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Objective The presence of insomnia in the general military population is not well known. This study aimed to determine the prevalence of probable clinical insomnia and identify factors leading to new-onset insomnia and/or sleep medication use in a large military population. Design Cross-sectional and longitudinal analyses of a prospective cohort study. Participants A tri-service US military and veteran cohort (sample range 99,383-137,114). Measurements Participants were surveyed in 2013 (Time 1 [T1]) and 2016 (Time 2 [T2]) using the clinically validated Insomnia Severity Index. The prevalence of insomnia and sleep medication use was quantified at both times. Multivariable models identified military factors associated with new-onset insomnia and/or sleep medication use while adjusting for covariates. Results The prevalence of insomnia at T1 and T2 was 16.3% and 11.2%, respectively. New-onset insomnia at T2 was reported by 6.0% of participants screening negative at T1; risk factors included Army service, combat deployment experience, and separation from military service. The prevalence of sleep medication use at T1 and T2 was 23.1% and 25.1%, respectively. Sleep medication use at T2 was newly-reported by 17.1% of participants not reporting sleep medication use at T1; risk factors included number of deployments and having a healthcare occupation. Conclusions The prevalence of probable clinical insomnia in this large general military population is within the range of previous reports in military and civilian populations. Certain military factors that predict new-onset insomnia and/or sleep medication use should be considered when designing and implementing sleep interventions in military populations.

Summary We conducted an updated epidemiological study of Leber hereditary optic neuropathy (LHON) in Australia by using registry data to establish the risk of vision loss among different LHON mutations, sex, age at onset, and mitochondrial haplogroup. We identified 96 genetically unrelated LHON pedigrees, including 56 unpublished pedigrees, and updated 40 previously known pedigrees, comprising 620 affected individuals and 4,948 asymptomatic carriers. The minimum prevalence of vision loss due to LHON in Australia in 2020 was one in 68,403 individuals. Although our data confirm some well-established features of LHON, the overall risk of vision loss among those with a LHON mutation was lower than reported previously—17.5% for males and 5.4% for females. Our findings confirm that women, older adults, and younger children are also at risk. Furthermore, we observed a higher incidence of vision loss in children of affected mothers as well as in children of unaffected women with at least one affected brother. Finally, we confirmed our previous report showing a generational fall in prevalence of vision loss among Australian men. Higher reported rates of vision loss in males with a LHON mutation are not supported by our work and other epidemiologic studies. Accurate knowledge of risk is essential for genetic counseling of individuals with LHON mutations. This knowledge could also inform the detection and validation of potential biomarkers and has implications for clinical trials of treatments aimed at preventing vision loss in LHON because an overestimated risk may lead to an underpowered study or a false claim of efficacy.

Understanding body size in relation to deployment readiness can inform Department of Defense fitness policies. This study examined longitudinal associations between deployment and changes in body mass index (BMI) among active duty service members.Service branch-specific changes in BMI post-deployment were examined using logistic regression models among active duty Millennium Cohort Study participants without obesity at baseline (Among the pooled population and specifically Army and Marine Corps service members without obesity, those with longer deployments were significantly less likely to maintain a non-obese BMI than those deploying for shorter lengths. Each additional deployment increased the likelihood of maintaining a non-obese BMI post-deployment for personnel in the Army, Marine Corps, and within the pooled population.Multiple deployments may support healthy weight maintenance; longer deployments may adversely impact weight maintenance. Future research should determine modifiable behaviors related to weight gain post-deployment to inform fitness policies designed to optimize service member readiness and deployability.

Acoustic angiography is a superharmonic contrast-enhanced ultrasound imaging method that produces high-resolution, three-dimensional maps of the microvasculature. Previous acoustic angiography studies have used two-element, annular, mechanically actuated transducers (called “wobblers”) to image microvasculature in preclinical tumor models with high contrast-to-tissue ratio and resolution, but these early wobbler transducers could not achieve the depth and sensitivity required for clinical acoustic angiography. In this work, we present a system for performing acoustic angiography with a novel dual-frequency transducer – a coaxially stacked dual-frequency array. We evaluate the dual-frequency array system both in vitro and in vivo and demonstrate improvements in sensitivity and imaging depth up to 13.1 dB and 10 mm, respectively, compared to previous wobbler probes.

During the COVID-19 pandemic, the disproportionate morbidity and mortality borne by racial minorities, patients of lower socioeconomic status, and patients lacking health insurance reflect the critical role of social determinants of health, which are manifestations of entrenched structural inequities. In radiology, social determinants of health lead to disparate use of imaging services through multiple intersecting contributors, on both the provider and patient side, affecting diagnosis and treatment. Disparities on the provider side include ordering of initial or follow-up imaging studies and providing standard-of-care interventional procedures, while patient factors include differences in awareness of screening exams and confidence in the healthcare system. Disparate utilization of mammography and lung cancer screening lead to delayed diagnosis, while differential provision of minimally invasive interventional procedures contributes to differential outcomes related to treatment. Interventions designed to mitigate social determinants of health could help to equalize the healthcare system. Here we review disparities in access and health outcomes in radiology. We investigate underlying contributing factors in order to identify potential policy changes that could promote more equitable health in radiology.

Accumulating evidence indicates that obesity with its associated metabolic dysregulation, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Caloric restriction can ameliorate the harmful metabolic effects of obesity and inhibit cancer progression but is difficult to implement and maintain outside of the clinic. In this study, we aim to test a time-restricted feeding (TRF) approach on mouse models of obesity-driven postmenopausal breast cancer. We show that TRF abrogates the obesity-enhanced mammary tumor growth in two orthotopic models in the absence of calorie restriction or weight loss. TRF also reduces breast cancer metastasis to the lung. Furthermore, TRF delays tumor initiation in a transgenic model of mammary tumorigenesis prior to the onset of obesity. Notably, TRF increases whole-body insulin sensitivity, reduces hyperinsulinemia, restores diurnal gene expression rhythms in the tumor, and attenuates tumor growth and insulin signaling. Importantly, inhibition of insulin secretion with diazoxide mimics TRF whereas artificial elevation of insulin through insulin pumps implantation reverses the effect of TRF, suggesting that TRF acts through modulating hyperinsulinemia. Our data suggest that TRF is likely to be effective in breast cancer prevention and therapy., Obesity and its associated metabolic changes, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Here, the authors show that restricting when mice eat, but not what or how much they eat, delays breast cancer initiation and reduces tumor growth in obese mice in addition to improving insulin sensitivity and restoring circadian rhythms.

Since March 2020, Spain (along with many other countries) has been severely affected by the ongoing coronavirus disease 19 (COVID‐19) pandemic caused by the rapid spread of a new virus (severe acute respiratory syndrome coronavirus 2; SARS‐CoV‐2). As part of global efforts to improve disease surveillance, we investigated how readily SARS‐CoV‐2 RNA could be detected in environmental samples collected from an isolated rural community in Spain with a high COVID‐19 prevalence (6% of the population of 883 inhabitants). The first diagnosis of COVID‐19‐compatible symptoms in the village was recorded on March 3, 2020 and the last known active case resolved on June 5, 2020. By May 15, two months after strict movement constraints were imposed (“lockdown”) the cumulative number of symptomatic cases had increased to 53. Of those cases, 22 (41%) had been tested and confirmed by RT‐PCR. On May 13 and June 5, samples were collected from high‐use surfaces and clothes in the homes of 13 confirmed cases, from surfaces in nine public service sites (e.g. supermarket and petrol station), and from the wastewater of the village sewage system. SARS‐CoV‐2 RNA was detected in 7 of 57 (12%) samples, including three households and three public sites. While there is not yet sufficient evidence to recommend environmental surveillance as a standard approach for COVID‐19 epidemiology, environmental surveillance research may contribute to advance knowledge about COVID‐19 by further elucidating virus shedding dynamics and environmental contamination, including the potential identification of animal reservoirs., This study had no specific funding although we benefitted from Universidad de Castilla-La Mancha support through the COVID Diagnosis Action. We would like to thank the local veterinarian Javier Camarena, the local healthcare staff, and the municipality of Horcajo de los Montes for help in wastewater sampling and logistics, and for providing detailed information on disinfection and patient support activities. Mariana Boadella (Sabiotec, Ciudad Real, Spain) kindly provided the sponges. IGFM is supported by the Research Plan of the University of Castilla- La Mancha (UCLM), Spain

Cancerous tumor growth is associated with the development of tortuous, chaotic microvasculature, and this aberrant microvascular morphology can act as a biomarker of malignant disease. Acoustic angiography is a contrast-enhanced ultrasound technique that relies on superharmonic imaging to form high-resolution, three-dimensional maps of the microvasculature. To date, acoustic angiography has been performed with dual-element transducers that can achieve high contrast-to-tissue ratio and resolution in preclinical small animal models. In this review, we first describe the development of acoustic angiography, including the principle, transducer design, and optimization of superharmonic imaging techniques. We then detail several preclinical applications of this microvascular imaging method, as well as the current and future development of acoustic angiography as a preclinical and clinical diagnostic tool.

BACKGROUND Stress echocardiography (SE) is an established technique for assessment of coronary artery disease (CAD) which is difficult to perform and interpret. Left ventricular stroke volume (SV) is readily estimated with Doppler echocardiography. It can be affected by myocardial ischemia, with possible adjunctive value during SE. METHODS Patients underwent Bruce protocol SE with SV estimated before and after maximal treadmill exertion post routine regional wall analysis. Incremental change in SV (ΔSV) with exercise was measured. RESULTS A derivation cohort (n = 273) was established to test the hypothesis. An optimal cutoff for detection on inducible ischemia was ΔSV ≤ +10 mL. The validation cohort of consecutive patients (n = 1093, 376 [34%] female; age 59 ± 12 years) were followed clinically after SE for 20 460 patient-months. There were 1000 patients with nonischemic SE, and 93 patients with studies suggestive of myocardial ischemia. Secondary analysis yielded 831 patients with a normal exercise response (ΔSV > +10 mL) and 192 with an abnormal ΔSV ≤ +10 mL. Time to first combined adverse cardiac event (composite of angina, acute coronary syndrome, cardiac revascularization, worsening New York Heart Association (NYHA) class, a reduction in EF, and cardiovascular death) was analyzed and adjusted using Cox proportional hazards regression. The hazard ratio for an adverse event with an abnormal ΔSV response (≤10 mL) was 10.3 (95% confidence intervals 5.6-19.1, P

© 2020 British Journal of AnaesthesiaBackground: Accidental dural puncture is an uncommon complication of epidural analgesia and can cause postdural puncture headache (PDPH). We aimed to describe management practices and outcomes after PDPH treated by epidural blood patch (EBP) or no EBP. Methods: Following ethics committee approval, patients who developed PDPH after accidental dural puncture were recruited from participating countries and divided into two groups, those receiving EBP or no EBP. Data registered included patient and procedure characteristics, headache symptoms and intensity, management practices, and complications. Follow-up was at 3 months. Results: A total of 1001 patients from 24 countries were included, of which 647 (64.6%) received an EBP and 354 (35.4%) did not receive an EBP (no-EBP). Higher initial headache intensity was associated with greater use of EBP, odds ratio 1.29 (95% confidence interval 1.19–1.41) per pain intensity unit increase. Headache intensity declined sharply at 4 h after EBP and 127 (19.3%) patients received a second EBP. On average, no or mild headache (numeric rating score≤3) was observed 7 days after diagnosis. Intracranial bleeding was diagnosed in three patients (0.46%), and backache, headache, and analgesic use were more common at 3 months in the EBP group. Conclusions: Management practices vary between countries, but EBP was more often used in patients with greater initial headache intensity. EBP reduced headache intensity quickly, but about 20% of patients needed a second EBP. After 7 days, most patients had no or mild headache. Backache, headache, and analgesic use were more common at 3 months in patients receiving an EBP.

Objective To examine whether military separation (Veteran), service component (active duty, Reserve/National Guard), and combat deployment are prospectively associated with continuing unhealthy alcohol use among US military service members. Methods Millennium Cohort Study participants were evaluated for continued or chronic unhealthy alcohol use, defined by screening positive at baseline and the next consecutive follow-up survey for heavy episodic, heavy weekly, or problem drinking. Participants meeting criteria for chronic unhealthy alcohol use were followed for up to 12 years to determine continued unhealthy use. Multivariable regression models-adjusted for demographics, military service factors, and behavioral and mental health characteristics-assessed whether separation status, service component, or combat deployment were associated with continuation of 3 unhealthy drinking outcomes: heavy weekly (sample n = 2653), heavy episodic (sample n = 22,933), and problem drinking (sample n = 2671). Results In adjusted models, Veterans (compared with actively serving personnel) and Reserve/Guard (compared with active duty members) had a significantly higher likelihood of continued chronic use for heavy weekly, heavy episodic, and problem drinking (Veteran odds ratio [OR] range 1.17-1.47; Reserve/Guard OR range 1.25-1.29). Deployers without combat experience were less likely than nondeployers to continue heavy weekly drinking (OR 0.75, 95% confidence interval 0.61-0.91). Conclusions The elevated likelihood of continued unhealthy alcohol use among Veterans and Reserve/Guard members suggests that strategies to reduce unhealthy drinking targeted to these populations may be warranted.

Acoustic angiography is a contrast-enhanced ultrasound technique that relies on superharmonic imaging to form high-resolution, three-dimensional maps of the microvasculature. In order to obtain signal separation between tissue and contrast, acoustic angiography has been performed with dual-frequency transducers with nonoverlapping bandwidths. This enables a high contrast-to-tissue ratio, and the choice of a high frequency receiving element provides high resolution. In this chapter, we describe the technology behind acoustic angiography as well as the step-by-step implementation of this contrast enhanced microvascular imaging technique.

The COVID-19 pandemic has negatively impacted the provision of Palliative Care (PC), challenging the teams aiming to provide adequate care. This is a qualitative study that intends to know, from the perspective of health professionals of a Palliative Care Unit (PCU), the main challenges in providing PC during a pandemic and describes the strategies to be adopted to solve the identified difficulties. We utilized the content analysis, according to Bardin, for data analysis of written narratives of health professionals from a PCU (n=14). In the analysis of the difficulties in providing PC, from the perspective of health professionals, were identified five themes: 1) Altered relationship between healthcare professional and patients, 2) altered relationship between healthcare professional and family, 3) altered communication with patients and their family, 4) altered working dynamic within the PCU, and 5) altered use of healthcare resources. Concerning the strategies to be implemented, the health professionals identified two themes: 1) Strategies to implement between the patient and family members and 2) strategies to implement for the healthcare professionals. The provision of PC is affected by changes in the relationship between the health professional and the patient/caregiver or family, in communication with the patient/caregiver or family, and the use of health resources. In an attempt to lessen the impact of these changes, participants identified strategies to improve PC delivery in these circumstances. During this pandemic, it is imperative to implement rigorous strategies for managing specialized human resources. Physical distance and personal protective equipment are barriers to communication and emotional support, which is essential in PC and this barrier is further accentuated by the required physical distance from family members and caregivers. PC´s main aim continues to be the mitigation of suffering.

The COVID-19 pandemic caused by SARS-CoV-2 challenges the understanding of factors affecting disease progression and severity. The identification of prognostic biomarkers and physiological processes associated with disease symptoms is relevant for the development of new diagnostic and therapeutic interventions to contribute to the control of this pandemic. To address this challenge, in this study, we used a quantitative proteomics together with multiple data analysis algorithms to characterize serum protein profiles in five cohorts from healthy to SARS-CoV-2-infected recovered (hospital discharge), nonsevere (hospitalized), and severe [at the intensive care unit (ICU)] cases with increasing systemic inflammation in comparison with healthy individuals sampled prior to the COVID-19 pandemic. The results showed significantly dysregulated proteins and associated biological processes and disorders associated to COVID-19. These results corroborated previous findings in COVID-19 studies and highlighted how the representation of dysregulated serum proteins and associated BPs increases with COVID-19 disease symptomatology from asymptomatic to severe cases. The analysis was then focused on novel disease processes and biomarkers that were correlated with disease symptomatology. To contribute to translational medicine, results corroborated the predictive value of selected immune-related biomarkers for disease recovery [Selenoprotein P (SELENOP) and Serum paraoxonase/arylesterase 1 (PON1)], severity [Carboxypeptidase B2 (CBP2)], and symptomatology [Pregnancy zone protein (PZP)] using protein-specific ELISA tests. Our results contributed to the characterization of SARS-CoV-2–host molecular interactions with potential contributions to the monitoring and control of this pandemic by using immune-related biomarkers associated with disease symptomatology., This research was partially funded by Junta de Comunidades de Castilla-La Mancha (JCCM), Spain and EU-FEDER (grants MYCOTRAINING SBPLY/19/180501/000174 and GALINFEC SBPLY/17/180501/000185). EF-C has a predoctoral grant from UCLM. MC was funded by the Ministerio de Ciencia, Innovación y Universidades, Spain (grant FJC-2018-038277-I). IGF was supported by UCLM. MV was supported by UCLM and EU-FEDER.

Induced pluripotent stem cells generated from patients with geographic atrophy as well as healthy individuals were differentiated to retinal pigment epithelium (RPE) cells. By integrating transcriptional profiles of 127,659 RPE cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identified 439 expression Quantitative Trait (eQTL) loci in cis that were associated with disease status and specific to subpopulations of RPE cells. We identified loci linked to two genes with known associations with geographic atrophy - PILRB and PRPH2, in addition to 43 genes with significant genotype x disease interactions that are candidates for novel genetic associations for geographic atrophy. On a transcriptome-only level, we identified molecular pathways significantly upregulated in geographic atrophy-RPE including in extracellular cellular matrix reorganisation, neurodegeneration, and mitochondrial functions. We subsequently implemented a large-scale proteomics analysis, confirming modification in proteins associated with these pathways. We also identified six significant protein (p) QTL that regulate protein expression in the RPE cells and in geographic atrophy - two of which share variants with cis-eQTL. Transcriptome-wide association analysis identified genes at loci previously associated with age-related macular degeneration. Further analysis conditional on disease status, implicated statistically significant RPE-specific eQTL. This study uncovers important differences in RPE homeostasis associated with geographic atrophy.

Cancer immunotherapy has emerged as a pillar of the cancer therapy armamentarium. Immune checkpoint therapy (ICT) is a mainstay of modern immunotherapy. Although ICT monotherapy has demonstrated remarkable clinical efficacy in some patients, the majority do not respond to treatment. In addition, many patients eventually develop resistance to ICT, disease recurrence, and toxicity from off-target effects. Combination therapy is a keystone strategy to overcome the limitations of monotherapy. With the integration of ICT and any therapy that induces tumor cell lysis and release of tumor-associated antigens (TAAs), ICT is expected to strengthen the coordinated innate and adaptive immune responses to TAA release and promote systemic, cellular antitumor immunity. Nanomedicine is well poised to facilitate combination ICT. Nanoparticles with delivery and/or immunomodulation capacities have been successfully combined with ICT in preclinical applications. Delivery nanoparticles protect and control the targeted release of their cargo. Inherently immunomodulatory nanoparticles can facilitate immunogenic cell death, modification of the tumor microenvironment, immune cell mimicry and modulation, and/or in situ vaccination. Nanoparticles are frequently multifunctional, combining multiple treatment strategies into a single platform with ICT. Nanomedicine and ICT combinations have great potential to yield novel, powerful treatments for patients with cancer. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Study Objectives Sleep loss is common in the military, which can negatively affect health and readiness; however, it is largely unknown how sleep varies over a military career. This study sought to examine the relationships between military-related factors and the new onset and reoccurrence of short sleep duration and insomnia symptoms. Methods Millennium Cohort Study data were used to track U.S. military service members over time to examine longitudinal changes in sleep. Outcomes were self-reported average sleep duration (categorized as ≤5 h, 6 h, or 7–9 h [recommended]) and/or insomnia symptoms (having trouble falling or staying asleep). Associations between military-related factors and the new onset and reoccurrence of these sleep characteristics were determined, after controlling for multiple health and behavioral factors. Results Military-related factors consistently associated with an increased risk for new onset and/or reoccurrence of short sleep duration and insomnia symptoms included active duty component, Army or Marine Corps service, combat deployment, and longer than average deployment lengths. Military officers and noncombat deployers had decreased risk for either sleep characteristic. Time-in-service and separation from the military were complex factors; they lowered risk for ≤5 h sleep but increased risk for insomnia symptoms. Conclusions Various military-related factors contribute to risk of short sleep duration and/or insomnia symptoms over time, although some factors affect these sleep characteristics differently. Also, even when these sleep characteristics remit, some military personnel have an increased risk of reoccurrence. Efforts to improve sleep prioritization and implement interventions targeting at-risk military populations, behaviors, and other significant factors are warranted.

[Background]: The world faces the challenge posed by the interaction between hosts and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) with potential role for arthropod vectors, and the effect of SARS-CoV-2 variants on acquired immunity, vaccine efficacy and coronavirus disease-19 (COVID-19) pandemic control. [Proposal]: The characterization of the role played by animal hosts and host-virus interactions is essential to address this challenge. Zoonotic (animal-to-human) and reverse zoonotic (human-to-animal) routes may be involved in virus transmission with a possible still unconfirmed role for arthropod vectors. Herein we propose to consider the risks posed by the possible role of arthropod vectors in COVID-19 and that immunity against SARS-CoV-2 may increase the risk for zoonotic virus transmission. These risks should be considered when evaluating vaccine efficacy and monitoring animal SARS-CoV-2 variants. [Conclusion]: Virus surveillance, epidemiology, sequencing and evaluation of susceptibility to antibodies and other protective immune mechanisms from vaccinated individuals should be improved. A One Health approach such as the one applied by our group SaBio is necessary for a more effective control of COVID-19 and prevention of future pandemics., We thank members of SaBio and collaborators worldwide for their contributions to COVID-19 research and acknowledge the University of Castilla La Mancha (UCLM, Spain) for support to Group SaBio.

Anna M Wahl,1 Daniel Bidstrup,1 Isabel G Smidt-Nielsen,1 Mads U Werner,2 Ole Hyldegaard,1,3 Per Rotbøll-Nielsen21Hyperbaric Unit, Department of Anesthesia, Head and Orthopedic Center, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark; 2Multidisciplinary Pain Center, Neuroscience Center, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark; 3Institute of Clinical Medicine, University of Copenhagen, Copenhagen, DenmarkPurpose: Animal studies have demonstrated anti-inflammatory, and anti-nociceptive properties of hyperbaric oxygen therapy (HBOT). However, physiological data are scarce in humans. In a recent experimental study, the authors used the burn injury (BI) model observing a decrease in secondary hyperalgesia areas (SHA) in the HBOT-group compared to a control-group. Surprisingly, a long-lasting neuroplasticity effect mitigating the BI-induced SHA-response was seen in the HBOT-preconditioned group. The objective of the present study, therefore, was to confirm our previous findings using an examiner-blinded, block-randomized, controlled, crossover study design.Patients and methods: Nineteen healthy subjects attended two BI-sessions with an inter-session interval of ≥28days. The BIs were induced on the lower legs by a contact thermode (12.5cm,2 47C°, 420s). The subjects were block-randomized to receive HBOT (2.4 ATA, 100% O2, 90min) or ambient conditions ([AC]; 1 ATA, 21% O2), dividing cohorts equally into two sequence allocations: HBOT-AC or AC-HBOT. All sensory assessments performed during baseline, BI, and post-intervention phases were at homologous time points irrespective of sequence allocation. The primary outcome was SHA, comparing interventions and sequence allocations.Results: Data are mean (95% CI). During HBOT-sessions a mitigating effect on SHA was demonstrated compared to AC-sessions, ie, 18.8 (10.5–27.0) cm2 vs 32.0 (20.1–43.9) cm2 (P=0.021), respectively. In subjects allocated to the sequence AC-HBOT a significantly larger mean difference in SHA in the AC-session vs the HBOT-session was seen 25.0 (5.4–44.7) cm2 (P=0.019). In subjects allocated to the reverse sequence, HBOT-AC, no difference in SHA between sessions was observed (P=0.55), confirming a preconditioning, long-lasting (≥28days) effect of HBOT.Conclusion: Our data demonstrate that a single HBOT-session compared to control is associated with both acute and long-lasting mitigating effects on BI-induced SHA, confirming central anti-inflammatory, neuroplasticity effects of hyperbaric oxygen therapy.Keywords: burns, hyperbaric oxygenation, inflammation, pathophysiology, secondary hyperalgesia &nbsp

Background In comparison with the general population, physicians, and physicians-in-training are at greater risk for suicide. Although key gender differences in suicide risk factors and behaviors have been identified in the general population, the extent to which these differences apply to physicians and physicians-in-training is unclear. Here, we aimed to identify gender differences in risk factors, clinical presentation, and help-seeking behaviors of medical students, house staff, and physician faculty at high risk for suicide. Methods We explored gender differences among 450 physicians and trainees meeting criteria for high suicide risk on anonymous online questionnaires completed between 2009 and 2017. Results High-risk female trainees and physicians had higher mean Patient Health Questionnaire-9 (PHQ-9) scores compared with the males (11.1, standard deviation [SD] 5.1 vs. 9.8, SD 4.7) and were more likely to endorse feeling worried (73.8% vs. 61.2%), irritable (60.4% vs. 49.4%), and stressed (79.6% vs. 70%). High-risk male trainees and physicians were more likely than females to endorse suicidal thoughts (31.2% vs. 22.1%), intense anger (24.3% vs. 16.1%), drinking too much (31.2% vs. 22.3%), and recreational drug or prescription medication use without clinically appropriate follow-up (9.4% vs. 4.3%). There were no gender differences in help-seeking behaviors. Conclusions This is the first study to report gender differences among risk factors, presentation, and help-seeking behaviors of physicians, and trainees at high risk for suicide. Our findings are mostly consistent with those of the general population and show that only a minority of at-risk men and women in healthcare sought treatment, highlighting the importance of intervention and suicide prevention in this population.

Protein recommendations are provided on a daily basis as defined by the recommended dietary allowance (RDA) at 0.80 g protein/kg/day. However, meal-based, as opposed to daily, dietary protein recommendations are likely more informative given the role of the daily protein distribution pattern in modulating the post-exercise muscle protein synthetic response. Current protein meal recommendations to plateau post-exercise muscle protein synthesis rates are based on the ingestion of isolated protein sources, and not protein-rich whole foods. It is generally more common to eat whole food sources of dietary protein within a normal eating pattern to meet dietary protein requirements. Yet, there is a need to define how dietary protein action on muscle protein synthesis rates can be modulated by other nutrients within a food matrix to achieve protein requirements for optimal muscle adaptations. Recent developments suggest that the identification of an “optimal” protein source should likely consider the characteristics of the protein and the food matrix in which it is consumed. This review aims to discuss recent concepts related to protein quality, and the potential interactive effects of the food matrix, to achieve optimal protein requirements and elicit a robust postprandial muscle protein synthetic response with an emphasis on the post-exercise recovery window.

Mitochondrial complex I dysfunction is the most common respiratory chain defect in human disorders and a hotspot for neurodegenerative diseases. Amyloid precursor protein (APP) and its non-amyloidogenic processing products, in particular soluble APP α (sAPPα), have been shown to provide neuroprotection in models of neuronal injury; however, APP-mediated protection from acute mitochondrial injury has not been previously reported. Here, we use the plant-derived pesticide rotenone, a potent complex I-specific mitochondrial inhibitor, to discover neuroprotective effects of APP and sAPPα in vitro, in neuronal cell lines over-expressing APP, and in vivo, in a retinal neuronal rotenone toxicity mouse model. Our results show that APP over-expression is protective against rotenone toxicity in neurons via sAPPα through an autocrine/paracrine mechanism that involves the Pi3K/Akt pro-survival pathway. APP−/− mice exhibit greater susceptibility to retinal rotenone toxicity, while intravitreal delivery of sAPPα reduces inner retinal neuronal death in wild-type mice following rotenone challenge. We also show a significant decrease in human retinal expression of APP with age. These findings provide insights into the therapeutic potential of non-amyloidogenic processing of APP in complex I-related neurodegeneration. Electronic supplementary material The online version of this article (10.1007/s12035-018-1460-7) contains supplementary material, which is available to authorized users.

Despite clear evidence of a neuroprotective physiological role of amyloid precursor protein (APP) and its non-amyloidogenic processing products, APP has been investigated mainly in animal and cellular models of amyloid pathology in the context of Alzheimer's disease. The rare familial mutations in APP and presenilin-1/2, which sometimes drive increased amyloid β (Aβ) production, may have unduly influenced Alzheimer's disease research. APP and its cleavage products play important roles in cellular and mitochondrial metabolism, but many studies focus solely on Aβ. Mitochondrial bioenergetic metabolism is essential for neuronal function, maintenance and survival, and multiple reports indicate mitochondrial abnormalities in patients with Alzheimer's disease. In this review, we focus on mitochondrial abnormalities reported in sporadic Alzheimer's disease patients and the role of full-length APP and its non-amyloidogenic fragments, particularly soluble APPα, on mitochondrial bioenergetic metabolism. We do not review the plethora of animal and in vitro studies using mutant APP/presenilin constructs or experiments using exogenous Aβ. In doing so, we aim to invigorate research and discussion around non-amyloidogenic APP processing products and the mechanisms linking mitochondria and complex neurodegenerative disorders such as sporadic Alzheimer's disease. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

Background The role of problematic anger in relation to economic difficulties is not well understood. This study examined the association of problematic anger with 4 elements of economic difficulties among service members and veterans. Methods Study participants (n = 95,895) were from the Millennium Cohort Study, and included U.S. service members and veterans; analyses were restricted to a Reserve/National Guard and/or veteran sample as appropriate. Key measures included the Dimensions of Anger Reactions scale and self-reported economic variables (involuntary job loss, financial problems, unemployment and homelessness). Covariates included demographics, military characteristics, disabling injury or illness, problem drinking, posttraumatic stress disorder, and major depressive disorder. The study design was cross-sectional. Results Among all participants, 17.4% screened positive for problematic anger, 29.7% reported involuntary job loss, and 6.4% reported financial problems. After adjustment for covariates, problematic anger was associated with involuntary job loss (AOR=1.28; 95% CI: 1.22, 1.33) and financial problems (AOR=1.46; 95% CI: 1.36, 1.57). Among veterans, 12.1% reported being unemployed; among Reserve/National Guard and veterans, 2.3% reported homelessness. Problematic anger was associated with unemployment (AOR=1.28, 95% CI: 1.18, 1.37) and homelessness (AOR=1.33; 95% CI: 1.16, 1.52) after adjusting for covariates. Limitations The study relied on self-report data and directionality could not be established. Conclusions Problematic anger was significantly associated with involuntary job loss, financial problems, unemployment and homelessness, even after adjusting for relevant covariates. These findings have clinical relevance in demonstrating the potential for targeting problematic anger in service members and veterans.

Mammalian mitochondrial ribosomes (mitoribosomes) synthesize a small subset of proteins, which are essential components of the oxidative phosphorylation machinery. Therefore, their function is of fundamental importance to cellular metabolism. The assembly of mitoribosomes is a complex process that progresses through numerous maturation and protein-binding events coordinated by the actions of several assembly factors. Dysregulation of mitoribosome production is increasingly recognized as a contributor to metabolic and neurodegenerative diseases. In recent years, mutations in multiple components of the mitoribosome assembly machinery have been associated with a range of human pathologies, highlighting their importance to cell function and health. Here, we provide a review of our current understanding of mitoribosome biogenesis, highlighting the key factors involved in this process and the growing number of mutations in genes encoding mitoribosomal RNAs, proteins, and assembly factors that lead to human disease.

Humans evolved by losing the capacity to synthesize the glycan Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal), which resulted in the capacity to develop a protective response mediated by anti-α-Gal IgM/IgG antibodies against pathogens containing this modification on membrane proteins. As an evolutionary trade-off, humans can develop the alpha-Gal syndrome (AGS), a recently diagnosed disease mainly associated with allergic reactions to mammalian meat consumption. The etiology of the AGS is the exposure to tick bites and the IgE antibody response against α-Gal-containing glycoproteins and glycolipids. The objective of this study was to characterize the anti-α-Gal antibody response in association with the immune-mediated peripheral neuropathy, Guillain-Barré syndrome (GBS), and compare it with different factors known to modulate the antibody response to α-Gal such as exposure to tick bites and development of allergic reactions in response to tick bites. The results showed a significant decrease in the IgM/IgG response to α-Gal in GBS patients when compared to healthy individuals. In contrast, the IgM/IgG levels to α-Gal did not change in patients with allergic reactions to tick bites. The IgE response was not affected in GBS patients, but as expected, the IgE levels significantly increased in individuals exposed to tick bites and patients with tick-associated allergies. These results suggest that the immune pathways of anti-α-Gal IgM/IgG and IgE production are independent. Further studies should consider the susceptibility to allergic reactions to tick bites in GBS patients., This work was supported by the Consejería de Educación, Cultura y Deportes, JCCM, Spain, project CCM17-PIC-036 (SBPLY/17/180501/000185). MV was supported by the University of Castilla La Mancha (UCLM, Spain) and the Fondo Europeo de Desarrollo Regional, FEDER, EU. IGFM was supported by the UCLM. MC was funded by the Ministerio de Ciencia, Innovación y Universidades, Spain (grant FJC-2018-038277-I).

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality and the only cancer for which the incidence and mortality are on the rise. Sensitive and specific screening and diagnostic approaches, robust staging regimens, multidisciplinary tumor boards, and patient/family education and engagement in the shared decision-making process help to identify a patient's optimal treatment options. Locoregional therapies have been the mainstay for treating intermediate-stage disease, but they are finding special applications for early and advanced disease. This review discusses the diagnosis of HCC, current accepted staging models, and treatment of HCC, with a focus on locoregional therapies.

Versión preprint disponible en: http://hdl.handle.net/10261/216781, The coronavirus disease 19 (COVID‐19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has affected millions of people worldwide. The characterization of the immunological mechanisms involved in disease symptomatology and protective response is important to advance in disease control and prevention. Humans evolved by losing the capacity to synthesize the glycan Galα1‐3Galβ1‐(3)4GlcNAc‐R (α‐Gal), which resulted in the development of a protective response against pathogenic viruses and other microorganisms containing this modification on membrane proteins mediated by anti‐α‐Gal IgM/IgG antibodies produced in response to bacterial microbiota. In addition to anti‐α‐Gal antibody‐mediated pathogen opsonization, this glycan induces various immune mechanisms that have shown protection in animal models against infectious diseases without inflammatory responses. In this study, we hypothesized that the immune response to α‐Gal may contribute to the control of COVID‐19. To address this hypothesis, we characterized the antibody response to α‐Gal in patients at different stages of COVID‐19 and in comparison with healthy control individuals. The results showed that while the inflammatory response and the anti‐SARS‐CoV‐2 (Spike) IgG antibody titers increased, reduction in anti‐α‐Gal IgE, IgM and IgG antibody titers and alteration of anti‐α‐Gal antibody isotype composition correlated with COVID‐19 severity. The results suggested that the inhibition of the α‐Gal‐induced immune response may translate into more aggressive viremia and severe disease inflammatory symptoms. These results support the proposal of developing interventions such as probiotics based on commensal bacteria with α‐Gal epitopes to modify the microbiota and increase the α‐Gal‐induced protective immune response and reduce the severity of COVID‐19., This work was partially supported by the Consejería de Educación, Cultura y Deportes, JCCM, Spain, project CCM17-PIC-036 (SBPLY/17/180501/000185). We acknowledge the University of Castilla La Mancha (UCLM, Spain) support to Grupo SaBio. MC was funded by the Ministerio de Ciencia, Innovación y Universidades, Spain (grant FJC-2018-038277-I). IGFM was supported by the UCLM. MV was supported by the UCLM and the Fondo Europeo de Desarrollo Regional, FEDER, EU.

The coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) has afected millions of people worldwide. Recent evidence raised the question about the possibility that cats may be a domestic host for SARS-CoV-2 with unknown implications in disease dissemination. Based on the fact that the domestic cat fea, Ctenocephalides felis, are abundant ectoparasites infesting humans, companion animals and wildlife and that coronavirus-like agents have been identifed in the ectoparasite tick vector, Ixodes uriae of seabirds, herein we considered the presence of coronaviruses in general and SARS-CoV-2 in particular in C. felis. We identi‑ fed coronavirus-derived and cell receptor angiotensin-converting enzyme RNA/proteins in C. felis. Although cur‑ rent evidence suggests that pets are probably dead-end-hosts with small risk of transmission to humans, our results suggested that cat fea may act as biological and/or mechanical vectors of SARS-CoV. Although preliminary, these results indicate a possibility of ectoparasites acting as reservoirs and vectors of SARS-CoV and related beta-coronavirus although with little disease risk due to systemic transmission route, low viremia, virus attenuation or other unknown factors. These results support the need to further study the role of animal SARS-CoV-2 hosts and their ectoparasite vectors in COVID-19 disease spread., MV was supported by the UCLM and the Fondo Europeo de Desarrollo Regional, FEDER, EU. IGFM was supported by the UCLM. SA-J was supported by a predoctoral fellowship of the UCLM. MC was funded by the Ministerio de Ciencia, Innovación y Universidades, Spain (Grant FJC-2018-038277-I).

The coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide. The characterization of the immunological mechanisms involved in disease symptomatology and protective response is important to advance in disease control and prevention. Humans evolved by losing the capacity to synthesize the glycan Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal), which resulted in the development of a protective response against pathogenic viruses and other microorganisms containing this modification on membrane proteins mediated by anti-α-Gal IgM/IgG antibodies produced in response to bacterial microbiota. In addition to anti-α-Gal antibody-mediated pathogen opsonization, this glycan induces various immune mechanisms that have shown protection in animal models against infectious diseases without inflammatory responses. In this study, we hypothesized that the immune response to α-Gal may contribute to the control of COVID-19. To address this hypothesis, we characterized the antibody response to α-Gal in patients at different stages of COVID-19 and in comparison with healthy control individuals. The results showed that while the inflammatory response and the anti-SARS-CoV-2 (Spike) IgG antibody titers increased, reduction in anti-α-Gal IgE, IgM and IgG antibody titers and alteration of anti-α-Gal antibody isotype composition correlated with COVID-19 severity. The results suggested that the inhibition of the α-Gal-induced immune response may translate into more aggressive viremia and severe disease inflammatory symptoms. These results support the proposal of developing interventions such as probiotics based on commensal bacteria with α-Gal epitopes to modify the microbiota and increase the α-Gal-induced protective immune response and reduce the severity of COVID-19., This work was partially supported by the Consejería de Educación, Cultura y Deportes, JCCM, Spain, project CCM17-PIC-036 (SBPLY/17/180501/000185). We thank Antonio Mas (University of Castilla La Mancha, UCLM, Spain) for the critical reading of the manuscript. We acknowledge UCLM, Spain support to Grupo SaBio. MC was funded by the Ministerio de Ciencia, Innovación y Universidades, Spain (grant FJC-2018-038277-I). IGFM was supported by the UCLM. MV was supported by the UCLM and the Fondo Europeo de Desarrollo Regional, FEDER, EU.

Incomplete non-sterile immunity to malaria is attained in endemic regions after recurrent infections by a large percentage of the adult population, who carry the malaria parasite asymptomatically. Although blood-stagePlasmodium falciparumrapidly elicits IgG responses, the target antigens of partially protective and non-protective IgG antibodies as well as the basis for the acquisition of these antibodies remain largely unknown. We performed IgG-immunomics to screen forP. falciparumantigens and to identify epitopes associated with exposure and clinical disease. Sera from malaria cases identified five prevalent antigens recognized by all analyzed patients’ IgGs. For further epitope mapping, peptide microarrays designed to cover their sequences were probed with a set of 38 sera samples from adult individuals of an endemic malaria region in Ghana. Eight 20-mer peptides with the highest affinity and frequency of recognition among the population were subsequently validated with 16 sera from the same region, segregated into patients with positive or negative subclinical detection ofP. falciparum. Significant binding specificity for two immunodominant antigenic regions was uncovered within the START-related lipid transfer protein and the protein disulfide isomerase PDI8. These 20-mer peptides challenged with sera samples from children under 5 years old displayed specific IgG binding in those with detectable parasitemia, even at subclinical level. These results suggest that the humoral response against START and PDI8 antigens may be triggered even at submicroscopic parasitemia levels in children and may eventually be used to differentially diagnose subclinical malaria in children.SignificanceMalaria in Africa is a leading cause of morbidity and mortality. The reservoirs of the malaria parasite are asymptomatic patients who carry it subclinically. Identifying the parasite antigens and its fragments that trigger the most common immunity response by immunoglobulin G that partially protect people can have profound implications for both, development of a malaria vaccine and diagnosis of the subclinical parasite carriers. Antigen discovery and mapping, validated with sera from subclinical carriers, showed that immunoglobulin G responses in children against parasite’s START and PDI8 may eventually be used to differentially diagnose non-infected from subclinical cases. Furthermore, anti-START and anti-PDI8 endemic immunodominance provides association of these antigens with long-term acquired immunity and immune evasion to malaria.

The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that aim to stimulate mitochondrial biogenesis to boost ATP generation above a critical disease threshold. Here, we examine the effects of the peroxisome proliferator-activated receptor γ (PPARγ) activator pioglitazone (PioG), in combination with deoxyribonucleosides (dNs), on mitochondrial biogenesis in cybrid cells containing >90% of the m.3243A>G mutation associated with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). PioG + dNs combination treatment increased mtDNA copy number and mitochondrial mass in both control (CON) and m.3243A>G (MUT) cybrids, with no adverse effects on cell proliferation. PioG + dNs also increased mtDNA-encoded transcripts in CON cybrids, but had the opposite effect in MUT cybrids, reducing the already elevated transcript levels. Steady-state levels of mature oxidative phosphorylation (OXPHOS) protein complexes were increased by PioG + dNs treatment in CON cybrids, but were unchanged in MUT cybrids. However, treatment was able to significantly increase maximal mitochondrial oxygen consumption rates and cell respiratory control ratios in both CON and MUT cybrids. Overall, these findings highlight the ability of PioG + dNs to improve mitochondrial respiratory function in cybrid cells containing the m.3243A>G MELAS mutation, as well as their potential for development into novel therapies to treat mitochondrial disease.

Leber hereditary optic neuropathy (LHON) is one of the most common primary mitochondrial diseases. It is caused by point mutations in mitochondrial DNA (mtDNA) genes and in some cases, it can result in irreversible vision loss, primarily in young men. It is currently unknown why LHON mutations affect only some carriers and whether bioenergetic compensation enables unaffected carriers to overcome mitochondrial impairment and preserve cellular function. Here, we conducted bioenergetic metabolic assays and RNA sequencing to address this question using male-only, age-matched, m.11778G > A lymphoblasts and primary fibroblasts from both unaffected carriers and affected individuals. Our work indicates that OXPHOS bioenergetic compensation in LHON peripheral cells does not explain disease phenotype. We show that complex I impairment is similar in cells from unaffected carrier and affected patients, despite a transcriptional downregulation of metabolic pathways including glycolysis in affected cells relative to carriers detected by RNA sequencing. Although we did not detect OXPHOS bioenergetic compensation in carrier cells under basal conditions, our results indicate that cells from affected patients suffer a growth impairment under metabolic challenge compared to carrier cells, which were unaffected by metabolic challenge. If recapitulated in retinal ganglion cells, decreased susceptibility to metabolic challenge in unaffected carriers may help preserve metabolic homeostasis in the face of the mitochondrial complex I bioenergetic defect.

Background: Acute pulmonary embolism (PE) is characterized hemodynamically by abrupt obstruction in trans-pulmonary blood flow. The echocardiographic Pulmonary to Left Atrial ratio (ePLAR, tricuspid regurgitation Vmax/mitral E/e&rsquo, ) has been validated as a non-invasive surrogate for trans-pulmonary gradient (TPG) that accurately differentiates pre-capillary from post-capillary chronic pulmonary hypertension. This study assessed ePLAR as an incremental echocardiographic assessment tool compared with traditional measures of right ventricular pressure and function. Methods: In total, 110 (57.4 &plusmn, 17.6 years) patients with confirmed sub-massive pulmonary emboli with contemporaneous echocardiograms (0.3 &plusmn, 0.9 days) were compared with 110 age-matched controls (AMC). Results: Tricuspid velocities were higher than AMC (2.6 &plusmn, 0.6 m/s vs. 2.4 &plusmn, 0.3 m/s, p &lt, 0.05), although still consistent with &ldquo, normal&rdquo, right ventricular systolic pressures (34.2 &plusmn, 13.5 mmHg vs. 25 &plusmn, 5.3 mmHg, p &lt, 0.05) with lower mitral E/e&rsquo, values (8.2 &plusmn, 3.8 vs. 10.8 &plusmn, 5.1, p &lt, 0.05). ePLAR values were higher than AMC (0.36 &plusmn, 0.14 m/s vs. 0.26 &plusmn, 0.10, p &lt, 0.05) suggesting significantly elevated TPG. Detection of abnormal echocardiographic findings increased from 29% (TRVmax &ge, 2.9 m/s) and 32% (reduced tricuspid annular plane systolic excursion) to 70% with ePLAR &ge, 0.3 m/s. Conclusions: Raised ePLAR values in acute sub-massive pulmonary embolism suggest elevated trans-pulmonary gradients even in the absence of acutely increased pulmonary artery pressures. ePLAR dramatically increases the sensitivity of echocardiography for detection of hemodynamic perturbations in sub-massive pulmonary embolism patients, which may offer clinical utility in diagnosis and management.