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Aging; Arteriosclerosis; Hemodynamics Envelliment; Arteriosclerosi; Hemodinàmica Envejecimiento; Arteriosclerosis; Hemodinámica Arterial pulse waves (PWs) such as blood pressure and photoplethysmogram (PPG) signals contain a wealth of information on the cardiovascular (CV) system that can be exploited to assess vascular age and identify individuals at elevated CV risk. We review the possibilities, limitations, complementarity, and differences of reduced-order, biophysical models of arterial PW propagation, as well as theoretical and empirical methods for analyzing PW signals and extracting clinically relevant information for vascular age assessment. We provide detailed mathematical derivations of these models and theoretical methods, showing how they are related to each other. Finally, we outline directions for future research to realize the potential of modeling and analysis of PW signals for accurate assessment of vascular age in both the clinic and in daily life. This article is based upon work from COST Action “Network for Research in Vascular Ageing” (VascAgeNet, CA18216), supported by COST (European Cooperation in Science and Technology, www.cost.eu). This work was supported by British Heart Foundation Grants PG/15/104/31913 (to J.A. and P.H.C.), FS/20/20/34626 (to P.H.C.), and AA/18/6/34223, PG/17/90/33415, SPG 2822621, and SP/F/21/150020 (to A.D.H.); Kaunas University of Technology Grant INP2022/16 (to B.P.); European Research Executive Agency, Marie-Sklodowska Curie Actions Individual Fellowship Grant 101038096 (to S.P.); Istinye University, BAP Project Grant 2019B1 (to S.P.); “la Caixa” Foundation Grant LCF/BQ/PR22/11920008 (to A.G.); and National Institute for Health and Care Research Grant AI AWARD02499 and EU Horizon 2020 Grant H2020 848109 (to A.D.H.).

Muscle atrophy is an extra-pulmonary complication of acute exacerbations (AE) in chronic obstructive pulmonary disease (COPD). The endogenous production and therapeutic application of glucocorticoids (GCs) have been implicated as drivers of muscle loss in AE-COPD. The enzyme 11 beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) activates GCs and contributes towards GC-induced muscle wasting. To explore the potential of 11betaHSD1 inhibition to prevent muscle wasting here, the objective of this study was to ascertain the contribution of endogenous GC activation and amplification by 11betaHSD1 in skeletal muscle wasting during AE-COPD. Emphysema was induced by intra-tracheal (IT) instillation of elastase to model COPD in WT and 11betaHSD1/KO mice, followed by vehicle or IT-LPS administration to mimic AE. microCT scans were obtained prior and at study endpoint 48h following IT-LPS, to assess emphysema development and muscle mass changes, respectively. Plasma cytokine and GC profiles were determined by ELISA. In vitro myonuclear accretion and cellular response to plasma and GCs were determined in C2C12 and human primary myotubes. Muscle wasting was exacerbated in LPS-11betaHSD1/KO animals compared to WT controls. RT-qPCR and western blot analysis showed elevated catabolic and suppressed anabolic pathways in muscle of LPS-11betaHSD1/KO animals relative to WTs. Plasma corticosterone levels were higher in LPS-11betaHSD1/KO animals, whilst C2C12 myotubes treated with LPS-11betaHSD1/KO plasma or exogenous GCs displayed reduced myonuclear accretion relative to WT counterparts. This study reveals that 11beta-HSD1 inhibition aggravates muscle wasting in a model of AE-COPD, suggesting that therapeutic inhibition of 11beta-HSD1 may not be appropriate to prevent muscle wasting in this setting.

Aims TASK-1 (K2P3.1) two-pore domain potassium channels are atrial-specific and significantly upregulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening. Doxapram was identified as a potent inhibitor of the TASK-1 channel. In the present study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF. Methods and results Doxapram successfully cardioverted pigs with artificially induced episodes of AF. We established a porcine model of persistent AF in domestic pigs via intermittent atrial burst stimulation using implanted pacemakers. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 d of doxapram treatment. Pigs in the treatment group received intravenous administration of doxapram once per day. In doxapram-treated AF pigs, the AF burden was significantly reduced. After 14 d of treatment with doxapram, TASK-1 currents were still similar to values of sinus rhythm animals. Doxapram significantly suppressed AF episodes and normalized cellular electrophysiology by inhibition of the TASK-1 channel. Patch-clamp experiments on human atrial cardiomyocytes, isolated from patients with and without AF could reproduce the TASK-1 inhibitory effect of doxapram. Conclusions Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients. Translational perspective Pharmacological suppression of atrial TASK 1 potassium currents prolongs atrial refractoriness with no effects on ventricular repolarization, resulting in atrial-specific class III antiarrhythmic effects. In our preclinical pilot study the respiratory stimulant doxapram was successfully administered for cardioversion of acute AF as well as rhythm control of persistent AF in a clinically relevant porcine animal model.

ObjectiveTo examine the effects of autoregulated (AUTO) and non-autoregulated (NAUTO) blood flow restriction (BFR) application on adverse effects, performance, cardiovascular and perceptual responses during resistance exercise.MethodsFifty-six healthy participants underwent AUTO and NAUTO BFR resistance exercise in a randomised crossover design using a training session with fixed amount of repetitions and a training session until volitional failure. Cardiovascular parameters, rate of perceived effort (RPE), rate of perceived discomfort (RPD) and number of repetitions were investigated after training, while the presence of delayed onset muscle soreness (DOMS) was verified 24 hours post-session. Adverse events during or following training were also monitored.ResultsAUTO outperformed NAUTO in the failure protocol (pConclusionAutoregulation appears to enhance safety and performance in both fixed and failure BFR-training protocols. AUTO BFR training did not seem to affect cardiovascular stress differently, but was associated with lower DOMS, perceived effort and discomfort compared with NAUTO.Trial registration numberNCT04996680.

Longitudinal motion of the carotid arterial wall, as measured with ultrasound, has shown promise as an indicator of vascular health. The underlying mechanisms are however not fully understood. We have found, in in vivo studies, that blood pressure has a strong relation to the antegrade longitudinal displacement in early systole. Further, we have identified that a tapered geometry and the intramural friction in-between two parts of a vessel wall influence the longitudinal displacement. We therefore studied the interaction between pressure, vessel geometry and intramural friction, tapered and straight ultrasound phantoms in a paralleled hydraulic bench study and corresponding numerical models. Profound antegrade longitudinal motion was induced in the innermost part of both tapered phantoms and the numerical models, but to a lesser extent when intramural friction was increased in the simulations. Strong correlations (R = 0.82-0.96; p < 1e-3; k = 9.3-14 mu m/mmHg) between longitudinal displacement and pulse pressure were found in six of seven regions of interest in tapered phantoms. The motion of the straight phantom and the corresponding numerical model was smaller, on average zero or close to zero. This study demonstrates that tapering of the lumen, low intramural friction, and pressure might be important conducive features to the antegrade longitudinal motion of the arterial wall in vivo.

Connexin: Ischemia-reperfusion injury; Mitochondria Conexina; Lesión por isquemia-reperfusión; Mitocondrias Connexina; Lesió per isquèmia-reperfusió; Mitocondris Connexins are known for their ability to mediate cell-cell communication via gap junctions and also form hemichannels that pass ions and molecules over the plasma membrane when open. Connexins have also been detected within mitochondria, with mitochondrial connexin 43 (Cx43) being the best studied to date. In this review, we discuss evidence for Cx43 presence in mitochondria of cell lines, primary cells and organs and summarize data on its localization, import and phosphorylation status. We further highlight the influence of Cx43 on mitochondrial function in terms of respiration, opening of the mitochondrial permeability transition pore and formation of reactive oxygen species, and also address the presence of a truncated form of Cx43 termed Gja1-20k. Finally, the role of mitochondrial Cx43 in pathological conditions, particularly in the heart, is discussed. KB is funded by the German Research Foundation (BO 2955/4-1). LL is supported by the Research Foundation Flanders (FWO) grant numbers G.0527.18N and G040720N. MR-M is supported by the Instituto de Salud Carlos III of the Spanish Ministry of Health (FIS-PI19-01196) and a grant from the Sociedad Española de Cardiología (SEC/FEC-INV- BAS 217003).

BackgroundAfter mating, female mosquitoes need animal blood to develop their eggs. In the process of acquiring blood, they may acquire pathogens, which may cause different diseases to humans such as malaria, zika, dengue, and chikungunya. Therefore, knowing the parity status of mosquitoes is useful in control and evaluation of infectious diseases transmitted by mosquitoes, where parous mosquitoes are assumed to be potentially infectious. Ovary dissections, which currently are used to determine the parity status of mosquitoes, are very tedious and limited to very few experts. An alternative to ovary dissections is near-infrared spectroscopy (NIRS), which can estimate the age in days and the infectious state of laboratory and semi-field reared mosquitoes with accuracies between 80 and 99%. No study has tested the accuracy of NIRS for estimating the parity status of wild mosquitoes.Methods and resultsIn this study, we train artificial neural network (ANN) models on NIR spectra to estimate the parity status of wild mosquitoes. We use four different datasets: An. arabiensis collected from Minepa, Tanzania (Minepa-ARA); An. gambiae collected from Muleba, Tanzania (Muleba-GA); An. gambiae collected from Burkina Faso (Burkina-GA); and An.gambiae from Muleba and Burkina Faso combined (Muleba-Burkina-GA). We train ANN models on datasets with spectra preprocessed according to previous protocols. We then use autoencoders to reduce the spectra feature dimensions from 1851 to 10 and re-train ANN models. Before the autoencoder was applied, ANN models estimated parity status of mosquitoes in Minepa-ARA, Muleba-GA, Burkina-GA and Muleba-Burkina-GA with out-of-sample accuracies of 81.9 ± 2.8% (N=927), 68.7 ± 4.8% (N=140), 80.3 ± 2.0% (N=158), and 75.7 ± 2.5% (N=298), respectively. With the autoencoder, ANN models tested on out-of-sample data achieved 97.1 ± 2.2%, (N=927), 89.8 ± 1.7% (N=140), 93.3 ± 1.2% (N=158), and 92.7 ± 1.8% (N=298) accuracies for Minepa-ARA, Muleba-GA, Burkina-GA, and Muleba-Burkina-GA, respectively.ConclusionThese results show that a combination of an autoencoder and an ANN trained on NIR spectra to estimate parity status of wild mosquitoes yields models that can be used as an alternative tool to estimate parity status of wild mosquitoes, especially since NIRS is a high-throughput, reagent-free, and simple-to-use technique compared to ovary dissections.

Estimates of the global burdens of morbidity attributable to acute attacks of Plasmodium falciparum malaria typically dwarf those of Plasmodium vivax, i.e., hundreds of millions versus tens of millions of cases. Global burden estimates take no account of latent and subpatent reservoirs of infections carrying more subtle burdens of illness and death in impoverished settings of malnutrition, coendemic infections, and limited access to quality healthcare. Impacts of chronic malaria on human health may be substantial and are excluded from estimates of burdens of acute malaria. Compartments of human infection by P. vivax beyond vascular patency—vascular subpatency, extravascular subpatency, sexual latency, and hepatic latency—obscure endemic transmission and burdens of infection and illness. Long thought to be absent from most of sub-Saharan Africa due to the high prevalence of the Duffy-negative phenotype among residents, recent investigations suggest that widespread reservoirs of transmission may occur across that region. Human glucose-6-phosphate dehydrogenase (G6PD) deficiency may also affect susceptibility to infection and directly impact access to effective antirelapse therapy of P. vivax using 8-aminoquinolines that are dangerous to those patients. Natural polymorphisms of the human cytochrome P-450 2D6 gene impact parasite susceptibility to primaquine antirelapse therapy at population levels. All these factors impose great complexity in considering estimates of burdens of P. vivax and access to effective mitigation of the harm caused. The conventional diagnostics underpinning epidemiological and clinical understanding of vivax malaria may be inadequate to the biology of this parasite.

Background Turner syndrome (TS) is a chromosomal disorder, in which a female is partially or entirely missing one of the two X chromosomes, with a prevalence of 1:2500 live female births. The present study aims to identify a circulating microRNA (miRNA) signature for TS patients with and without congenital heart disease (CHD). Methods Microarray platform interrogating 2549 miRNAs were used to detect the miRNA abundance levels in the blood of 33 TS patients and 14 age-matched healthy volunteer controls (HVs). The differentially abundant miRNAs between the two groups were further validated by RT-qPCR. Results We identified 60 differentially abundant miRNA in the blood of TS patients compared to HVs, from which, 41 and 19 miRNAs showed a higher and a lower abundance levels in TS patients compared to HVs, respectively. RT-qPCR confirmed the significantly higher abundance levels of eight miRNAs namely miR-374b-5p, miR-199a-5p, miR-340-3p, miR-125b-5p, miR-30e-3p, miR-126-3p, miR-5695, and miR-26b-5p in TS patients as compared with the HVs. The abundance level of miR-5695 was higher in TS patients displaying CHD as compared to TS patients without CHD (p = 0.0265; log2-fold change 1.99); whereas, the abundance level of miR-126-3p was lower in TS patients with congenital aortic valve disease (AVD) compared to TS patients without BAV (p = 0.0139, log2-fold change 1.52). The clinical feature statistics revealed that miR-126-3p had a significant correlation with sinotubular junction Z-score (r = 0.42; p = 0.0154). Conclusion The identified circulating miRNAs signature for TS patients with manifestations associated with cardiovascular diseases provide new insights into the molecular mechanism of TS that may guide the development of novel diagnostic approaches.

Current methods for identification of oxygenator clotting during prolonged extracorporeal life support include visual inspection, evaluation of oxygenator resistance and oxygen exchange performance, and assessment of clotting-related laboratory parameters. However, these observations do not provide a quantitative assessment of oxygenator clot formation. By measuring changes in the dynamic oxygenator blood volume this study aimed to evaluate the relation to oxygenator resistance and oxygen transfer performance. Sixty-seven oxygenators were studied during adult extracorporeal life support. Oxygenator blood volume, oxygenator resistance, and oxygen transfer efficiency were monitored. Oxygenator blood volume decreased with increasing runtime (r = -0.462; p 2 transfer was found. Oxygenator blood volume declined over time and was clearly associated with an increasing oxygenator resistance during prolonged extracorporeal life support, though O2 transfer was less affected.

Background The infestation with Echinococcus multilocularis larvae may persist in humans for up to decades without evident clinical symptoms. Longitudinal investigations are needed to understand the dynamic immunological processes in alveolar echinococcosis (AE) patients associated with an active and progressive, a stable or a regressive course of disease. Methodology/Principal findings This study evaluated the E. multilocularis specific antibody responses, systemic cytokine, and chemokine serum levels over a 10-year follow-up period, as well as cellular responsiveness in AE patients. Our results demonstrate a rapid decrease in antibodies against E. multilocularis specific antigen Em2+. Especially in cured patients, these antibodies remained negative, making them a significant predictor for cured AE. E. multilocularis specific IgG4, and indirect hemagglutination IHA decreased later in time, after around 5 years. While total IgE did not show significant dynamics over the course of disease, E. multilocularis specific IgE decreased after one to two years, and increasing levels were a significant predictor of progressive disease. There was no significant change in systemic IL-8, IL-9, CCL18 or CCL20 serum levels over time. Univariate analysis across groups indicated lower IL-8 levels in cured patients; however, this result could not be confirmed by multivariate analysis. Levels of CCL17 decreased during treatment, especially in cured patients, and thus might serve as a predictive or risk factor for progressive disease. Levels of IL-10 and CCL13 decreased during disease, especially after five and ten years of intervention. The E. multilocularis antigen (EmAg) inducible cellular productions of MCP1(CCL13), TARC(CCL17) and PARC(CCL18) were lowest in patients with cured AE and infection-free controls, while the EmAg inducible cellular production of IFN-γ increased after cure. Significant positive cytokine and chemokine correlations were observed in AE patients for IL-9, IL-10, CCL13(MCP-4), CCL17(TARC) and CCL20(LARC)(for all p, Author summary Alveolar echinococcosis (AE) is a severe disease caused by Echinococcus multilocularis, the fox tapeworm. Humans exposed to E. multilocularis may develop severe AE with progressive tissue and organ infiltrating growth of the larval stage. The E. multilocularis larvae appear to have developed effective immune evasion mechanisms which facilitate an asymptomatic incubation and an extended host and parasite coexistence for decades. Over a 10-year follow-up, this investigation aimed to gain a better understanding of the immunological process associated with an active and progressive, a stable or a regressive course of AE. In summary, the rapid decrease of antibodies against the E. multilocularis specific antigen Em2+, especially in cured patients, makes them a significant predictor for cured AE. The positive relation of E. multilocularis specific IgG4 responses and chemokine levels of TARC can indicate AE progression when both enhance over time. Enhanced levels of cytokines IL-8, IL-10, and chemokines MCP4 and LARC may predict AE regression. Repeated biomarker surveys are advisable to evaluate progression or regression of AE during longitudinal follow up, and such analyses can support imaging techniques and improve staging of AE patients.

Dysregulation of calcium homeostasis has been hypothesized to play a role in Alzheimer’s disease (AD) pathogenesis. Increased calcium levels can impair axonal transport, disrupt synaptic transmission, and ultimately lead to cell death. Given the potential role of calcium dyshomeostasis in AD, there is interest in testing the ability of already approved drugs targeting various calcium channels to affect amyloid pathology and other aspects of disease. The objective of this study was to test the effects of FDA-approved L-type calcium channel antagonist nimodipine on amyloid accumulation and dystrophic neurite formation in 5XFAD mice, a mouse model of amyloid pathology. 5XFAD transgenic mice and non-transgenic littermates were treated with vehicle or nimodipine-containing chow from two to eight months of age, then brains were harvested and amyloid pathology assessed by immunoblot and immunofluorescence microscopy analyses. Nimodipine was well tolerated and crossed the blood brain barrier, as expected, but there was no effect on Aβ accumulation or on the relative amount of neuritic dystrophy, as assessed by either immunoblot, dot blot or immunofluorescence imaging of Aβ42 and dystrophic neurite marker LAMP1. While we conclude that nimodipine treatment is not likely to improve amyloid pathology or decrease neuritic dystrophy in AD, it is worth noting that nimodipine did not worsen the phenotype suggesting its use is safe in AD patients.

Background The variations in ABO blood groups are reported to be associated with multiple disorders, including ulcerative colitis (UC). We aimed to investigate the distribution of ABO blood groups in UC patients and explore its impact on disease severity. Methods We retrospectively collected 129 UC patients diagnosed at our hospital between January 2000 and November 2019. Clinical characteristics, ABO blood groups, and operation rates were analyzed. Results The mean diagnostic age of patients was 38.97 years. Males accounted for the majority of all patients (62.8%). Of 129 patients, 43 (33.3%) were blood type O, 41 (31.8%) were blood type A, 38 (29.5%) were blood type B, and 7 (5.4%) were blood type AB. Although our patients had higher ratio of blood type A comparing our general population, there was no statistically significant association of ABO blood types distribution between these two groups (p = 0.1906). In the subgroup analysis, there were no significant difference of disease locations and operation rates between different ABO blood groups. Furthermore, blood type A patients had higher serum hemoglobin (Hb) levels compared to blood type O patients (13.31 g/dL vs. 12.30 g/dL, p = 0.0347). Blood type A patients had lower serum erythrocyte sedimentation rate (ESR) levels compared to blood type O patients (12.46 mm/hour vs. 21.5 mm/hour, p = 0.0288). Blood type O had higher serum ESR levels compared to non-O groups (p = 0.0228). In the ABO blood groups and mean diagnostic age (≤ 40 years or > 40 years), there were no statistically significant difference between these two age groups, p = 0.5515. Conclusions Our results showed ABO blood groups are not associated with UC in spite of a higher ratio of blood type A in our patients. Blood type O patients had higher serum ESR levels; however, blood type A patients had higher Hb levels.

Objectives Pain can have a negative impact on sleep and emotional well-being. This study investigated whether this may be partly explained by maladaptive sleep-related cognitive and behavioural responses to pain, including heightened anxiety about sleep and suboptimal sleep hygiene. Methods This cross-sectional study used data from an online survey that collected information about pain (Brief Pain Inventory), sleep (Pittsburgh Sleep Quality Index; Sleep Hygiene Index; Anxiety and Preoccupation about Sleep Questionnaire) and emotional distress (PROMIS measures; Perceived Stress Scale). Structural equation modelling examined the tenability of a framework linking these factors. Results Of 468 survey respondents (mean age 39 years, 60% female), 29% reported pain (mean severity 1.12), most commonly in the spine or low back (28%). Pain severity correlated with poor sleep quality, poor sleep hygiene, anxiety about sleep and emotional distress. In the first structural equation model, indirect effects were identified between pain severity and sleep quality through anxiety about sleep (β = .08, p < .001) and sleep hygiene (β = .12, p < .001). In the second model, an indirect effect was identified between pain severity and emotional distress through sleep quality (β = .19, p < .01). Combining these models, indirect effects were identified between pain severity and emotional distress through anxiety about sleep, sleep hygiene and sleep quality. Conclusions This study provides data to support the tenability of a theoretically guided framework linking pain, sleep and emotional distress. If upheld by experimental and/or longitudinal study, this framework holds the potential to inform public health initiatives and more comprehensive pain assessment.

Background Low participation rates (1–31%) and unique barriers to strength training (e.g., specialized knowledge, equipment, perceived complexity) suggest effective strength training interventions may differ from effective aerobic or general physical activity interventions. The purpose of this scoping review was to examine interventions used to improve strength training participation through mapping theory, intervention characteristics, prescription parameters, and behaviour change techniques. Methods Recommendations by Levac et al. (2010) and PRISMA-ScR were followed in the conduct and reporting of this review, respectively. Patients and exercise professionals participated in developing the research question and data extraction form, interpreting the findings, and drafting the manuscript. Medline, Embase, PsycINFO, CINAHL, SPORTDiscus, and PubMed databases (inception–December 2020) were searched. The inclusion criteria were (a) original peer-reviewed articles and grey literature, (b) intervention study design, and (c) behavioural interventions targeted towards improving strength training participation. Two reviewers performed data screening, extraction, and coding. The interventions were coded using the Behaviour Change Technique Taxonomy version 1. Data were synthesized using descriptive and frequency reporting. Results Twenty-seven unique interventions met the inclusion criteria. Social cognitive theory (n = 9), the transtheoretical model (n = 4), and self-determination theory (n = 2) were the only behaviour change theories used. Almost all the interventions were delivered face-to-face (n = 25), with the majority delivered by an exercise specialist (n = 23) in community or home settings (n = 24), with high variability in exercise prescription parameters. Instructions on how to perform the behaviour, behavioural practice, graded tasks, goal setting, adding objects to the environment (e.g., providing equipment), and using a credible source (e.g., exercise specialist delivery) comprised the most common behaviour change techniques. Conclusions Our results highlight gaps in theory, intervention delivery, exercise prescription parameters, and behaviour change techniques for future interventions to examine and improve our understanding of how to most effectively influence strength training participation.

The intensity of malaria transmission is measured by parous rate, daily survival rate, human blood meal frequency, sporozoite rate, and entomological inoculation rates. Female parous status is a key index of vector competence, adult vector longevity, recruitment rate of adult, and the length of a gonotrophic cycle. Hence, the present study was aimed to investigate the parous rate and the longevity of Anopheles mosquitoes in Bure District, Northwestern Ethiopia. Parous rate was estimated as the number of mosquitoes with parous ovaries divided by the number of females dissected multiplied by 100. Mosquito life expectancy (longevity as d) was estimated by. One way- ANOVA was applied to confirm the presence of parous rate difference in the villages (p < 0.05). A total of 952 unfed hosts-seeking Anopheles mosquitoes was dissected for parous rate determination. The overall parous rate of An. arabiensis in the district was 52.0%, and the highest parous rate was recorded in Shnebekuma than other villages (F 2, 33 = 6.974; p = 0.003). Similarly, the parous rate of An. cinereus showed significant variation among villages (F 2, 33 = 5.044, p = 0.012) and the highest rate (63.0%) was recorded in Bukta. The mean longevity of An. funestus, An. arabiensis, An. coustani, An. squamosus, An. pharoensis, and An. cinereus was 6.5 days, 4.6 days, 3.5 days, 3.7 days, 2.7 days, and 2.2 days, respectively. The longevity of each species was not sufficient to complete the life cycle of malaria parasite for malaria transmission throughout the year because P. falciparum requires from 12–14 day.

Schistosomiasis, which is caused by infection with Schistosoma spp., is characterized by granuloma and fibrosis in response to egg deposition. Pattern recognition receptors are important to sense invading Schistosoma, triggering an innate immune response, and subsequently shaping adaptive immunity. Cyclic GMP-AMP synthase (cGAS) was identified as a major cytosolic DNA sensor, which catalyzes the formation of cyclic GMP-AMP (cGAMP), a critical second messenger for the activation of the adaptor protein stimulator of interferon genes (STING). The engagement of STING by cGAMP leads to the activation of TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), and the subsequent type I interferon (IFN) response. cGAS is suggested to regulate infectious diseases, autoimmune diseases, and cancer. However, the function of cGAS in helminth infection is unclear. In this study, we found that Cgas deficiency enhanced the survival of mice infected with S. japonicum markedly, without affecting the egg load in the liver. Consistently, Cgas deletion alleviated liver pathological impairment, reduced egg granuloma formation, and decreased fibrosis severity. In contrast, Sting deletion reduced the formation of egg granulomas markedly, but not liver fibrosis. Notably, Cgas or Sting deficiency reduced the production of IFNβ drastically in mice infected with S. japonicum. Intriguingly, intravenous administration of recombinant IFNβ exacerbated liver damage and promoted egg granuloma formation, without affecting liver fibrosis. Clodronate liposome-mediated depletion of macrophages indicated that macrophages are the major type of cells contributing to the induction of the type I IFN response during schistosome infection. Moreover, cGAS is important for type I IFN production and phosphorylation of TBK1 and IRF3 in response to stimulation with S. japonicum egg- or adult worm-derived DNA in macrophages. Our results clarified the immunomodulatory effect of cGAS in the regulation of liver granuloma formation during S. japonicum infection, involving sensing schistosome-derived DNA and producing type I IFN. Additionally, we showed that cGAS regulates liver fibrosis in a STING-type I–IFN-independent manner., Author summary The sensing of invading pathogens by pattern recognition receptors (PRRs) is important for the host to mount an immune response. Cytosolic DNA receptor cGAS has been documented as critical for the induction of innate immunity, manifesting as a type I IFN response. However, little is known about the role of cGAS or type I IFN in the process of helminth infection. In this study, we identified an important role of the cGAS-STING-type I IFN signaling axis in driving schistosome infection-induced liver inflammation. Moreover, we revealed a hitherto unknown role of cGAS in the regulation of liver fibrosis during Schistosoma infection, a process that is independent of STING. Our study revealed cGAS as a novel functional receptor for the recognition of invading Schistosoma, paving the way for the development of novel strategies to treat schistosomiasis.

Hypothermia is a common adverse event during continuous renal replacement therapy (CRRT), affecting multiple organ systems and increasing risk of poor health outcomes among patients with acute kidney injury (AKI) undergoing CRRT. TheraMax blood warmers are the next generation of extracorporeal blood warmers which reduce risk of hypothermia during CRRT. The purpose of this study is to elucidate the potential health economic impacts of avoiding CRRT-induced hypothermia by using the novel TherMax blood warming device. This study compares health care costs associated with use of the new TherMax blood warmer unit integrated with the PrisMax system compared to CRRT with a standalone blood warming device to avoid hypothermia in continuous renal replacement therapy (CRRT). An economic model was developed in which relevant health states for each intervention were normothermia, hypothermia, discharge, and death. Clinical inputs and costs were obtained from a combination of retrospective chart review and publicly available summary estimates. The proportion of AKI patients treated with CRRT who became hypothermic (

The cytokine Interferon-γ (IFN-γ) exerts powerful immunoregulatory effects on the adaptive immune system and also enhances functions of the neutrophil (PMN). The clinical use of IFN-γ has been driven by the finding that its administration to patients with chronic granulomatous disease (CGD) results in decreased incidence and severity of infections. However, IFN-γ has no effect on the characteristic defect of CGD, the inability to convert oxygen to microbicidal metabolites including superoxide anion (O2-) during the phagocytosis associated oxidative burst. We administered varying doses of IFN-γ to adult volunteers and studied the effects on plasma drug levels and response molecules and PMNs isolated from blood drawn at intervals over a 96- hour period. Plasma concentrations of IFN-γ, IP-10 and neopterin, and stimulated release of O2-from PMNs exhibited dose- and time-dependent increases after IFN-γ administration. Gene expression in PMNs was altered for 2775 genes; changes occurred rapidly after administration and returned to baseline in 24–36 hours. Several genes involved with neutrophil host defense were upregulated including those for components of the O2-generating NADPH oxidase; innate-immune and Fc receptors; proteins involved in MHCI and II; a regulator of circulating PMN number; guanylate binding proteins; and a key enzyme in synthesis of an essential NOS cofactor. Coordinate changes were detected in protein levels of representative products from several of these genes. Lysates from isolated neutrophils also demonstrated a spike in NO following IFN-γ administration. IFN-γ appears to increase non-oxygen dependent microbicidal functions of PMNs which could provide strategies to compensate for deficiencies, explain its clinical benefit for CGD patients and expand therapeutic applications of IFN-γ to other disorders.Trial registration:Protocol registered in ClinicalTrials.gov,NCT02609932, Effect of IFN-γ on Innate Immune Cells.

Within the human respiratory tract (HRT), virus diffuses through the periciliary fluid (PCF) bathing the epithelium. But virus also undergoes advection: as the mucus layer sitting atop the PCF is pushed along by the ciliated cell’s beating cilia, the PCF and its virus content are also pushed along, upwards towards the nose and mouth. While many mathematical models (MMs) have described the course of influenza A virus (IAV) infections in vivo, none have considered the impact of both diffusion and advection on the kinetics and localization of the infection. The MM herein represents the HRT as a one-dimensional track extending from the nose down towards the lower HRT, wherein stationary cells interact with IAV which moves within (diffusion) and along with (advection) the PCF. Diffusion was found to be negligible in the presence of advection which effectively sweeps away IAV, preventing infection from disseminating below the depth at which virus first deposits. Higher virus production rates (10-fold) are required at higher advection speeds (40 μm/s) to maintain equivalent infection severity and timing. Because virus is entrained upwards, upper parts of the HRT see more virus than lower parts. As such, infection peaks and resolves faster in the upper than in the lower HRT, making it appear as though infection progresses from the upper towards the lower HRT, as reported in mice. When the spatial MM is expanded to include cellular regeneration and an immune response, it reproduces tissue damage levels reported in patients. It also captures the kinetics of seasonal and avian IAV infections, via parameter changes consistent with reported differences between these strains, enabling comparison of their treatment with antivirals. This new MM offers a convenient and unique platform from which to study the localization and spread of respiratory viral infections within the HRT., Author summary This work proposes a new way to think about and model the dissemination of an influenza A virus (IAV) infection within the human respiratory tract (HRT). The computational model takes into account the physiological environment in which the infection takes place by representing the HRT spatially in one dimension (depth), and by incorporating the effect of virion diffusion within the periciliary fluid that bathes infectable cells, and the remarkable physiological barrier that is the mucus escalator, sweeping virus upwards. Cell regeneration, the immune response, and infection with human vs avian IAV strains are explored in this spatial context. The numerical efficiency of this model, compared to agent-based models, makes it an attractive alternative to model respiratory virus infections in vivo.

Aim To evaluate the association between the value of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to high-density lipoprotein ratio (MHR) and the development of retinal artery occlusion (RAO) and retinal vein occlusion (RVO). Methods This retrospective study assessed 41 RAO, 50 RVO and 50 control (age and gender matched senile cataract) participants. The NLR, PLR and MHR parameters of patients’ peripheral blood were analyzed. A receiver operating characteristics (ROC) curve analysis and the best cutoff value were used to specify the predictive value of NLR, PLR and MHR in RAO and RVO. Results The NLR, PLR and MHR were significantly higher in RAO group compared to the control group (p2.99, with 90.2% sensitivity and 100% specificity. The PLR to predict RAO was > 145.52, with 75.6% sensitivity and 80.0% specificity. Conclusion Higher NLR, PLR and MHR are related to the occurrence of RAO and RVO. NLR and PLR are more prominent in RAO compared to RVO.

The attentional blink (AB) phenomenon reveals a bottleneck of human information processing: the second of two targets is often missed when they are presented in rapid succession among distractors. In our previous work, we showed that the size of the AB can be changed by applying transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (lDLPFC) (London & Slagter, Journal of Cognitive Neuroscience, 33, 756–68, 2021). Although AB size at the group level remained unchanged, the effects of anodal and cathodal tDCS were negatively correlated: if a given individual’s AB size decreased from baseline during anodal tDCS, their AB size would increase during cathodal tDCS, and vice versa. Here, we attempted to replicate this finding. We found no group effects of tDCS, as in the original study, but we no longer found a significant negative correlation. We present a series of statistical measures of replication success, all of which confirm that both studies are not in agreement. First, the correlation here is significantly smaller than a conservative estimate of the original correlation. Second, the difference between the correlations is greater than expected due to sampling error, and our data are more consistent with a zero-effect than with the original estimate. Finally, the overall effect when combining both studies is small and not significant. Our findings thus indicate that the effects of lDPLFC-tDCS on the AB are less substantial than observed in our initial study. Although this should be quite a common scenario, null findings can be difficult to interpret and are still under-represented in the brain stimulation and cognitive neuroscience literatures. An important auxiliary goal of this paper is therefore to provide a tutorial for other researchers, to maximize the evidential value from null findings.

Background Schistosomiasis is a neglected tropical parasitic and chronic disease affecting hundreds of millions of people. Adult schistosomes reside in the blood stream of the definitive mammalian host. These helminth parasites possess two epithelial surfaces, the tegument and the gastrodermis, both of which interact with the host during immune evasion and in nutrient uptake. Methods Female ARC Swiss mice (4–6 weeks old) were infected percutaneously with Schistosoma japonicum cercariae freshly shed from Oncomelania hupensis quadrasi snails (Philippines strain). Fluorescent in situ hybridisation (FISH) was performed by using fresh adult S. japonicum perfused from those infected mice. Adult S. japonicum worms were processed to isolate the tegument from the carcass containing the gastrodermis; blood and bile were collected individually from infected and uninfected mice. Total DNA extracted from all those samples were used for microbiome profiling. Results FISH and microbiome profiling showed the presence of bacterial populations on two epithelial surfaces of adult worms, suggesting they were distinct not only from the host blood but also from each other. Whereas microbial diversity was reduced overall in the parasite epithelial tissues when compared with that of host blood, specific bacterial taxa, including Anoxybacillus and Escherichia, were elevated on the tegument. Minimal differences were evident in the microbiome of host blood during an active infection, compared with that of control uninfected blood. However, sampling of bile from infected animals identified some differences compared with controls, including elevated levels of Limnohabitans, Clostridium and Curvibacter. Conclusions Using FISH and microbial profiling, we were able to demonstrate, for the first time, that bacteria are presented on the epithelial surfaces of adult schistosomes. These schistosome surface-associated bacteria, which are distinct from the host blood microenvironment, should be considered as a new and important component of the host-schistosome interaction. The importance of individual bacterial species in relation to schistosome parasitism needs further elucidation.

Francisella tularensis is a highly pathogenic intracellular bacterium that causes the disease tularemia. While its ability to replicate within cells has been studied in much detail, the bacterium also encodes a less characterised type 4 pili (T4P) system. T4Ps are dynamic adhesive organelles identified as major virulence determinants in many human pathogens. In F. tularensis, the T4P is required for adherence to the host cell, as well as for protein secretion. Several components, including pilins, a pili peptidase, a secretin pore and two ATPases, are required to assemble a functional T4P, and these are encoded within distinct clusters on the Francisella chromosome. While some of these components have been functionally characterised, the role of PilO, if any, still is unknown. Here, we examined the role of PilO in the pathogenesis of F. novicida. Our results show that the PilO is essential for pilus assembly on the bacterial surface. In addition, PilO is important for adherence of F. novicida to human monocyte-derived macrophages, secretion of effector proteins and intracellular replication. Importantly, the pilO mutant is attenuated for virulence in BALB/c mice regardless of the route of infection. Following intratracheal and intradermal infection, the mutant caused no histopathology changes, and demonstrated impaired phagosomal escape and replication within lung liver as well as spleen. Thus, PilO is an essential virulence determinant of F. novicida.

Humans deploy a number of specific behaviours for forming social bonds, one of which is laughter. However, two questions have not yet been investigated with respect to laughter: (1) Does laughter increase the sense of bonding to those with whom we laugh? and (2) Does laughter facilitate prosocial generosity? Using changes in pain threshold as a proxy for endorphin upregulation in the brain and a standard economic game (the Dictator Game) as an assay of prosociality, we show that laughter does trigger the endorphin system and, through that, seems to enhance social bonding, but it does not reliably influence donations to others. This suggests that social bonding and prosociality may operate via different mechanisms, or on different time scales, and relate to different functional objectives.

The epidemiology of typhoid fever in Lao People`s Democratic Republic is poorly defined. Estimating the burden of typhoid fever in endemic countries is complex due to the cost and limitations of population-based surveillance; serological approaches may be a more cost-effective alternative. ELISAs were performed on 937 serum samples (317 children and 620 adults) from across Lao PDR to measure IgG antibody titers against Vi polysaccharide and the experimental protein antigens, CdtB and HlyE. We measured the significance of the differences between antibody titers in adults and children and fitted models to assess the relationship between age and antibody titers. The median IgG titres of both anti-HylE and CdtB were significantly higher in children compared to adults (anti-HylE; 351.7 ELISA Units (EU) vs 198.1 EU, respectively; p, Author summary Typhoid fever is a serious bloodstream infection caused by the bacterium Salmonella Typhi. Estimating the burden of typhoid fever is complex due to the limitations, cost, and scalability of current diagnostic surveillance methods. The detection of specific antibody responses against the organism may be a more sustainable manner of measuring exposure and disease burden in endemic location. We measured antibody (IgG) in 937 serum samples (317 children and 620 adults) from across the Lao People`s Democratic Republic against a polysaccharide (Vi) and two experimental protein antigens, CdtB and HlyE, that may more appropriate markers of disease exposure. We measured the significance of the differences between antibody titers in adults and children and fitted models to assess the relationship between age and antibody titers. The median IgG titres against HylE and CdtB were significantly higher in children than adults. Conversely, the median IgG titres against Vi was significantly higher in adults than children. We identified a significant association between a peak in IgG titres against CdtB and HlyE in children aged under 5 years. These data are indicative of high level of typhoid fever exposure in children under 5 years of age in Lao PDR and we surmise that IgG titres against HylE and CdtB may be a superior measure of typhoid disease burden than IgG titres against Vi. Our approach is scalable and can be further validated to assess the burden of typhoid fever in countries where the disease may be endemic, and evidence is required for the introduction of typhoid vaccines.

Population risks for neonatal hyperbilirubinaemia (NH) vary. Knowledge of local risks permits interventions that may reduce the proportion becoming severe. Between January 2015 and May 2016, in a resource-limited setting on the Thailand-Myanmar border, neonates from 28 weeks’ gestation were enrolled into a prospective birth cohort. Each neonate had total serum bilirubin measurements: scheduled (24, 48, 72 and 144 hours of life) and clinically indicated; and weekly follow up until 1 month of age. Risk factors for developing NH were evaluated using Cox proportional hazard mixed model. Of 1710 neonates, 22% (376) developed NH (83% preterm, 19% term). All neonates born vs 59 hours [48, 84] for neonates born ≥38 weeks. Risk factors for NH in the first week of life independent of gestational age were: neonatal G6PD deficiency, birth bruising, Sgaw Karen ethnicity, primigravidae, pre-eclampsia, and prolonged rupture of membranes. The genetic impact of G6PD deficiency on NH was partially interpreted by using the florescent spot test and further genotyping work is in progress. The risk of NH in Sgaw Karen refugees may be overlooked internationally as they are most likely regarded as Burmese in countries of resettlement. Given high levels of pathological jaundice in the first 24 hours and overall high NH burden, guidelines changes were implemented including preventive PT for all neonates

Background: Truncated tissue factor (tTF) retargeted by NGR-peptides to aminopeptidase N (CD13) in tumor vasculature is effective in experimental tumor therapy. tTF-NGR induces tumor growth inhibition in a variety of human tumor xenografts of different histology. To improve on the therapeutic efficacy we have combined tTF-NGR with radiotherapy. Methods: Serum-stimulated human umbilical vein endothelial cells (HUVEC) and human HT1080 sarcoma cells were irradiated in vitro, and upregulated early-apoptotic phosphatidylserine (PS) on the cell surface was measured by standard flow cytometry. Increase of cellular procoagulant function in relation to irradiation and PS cell surface concentration was measured in a tTF-NGR-dependent Factor X activation assay. In vivo experiments with CD-1 athymic mice bearing human HT1080 sarcoma xenotransplants were performed to test the systemic therapeutic effects of tTF-NGR on tumor growth alone or in combination with regional tumor ionizing radiotherapy. Results: As shown by flow cytometry with HUVEC and HT1080 sarcoma cells in vitro, irradiation with 4 and 6 Gy in the process of apoptosis induced upregulation of PS presence on the outer surface of both cell types. Proapoptotic HUVEC and HT1080 cells both showed significantly higher procoagulant efficacy on the basis of equimolar concentrations of tTF-NGR as measured by FX activation. This effect can be reverted by masking of PS with Annexin V. HT1080 human sarcoma xenografted tumors showed shrinkage induced by combined regional radiotherapy and systemic tTF-NGR as compared to growth inhibition achieved by either of the treatment modalities alone. Conclusions: Irradiation renders tumor and tumor vascular cells procoagulant by PS upregulation on their outer surface and radiotherapy can significantly improve the therapeutic antitumor efficacy of tTF-NGR in the xenograft model used. This synergistic effect will influence design of future clinical combination studies.

Background The subjective experience of fatigue impairs an individual’s ability to sustain physical endurance performance. However, precise understanding of the specific role perceived fatigue plays in the central regulation of performance remains unclear. Here, we examined whether the subjective intensity of a perceived state of fatigue, pre-induced through prior upper body activity, differentially impacted performance and altered perceived effort and affect experienced during a sustained, isometric contraction in lower body. We also explored whether (cardiac) interoception predicted the intensity of experienced perceptual and affective responses and moderated the relationships between constructs during physical activity. Methods Using a repeated-measures study design, thirty male participants completed three experimental conditions, with the intensity of a pre-induced state of fatigue manipulated to evoke moderate (MOD), severe (SEV) and minimal (control; CON) intensity of perceptions prior to performance of the sustained contraction. Results Performance of the sustained contraction was significantly impaired under a perceived state of fatigue, with reductions of 10% and 14% observed in the MOD and SEV conditions, respectively. Performance impairment was accompanied by greater perceived effort and more negative affective valence reported during the contraction. However, effects were limited to comparisons to CON, with no difference evident between the two experimental trials (i.e. MOD vs. SEV). Individuals’ awareness of their accuracy in judging resting heartbeats was shown to predict the subjective intensity of fatigue experienced during the endurance task. However, interoception did not moderate the relationships evident between fatigue and both perceived effort and affective valence. Conclusions A perceived state of fatigue limits endurance performance, influencing both how effortful activity is perceived to be and the affective experience of activity. Though awareness of interoceptive representations of bodily states may be important to the subjective experience of fatigue, interoception does not modulate the relationships between perceived fatigue and other perceptual (i.e. effort) and affective constructs.

With the development of measurement technology, data on the movements of actual games in various sports can be obtained and used for planning and evaluating the tactics and strategy. Defense in team sports is generally difficult to be evaluated because of the lack of statistical data. Conventional evaluation methods based on predictions of scores are considered unreliable because they predict rare events throughout the game. Besides, it is difficult to evaluate various plays leading up to a score. In this study, we propose a method to evaluate team defense from a comprehensive perspective related to team performance by predicting ball recovery and being attacked, which occur more frequently than goals, using player actions and positional data of all players and the ball. Using data from 45 soccer matches, we examined the relationship between the proposed index and team performance in actual matches and throughout a season. Results show that the proposed classifiers predicted the true events (mean F1 score $>$ 0.483) better than the existing classifiers which were based on rare events or goals (mean F1 score $, Comment: 15 pages, 5 figures

Yellow fever virus (YFV) is a zoonotic pathogen re-emerging in parts of the world, causing a viral hemorrhagic fever associated with high mortality rates. While an effective vaccine is available, having an effective antiviral against YFV is critical against unexpected outbreaks, or when vaccination is not recommended. We have previously identified AT-281, the free base of AT-752, an orally available double prodrug of a guanosine nucleotide analog, as a potent inhibitor of YFV in vitro, with a 50% effective concentration (EC50) of 0.31 μM. In hamsters infected with YFV (Jimenez strain), viremia rose about 4 log10-fold and serum alanine aminotransferase (ALT) 2-fold compared to sham-infected animals. Treatment with 1000 mg/kg AT-752 for 7 days, initiated 4 h prior to viral challenge, reduced viremia to below the limit of detection by day 4 post infection (pi) and returned ALT to normal levels by day 6 pi. When treatment with AT-752 was initiated 2 days pi, the virus titer and ALT dropped >2 log10 and 53% by day 4 and 6 pi, respectively. In addition, at 21 days pi, 70–100% of the infected animals in the treatment groups survived compared to 0% of the untreated group (p, Author summary Yellow fever virus (YFV) is transmitted by mosquitoes, and its infection can lead to a lethal viral hemorrhagic fever associated with liver damage. While an effective vaccine is available, in places where the vaccination rate is low, in the event of an unexpected outbreak, or where vaccination is not recommended individually, having an effective antiviral treatment is critical. We previously reported that the nucleotide analog prodrug AT-752 potently inhibited the YFV in cultured cells. Here we showed that in hamsters infected with YFV, oral treatment with 1000 mg/kg AT-752 for 7 days reduced the production of infectious virus particles in the blood, and decreased serum alanine aminotransferase, a marker of liver damage, to levels measured in uninfected animals. In addition, at 21 days after infection, 70–100% of the infected animals in the treatment groups survived compared to 0% in the untreated group. Moreover, the amount of the active metabolite formed from AT-752 was highest in the livers and kidneys of the treated animals, organs that are targeted by the virus. These results suggest that AT-752 is a promising compound to develop for the treatment of YFV infection.

Objectives To investigate the effects of integrative neuromuscular training (INT) on physical performance in elite female table tennis players. Methods Twenty-four Chinese elite female table tennis players were randomized into either INT (n = 12) group or control group (CON; n = 12). INT group performed four INT sessions every week for 8 weeks, while CON group performed traditional physical fitness training. One repetition maximal (1RM), vertical jump, Y balance test and 30-meter sprinting performance were tested before and after intervention. Results No between groups differences were detected for any tests before intervention. Significant group by time (before or after intervention) interaction effects were observed in 1RM, vertical jump, bilateral lower limb reaching distance at posteromedial and posterolateral directions, and right leg at the anterior direction for the Y balance test (all p < 0.05), but not for the left leg at the anterior direction or the 30-meter sprinting performance (both p > 0.05). Post-hoc analysis for measurements with significant interactions revealed that all significant changes were at the ING group (all p < 0.05), while no changes for the CON group were observed (all p > 0.05). Conclusion Eight weeks INT significantly improved strength, power and balance in Chinese elite female table tennis players. Adopting INT in table tennis players may improve their physical performance and lead to better sports performance.

Results from sampling healthcare surfaces for pathogens are difficult to interpret without understanding the factors that influence pathogen detection. We investigated the recovery of four healthcare-associated pathogens from three common surface materials, and how a body fluid simulant (artificial test soil, ATS), deposition method, and contamination levels influence the percent of organisms recovered (%R). Known quantities of carbapenemase-producing KPC+ Klebsiella pneumoniae (KPC), Acinetobacter baumannii, vancomycin-resistant Enterococcus faecalis, and Clostridioides difficile spores (CD) were suspended in Butterfield’s buffer or ATS, deposited on 323cm2 steel, plastic, and laminate surfaces, allowed to dry 1h, then sampled with a cellulose sponge wipe. Bacteria were eluted, cultured, CFU counted and %R determined relative to the inoculum. The %R varied by organism, from 1 log10 within the 60 min drying time. For all organisms, the %R was significantly greater if suspended in ATS than if suspended in Butterfield’s buffer (p

Bacillus cereusis a spore forming bacteria recognized among the leading agents responsible for foodborne outbreaks in Europe.B.cereusis also gaining notoriety as an opportunistic human pathogen inducing local and systemic infections. The real incidence of such infection is likely underestimated and information on genetic and phenotypic characteristics of the incriminated strains is generally scarce. We have recently analyzed a large strain collection of varying pathogenic potential. Screening for biomarkers to differentiate among clinical and non-clinical strains, a gene encoding an alcohol dehydrogenase-like protein was identified among the leading candidates. This family of proteins has been demonstrated to be involved in the virulence of several bacterial species. The relevant gene was knocked out to elucidate its function with regards to resistance to host innate immune response, bothin vitroandin vivo. Our results demonstrate that theadhBgene plays a significant role in resistance to nitric oxide and oxidative stressin vitro, as well as its pathogenic ability with regards toin vivotoxicity. These properties may explain the pathogenic potential of strains carrying this newly identified virulence factor.

Background Reason for dysphagia in a significant number of patients remains unclear even after a thorough workup. Each swallow induces esophageal distension followed by contraction of the esophagus, both of which move sequentially along the esophagus. Manometry technique and current system of classifying esophageal motility disorders (Chicago Classification) is based on the analysis of the contraction phase of peristalsis. Goal Whether patients with unexplained dysphagia have abnormalities in the distension phase of esophageal peristalsis is not known. Methods Using Multiple Intraluminal esophageal impedance recordings, which allow determination of the luminal cross-sectional area during peristalsis, we studied patients with nutcracker esophagus (NC), esophagogastric junction outflow obstruction (EGJOO), and functional dysphagia (FD). Results Distension contraction plots revealed that swallowed bolus travels significantly faster through the esophagus in all patient groups as compared to normals. The luminal cross-sectional area (amplitude of distension), and the area under the curve of distension were significantly smaller in patients with NC, EGJOO, and FD as compared to normals. Bolus traverses the esophagus in the shape of an “American Football” in normal subjects. On the other hand, in patients the bolus flow was fragmented. ROC curves revealed that bolus flow abnormalities during peristalsis are a sensitive and specific marker of dysphagia. Conclusion Our findings reveal abnormality in the distension phase of peristalsis (a narrow lumen esophagus) in patients with dysphagia. We propose that the esophageal contraction forcing the swallowed bolus through a narrow lumen esophagus is the cause of dysphagia sensation in patients with normal contraction phase of peristalsis.

Cache Valley virus (CVV) is a mosquito-borne virus in the genus Orthobunyavirus, family Peribunyaviridae. It was first isolated from a Culiseta inorata mosquito in Cache Valley, Utah in 1956 and is known to circulate widely in the Americas. While only a handful of human cases have been reported since its discovery, it is the causative agent of fetal death and severe malformations in livestock. CVV has recently emerged as a potential viral pathogen causing severe disease in humans. Currently, the only serological assay available for diagnostic testing is plaque reduction neutralization test which takes several days to perform and requires biocontainment. To expand diagnostic capacity to detect CVV infections by immunoassays, 12 hybridoma clones secreting anti-CVV murine monoclonal antibodies (MAbs) were developed. All MAbs developed were found to be non-neutralizing and specific to the nucleoprotein of CVV. Cross-reactivity experiments with related orthobunyaviruses revealed several of the MAbs reacted with Tensaw, Fort Sherman, Tlacotalpan, Maguari, Playas, and Potosi viruses. Our data shows that MAbs CVV14, CVV15, CVV17, and CVV18 have high specific reactivity as a detector in an IgM antibody capture test with human sera., Author summary Cache Valley virus is a mosquito-borne virus found throughout the Americas. It causes fetal death and severe malformations in livestock, and only a few cases of human viral disease have been identified. Currently, we do not fully understand the spectrum of disease in humans including its potential to cause fetal malformations. The only serological diagnostic assay available to detect recent viral infection is plaque reduction neutralization test which requires the use of live virus in biocontainment. In order to develop faster and safer serodiagnostics we generated 12 monoclonal antibodies for incorporation into new assays. These antibodies are specific to the nucleoprotein of the virus and cross-react with other closely related mosquito-borne viruses. Four of these antibodies were incorporated into an immunoassay for the detection of IgM from human sera demonstrating their utility in serodiagnosis. Rapid and higher throughput assays utilizing these antibodies will expand diagnostic capacity and facilitate research to increase our understanding of Cache Valley disease prevalence and the virus’s impact on at-risk populations.

Emerging evidence has indicated a possible link between obesity in early life with subsequent cancer risks, but its association with gastric cancer remains unknown. This study aimed to investigate the association of obesity at ages 18–20 and 35 with the later risk of gastric cancer among the Korean population. Included were 122,724 individuals who participated in the large-scale prospective cohort study, the Health Examinees-Gem (HEXA-G) study, during 2004–2017. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for gastric cancer risk associated with body mass index (BMI) at ages 18–20 and 35 years. During a mean follow-up period of 8.6±2.1 years, a total 927 gastric cancer cases (531 men and 396 women) were identified. When compared to normal BMI (18.5–23.0 kg/m2), obesity (BMI ≥30 kg/m2) at age 35 was significantly associated with increased risk of gastric cancer later in life among total participants (HR 1.94, 95% CI 1.26–2.97, p 0.01). When analyzed separately by sex, obesity at 35 years of age was significantly associated with increased risk of gastric cancer among both men (HR 1.79, 95% CI 1.02–3.13, p 0.05) and women (HR 2.35, 95% CI 1.21–4.60, p 0.02). No significant associations were found for obesity at late adolescence in both men and women. Our findings suggest that obesity in early adulthood may be associated with an increased risk of gastric cancer. The results may aid in understanding the etiology of GC in a population with a divergent trend of gastric cancer.

Recent advancements in Inertial Measurement Units (IMUs) offers the possibility of its use as a cost effective and portable alternative to traditional optoelectronic motion capture systems in analyzing biomechanical performance. One such commercially available IMU is the Perception Neuron motion capture system (PNS). The accuracy of the PNS had been tested and was reported to be a valid method for assessing the upper body range of motion to within 5° RMSE. However, testing of the PNS was limited to upper body motion involving functional movement within a single plane. Therefore, the purpose of this study is to further validate the Perception Neuron system with reference to a conventional optoelectronic motion capture system (VICON) through the use of dynamic movements (e.g., walking, jogging and a multi-articular sports movement with object manipulation) and to determine its feasibility through full-body kinematic analysis. Validation was evaluated using Pearson’s R correlation, RMSE and Bland-Altman estimates. Present findings suggest that the PNS performed well against the VICON motion analysis system with most joint angles reporting a RMSE of < 4° and strong average Pearson’s R correlation of 0.85, with the exception of the shoulder abduction/adduction where RMSE was larger and Pearson’s R correlation at a moderate level. Bland-Altman analysis revealed that most joint angles across the different movements had a mean bias of less than 10°, except for the shoulder abduction/adduction and elbow flexion/extension measurements. It was concluded that the PNS may not be the best substitute for traditional motion analysis technology if there is a need to replicate raw joint angles. However, there was adequate sensitivity to measure changes in joint angles and would be suitable when normalized joint angles are compared and the focus of analysis is to identify changes in movement patterns.

The primary role of muscles is to move, and control joints. It is therefore important to understand how degenerative joint disease changes this role with the resulting effect on mechanical joint loading. Muscular control strategies can vary depending on strength and coordination which in turn influences joint control and loading. The purpose of this study was to investigate the variation in neuromuscular control mechanisms and joint biomechanics for three subject groups including those with: uni-compartmental knee osteoarthritis (OA), listed for high tibial osteotomy surgery (pre-HTO, n = 10); multi-compartmental knee OA listed for total knee replacement (pre-TKR, n = 9), and non-pathological knees (NP, n = 11). Lower limb kinematics and electromyography (EMG) data for subjects walking at self-selected speed, were input to an EMG-driven musculoskeletal knee model which was scaled and calibrated to each individual to estimate muscle forces. Compared to NP, the peak gastrocnemius muscle force reduced by 30% and 18% for pre-HTO and pre-TKR respectively, and the peak force estimated for hamstring muscle increased by 25% for pre-HTO. Higher quadriceps and hamstring forces suggest that co-contraction with the gastrocnemius could lead to higher joint contact forces. Combined with the excessive loading due to a high external knee adduction moment this may exacerbate joint destruction. An increased lateral muscle co-contraction reflects the progression from NP to uni-compartmental OA (pre-HTO). Pre-TKR patients adopt a different gait pattern to pre-HTO patients. Increased medial muscle co-activation could potentially differentiate between uni- or multi-compartmental OA.

Background Sickle cell disease (SCD) incurs vaso-occlusive episodes and organ damage, including nephropathy. Despite displaying characteristics of vascular dysfunction, SCD patients tend to present relatively lower systemic blood pressure (BP), via an unknown mechanism. We investigated associations between BP and renin-angiotensin-system (RAS) components in SCD and determined whether an inhibitor of angiotensin converting enzyme (ACE; often used to slow SCD glomerulopathy) further modulates BP and RAS components in a murine model of SCD. Methods BP was compared in human subjects and mice with/without SCD. Plasma angiotensin II, ACE and renin were measured by immunoassay. BP was reevaluated after treating mice with enalapril (25 mg/kg, 5x/week) for 5 weeks; plasma and organs were stored for angiotensin II and ACE activity measurement, and quantitative real-time PCR. Results Diastolic BP and systolic BP were significantly lower in patients and mice with SCD, respectively, compared to controls. Reduced BP was associated with increased plasma renin and markers of kidney damage (mice) in SCD, as well as significantly decreased plasma ACE concentrations and ACE enzyme activity. As expected, enalapril administration lowered BP, plasma angiotensin II and organ ACE activity in control mice. In contrast, enalapril did not further reduce BP or organ ACE activity in SCD mice; however, plasma angiotensin II and renin levels were found to be significantly higher in enalapril-treated SCD mice than those of treated control mice. Conclusion Relative hypotension was confirmed in a murine model of SCD, in association with decreased ACE concentrations in both human and murine disease. Given that ACE inhibition has an accepted role in decreasing BP, further studies should investigate mechanisms by which ACE depletion, via both Ang II-dependent and alternative pathways, could contribute to reduce BP in SCD and understand how ACE inhibition confers Ang II-independent benefits on kidney function in SCD.

Background Robotic assisted gait training (RAGT) uses a powered exoskeleton to support an individual’s body and move their limbs, with the aim of activating latent, pre-existing movement patterns stored in the lower spinal cord called central pattern generators (CPGs) to facilitate stepping. The parameters that directly stimulate the stepping CPGs (hip extension and ipsilateral foot unloading) should be targeted to maximise the rehabilitation benefits of these devices. Aim To compare the biomechanical profiles of individuals with a spinal cord injury (SCI) and able-bodied individuals inside the ReWalkTM powered exoskeleton and to contrast the users’ profiles with the exoskeleton. Methods Eight able-bodied and four SCI individuals donned a ReWalkTM and walked along a 12-meter walkway, using elbow crutches. Whole-body kinematics of the users and the ReWalkTM were captured, along with GRF and temporal-spatial characteristics. Discreet kinematic values were analysed using a Kruskall-Wallis H and Dunn’s post-hoc analysis. Upper-body differences, GRF and temporal-spatial characteristics were analysed using a Mann-Whitney U test (P Results Walking speed ranged from 0.32–0.39m/s. Hip abduction, peak knee flexion and ankle dorsiflexion for both the SCI and able-bodied groups presented with significant differences to the ReWalkTM. The able-bodied group presented significant differences to the ReWalkTM for all kinematic variables except frontal plane hip ROM (P = 0.093,δ = -0.56). Sagittal plane pelvic and trunk ROM were significantly greater in the SCI vs. able-bodied (P = 0.004,δ = -1; P = 0.008,δ = -0.94, respectively). Posterior braking force was significantly greater in the SCI group (P = 0.004, δ = -1). Discussion The different trunk movements used by the SCI group and the capacity for the users’ joint angles to exceed those of the device suggest that biomechanical profiles varied according to the user group. However, upright stepping with the ReWalkTM device delivered the appropriate afferent stimulus to activate CPGs as there were no differences in key biomechanical parameters between the two user groups.

Background Cognitive models indicated that social anxiety disorder (SAD) would be caused and maintained by a biased attentional processing of threatening information. This study investigates whether socially anxious children may present impaired attentional engagement and disengagement from negative emotional faces, as well as their underlying event-related potential responses. Methods and findings Fifteen children with high levels of social anxiety (HSA; 9 boys; mean age = 9.99y; SD = 1.14) and twenty low socially anxious children (LSA; 16 boys; mean age = 10.47y; SD = 1.17) participated in a spatial cueing task in which they had to detect targets following neutral/disgusted faces in a valid or invalid location. No group effect was reported on reaction times [p>.05]. However, electrophysiological data showed lower P3a amplitude in HSA children compared with the LSA group when processing facial stimuli. They also reported larger N2 amplitudes for valid-disgusted targets and a larger P3a amplitude for the invalid-disgusted ones. Conclusion In terms of electrophysiological data, our results validated, the hypothesis of attentional disengagement difficulties in SAD children. We also confirm the idea that high levels of social anxiety are associated with cognitive control impairments and have a greater impact on the processing efficiency than on the performance effectiveness.

The digitalization process for organizations, which was inevitably accelerated by the COVID-19 pandemic, raises relevant challenges for Human Resource Management (HRM) because every technological implementation has a certain impact on human beings. Between many organizational HRM practices, recruitment and assessment interviews represent a significant moment where a social interaction provides the context for evaluating candidates’ skills. It is therefore relevant to investigate how different interaction frames and relational conditions affect such task, with a specific focus on the differences between face-to-face (FTF) and remote computer-mediated (RCM) interaction settings. In particular, the possibility of qualifying and quantifying the mechanisms shaping the efficiency of interaction in the recruiter-candidate dyad—i.e. interpersonal attunement—is potentially insightful. We here present a neuroscientific protocol aimed at elucidating the impact of FTF vs. RCM modalities on social dynamics within assessment interviews. Specifically, the hyperscanning approach, understood as the concurrent recording and integrated analysis of behavioural-physiological responses of interacting agents, will be used to evaluate recruiter-candidate dyads while they are involved in either FTF or RCM conditions. Specifically, the protocol has been designed to collect self-report, oculometric, autonomic (electrodermal activity, heart rate, heart rate variability), and neurophysiological (electroencephalography) metrics from both inter-agents to explore the perceived quality of the interaction, automatic visual-attentional patterns of inter-agents, as well as their cognitive workload and emotional engagement. The proposed protocol will provide a theoretical evidence-based framework to assess possible differences between FTF vs. RMC settings in complex social interactions, with a specific focus on job interviews.

Aedes simpsoni complex has a wide distribution in Africa and comprises at least three described sub-species including the yellow fever virus (YFV) vector Ae. bromeliae. To date, the distribution and relative contributions of the sub-species and/or subpopulations including bionomic characteristics in relation to YF transmission dynamics remain poorly studied. In this study conducted in two areas with divergent ecosystems: peri-urban (coastal Rabai) and rural (Rift Valley Kerio Valley) in Kenya, survival rate was estimated by parity in Ae. simpsoni s.l. mosquitoes sampled using CO2-baited BG Sentinel traps. We then applied PCR targeting the nuclear internal transcribed spacer 2 (ITS2), region followed by sequencing and phylogenetic analytics to identify the sibling species in the Ae. simpsoni complex among parous and blood fed cohorts. Our results show that Ae. bromeliae was the most dominant sub-species in both areas, exhibiting high survival rates, human blood-feeding, and potentially, high vectorial capacity for pathogen transmission. We document for the first time the presence of Ae. lilii in Kenya and potentially yet-to-be described species in the complex displaying human feeding tendencies. We also infer a wide host feeding range on rodents, reptile, and domestic livestock besides humans especially for Ae. bromeliae. This feeding trend could likely expose humans to various zoonotic pathogens. Taken together, we highlight the utility of genotype-based analyses to generate precision surveillance data of vector populations for enhanced disease risk prediction and to guide cost-effective interventions (e.g. YF vaccinations)., Author summary Yellow fever (YF) remains a significant public health risk in East Africa, however, with gaps in the transmission ecology. Important YF virus vectors include Aedes simpsoni mosquitoes that comprise subspecies with varying vectoring abilities and, poorly described ecology and biologic traits relevant to disease transmission. Through active surveillance, we analyzed the survival, human blood feeding habits and genetics of wild populations of Aedes simpsoni s.l. in two contrasting ecosystems in Kenya: peri-urban, coastal Rabai, and rural, Rift Valley Kerio Valley. Our findings reveal i) Aedes bromeliae as the most abundant subspecies in both areas exhibiting high survival rates, human blood-feeding, and potentially, high vectoring ability, ii) occurrence of Ae. lilii contrary to previous reports albeit in low numbers, iii) potential undescribed species in the group displaying human feeding tendencies. Knowledge of the locally adapted subspecies and associated traits that underlie vectorial capacity, impinges on YF distribution risk useful for guiding vector control or cost-effective vaccination.

Every person diagnosed with diabetes mellitus (T2DM) is at risk of developing Diabetic retinopathy (DR). Thus, DR is one of the major chronic microvascular complications of T2DM. However, in Malaysia, research about DR is still scarce. This study aimed to determine the prevalence of DR among diabetic patients across 46 primary healthcare clinics in Sabah, Malaysia. Secondly, it purported to identify the factors influencing the development of DR. This cross-sectional study involved a total of 22,345 Type 2 diabetes mellitus (T2DM) patients in the Sabah Diabetic Registry from 2008 to 2015. Of the 22,345 T2DM patients, 13.5% (n = 3,029) of them were diagnosed with DR. Multiple logistic regression revealed seven major risk factors of DR, i.e. patients with diabetic foot ulcer [aOR: 95% CI 3.08 (1.96–4.85)], patients with diabetic nephropathy [aOR: 95% CI 2.47 (2.13–2.86)], hypertension [aOR: 95% CI 1.63 (1.43–1.87)], dyslipidaemia [aOR: 95% CI 1.30 (1.17–1.44)], glycated haemoglobin [(HbA1c) > 6.5 (aOR: 95% CI 1.25 (1.14–1.38)], duration of diabetes mellitus (T2DM) [aOR: 95% CI 1.06 (1.05–1.07)] and age of patient [aOR: 95% CI 1.01 (1.00–1.02)] respectively. DR is a preventable complication. The effective glycaemic control is crucial in preventing DR. In minimizing the prevalence of DR, the healthcare authorities should institute programmes to induce awareness on the management of DR’s risk factors among patient and practitioner.

Participation in women’s rugby league has been growing since the foundation of the English women’s rugby league Super League in 2017. However, the evidence base to inform women’s rugby league remains sparse. This study provides the largest quantification of anthropometric and physical qualities of women’s rugby league players to date, identifying differences between positions (forwards & backs) and playing level (Women’s Super League [WSL] vs. International). The height, weight, body composition, lower body strength, jump height, speed and aerobic capacity of 207 players were quantified during the pre-season period. Linear mixed models and effects sizes were used to determine differences between positions and levels. Forwards were significantly (p < 0.05) heavier (forwards: 82.5 ± 14.8kg; backs: 67.7 ± 9.2kg) and have a greater body fat % (forwards: 37.7 ± 6.9%; backs: 30.4 ± 6.3%) than backs. Backs had significantly greater lower body power measured via jump height (forwards: 23.5 ± 4.4cm; backs: 27.6 ± 4.9cm), speed over 10m (forwards: 2.12 ± 0.14s; backs: 1.98 ± 0.11s), 20m (forwards: 3.71 ± 0.27s; backs: 3.46 ± 0.20s), 30m (forwards: 5.29 ± 0.41s; backs: 4.90 ± 0.33s), 40m (forwards: 6.91 ± 0.61s; backs: 6.33 ± 0.46s) and aerobic capacity (forwards: 453.4 ± 258.8m; backs: 665.0 ± 298.2m) than forwards. Additionally, international players were found to have greater anthropometric and physical qualities in comparison to their WSL counterparts. This study adds to the limited evidence base surrounding the anthropometric and physical qualities of elite women’s rugby league players. Comparative values for anthropometric and physical qualities are provided which practitioners may use to evaluate the strengths and weaknesses of players, informing training programs to prepare players for the demands of women’s rugby league.

BackgroundExtracellular vesicles are released into body fluids from the majority of, if not all, cell types. Because their secretion and specific cargo (e.g., proteins) varies according to pathology, extracellular vesicles may prove a rich source of biomarkers. However, their biological and pathophysiological functions are poorly understood in hematological malignancies.ObjectiveHere, we investigated proteome changes in the exosome-rich fraction of the plasma of myelodysplastic syndrome patients and healthy donors.MethodsExosome-rich fraction of the plasma was isolated using ExoQuick™: proteomes were compared and statistically processed; proteins were identified by nanoLC-MS/MS and verified using the ExoCarta and QuickGO databases. Mann-Whitney and Spearman analyses were used to statistically analyze the data. 2D western blot was used to monitor clusterin proteoforms.ResultsStatistical analyses of the data highlighted clusterin alterations as the most significant. 2D western blot showed that the clusterin changes were caused by posttranslational modifications. Moreover, there was a notable increase in the clusterin proteoform in the exosome-rich fraction of plasma of patients with more severe myelodysplastic syndrome; this corresponded with a simultaneous decrease in their plasma.ConclusionsThis specific clusterin proteoform seems to be a promising biomarker for myelodysplastic syndrome progression.

Background Immunotherapy has emerged as a promising treatment for non-small cell lung cancer (NSCLC). Yet, some patients cannot benefit from immunotherapy, and reliable biomarkers for selecting sensitive patients are needed. Herein, we performed a meta-analysis to evaluate the predictive value of tumor mutational burden (TMB) in NSCLC patients treated with immunotherapy. Methods Eligible studies were comprehensively searched from electronic databases prior to August 31, 2021. Meta-analyses of high TMB versus low TMB as well as immunotherapy versus chemotherapy in patients with high/low TMB were conducted. Hazard ratio (HR) with corresponding 95% confidence interval (95%CI) for progression-free survival (PFS) and overall survival (OS) and odds ratio (OR) with 95%CI for objective response rate (ORR) were calculated. Results A total of 31 datasets (3437 patients) and 6 randomized controlled trials (3662 patients) were available for meta-analyses of high TMB versus low TMB and immunotherapy versus chemotherapy, respectively. High TMB predicted significantly favorable PFS (HR = 0.54, 95%CI: 0.46–0.63, P Conclusion This meta-analysis demonstrates more clinical benefits concerning treatment response and survival outcomes in high-TMB NSCLC patients who are treated with immunotherapy. TMB is a promising biomarker for discriminating NSCLC patients who can benefit more from immunotherapy.

AimsPatients with rheumatoid arthritis (RA) have increased risk of heart failure (HF). The mechanisms and cardiac prerequisites explaining this association remain unresolved. In this study, we sought to determine the potential cardiac impact of an experimental model of RA in mice subjected to HF by constriction of the ascending aorta.MethodsAorta was constricted via thoracotomy and placement of o-rings with inner diameter 0.55 mm or 0.66 mm, or sham operated. RA-like phenotype was instigated by delayed-type hypersensitivity arthritis (DTHA) two weeks after surgery and re-iterated after additional 18 days. Cardiac magnetic resonance imaging (MRI) was performed before surgery and at successive time points throughout the study. Six weeks after surgery the mice were euthanized, blood and tissue were collected, organ weights were documented, and expression levels of cardiac foetal genes were analysed. In a supplemental study, DTHA-mice were euthanized throughout 14 days after induction of arthritis, and blood was analysed for important markers and mediators of RA (SAP, TNF-α and IL-6). In order to put the latter findings into clinical context, the same molecules were analysed in serum from untreated RA patients and compared to healthy controls.ResultsSignificant elevations of inflammatory markers were found in both patient- and murine blood. Furthermore, the DTHA model appeared clinically relevant when compared to the inflammatory responses observed in three prespecified RA severity disease states. Two distinct trajectories of cardiac dysfunction and HF development were found using the two o-ring sizes. These differences were consistent by both MRI, organ weights and cardiac foetal gene expression levels. Still, no difference within the HF groups, nor within the sham groups, could be found when DTHA was induced.ConclusionDTHA mediated systemic inflammation did not cause, nor modify HF caused by aortic constriction. This indicates other prerequisites for RA-induced cardiac dysfunction.

Every year, billions of egg layer chicks around the world are hatched under highly stressful, industrial circumstances. Here, it is investigated how the stressful procedure in the commercial hatchery, including incubation, hatching, processing, and transport affects the chicks with regards to traits relevant for the egg production industry. These traits were compared to those of a control group hatched in a small incubator and handled gently och quietly in a quiet room without any processing and transport. The chicks were weighed at hatch and at eight additional time points: 4 days, 1 week (w), 2 w, 3 w, 5 w, 8 w, 20 w and 25 w of age. Feather pecking was studied at 15 w of age and damages to the feathers and injuries on the comb and wattle were assessed at 25 w of age. From 19 w of age, eggs were collected on three days per week, counted and weighed. Chicks from a commercial hatchery had a lower hatch weight than control chicks (pFunding: FORMAS [2016-01728]