EGF receptor modulates HEV entry in human hepatocytes.

BACKGROUND AND AIMS: Being the most common cause of acute viral hepatitis with >20 million cases per year and 70,000 deaths annually, HEV presents a long-neglected and underinvestigated health burden. Although the entry process of viral particles is an attractive target for pharmacological intervention, druggable host factors to restrict HEV entry have not been identified so far. APPROACH AND RESULTS: Here we identify the EGF receptor (EGFR) as a novel host factor for HEV and reveal the significance of EGFR for the HEV entry process. By utilizing RNAi, chemical modulation with Food and Drug Administration-approved drugs, and ectopic expression of EGFR, we revealed that EGFR is critical for HEV infection without affecting HEV RNA replication or assembly of progeny virus. We further unveiled that EGFR itself and its ligand-binding domain, rather than its signaling function, is responsible for the proviral effect. Modulation of EGF expression in HepaRG cells and primary human hepatocytes affected HEV infection. CONCLUSIONS: Taken together, our study provides novel insights into the life cycle of HEV and identified EGFR as a possible target for future antiviral strategies against HEV.

MicroRNAs modulate SARS-CoV-2 infection of primary human hepatocytes by regulating the entry factors ACE2 and TMPRSS2.

BACKGROUND AND AIMS: Severe acute respiratory syndrome coronavirus (SARS-CoV-2) preferentially infects the respiratory tract; however, several studies have implicated a multi-organ involvement. Hepatic dysfunctions caused by SARS-CoV-2 infection have been increasingly recognized and described to correlate with disease severity. To elucidate molecular factors that could contribute towards hepatic infection, we concentrated on microRNAs (miRNAs), a class of small non-coding RNAs that modulate various cellular processes and which are reported to be differentially regulated during liver injury. We aimed to study the infection of primary human hepatocytes (PHH) with SARS-CoV-2 and to evaluate the potential of miRNAs for modulating viral infection. METHODS: We analysed liver autopsies from a coronavirus disease 19 (COVID-19)-positive cohort for the presence of viral RNA using Nanopore sequencing. PHH were used for the infection with SARS-CoV-2. The candidate miRNAs targeting angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) were identified using in silico approaches. To discover the potential regulatory mechanism, transfection experiments, qRT-PCRs, western blots and luciferase reporter assays were performed. RESULTS: We could detect SARS-CoV-2 RNA in COVID-19-positive liver autopsies. We show that PHH express ACE2 and TMPRSS2 and can be readily infected with SARS-CoV-2, resulting in robust replication. Transfection of selected miRNA mimics reduced SARS-CoV-2 receptor expression and SARS-CoV-2 burden in PHH. In silico and biochemical analyses supported a potential direct binding of miR-141-3p to the SARS-CoV-2 genome. CONCLUSION: We confirm that PHH are susceptible to SARS-CoV-2 infection and demonstrate selected miRNAs targeting SARS-CoV-2 entry factors and/or the viral genome reduce viral loads. These data provide novel insights into hepatic susceptibility to SARS-CoV-2 and associated dysfunctions in COVID-19.

A comprehensive approach for evaluating the virucidal performance of domestic laundry detergents under practical conditions.

AIMS: We aimed to develop a method to assess the virucidal performance of domestic laundry in a lab-scale washing machine (Rotawash) based on EN 17658. METHODS AND RESULTS: For method development, virus recovery was investigated after drying on cotton carriers for three test viruses murine norovirus (MNV), modified vaccinia virus Ankara (MVA), and bovine coronavirus (BCoV), followed by washing simulations in flasks and Rotawash. MNV and MVA demonstrated sufficient recovery from carriers after drying and washing (up to 40°C and 60 min). BCoV exhibited lower recovery, indicating less relevance as a test virus. Rotawash efficacy tests conducted with MNV, a resistant, non-enveloped virus, showed limited efficacy of a bleach-free detergent, aligning with results from a domestic washing machine. Rotawash washes achieved higher reductions in infectious virus titers than suspension tests, indicating the role of washing mechanics in virus removal. CONCLUSIONS: This study established a practical method to test the virucidal efficacy of laundry detergents in Rotawash, simulating domestic washing.

Comparison of 16 Pediatric Acute Respiratory Distress Syndrome-Associated Plasma Biomarkers With Changing Lung Injury Severity.

OBJECTIVES: Pediatric acute respiratory distress syndrome (PARDS) is a source of substantial morbidity and mortality in the PICU, and different plasma biomarkers have identified different PARDS and ARDS subgroups. We have a poor understanding of how these biomarkers change over time and with changing lung injuries. We sought to determine how biomarker levels change over PARDS course, whether they are correlated, and whether they are different in critically ill non-PARDS patients. DESIGN: Two-center prospective observational study. SETTING: Two quaternary care academic children's hospitals. PATIENTS: Subjects under 18 years of age admitted to the PICU who were intubated and met the Second Pediatric Acute Lung Injury Consensus Conference-2 PARDS diagnostic criteria and nonintubated critically ill subjects without apparent lung disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma samples were obtained on study days 1, 3, 7, and 14. The levels of 16 biomarkers were measured using a fluorometric bead-based assay. Compared with non-PARDS subjects, on day 1 PARDS subjects had increased concentrations of tumor necrosis factor-alpha, interleukin (IL)-8, interferon-γ, IL17, granzyme B, soluble intercellular adhesion molecule-1 (sICAM1), surfactant protein D, and IL18 but reduced matrix metalloproteinase 9 (MMP-9) concentrations (all p < 0.05). Day 1 biomarker concentrations and PARDS severity were not correlated. Over PARDS course, changes in 11 of the 16 biomarkers positively correlated with changing lung injury with sICAM1 ( R = 0.69, p = 2.2 × 10 -16 ) having the strongest correlation. By Spearman rank correlation of biomarker concentrations in PARDS subjects, we identified two patterns. One had elevations of plasminogen activator inhibitor-1, MMP-9, and myeloperoxidase, and the other had higher inflammatory cytokines. CONCLUSIONS: sICAM1 had the strongest positive correlation with worsening lung injury across all study time points suggesting that it is perhaps the most biologically relevant of the 16 analytes. There was no correlation between biomarker concentration on day 1 and day 1 PARDS severity; however, changes in most biomarkers over time positively correlated with changing lung injury. Finally, in day 1 samples, 7 of the 16 biomarkers were not significantly different between PARDS and critically ill non-PARDS subjects. These data highlight the difficulty of using plasma biomarkers to identify organ-specific pathology in critically ill patients.

Efficient Inactivation of Monkeypox Virus by World Health Organization‒Recommended Hand Rub Formulations and Alcohols.

Increasing nonzoonotic human monkeypox virus (MPXV) infections urge reevaluation of inactivation strategies. We demonstrate efficient inactivation of MPXV by 2 World Health Organization‒recommended alcohol-based hand rub solutions. When compared with other (re)emerging enveloped viruses, MPXV displayed the greatest stability. Our results support rigorous adherence to use of alcohol-based disinfectants.

Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study.

BACKGROUND: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated. OBJECTIVE: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group. METHODS: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated. RESULTS: Overall, people with PD had a regionally smaller posterior lobe (dmax = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17). CONCLUSIONS: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Increased SARS-CoV-2 reactive low avidity T cells producing inflammatory cytokines in pediatric post-acute COVID-19 sequelae (PASC).

BACKGROUND: A proportion of the convalescent SARS-CoV-2 pediatric population presents nonspecific symptoms, mental health problems, and a reduction in quality of life similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID-19 symptomatic. However, data regarding its clinical manifestation and immune mechanisms are currently scarce. METHODS: In this study, we perform a comprehensive clinical and immunological profiling of 17 convalescent COVID-19 children with post-acute COVID-19 sequelae (PASC) manifestation and 13 convalescent children without PASC manifestation. A detailed medical history, blood and instrumental tests, and physical examination were obtained from all patients. SARS-CoV-2 reactive T-cell response was analyzed via multiparametric flow cytometry and the humoral immunity was addressed via pseudovirus neutralization and ELISA assay. RESULTS: The most common PASC symptoms were shortness of breath/exercise intolerance, paresthesia, smell/taste disturbance, chest pain, dyspnea, headache, and lack of concentration. Blood count and clinical chemistry showed no statistical differences among the study groups. We detected higher frequencies of spike (S) reactive CD4+ and CD8+ T cells among the PASC study group, characterized by TNFα and IFNγ production and low functional avidity. CRP levels are positively correlated with IFNγ producing reactive CD8+ T cells. CONCLUSIONS: Our data might indicate a possible involvement of a persistent cellular inflammatory response triggered by SARS-CoV-2 in the development of the observed sequelae in pediatric PASC. These results may have implications on future therapeutic and prevention strategies.

Fading SARS-CoV-2 humoral VOC cross-reactivity and sustained cellular immunity in convalescent children and adolescents.

Cross-reactive cellular and humoral immunity can substantially contribute to antiviral defense against SARS-CoV-2 variants of concern (VOC). While the adult SARS-CoV-2 cellular and humoral immunity and its cross-recognition potential against VOC is broadly analyzed, similar data regarding the pediatric population are missing. In this study, we perform an analysis of the humoral and cellular SARS-CoV-2 response immune of 32 convalescent COVID-19 children (children), 27 convalescent vaccinated adults(C + V+) and 7 unvaccinated convalescent adults (C + V-). Similarly to adults, a significant reduction of cross-reactive neutralizing capacity against delta and omicron VOC was observed 6 months after SARS-CoV-2 infection. While SAR-CoV-2 neutralizing capacity was comparable among children and C + V- against all VOC, children demonstrated as expected an inferior humoral response when compared to C + V+. Nevertheless, children generated SARS-CoV-2 reactive T cells with broad cross-recognition potential. When compared to V + C+, children presented even comparable frequencies of WT-reactive CD4 + and CD8 + T cells with high avidity and functionality. Taking into consideration the limitations of study - unknown disease onset for 53% of the asymptomatic pediatric subjects, serological detection of SARS-CoV-2 infection-, our results suggest that following SARS-CoV-2 infection children generate a humoral SARS-CoV-2 response with neutralizing potential comparable to unvaccinated COVID-19 convalescent adults as well a sustained SARS-CoV-2 cellular response cross-reactive to VOC.

Effects in air-exposed corn silage of medium chain fatty acids on select spoilage microbes, zoonotic pathogens, and in vitro rumen fermentation.

Medium chain fatty acid (MCFA) treatment (0.75% C6, hexanoic; C8, octanoic; C10, decanoic; or equal proportion mixtures of C6:C8:C10:C12 or C8:C10/g; C12 = dodecanoic acid) of aerobically-exposed corn silage on spoilage and pathogenic microbes and rumen fermentation were evaluated in vitro. After 24 h aerobic incubation (37 °C), microbial enumeration revealed 3 log10 colony-forming units (CFU)/g fewer (P = 0.03) wild-type yeast and molds in C8:C10-treated silage than controls. Compared with controls, wild-type enterococci decreased (P < 0.01) in all treatments except the C6:C8:C10:C12 mixture; lactic acid bacteria were decreased (P < 0.01) in all treatments except C6 and the C6:C8:C10:C12 mixture. Total aerobes and inoculated Staphylococcus aureus or Listeria monocytogenes were unaffected by treatment (P > 0.05). Anaerobic incubation (24 h at 39 °C) of ruminal fluid (10 mL) with 0.02 g overnight air-exposed MCFA-treated corn silage revealed higher hydrogen accumulations (P = 0.03) with the C8:C10 mixture than controls. Methane, acetate, propionate, butyrate, or estimates of fermented hexose were unaffected. Acetate:propionate ratios were higher (P < 0.01) and fermentation efficiencies were marginally lower (P < 0.01) with C8- or C8:C10-treated silage than controls. Further research is warranted to optimize treatments to target unwanted microbes without adversely affecting beneficial microbes.

Comparison of MiniMed 780G system performance in users aged younger and older than 15 years: Evidence from 12 870 real-world users.

AIM: To investigate real-world glycaemic outcomes and goals achieved by users of the MiniMed 780G advanced hybrid closed loop (AHCL) system aged younger and older than 15 years with type 1 diabetes (T1D). MATERIALS AND METHODS: Data uploaded by MiniMed 780G system users from 27 August 2020 to 22 July 2021 were aggregated and retrospectively analysed based on self-reported age (≤15 years and >15 years) for three cohorts: (a) post-AHCL initiation, (b) 6-month longitudinal post-AHCL initiation and (c) pre- versus post-AHCL initiation. Analyses included mean percentage of time spent in AHCL and at sensor glucose ranges, insulin delivered and the proportion of users achieving recommended glucose management indicator (GMI < 7.0%) and time in target range (TIR 70-180 mg/dl > 70%) goals. RESULTS: Users aged 15 years or younger (N = 3211) achieved a GMI of 6.8% ± 0.3% and TIR of 73.9% ± 8.7%, while spending 92.7% of time in AHCL. Users aged older than 15 years (N = 8874) achieved a GMI of 6.8% ± 0.4% and TIR of 76.5% ± 9.4% with 92.3% of time in AHCL. Time spent at less than 70 mg/dl was within the recommended target of less than 4% (3.2% and 2.3%, respectively). Similar outcomes were observed for each group (N = 790 and N = 1642, respectively) in the first month following AHCL initiation, and were sustained over the 6-month observation period. CONCLUSIONS: This real-world analysis shows that more than 75% of users with T1D aged 15 years or younger using the MiniMed 780G system achieved international consensus-recommended glycaemic control, mirroring the achievements of the population aged older than 15 years.

RS 2247911 polymorphism of GPRC6A gene and serum undercarboxylated-osteocalcin are associated with testis function.

PURPOSE: Undercarboxylated-Osteocalcin (ucOCN), acting on its putative receptor GPRC6A, was shown to stimulate testosterone (T) production by Leydig cells in rodents, in parallel with the hypothalamus-pituitary-gonadal axis (HPG) mediated by luteinizing hormone (LH). The aim of this cross-sectional study was to evaluate the association among serum ucOCN, rs2247911 polymorphism of GPRC6A gene and the endocrine/semen pattern in a cohort of infertile males, possibly identifying an involvement of the ucOCN-GPRC6A axis on testis function. METHODS: 190 males, including 74 oligozoospermic subjects, 58 azoosperminc patients and 58 normozoospermic controls, were prospectively recruited at the Orient Hospital for Infertility, Assisted Reproduction and Genetics in Syria (Study N. 18FP), from July 2018 to June 2020. Outpatient evaluation included the clinical history, anthropometrics and a fasting blood sampling for hormonals, serum OCN (both carboxylated and undercarboxylated), glycemic and lipid profile and screening for rs2247911 GPRC6A gene polymorphism. RESULTS: Higher serum ucOCN associated with higher T and HDL-cholesterol (respectively: r = 0.309, P < 0.001 and r = 0.248, P = 0.001), and with lower FSH (r = - 0.327, P < 0.001) and LDL-cholesterol (r = - 0.171; P = 0.018). Patients bearing the GG genotype of rs2247911 had higher sperm count compared to GA genotype (P = 0.043) and, compared to both AG and AA genotypes, had higher serum T (P = 0.004, P = 0.001) and lower triglycerides levels (P = 0.002, P < 0.001). Upon normalization for LH levels and body mass index, rs2274911 and ucOCN were significantly associated with higher serum T at linear stepwise regression analysis (P = 0.013, P = 0.007). CONCLUSIONS: Our data suggest the involvement of ucOCN-GPRC6A axis in the regulation of T production by the testis, subsidiary to HPG.

Expanding Benevolent Ageism: Replicating Attitudes of Overaccommodation to Older Men.

BACKGROUND: Older adults are stereotyped in a paternalistic manner (warm, but incompetent), deserving of assistance regardless of their need; however, little is known about how gender contextualizes these attitudes. The purpose of this study was to extend previous work that examined the malleability of the paternalistic older adult stereotype using a two-part experimental vignette. The goals of the current study included: (1) to examine attitudes of benevolent ageist behavior toward a male target, (2) to confirm whether attributions made toward an older male target change if they defy or confirm the paternalistic stereotype, and (3) to examine the distinct roles of age and gender on an act of benevolent ageism. METHOD: In prior work, a female target was offered unnecessary assistance, which is replicated in the current study with a male target. The age (young vs. old), response (accepting vs. declining assistance), and gender (male vs. female) of the target were manipulated and then rated by a young adult sample (N = 698). RESULTS: Our findings replicated earlier work in that overaccommodative behaviors were endorsed more so for the older target than the younger target, which corroborates support for the Stereotype Content Model in that older adults are viewed paternalistically. Additionally, the older male target and the older female target were viewed differently when they respectively defied the paternalistic stereotype indicating distinctness between benevolent ageism and benevolent sexism. CONCLUSIONS: These findings add to the growing body of benevolent ageism literature and highlight the intersection of gender and age.

Reducing Mask-Related Pressure Injuries in Pediatric Patients During Noninvasive Ventilation by Targeting Patient Mask Leak: A Quality Improvement Initiative.

PURPOSE: To compare outcomes following implementation of patient mask leak range of 25 to 55 liters per minute (lpm) to guide strap tension of sleep masks during noninvasive ventilation against baseline data with no patient mask leak range on number of noninvasive mask-related pressure injuries (PIs). PARTICIPANTS AND SETTING: All noninvasively ventilated pediatric acute care patients admitted to general wards and intensive care units between February 1, 2018, and February 1, 2019, in a quaternary hospital in the southwest United States. APPROACH: Using the Plan Do Study Act model, we employed an intervention to examine the rate of PIs per noninvasive positive pressure ventilation (NIPPV) days and patient-days before and after implementation of patient mask leak parameters between 25 and 55 lpm to guide mask strap tension. Since patients are at an increased risk of sleep mask-related PIs only when on NIPPV, we sought to describe that as number or PIs per number of days at risk, described as NIPPV days, and patient days which is the traditional denominator for wounds and hospital-acquired conditions. OUTCOMES: Preintervention, 6 out of 115 subjects (5.2 %) incurred PI at a rate of 0.51 per 100 NIPPV days or 0.26 per 1000 patient-days. Of the 1932 NIPPV days since education was completed, only 1 subject out of 87 (1.1%) incurred a high-stage PI (0.05/100 NIPPV days-a 96.79% reduction or 0.05/1000 patient-days-a 92.86% reduction). Upon reaching more than 90% compliance with patient mask leak range in December 2018, 1221 NIPPV days resulted in 0 noninvasive mask-related PIs. Greater than 90% compliance with a patient mask leak of 25 to 55 lpm allowed us to successfully achieve our hospital's operating plan goal of 0.15 of 1000 patient-days within this group. IMPLICATIONS FOR PRACTICE: Maintaining a patient mask leak range between 25 and 55 lpm should be considered as part of proper fit for pediatric patients using NIPPV with a mask. Additional work is needed to assess this leak range in more children and in studies conducted at multiple sites.

International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson's Disease.

BACKGROUND: Brain structure abnormalities throughout the course of Parkinson's disease have yet to be fully elucidated. OBJECTIVE: Using a multicenter approach and harmonized analysis methods, we aimed to shed light on Parkinson's disease stage-specific profiles of pathology, as suggested by in vivo neuroimaging. METHODS: Individual brain MRI and clinical data from 2357 Parkinson's disease patients and 1182 healthy controls were collected from 19 sources. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effects models. Patients grouped according to Hoehn and Yahr stage were compared with age- and sex-matched controls. Within the patient sample, we investigated associations with Montreal Cognitive Assessment score. RESULTS: Overall, patients showed a thinner cortex in 38 of 68 regions compared with controls (dmax  = -0.20, dmin  = -0.09). The bilateral putamen (dleft  = -0.14, dright  = -0.14) and left amygdala (d = -0.13) were smaller in patients, whereas the left thalamus was larger (d = 0.13). Analysis of staging demonstrated an initial presentation of thinner occipital, parietal, and temporal cortices, extending toward rostrally located cortical regions with increased disease severity. From stage 2 and onward, the bilateral putamen and amygdala were consistently smaller with larger differences denoting each increment. Poorer cognition was associated with widespread cortical thinning and lower volumes of core limbic structures. CONCLUSIONS: Our findings offer robust and novel imaging signatures that are generally incremental across but in certain regions specific to disease stages. Our findings highlight the importance of adequately powered multicenter collaborations. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Lung function trajectories and bronchial hyperresponsiveness during childhood following severe RSV bronchiolitis in infancy.

BACKGROUND: Children with severe respiratory syncytial virus (RSV) bronchiolitis in infancy have increased risks of asthma and reduced lung function in later life. There are limited studies on the longitudinal changes of lung function and bronchial hyperreactivity from early to late childhood in infants hospitalized for RSV bronchiolitis. METHODS: In a prospective cohort of 206 children with their first episode of RSV-confirmed bronchiolitis in the first year of life, 122 had spirometry performed at least twice between 5-16 years of age. Methacholine bronchoprovocation was available in 127 and 79 children at 7 and 12 years of age, respectively. Longitudinal changes in FEV1 , FVC, and FEV1 /FVC z-scores and methacholine PC20 were analyzed. RESULTS: 55% of the study cohort (N = 122) were male, and 55% were Caucasian. During follow-up, longitudinal changes in z-scores for pre- and post-bronchodilator FEV1 (P < .0001) FVC (P < .0001) and FEV1 /FVC (P < .0001 for pre- and 0.007 for post-bronchodilator) from age 5 to 10-16 years were observed. Declined lung function in late childhood was significantly associated with gender, physician diagnosis of asthma, and allergic sensitization. PC20 geometric mean increased from 0.28 mg/mL at 7 years to 0.53 mg/mL at 12 years of age, and the frequency of abnormal bronchial hyperreactivity decreased from 96% to 78% (P = .0003). CONCLUSIONS: Following severe RSV bronchiolitis, there appear to be significant longitudinal changes in pre- and post-bronchodilator lung function during childhood. The study has several limitations including significant dropouts and the lack of a control group and post-bronchodilator measurements. Bronchial hyperreactivity is common in children following severe RSV bronchiolitis; however, it appears to decrease as they enter late childhood.

Real-world performance of the MiniMed™ 670G system in Europe.

AIM: To evaluate the real-world performance of the MiniMed 670G system in Europe, in individuals with diabetes. MATERIALS AND METHODS: Data uploaded from October 2018 to July 2020 by individuals living in Europe were aggregated and retrospectively analysed. The mean glucose management indicator (GMI), percentage of time spent within (TIR), below (TBR) and above (TAR) glycaemic ranges, system use and insulin consumed in users with 10 or more days of sensor glucose data after initial Auto Mode start were determined. Another analysis based on suboptimally (GMI > 8.0%) and well-controlled (GMI < 7.0%) glycaemia pre-Auto Mode initiation was also performed. RESULTS: Users (N = 14 899) spent a mean of 81.4% of the time in Auto Mode and achieved a mean GMI of 7.0% ± 0.4%, TIR of 72.0% ± 9.7%, TBR less than 3.9 mmol/L of 2.4% ± 2.1% and TAR more than 10 mmol/L of 25.7% ± 10%, after initiating Auto Mode. When compared with pre-Auto Mode initiation, GMI was reduced by 0.3% ± 0.4% and TIR increased by 9.6% ± 9.9% (P < .0001 for both). Significantly improved glycaemic control was observed irrespective of pre-Auto Mode GMI levels of less than 7.0% or of more than 8.0%. While the total daily dose of insulin increased for both groups, a greater increase was observed in the latter, an increase primarily due to increased basal insulin delivery. By contrast, basal insulin decreased slightly in well-controlled users. CONCLUSIONS: Most MiniMed 670G system users in Europe achieved TIR more than 70% and GMI less than 7% while minimizing hypoglycaemia, in a real-world environment. These international consensus-met outcomes were enabled by automated insulin delivery meeting real-time insulin requirements adapted to each individual user.

Behaviours that prompt primary school teachers to adopt and implement physically active learning: a meta synthesis of qualitative evidence.

BACKGROUND: Physically active learning (PAL) - integration of movement within delivery of academic content - is a core component of many whole-of-school physical activity approaches. Yet, PAL intervention methods and strategies vary and frequently are not sustained beyond formal programmes. To improve PAL training, a more comprehensive understanding of the behavioural and psychological processes that influence teachers' adoption and implementation of PAL is required. To address this, we conducted a meta-synthesis to synthesise key stakeholders' knowledge of facilitators and barriers to teachers' implementing PAL in schools to improve teacher-focussed PAL interventions in primary (elementary) schools. METHODOLOGY: We conducted a meta-synthesis using a five-stage thematic synthesis approach to; develop a research purpose and aim, identify relevant articles, appraise studies for quality, develop descriptive themes and interpret and synthesise the literature. In the final stage, 14 domains from the Theoretical Domain Framework (TDF) were then aligned to the final analytical themes and subthemes. RESULTS: We identified seven themes and 31 sub-themes from 25 eligible papers. Four themes summarised teacher-level factors: PAL benefits, teachers' beliefs about own capabilities, PAL teacher training, PAL delivery. One theme encompassed teacher and school-level factors: resources. Two themes reflected school and external factors that influence teachers' PAL behaviour: whole-school approach, external factors. Ten (of 14) TDF domains aligned with main themes and sub-themes: Knowledge, Skills, Social/Professional Role and Identity, Beliefs about Capabilities, Beliefs about Consequences, Reinforcement, Goals, Environmental Context and Resources, Social influences and Emotion. CONCLUSIONS: Our synthesis illustrates the inherent complexity required to change and sustain teachers' PAL behaviours. Initially, teachers must receive the training, resources and support to develop the capability to implement and adapt PAL. The PAL training programme should progress as teachers' build their experience and capability; content should be 'refreshed' and become more challenging over time. Subsequently, it is imperative to engage all levels of the school community for PAL to be fully integrated into a broader school system. Adequate resources, strong leadership and governance, an engaged activated community and political will are necessary to achieve this, and may not currently exist in most schools.

COVID-19-Induced ARDS Is Associated with Decreased Frequency of Activated Memory/Effector T Cells Expressing CD11a+.

Preventing the progression to acute respiratory distress syndrome (ARDS) in COVID-19 is an unsolved challenge. The involvement of T cell immunity in this exacerbation remains unclear. To identify predictive markers of COVID-19 progress and outcome, we analyzed peripheral blood of 10 COVID-19-associated ARDS patients and 35 mild/moderate COVID-19 patients, not requiring intensive care. Using multi-parametric flow cytometry, we compared quantitative, phenotypic, and functional characteristics of circulating bulk immune cells, as well as SARS-CoV-2 S-protein-reactive T cells between the two groups. ARDS patients demonstrated significantly higher S-protein-reactive CD4+ and CD8+ T cells compared to non-ARDS patients. Of interest, comparison of circulating bulk T cells in ARDS patients to non-ARDS patients demonstrated decreased frequencies of CD4+ and CD8+ T cell subsets, with activated memory/effector T cells expressing tissue migration molecule CD11a++. Importantly, survival from ARDS (4/10) was accompanied by a recovery of the CD11a++ T cell subsets in peripheral blood. Conclusively, data on S-protein-reactive polyfunctional T cells indicate the ability of ARDS patients to generate antiviral protection. Furthermore, decreased frequencies of activated memory/effector T cells expressing tissue migratory molecule CD11a++ observed in circulation of ARDS patients might suggest their involvement in ARDS development and propose the CD11a-based immune signature as a possible prognostic marker.

Age Differences in Sexual Minority Stress and the Importance of Friendship in Later Life.

OBJECTIVES: This study examined whether younger and middle-aged and older sexual minorities (YSM, MAOSM) experience minority stress differently in relation to social support and depressive symptomatology. METHODS: Cross-sectional data from 238 sexual minorities (18-80; M = 40.93) comprised the sample, who were strategically separated into cohorts. Group difference and regression methods were used to examine differences in minority stress between groups and the relationships between minority stress-social support-depressive symptomatology within groups. RESULTS: MAOSM had greater outness and lower IH. Additionally, outness and IH were the best predictors for the MAOSM and YSM group, respectively. MAOSM indicated better adaption to minority stresses, highlighting the importance of friend support as a protective mechanism. CONCLUSIONS: The minority stress-depressive symptomatology is mitigated by friend support in MAOSM. CLINICAL IMPLICATIONS: OSM and YSM demonstrate different susceptibility of minority stress on depressive symptomatology, with outness being a stronger indicator in MAOSM and IH being a stronger predictor in YSM. Social support does not work uniformly in different cohorts; however, multiple sources (i.e., family, friends) should be discussed with clients. Clinicians should treat cohort as one of the defining features of a sexual minority's lifelong experience with minority stress.

Immune monitoring facilitates the clinical decision in multifocal COVID-19 of a pancreas-kidney transplant patient.

The optimal management in transplant recipients with coronavirus disease 2019 (COVID-19) remains uncertain. The main concern is the ability of immunosuppressed patients to generate sufficient immunity for antiviral protection. Here, we report on immune monitoring facilitating a successful outcome of severe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated pneumonia, meningoencephalitis, gastroenteritis, and acute kidney and pancreas graft failure in a pancreas-kidney transplant recipient. Despite the very low numbers of circulating B, NK, and T cells identified in follow-up, a strong SARS-CoV-2 reactive T cell response was observed. Importantly, we detected T cells reactive to Spike, Membrane, and Nucleocapsid proteins of SARS-CoV-2 with majority of T cells showing polyfunctional proinflammatory Th1 phenotype at all analyzed time points. Antibodies against Spike protein were also detected with increasing titers in follow-up. Neutralization tests confirmed their antiviral protection. A correlation between cellular and humoral immunity was observed underscoring the specificity of demonstrated data. We conclude that analyzing the kinetics of nonspecific and SARS-CoV-2-reactive cellular and humoral immunity can facilitate the clinical decision on immunosuppression adjustment and allow successful outcome as demonstrated in the current clinical case. Although the antiviral protection of the detected SARS-CoV-2-reactive T cells requires further evaluation, our data prove an ability mounting a strong SARS-CoV-2-reactive T cell response with functional capacity in immunosuppressed patients.