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There was inconsistent evidence regarding the use of matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS) for microorganism identification with/without antibiotic stewardship team (AST) and the clinical outcome of patients with bloodstream infections (BSI). In a systematic review and meta‐analysis, we evaluated the effectiveness of rapid microbial identification by MALDI‐TOF MS with and without AST on clinical outcomes. We searched PubMed and EMBASE databases from inception to 1 February 2022 to identify pre–post and parallel comparative studies that evaluated the use of MALDI‐TOF MS for microorganism identification. Pooled effect estimates were derived using the random‐effects model. Twenty‐one studies with 14,515 patients were meta‐analysed. Compared with conventional phenotypic methods, MALDI‐TOF MS was associated with a 23% reduction in mortality (RR = 0.77; 95% CI: 0.66; 0.90; I2 = 35.9%; 13 studies); 5.07‐h reduction in time to effective antibiotic therapy (95% CI: −5.83; −4.31; I2 = 95.7%); 22.86‐h reduction in time to identify microorganisms (95% CI: −23.99; −21.74; I2 = 91.6%); 0.73‐day reduction in hospital stay (95% CI: −1.30; −0.16; I2 = 53.1%); and US $4140 saving in direct hospitalization cost (95% CI: $ ‐8166.75; $‐113.60; I2 = 66.1%). No significant heterogeneity sources were found, and no statistical evidence for publication bias was found. Rapid pathogen identification by MALDI‐TOF MS with or without AST was associated with reduced mortality and improved outcomes of BSI, and may be cost‐effective among patients with BSI. Our meta‐analysis found that MALDI‐TOF MS significantly reduced the time to identify microorganisms, was able to prescribe antibiotics earlier, and that it decreased mortality rates, hospital stays, and medical costs.

Physical activity has benefits on physical and psychological health. The aims of this study were to investigate (1) the relationships between physical activity and life satisfaction and happiness in young, middle-aged, and older adults while controlling for demographic characteristics, and (2) the relationships between age and life satisfaction and happiness for different physical activity levels. A total of 2345 healthy adults were recruited. Demographic characteristic, physical activity, life satisfaction, and happiness were collected. Participants were divided into young, middle-aged, and older adult groups based on age, and physical activity was categorized as high, moderate, and low. After controlling for demographic characteristics, participants with high and moderate activity levels had significantly higher life satisfaction and happiness than those with a low activity level across the total population and the three age groups. Age squared was a significant predictor of a positive curvilinear between age and life satisfaction and happiness. Physical activity was significantly related to life satisfaction and happiness in young, middle-aged, and older adults. In addition, life satisfaction and happiness increased with increasing age. The results support the promotion of physical activity.

Ischemia-reperfusion injury is associated with serious clinical manifestations, including myocardial hibernation, acute heart failure, cerebral dysfunction, gastrointestinal dysfunction, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome. Ischemia-reperfusion injury is a critical medical condition that poses an important therapeutic challenge for physicians. In this review article, we present recent advances focusing on the basic pathophysiology of ischemia-reperfusion injury, especially the involvement of reactive oxygen species and cell death pathways. The involvement of the NADPH oxidase system, nitric oxide synthase system, and xanthine oxidase system are also described. When the blood supply is re-established after prolonged ischemia, local inflammation and ROS production increase, leading to secondary injury. Cell damage induced by prolonged ischemia-reperfusion injury may lead to apoptosis, autophagy, necrosis, and necroptosis. We highlight the latest mechanistic insights into reperfusion-injury-induced cell death via these different processes. The interlinked signaling pathways of cell death could offer new targets for therapeutic approaches. Treatment approaches for ischemia-reperfusion injury are also reviewed. We believe that understanding the pathophysiology ischemia-reperfusion injury will enable the development of novel treatment interventions.

Pre-existing immunity to seasonal endemic coronaviruses could have profound consequences for antibody responses to SARS-CoV-2, induced from natural infection or vaccination. A first step to establish whether pre-existing responses can impact SARS-CoV-2 infection is to understand the nature and extent of cross-reactivity in humans to coronaviruses. Here we compare serum antibody and memory B cell responses to coronavirus spike proteins from pre-pandemic and SARS-CoV-2 convalescent donors using binding and functional assays. We show weak evidence of pre-existing SARS-CoV-2 cross-reactive serum antibodies in pre-pandemic donors. However, we find evidence of pre-existing cross-reactive memory B cells that are activated during SARS-CoV-2 infection. Monoclonal antibodies show varying degrees of cross-reactivity with betacoronaviruses, including SARS-CoV-1 and endemic coronaviruses. We identify one cross-reactive neutralizing antibody specific to the S2 subunit of the S protein. Our results suggest that pre-existing immunity to endemic coronaviruses should be considered in evaluating antibody responses to SARS-CoV-2. Pre-existing immune responses between antigenically related viruses can influence responses in viral infections or vaccinations. Here the authors assess and characterize the presence of antibody and memory B cell populations specific to SARS-CoV2 and endemic human coronaviruses.

Mixed lineage kinase domain-like protein （MLKL） was identified to function downstream of receptor interacting protein 3 （RIP3） in tumor necrosis factor-α （TNF）-induced necrosis （also called necroptosis）. However, how MLKL functions to mediate necroptosis is unknown. By reconstitution of MLKL function in MLKL-knockout cells, we showed that the N-terminus of MLKL is required for its function in necroptosis. The oligomerization of MLKL in TNF-treated cells is essential for necroptosis, as artificially forcing MLKL together by using the hormone-binding domain （HBD＊） triggers necroptosis. Notably, forcing together the N-terminal domain （ND） but not the C-terminal kinase domain of MLKL causes necroptosis. Further deletion analysis showed that the four-α-helix bundle of MLKL （1-130 amino acids） is sufficient to trigger necroptosis. Both the HBD＊-mediated and TNF-induced complexes of MLKL（ND） or MLKL are tetramers, and translocation of these complexes to lipid rafts of the plasma membrane precedes cell death. The homo-oligomerization is required for MLKL translocation and the signal sequence for plas- ma membrane location is located in the junction of the first and second a-helices of MLKL. The plasma membrane translocation of MLKL or MLKL（ND） leads to sodium influx, and depletion of sodium from the cell culture medium inhibits necroptosis. All of the above phenomena were not seen in apoptosis. Thus, the MLKL oligomerization leads to translocation of MLKL to lipid rafts of plasma membrane, and the plasma membrane MLKL complex acts either by itself or via other proteins to increase the sodium influx, which increases osmotic pressure, eventually leading to membrane rupture.

Background: Diabetic retinopathy (DR), whose standard diagnosis is performed by human experts, has high prevalence and requires a more efficient screening method. Although machine learning (ML)–based automated DR diagnosis has gained attention due to recent approval of IDx-DR, performance of this tool has not been examined systematically, and the best ML technique for use in a real-world setting has not been discussed. Objective: The aim of this study was to systematically examine the overall diagnostic accuracy of ML in diagnosing DR of different categories based on color fundus photographs and to determine the state-of-the-art ML approach. Methods: Published studies in PubMed and EMBASE were searched from inception to June 2020. Studies were screened for relevant outcomes, publication types, and data sufficiency, and a total of 60 out of 2128 (2.82%) studies were retrieved after study selection. Extraction of data was performed by 2 authors according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), and the quality assessment was performed according to the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). Meta-analysis of diagnostic accuracy was pooled using a bivariate random effects model. The main outcomes included diagnostic accuracy, sensitivity, and specificity of ML in diagnosing DR based on color fundus photographs, as well as the performances of different major types of ML algorithms. Results: The primary meta-analysis included 60 color fundus photograph studies (445,175 interpretations). Overall, ML demonstrated high accuracy in diagnosing DR of various categories, with a pooled area under the receiver operating characteristic (AUROC) ranging from 0.97 (95% CI 0.96-0.99) to 0.99 (95% CI 0.98-1.00). The performance of ML in detecting more-than-mild DR was robust (sensitivity 0.95; AUROC 0.97), and by subgroup analyses, we observed that robust performance of ML was not limited to benchmark data sets (sensitivity 0.92; AUROC 0.96) but could be generalized to images collected in clinical practice (sensitivity 0.97; AUROC 0.97). Neural network was the most widely used method, and the subgroup analysis revealed a pooled AUROC of 0.98 (95% CI 0.96-0.99) for studies that used neural networks to diagnose more-than-mild DR. Conclusions: This meta-analysis demonstrated high diagnostic accuracy of ML algorithms in detecting DR on color fundus photographs, suggesting that state-of-the-art, ML-based DR screening algorithms are likely ready for clinical applications. However, a significant portion of the earlier published studies had methodology flaws, such as the lack of external validation and presence of spectrum bias. The results of these studies should be interpreted with caution.

Necroptosis and pyroptosis are two forms of programmed cell death with a common feature of plasma membrane rupture. Here we studied the morphology and mechanism of pyroptosis in comparison with necroptosis. Different from necroptosis, pyroptosis undergoes membrane blebbing and produces apoptotic body-like cell protrusions （termed pyroptotic bodies） prior to plasma membrane rupture. The rupture in necroptosis is explosion-like, whereas in pyroptosis it leads to flattening of cells. It is known that the execution of necroptosis is mediated by mixed lineage kinase domain-like （MLKL） oligomers in the plasma membrane, whereas gasdermin-D （GSDMD） mediates pyroptosis after its cleavage by caspase-1 or caspase-11. We show that N-terminal fragment of GSDMD （GSDMD-N） generated by caspase cleavage also forms oligomer and migrates to the plasma membrane to kill cells. Both MLKL and GSDMD-N are lipophilic and the N-terminal sequences of both proteins are important for their oligomerization and plasma membrane translocation. Unlike MLKL which forms channels on the plasma membrane that induces influx of selected ions which osmotically swell the cells to burst, GSDMD-N forms non-selective pores and does not rely on increased osmolarity to disrupt cells. Our study reveals the pore-forming activity of GSDMD and channel-forming activity of MLKL determine different ways of plasma membrane rupture in pyroptosis and necroptosis.

Background Extreme precipitation events often cause sudden drops in salinity, leading to disease outbreaks in shrimp aquaculture. Evidence suggests that environmental stress increases animal host susceptibility to pathogens. However, the mechanisms of how low salinity stress induces disease susceptibility remain poorly understood. Methods We investigated the acute response of shrimp gut microbiota exposed to pathogens under low salinity stress. For comparison, shrimp were exposed to Vibrio infection under two salinity conditions: optimal salinity (Control group) and low salinity stress (Stress group). High throughput 16S rRNA sequencing and real-time PCR were employed to characterize the shrimp gut microbiota and quantify the severity level of Vibrio infection. Results The results showed that low salinity stress increased Vibrio infection levels, reduced gut microbiota species richness, and perturbed microbial functions in the shrimp gut, leading to significant changes in lipopolysaccharide biosynthesis that promoted the growth of pathogens. Gut microbiota of the bacterial genera Candidatus Bacilliplasma, Cellvibrio , and Photobacterium were identified as biomarkers of the Stress group. The functions of the gut microbiota in the Stress group were primarily associated with cellular processes and the metabolism of lipid-related compounds. Conclusions Our findings reveal how environmental stress, particularly low salinity, increases shrimp susceptibility to Vibrio infection by affecting the gut microbiota. This highlights the importance of avoiding low salinity stress and promoting gut microbiota resilience to maintain the health of shrimp.

As the climate warms, increasing heat-related health risks are expected, and can be exacerbated by the urban heat island (UHI) effect. UHIs can also offer protection against cold weather, but a clear quantification of their impacts on human health across diverse cities and seasons is still being explored. Here we provide a 500 m resolution assessment of mortality risks associated with UHIs for 85 European cities in 2015-2017. Acute impacts are found during heat extremes, with a 45% median increase in mortality risk associated with UHI, compared to a 7% decrease during cold extremes. However, protracted cold seasons result in greater integrated protective effects. On average, UHI-induced heat-/cold-related mortality is associated with economic impacts of €192/€ − 314 per adult urban inhabitant per year in Europe, comparable to air pollution and transit costs. These findings urge strategies aimed at designing healthier cities to consider the seasonality of UHI impacts, and to account for social costs, their controlling factors, and intra-urban variability. Urban heat islands have the greatest acute impacts on human mortality risk during extreme heat. However, protracted cold seasons result in greater annually integrated protective effects in most European cities under the current climate.

Background Adolescent depressive patients generally have clinical manifestations such as emotional depression and cognitive decline, and family caregivers play an irreplaceable and important role in the disease management and rehabilitation process. Despite the heavy burden of caring for adolescent depressed patients, it is possible that family caregivers are also experiencing anxiety, which may increase their burden, and previous research has reported that psychological resilience plays an important role in reducing the physical and mental burden on caregivers. Objective This study aims to assess the current status of caregiver burden, psychological resilience, and anxiety among family caregivers of adolescents with depression and to explore whether psychological resilience mediates the relationship between caregiver burden and anxiety. Methods A cross-sectional study design was employed to recruit 256 family caregivers of adolescents with depression. The caregivers completed questionnaires, including general demographic information, the Zarit Caregiver Burden Scale, the Self-Rating Anxiety Scale, and the Psychological Resilience Scale. Data analysis was performed via SPSS 26.0. Results There was a significant positive correlation between care burden and anxiety ( r  = 0.561, P  < 0.01), psychological resilience and care burden and anxiety showed a significant negative correlation ( r = -0.895, -0.556, P  < 0.01), and psychological resilience played a partial mediating role between care burden and anxiety (β = 0.198, P  < 0.01), and the indirect effect accounted for 42.95%. Conclusion Perceived resilience plays a mediating role in the association between caregiving burden and anxiety among family caregivers of adolescent patients with depression, and it can be considered as a longitudinal follow-up or intervention study in the future. Implications for clinical practice This study emphasizes that caregiver burden is associated with higher anxiety levels, and psychological resilience may play a moderating role in this association, suggesting that clinicians need to include resilience assessment in routine screening and implement hierarchical interventions based on the “burden-resilience” combined risk: priority is given to providing structured psychological support to high-burden-low resilience groups. The final realization: (1) reduce the burden on caregivers (2) improve the quality of care.