, for the same volume of MVPA, a higher proportion of VPA to total physical activity was associated with lower all-cause mortality. Clinicians and public health interventions should recommend 150 minutes or more per week of MVPA but also advise on the potential benefits associated with VPA to maximize population health.

Chronic activation and dysregulation of the neuroendocrine stress response have severe physiological and psychological consequences, including the development of metabolic and stress-related psychiatric disorders. We provide the first unbiased, cell type-specific, molecular characterization of all three components of the hypothalamic-pituitary-adrenal axis, under baseline and chronic stress conditions. Among others, we identified a previously unreported subpopulation of Abcb1b + cells involved in stress adaptation in the adrenal gland. We validated our findings in a mouse stress model, adrenal tissues from patients with Cushing's syndrome, adrenocortical cell lines, and peripheral cortisol and genotyping data from depressed patients. This extensive dataset provides a valuable resource for researchers and clinicians interested in the organism's nervous and endocrine responses to stress and the interplay between these tissues. Our findings raise the possibility that modulating ABCB1 function may be important in the development of treatment strategies for patients suffering from metabolic and stress-related psychiatric disorders., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Excess dietary sodium contributes to the burden of chronic disease, including cardiovascular disease and stroke. Media-based health education campaigns are one strategy to raise awareness among populations at greater risk for stroke, including African Americans. During 2014-2015, the Philadelphia Department of Public Health conducted a health education campaign using radio, print news, and transit ads, to promote awareness of the link between dietary sodium, hypertension and stroke, and encourage reduced consumption of high sodium foods. Using a repeated cross-sectional design, street intercept surveys were conducted with ~400 Philadelphia residents representing the campaign's priority audience (African Americans ages 35-55) before and 6-13 weeks after the campaign, to evaluate both process (campaign exposure) and impact (recall of key health messages). Thirty percent of post-campaign respondents reported familiarity with one of the most engaging radio spots, and 17% provided accurate unaided recall of its key content, with greater recall among older respondents and frequent radio listeners. Forty-one percent of post-campaign respondents named stroke as a consequence of excess salt consumption, compared to only 17% of pre-campaign respondents, with greater awareness of the salt-stroke connection among those accurately recalling the radio spot from the campaign. Results suggest that priority populations for sodium reduction can be effectively reached through radio and transit campaigns. From a pragmatic perspective, street intercept surveys may offer one low resource strategy for evaluating public health education campaigns conducted by local health departments, especially among urban populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Klassen, Sood, Summers, Perera, Shuster, Lopez, McCord, Stokes, White and Wagner.)

Major depressive disorder (MDD) is one of the most severe global health problems with millions of people affected, however, the mechanisms underlying this disorder is still poorly understood. Genome-wide association studies have highlighted a link between the neutral amino acid transporter SLC6A15 and MDD. Additionally, a number of preclinical studies support the function of this transporter in modulating levels of brain neurotransmitters, stress system regulation and behavioural phenotypes related to MDD. However, the molecular and functional mechanisms involved in this interaction are still unresolved. Therefore, to investigate the effects of the SLC6A15 transporter, we used hippocampal tissue from Slc6a15-KO and wild-type mice, together with several in-vitro assays in primary hippocampal neurons. Utilizing a proteomics approach we identified differentially regulated proteins that formed a regulatory network and pathway analysis indicated significantly affected cellular domains, including metabolic, mitochondrial and structural functions. Furthermore, we observed reduced release probability at glutamatergic synapses, increased mitochondrial function, higher GSH/GSSG redox ratio and an improved neurite outgrowth in primary neurons lacking SLC6A15. In summary, we hypothesize that by controlling the intracellular concentrations of neutral amino acids, SLC6A15 affects mitochondrial activity, which could lead to alterations in neuronal structure and activity. These data provide further indication that a pharmacological or genetic reduction of SLC6A15 activity may indeed be a promising approach for antidepressant therapy., (© 2020 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: To investigate whether the excess risk of adverse health outcomes associated with a lower physical capability in adulthood differs by deprivation levels., Methods: 279,030 participants from the UK Biobank were included. Handgrip strength and walking pace were the exposures. All-cause mortality, CVD mortality and incidence were the outcomes. Townsend deprivation index was treated as a potential effect modifier. The associations were investigated using Cox-regression models with years of follow-up as the time-varying covariate., Results: A significant interaction between deprivation and handgrip strength was found for all-cause mortality (p = 0.024), CVD mortality (p = 0.006) and CVD incidence (p = 0.001). The hazard ratio for all-cause mortality was 1.18 [1.09; 1.29] per 1-tertile higher level of grip strength in the least deprived group, whereas it was 1.30 [1.18; 1.43] in the most deprived individuals. Similar results were found for CVD mortality and incidence per tertile increment in handgrip strength in the least and most deprived quintiles, respectively. No significant interactions between deprivation and walking pace were found for any of the outcomes., Conclusion: Low handgrip strength is a stronger predictor of morbidity and mortality in individuals living in more deprived areas.

Objective: To examine whether vigorous-intensity physical activity confers additional reductions on all-cause and cause-specific mortality compared with moderate-intensity physical activity., Design: A systematic review (registered in PROSPERO CRD42019138995) and meta-analysis., Data Sources: Three electronic databases up to April 14 2020., Eligibility Criteria: Inclusion criteria were prospective studies that contained information about (1) moderate-intensity (3-5.9 metabolic equivalent tasks (METs)) and vigorous-intensity (≥6 METs) physical activities and (2) all-cause and/or cause-specific mortality. Exclusion criteria were prospective studies that (1) exclusively recruited diseased patients (eg, hypertensive patients and diabetics) or (2) did not account for total physical activity in their multivariable models (3) or did not adjust or exclude individuals with comorbidities at baseline or (4) used physically inactive participants as reference group., Results: Five studies (seven cohorts using sex-specific results) were pooled into a meta-analysis. For all-cause mortality and controlling by total physical activity, vigorous-intensity physical activity (vs moderate) was not associated with a larger reduction in mortality (HR 0.95, 95% CI 0.83 to 1.09). After the exclusion of one study judged with critical risk of bias (Risk Of Bias in Non randomized Studies, ROBINS tool) from meta-analysis, results remained similar (HR 0.98, 95% CI 0.85 to 1.12). Due to the limited number of studies, meta-analyses for cancer and cardiovascular mortality were not performed., Conclusions: Prospective studies suggest that, for the same total physical activity, both vigorous-intensity and moderate-intensity physical activities reduce all-cause mortality to the same extent. However, absence of evidence must not be interpreted as evidence of absence due to the existing methodological flaws in the literature., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Modafinil and methylphenidate are medications that inhibit the neuronal reuptake of dopamine, a mechanism shared with cocaine. Their use as "smart drugs" by healthy subjects poses health concerns and requires investigation. We show that methylphenidate, but not modafinil, maintained intravenous self-administration in Sprague-Dawley rats similar to cocaine. Both modafinil and methylphenidate pretreatments potentiated cocaine self-administration. Cocaine, at self-administered doses, stimulated mesolimbic dopamine levels. This effect was potentiated by methylphenidate, but not by modafinil pretreatments, indicating dopamine-dependent actions for methylphenidate, but not modafinil. Modafinil is known to facilitate electrotonic neuronal coupling by actions on gap junctions. Carbenoxolone, a gap junction inhibitor, antagonized modafinil, but not methylphenidate potentiation of cocaine self-administration. Our results indicate that modafinil shares mechanisms with cocaine and methylphenidate but has a unique pharmacological profile that includes facilitation of electrotonic coupling and lower abuse liability, which may be exploited in future therapeutic drug design for cocaine use disorder.

Intestinal inflammation is a condition shared by several intestinal chronic diseases, such as Crohn's disease and ulcerative colitis, with severely detrimental consequences in the long run. Current mammalian models have considerably increased understanding of this pathological condition, highlighting the fact that, in most of the cases, it is a highly complex and multifactorial problem and difficult to deal with. Thus, there is an increasingly evident need for alternative animal models that could offer complementary approaches that have not been exploited in rodents, thereby contributing to a different view on the disease. Here, we report the effects of a soybean meal-induced intestinal inflammation model on intestinal integrity and function as well as on neutrophil recruitment and microbiota composition in zebrafish. We find that the induced intestinal inflammation process is accompanied by an increase in epithelial permeability in addition to changes in the mRNA levels of different tight junction proteins. Conversely, there was no evidence of damage of epithelial cells nor an increase in their proliferation. Of note, our results show that this intestinal inflammatory model is induced independently of the presence of microbiota. On the other hand, this inflammatory process affects intestinal physiology by decreasing protein absorption, increasing neutrophil replacement, and altering microbiota composition with a decrease in the diversity of cultivable bacteria., (Copyright © 2020 Solis, Hamilton, Caruffo, Garcia-Lopez, Navarrete, Guillemin and Feijoo.)

We report on a new, to the best of our knowledge, type of optical memory that allows for the amplification of the optical signal carrying the stored information during its reading process. The memory mechanism is demonstrated in an ensemble of cold cesium atoms and is based on the multiple parametric four-wave mixing exploring the external atomic degrees of freedom via recoil-induced resonances. We have particularly demonstrated the storage of light carrying orbital angular momentum with a fourfold amplifying factor for the retrieved signal during the reading process. Memory lifetimes of the order of hundreds of microseconds have been measured, and possible applications for this self-amplifying memory are discussed.

Post-mortem brain studies suggest that miRNAs may be involved in suicide, but their role as peripheral biomarkers or targets of preventive pharmacological treatments in suicide has yet to be elucidated. We used nCounter miRNA Expression assay to measure miRNAs expression in lymphoblastoid cell lines (LCLs) from patients with Bipolar Disorder (BD) who died by suicide (SC, n = 7) and with low risk of suicide (LR, n = 11). Five miRNAs were differentially expressed in SC compared to LR (false discovery rate p<0.05). The two most significant miRNAs were measured with RT-qPCR in the same sample and in 12 healthy controls (HC): miR-4286 was increased while miR-186-5p was decreased in SC compared to LR and HC (ANOVA F = 14.92, p = 0.000043 and F = 3.95, p = 0.032 respectively). miR-4286 was also decreased in postmortem brains from 12 patients with BD who died by suicide compared to 13 controls, even though it did not reach statistical significance (FC=0.51, p = 0.07). Treatment with lithium of human neural progenitor cells reduced the expression of miR-4286 (FC=0.30, p = 0.038). Pathway analysis on predicted miR-4286 targets showed that "insulin resistance" was significantly enriched after correction for multiple testing. This pathway comprised 17 genes involved in lipid and glucose metabolism, several of which were also dysregulated in postmortem brains from patients with BD who died by suicide from the Stanley-foundation array collection. In conclusion, our study suggests that miR-4286 could be a biomarker of suicide but further studies are warranted to investigate its targeted genes and how these could be involved in the neurobiology of suicide., (Copyright © 2020. Published by Elsevier B.V.)

It remains unclear why many patients with depression do not respond to antidepressant treatment. In three cohorts of individuals with depression and treated with serotonin-norepinephrine reuptake inhibitor (N = 424) we show that responders, but not non-responders, display an increase of GPR56 mRNA in the blood. In a small group of subjects we also show that GPR56 is downregulated in the PFC of individuals with depression that died by suicide. In mice, we show that chronic stress-induced Gpr56 downregulation in the blood and prefrontal cortex (PFC), which is accompanied by depression-like behavior, and can be reversed by antidepressant treatment. Gpr56 knockdown in mouse PFC is associated with depressive-like behaviors, executive dysfunction and poor response to antidepressant treatment. GPR56 peptide agonists have antidepressant-like effects and upregulated AKT/GSK3/EIF4 pathways. Our findings uncover a potential role of GPR56 in antidepressant response.

More than two-thirds of patients suffering from stress-related disorders are women but over two-thirds of suicide completers are men. These are just some examples of the many sex differences in the prevalence and manifestations of stress-related disorders, such as major depressive disorder, post-traumatic stress disorder, and anxiety disorders, which have been extensively documented in clinical research. Nonetheless, the molecular origins of this sex dimorphism are still quite obscure. In response to this lack of knowledge, the NIH recently advocated implementing sex as biological variable in the design of preclinical studies across disciplines. As a result, a newly emerging field within psychiatry is trying to elucidate the molecular causes underlying the clinically described sex dimorphism. Several studies in rodents and humans have already identified many stress-related genes that are regulated by acute and chronic stress in a sex-specific fashion. Furthermore, current transcriptomic studies have shown that pathways and networks in male and female individuals are not equally affected by stress exposure. In this review, we give an overview of transcriptional studies designed to understand how sex influences stress-specific transcriptomic changes in rodent models, as well as human psychiatric patients, highlighting the use of different methodological techniques. Understanding which mechanisms are more affected in males, and which in females, may lead to the identification of sex-specific mechanisms, their selective contribution to stress susceptibility, and their role in the development of stress-related psychiatric disorders., (© 2020 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

The controlled and continuous production of nanoparticles (NPs) with functionalized surfaces remains a technological challenge. We present a multistage synthetic platform, consisting of 3D-printed miniature continuous stirred-tank reactor (CSTR) cascades, for the continuous synthesis and functionalization of SiO 2 NPs. The use of the CSTR platform provides ideal and rapid mixing of precursor solutions, precise injection of additional reagents for multistep reactions, and facile operation when using viscous solutions and handling of syntheses with longer reaction times. To exemplify the use of such custom-designed CSTR cascades, amine- and carbohydrate-functionalized SiO 2 NPs are chosen as model reaction systems. In particular, the intensified flow reactor units allowed for the reproducible formation of SiO 2 NPs with diameters less than 100 nm and narrow size distributions (3-8%). Most importantly, by assembling various 3D-printed CSTR cascades, we synthesized gluconolactone-capped polyethylenimine-modified silica NPs in a fully continuous manner. The inherent control over NP surface charge, reactor scalability, and the significant shortening of processing times (less than 10 min) compared to batch methodologies (several days) strongly indicate the ability of the reactor technology to accelerate continuous nanomanufacturing. In general, it provides a simple route for the reproducible preparation of functionalized NPs, thus expanding the gamut of flow reactors for material synthesis.

Background: Physical activity recommendations state that for the same energy expenditure, moderate-to-vigorous physical activities (MVPAs) produce similar health benefits. However, few epidemiological studies have tested this hypothesis., Design: We examined whether, compared with moderate, vigorous activity was associated with larger mortality risk reductions., Methods: Data from 11 cohorts of the Health Survey for England and the Scottish Health Survey, collected from 1994 to 2011 (mean (SD) follow-up, 9.0 (3.6) years). Adults aged ≥30 years reported MVPA and linkage to mortality records. Exposure was the proportion of self-reported weighted MVPA through vigorous activity. Outcomes were all-cause, cardiovascular disease (CVD) and cancer mortality., Results: Among 64 913 adult respondents (44% men, 56% women, mean (SD) age, 49.8 (13.6) years), there were 5064 deaths from all-causes, 1393 from CVD and 1602 from cancer during 435 743 person-years of follow-up. Compared with those who reported no vigorous physical activity, and holding constant the volume of weighted MVPA, vigorous activity was associated with additional reductions in mortality risk. For all-cause mortality, the adjusted HR was HR=0.84 (95% CI 0.71, 0.99) and HR=0.84 (95% CI 0.76, 0.94) among those who reported between >0% and<30%, or ≥30% of their activity as vigorous, respectively. For CVD and cancer mortality, point estimates showed similar beneficial associations yet CIs were wider and crossed unity., Conclusion: Vigorous activities were associated with larger reductions in mortality risk than activities of moderate intensity, but no evidence of dose-response effects was found., Competing Interests: Competing interests: None declared.

Background: Kuwait is one of the Arab countries with the highest prevalence of overweight or obesity. However, few studies have described the prevalence of obesity in this country. The aim of this study is to describe the prevalence of overweight and obesity among Kuwaiti adolescents; and to examine the association of overweight and obesity status with familial socioeconomic status (SES)., Methods: Cross-sectional data from 591 adolescent students (47% boys, median age: 16 years) from the Study of Health and Activity among Adolescents in Kuwait in 2012 and 2013. Body weight status was determined using the International Obesity Task Force (IOTF) body mass index standards. SES was based on parental education. Odds ratio for overweight and obesity were calculated using multiple logistic regression., Results: In our study, over half of the adolescents were overweight or obese 54.3% (95% CI: 49.9-58.4). The prevalence of overweight (including obesity) was higher in boys (59.8%, 95% CI: 54.3-66.3) than girls (49.2%, 95% CI: 43.5-54.8). No association between parental education and the risk of overweight/obesity was found., Conclusions: There is an alarmingly high rate of overweight/obesity among Kuwaiti adolescents, but we did not find evidence of a social gradient in obesity risk. Urgent actions are needed to reverse this epidemic across all social groups.

This study leverages psychiatric intake data from treatment-seeking perinatal women aiming to explore the understudied associations between childhood adversity, sleep quality, and severity of perinatal mental illness in this population. The sample is 578 perinatal women presenting for initial evaluation to a university-based perinatal psychiatry clinic. At intake, we collected demographics, adverse childhood experiences (ACEs), sleep quality, and diagnosis and symptom severity of depression, anxiety, and posttraumatic stress disorder (PTSD). Clinician-rated diagnoses showed that 65% of women met criteria for major depression, 23% for generalized anxiety disorder and 4% for PTSD; almost 30% of women had childhood adversity and 98.2% reported poor perinatal sleep quality. Regression analyses revealed differential associations between ACEs and sleep quality and perinatal mood symptoms; ACEs were significantly associated with pregnancy and postpartum PTSD, whereas sleep quality was associated with perinatal depression and generalized anxiety. Screening for ACEs and sleep quality during perinatal intake has high clinical utility, as these two factors significantly contribute to symptom severity across peripartum.