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Human cytomegalovirus (HCMV) is a β-herpesvirus that increases morbidity and mortality in immunocompromised individuals including transplant recipients and newborns. New anti-HCMV therapies are an urgent medical need for diverse patient populations. HCMV infection of a broad range of host tissues is dependent on the gH/gL/gO trimer and gH/gL/UL28/UL130/UL131A pentamer complexes on the viral envelope. We sought to develop safe and effective therapeutics against HCMV by generating broadly-neutralizing, human monoclonal antibodies (mAbs) from VelocImmune® mice immunized with gH/gL cDNA. Following high-throughput binding and neutralization screening assays, 11 neutralizing antibodies were identified with unique CDR3 regions and a high-affinity (K D 1.4-65 nM) to the pentamer complex. The antibodies bound to distinct regions within Domains 1 and 2 of gH and effectively neutralized diverse clinical strains in physiologically relevant cell types including epithelial cells, trophoblasts, and monocytes. Importantly, combined adminstration of mAbs with ganciclovir, an FDA approved antiviral, greatly limited virus dissemination. Our work identifies several anti-gH/gL mAbs and sheds light on gH neutralizing epitopes that can guide future vaccine strategies. A panel of neutralizing human monoclonal antibodies targeting human cytomegalovirus offers a combination approach geared toward virus entry and replication to prevent viral dissemination.

BackgroundSevere COVID-19, with the need in supplemental oxygen and hospitalization, leads to major burden on patients and healthcare systems. As a result, safe and effective ambulatory treatment strategies for severe COVID-19 are of urgent need. In this systematic review, we aimed to evaluate interventions to transition care to the ambulatory setting for patients with active severe COVID-19 that required supplemental oxygen.MethodsWe searched Medline, Scopus, Web of Science, and DOAJ databases to identify articles with original data published until the 1st of April 2023. Characteristics and outcomes of interventions to transition care to home management were reviewed. Given the heterogeneous settings and outcomes studied, a meta-analysis was not performed.ResultsOf the 235 studies identified, 11 observational studies, with 2645 patients, were included. The interventions were initiated from the emergency department, observation units or inpatient units, and included continuous home telemonitoring (n = 8), mobile applications (n = 2), and patient-initiated medical contact (n = 3). Included patients had an overall short length of hospital stay, high readmission rates, and positive patients’ feedback. There was a lack of prospective controlled data and cost-effectiveness analyses.ConclusionOur findings highlight the potential in treating severe COVID-19 at the ambulatory setting and the lack of high-quality data in this field. Dedicated medical teams, adjusted monitoring methods, improving clinical trajectory, and correct inclusion settings are needed for safe and effective transition of care.

Background Performance monitoring is pivotal for learning and decision‐making across the lifespan. While evidence suggests that these abilities decline with age and older individuals often tend to overestimate their abilities, that is, show imprecise metacognitive evaluations of their performance. Recent evidence indicates that increased activity of the locus coeruleus‐noradrenaline (LC‐NA) system may subserve performance monitoring processes. The locus coeruleus (LC), which plays a critical role in various cognitive functions, is known to undergo structural and functional decline with age. This study aimed to investigate whether changes in pupil size—an indirect and non‐exclusive distal measure of LC activation—are associated with performance appraisal impairments in aging. Method 40 healthy younger adults (20‐30 y.o.) and 27 healthy older adults (60‐75 y.o.) completed working memory, perceptual decisions and mental rotation tasks while providing trial‐by‐trial confidence judgments during eye‐tracking recordings. Result Results indicated that older adults made more errors, exhibited slower responses and were less confident about performance than younger adults across all tasks. In both age groups, higher confidence in performance accuracy was associated with greater accuracy and faster responses, suggesting that confidence judgments were well‐aligned with behavioral performance across groups. Notably, pupil size was larger during higher confidence trials for both groups but was consistently larger in older adults across all tasks Conclusion Our findings suggest that pupil dilation serves as a reliable marker of performance monitoring across cognitive domains in different age groups. They do not support the notion that performance monitoring declines with age. Furthermore, our findings align with the notion that the LC‐NA system may become overactive in aging, potentially compensating for neuronal loss to sustain cognitive function.

Pupil dilation (PD) is an indirect and non-exclusive marker of firing of the noradrenergic locus coeruleus (LC-NA) system. The LC-NA system undergoes both structural and functional decline in healthy and pathological aging. PD is known to increase with cognitive load or effort as well as an increased allocation of attentional resources. Findings on age-related differences are mixed, with some evidence showing greater or more sustained pupil responses in older adults with increasing cognitive load, possibly reflecting compensatory mechanisms, while others show reduced or blunted responses. This study aimed to investigate whether changes in pupil size are associated with task-dependent variations in performance in older and younger adults. 40 healthy younger adults (20-30 years old) and 27 healthy older adults (60-75 years old) completed three experimental tasks during eye-tracking recordings. The tasks assessed different types of cognitive abilities and employed cube structure stimuli with varying levels of difficulty: a) a mental rotation tasks with varying levels of angle disparity; b) a perceptual decision task with varying levels of stimulus sizes; c) a working memory tasks with varying levels of memory load. In both groups, behavioural performance was modulated by task difficulty with higher accuracy and faster responses in easier as compared to difficult conditions in all the tasks. Across all three tasks, older adults were slower and committed more errors than younger adults. Interestingly, age-related differences in pupil dilation were detected only in the working memory task, where older participants showed greater pupil responses than younger participants. Furthermore, in the working memory tasks, pupil dilation was larger in difficult conditions. Our findings suggest that pupil dilation is not a general marker of cognitive effort but can be specifically sensitive to memory load. Moreover, the results are in line with the idea that larger PD may reflect age-related compensatory mechanisms, occurring in a task-specific fashion. In conclusion, the study offers novel hypotheses on the role of the LC-NA system in cognitive function and its decline.

Background Pupil dilation (PD) is an indirect and non‐exclusive marker of firing of the noradrenergic locus coeruleus (LC‐NA) system. The LC‐NA system undergoes both structural and functional decline in healthy and pathological aging. PD is known to increase with cognitive load or effort as well as an increased allocation of attentional resources. Findings on age‐related differences are mixed, with some evidence showing greater or more sustained pupil responses in older adults with increasing cognitive load, possibly reflecting compensatory mechanisms, while others show reduced or blunted responses. This study aimed to investigate whether changes in pupil size are associated with task‐dependent variations in performance in older and younger adults. Method 40 healthy younger adults (20‐30 years old) and 27 healthy older adults (60‐75 years old) completed three experimental tasks during eye‐tracking recordings. The tasks assessed different types of cognitive abilities and employed cube structure stimuli with varying levels of difficulty: a) a mental rotation tasks with varying levels of angle disparity; b) a perceptual decision task with varying levels of stimulus sizes; c) a working memory tasks with varying levels of memory load. Result In both groups, behavioural performance was modulated by task difficulty with higher accuracy and faster responses in easier as compared to difficult conditions in all the tasks. Across all three tasks, older adults were slower and committed more errors than younger adults. Interestingly, age‐related differences in pupil dilation were detected only in the working memory task, where older participants showed greater pupil responses than younger participants. Furthermore, in the working memory tasks, pupil dilation was larger in difficult conditions. Conclusion Our findings suggest that pupil dilation is not a general marker of cognitive effort but can be specifically sensitive to memory load. Moreover, the results are in line with the idea that larger PD may reflect age‐related compensatory mechanisms, occurring in a task‐specific fashion. In conclusion, the study offers novel hypotheses on the role of the LC‐NA system in cognitive function and its decline.

Performance monitoring is pivotal for learning and decision-making across the lifespan. While evidence suggests that these abilities decline with age and older individuals often tend to overestimate their abilities, that is, show imprecise metacognitive evaluations of their performance. Recent evidence indicates that increased activity of the locus coeruleus-noradrenaline (LC-NA) system may subserve performance monitoring processes. The locus coeruleus (LC), which plays a critical role in various cognitive functions, is known to undergo structural and functional decline with age. This study aimed to investigate whether changes in pupil size-an indirect and non-exclusive distal measure of LC activation-are associated with performance appraisal impairments in aging. 40 healthy younger adults (20-30 y.o.) and 27 healthy older adults (60-75 y.o.) completed working memory, perceptual decisions and mental rotation tasks while providing trial-by-trial confidence judgments during eye-tracking recordings. Results indicated that older adults made more errors, exhibited slower responses and were less confident about performance than younger adults across all tasks. In both age groups, higher confidence in performance accuracy was associated with greater accuracy and faster responses, suggesting that confidence judgments were well-aligned with behavioral performance across groups. Notably, pupil size was larger during higher confidence trials for both groups but was consistently larger in older adults across all tasks CONCLUSION: Our findings suggest that pupil dilation serves as a reliable marker of performance monitoring across cognitive domains in different age groups. They do not support the notion that performance monitoring declines with age. Furthermore, our findings align with the notion that the LC-NA system may become overactive in aging, potentially compensating for neuronal loss to sustain cognitive function.

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common cause for emergency department (ED) visits. Still, large scale studies that assess the management of AECOPD in the ED are limited. Our aim was to evaluate treatment characteristics of AE-COPD in the ED on a national scale. A prospective study as part of the COPD Israeli survey, conducted between 2017 and 2019, in 13 medical centers. Patients hospitalized with AECOPD were included and interviewed. Clinical data related to their ED and hospital stay were collected. 344 patients were included, 38% females, mean age of 70 ± 11 years. Median (IQR) time to first ED treatment was 59 (23–125) minutes and to admission 293 (173–490) minutes. Delayed ED treatment (> 1 h) was associated with older age (p = 0.01) and lack of a coded diagnosis of COPD in hospital records (p = 0.01). Long ED length-of-stay (> 5 h) was linked with longer hospitalizations (p = 0.01). Routine ED care included inhalations of short-acting bronchodilators (246 patients, 72%) and systemic steroids (188 patients, 55%). Receiving routine ED care was associated with its continuation during hospitalization (p < 0.001). In multivariate analysis, predictors for patients not receiving routine care were obesity (adjusted odds ratio 0.5, 95% CI 0.3–0.8, p = 0.01) and fever (AOR 0.3, 95% CI 0.1–0.6, p < 0.01), while oxygen saturation < 91% was an independent predictor for ED routine treatment (AOR 3.6, 95% CI 2.1–6.3, p < 0.01). Our findings highlight gaps in the treatment of AECOPD in the ED on a national scale, with specific predictors for their occurrence.

The cell fate decisions of stem cells (SCs) largely depend on signals from their microenvironment (niche). However, very little is known about how biochemical niche cues control cell behavior in vivo. To address this question, we focused on the corneal epithelial SC model in which the SC niche, known as the limbus, is spatially segregated from the differentiation compartment. We report that the unique biomechanical property of the limbus supports the nuclear localization and function of Yes-associated protein (YAP), a putative mediator of the mechanotransduction pathway. Perturbation of tissue stiffness or YAP activity affects SC function as well as tissue integrity under homeostasis and significantly inhibited the regeneration of the SC population following SC depletion. In vitro experiments revealed that substrates with the rigidity of the corneal differentiation compartment inhibit nuclear YAP localization and induce differentiation, a mechanism that is mediated by the TGFβ−SMAD2/3 pathway. Taken together, these results indicate that SC sense biomechanical niche signals and that manipulation of mechano-sensory machinery or its downstream biochemical output may bear fruits in SC expansion for regenerative therapy.

Medical follow-up of symptomatic patients after acute Coronavirus Disease 2019 (COVID-19) results in major burdens on patients and healthcare systems. The value of serological markers as part of this follow-up remains undetermined. We aimed to evaluate the clinical implications of serological markers for follow-up of acute COVID-19. For this purpose, we conducted an observational cohort study of patients 3 months after acute COVID-19. Participants visited a respiratory-clinic between October 2020 and March 2021, and completed pulmonary function tests (PFTs), serological tests, symptom-related questionnaires, and chest CT scans. Overall, 275 patients were included at a median of 82 days (IQR 64–111) post infection. 162 (59%) patients had diffusing capacity for carbon monoxide corrected for hemoglobin (DLCOc) below 80%, and 69 (25%) had bilateral chest abnormalities on CT scan. In multivariate analysis, anti-S levels were an independent predictor for DLCOc (β = − 0.14, p  = 0.036). Anti-S levels were also associated with severe COVID-19 and older age, and correlated with anti-nucleocapsid (r = 0.30, p  < 0.001) and antibodies to receptor binding domain (RBD, r = 0.37, p  < 0.001). Other serological variables were not associated with clinical outcomes. In conclusion, symptomatic patients 3-months after COVID-19 had high respiratory symptomatic burden, in which anti-S levels were significantly associated with previous severe COVID-19 and DLCOc.

Precision medicine has the potential to provide more accurate diagnosis, appropriate treatment and timely prevention strategies by considering patients’ biological makeup. However, this cannot be realized without integrating clinical and omics data in a data-sharing framework that achieves large sample sizes. Systems that integrate clinical and genetic data from multiple sources are scarce due to their distinct data types, interoperability, security and data ownership issues. Here we present a secure framework that allows immutable storage, querying and analysis of clinical and genetic data using blockchain technology. Our platform allows clinical and genetic data to be harmonized by combining them under a unified framework. It supports combined genotype–phenotype queries and analysis, gives institutions control of their data and provides immutable user access logs, improving transparency into how and when health information is used. We demonstrate the value of our framework for precision medicine by creating genotype–phenotype cohorts and examining relationships within them. We show that combining data across institutions using our secure platform increases statistical power for rare disease analysis. By offering an integrated, secure and decentralized framework, we aim to enhance reproducibility and encourage broader participation from communities and patients in data sharing. A secure framework that harmonizes storage and querying of clinical and genetic data using blockchain technology was developed to support combined genotype–phenotype queries, improving transparency into how and when health information is used.