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Risk analysis for outpatient experimental infection as a pathway for affordable RSV vaccine development
Controlled human infection models (CHIMs) are an important tool for accelerating clinical development of vaccines. CHIM costs are driven by quarantine facilities but may be reduced by performing CHIM in the outpatient setting. Furthermore, outpatient CHIMs offer benefits beyond costs, such as a participant-friendly approach and increased real-world aspect. We analyze safety, logistic and ethical risks of respiratory syncytial virus (RSV) CHIM in the outpatient setting. A review of the literature identified outpatient CHIMs involving respiratory pathogens. RSV transmission risk was assessed using data from our inpatient and outpatient RSV CHIMs (EudraCT 020-004137-21). Fifty-nine outpatient CHIMs using RSV, Streptococcus pneumoniae, rhinovirus, and an ongoing Bordetella Pertussis outpatient CHIM were included. One transmission event was recorded. In an inpatient RSV CHIM, standard droplet and isolation measures were sufficient to limit RSV transmission and no symptomatic third-party transmission was measured in the first outpatient RSV CHIM. Logistic and ethical advantages support outpatient CHIM adoption. We propose a framework for outpatient RSV CHIM with risk mitigation strategies to enhance affordable vaccine development.
Association of Daily Steps with Incident Non-Alcoholic Fatty Liver Disease: Evidence from the UK Biobank Cohort.
PURPOSE: Low physical activity has been shown to be associated with higher risk of non-alcoholic fatty liver disease (NAFLD). However, the strength and shape of this association are currently uncertain due to a reliance on self-reported physical activity measures. This report aims to investigate the relationship of median daily step count with NAFLD using accelerometer-derived step count from a large prospective cohort study. METHODS: The wrist-worn accelerometer sub-study of the UK Biobank (N = ~100,000) was used to characterise median daily step count over a seven-day period. NAFLD cases were ascertained via record linkage with hospital inpatient data and death registers or by using a measure of liver fat from imaging. Cox proportional hazards models were employed to assess the association between step count and NAFLD, adjusting for age, sociodemographic, and lifestyle factors. Mediation analyses were conducted. RESULTS: Among 91,031 participants (709,440 person-years of follow-up), there were 762 incident NAFLD cases. Higher step count was log-linearly and inversely associated with risk of NAFLD. A 1000-step increase (representing 10 minutes of walking) was associated with a 12% (95% CI: 10%-14%) lower hazard of NAFLD. When using imaging to identify NAFLD, a 1,000-step increase was associated with a 6% (95% CI: 6%-7%) lower risk. There was evidence for mediation by adiposity, accounting for 39% of the observed association. CONCLUSIONS: Daily step count, a modifiable risk factor, is log-linearly and inversely associated with NAFLD. This association was only partially explained by adiposity. These findings from a large cohort study may have important implications for strategies to lower NAFLD risk.
Prevalence Rates of Frequent Dream Recall and Nightmares by Age, Gender and Sleep Duration in 16 Countries.
The present study aimed to describe the prevalence rates of frequent (i.e., at least weekly) dream recall and nightmares with consideration for differences in age, gender and sleep duration in 16 countries using equivalent assessment methods. The study sample included 15,854 participants (69.9% women) aged 18-99 years (M = 42.39, SD = 16.43) collected by the International COVID-19 Sleep Study collaboration, which used a unified online survey to collect data from May to November 2021 across 16 countries. Participants provided demographic information as well as self-reported estimates of their dream recall and nightmare frequency and sleep duration in 2021 and retrospectively for 2019. Frequent dream recall occurred in 54.0% of participants in 2021 and 51.1% in 2019. Frequent nightmares were reported by 11.0% of participants in 2021 and 6.9% in 2019. Ad hoc regression models found dream recall and sleep duration to have a linear relation, whereas nightmare frequency demonstrated a quadratic relation to sleep duration. Frequent dream recall and nightmare prevalence rates are reported for each of the 16 study countries by age, gender and sleep duration. This is the first multi-continent study to estimate frequent dream recall and nightmare prevalence, which both provides updated prevalence rates during the COVID-19 pandemic as well as extends existing knowledge to previously never studied countries.
Sleep During Pandemic Times: Summary of Findings and Future Outlook Through the Lens of the International COVID Sleep Study (ICOSS).
To study the impact of the COVID-19 pandemic on sleep and circadian rhythms-two fundamental pillars for health-the collaboration International COVID-19 Sleep Study (ICOSS) was established. The present overview comprehensively discusses the findings from this collaboration. Involving sleep researchers across the globe, ICOSS used a harmonised questionnaire to cover changes in sleep and sleep disorders, as well as physical and mental health. Two survey waves were conducted, one in 2020 and another one in 2021. In ICOSS-1, a total of 26,539 people from 14 countries across four continents (Europe, Asia, North and South America) participated. In ICOSS-2, two more countries joined ICOSS, and 15,813 people participated. The focus in ICOSS-2 was on Long COVID. Participants accessed the widely disseminated online surveys in their native language. In the 20 papers published so far, the surveys have uncovered several novel findings, including how the pandemic impacted sleep patterns, the prevalence of sleep disorders, chronotype-based differences and sleep-immune system interactions. To the best of our knowledge, there is no other large-scale multinational study targeting the general population investigating the role of sleep and sleep disorders alongside a variety of psychological, biological, social and economic factors during the recent COVID-19 pandemic.
Dehydration-induced AVP stimulates glucagon release and ketogenesis.
Gliflozins, such as dapagliflozin, belong to a class of drugs that inhibit the sodium-glucose cotransporter 2. Gliflozins have been found to raise glucagon levels, a hormone secreted from pancreatic islet alpha-cells, which can trigger ketosis. However, the precise mechanisms through which gliflozins increase glucagon secretion remain poorly understood. Additionally, gliflozins induce osmotic diuresis, resulting in increased urine volume and plasma osmolality. In this study, we investigated the hypothesis that a compensatory increase in arginine-vasopressin (AVP) mediates dapagliflozin-induced increases in glucagon in vivo. We show that dapagliflozin does not increase glucagon secretion in the perfused mouse pancreas, neither at clinical nor at supra-clinical doses. In contrast, AVP potently increases glucagon secretion. In vivo, dapagliflozin increased plasma glucagon, osmolality, and AVP. An oral load with hypertonic saline amplified dapagliflozin-induced glucagon secretion. Notably, a similar increase in glucagon could also be elicited by dehydration, evoked by 24-hour water restriction. Conversely, blockade of vasopressin 1b receptor signaling, with either pharmacological antagonism or knockout of the receptor, resulted in reduced dapagliflozin-induced glucagon secretion in response to both dapagliflozin and dehydration. Lastly, blocking vasopressin 1b receptor signaling in a mouse model of type 1 diabetes diminished the glucagon-promoting and ketogenic effects of dapagliflozin. Collectively, our data suggest that AVP is an important regulator of glucagon release during both drug-induced and physiological dehydration.
An orexin-sensitive subpopulation of layer 6 neurons regulates cortical excitability and anxiety behaviour.
Cortical layer 6 neurons are the only projection neuron population in the cortical mantle known to electrophysiologically respond to orexin-a neuropeptide involved in cortical arousal and emotive behaviour. These neurons exhibit extensive intercortical and thalamic projections, yet the exact mechanisms underlying these responses are not fully understood. We hypothesize that cortical circuits activated by orexin sensitive L6 neurons in the medial prefrontal cortex (mPFC) are responsible for detecting salient features of sensory stimuli and are therefore involved in regulating emotional states. Here, we show that Drd1a-Cre+ neurons in the mPFC are selectively sensitive to orexin and gate the activation of the prefrontal network in vivo. Moreover, we demonstrated that chronically "silencing" this subpopulation of L6 neurons (Drd1a-Cre+/+:Snap25fl/fl) across the cortical mantle from birth abolishes the orexin-induced prefrontal activation. Consequently, the chronic silencing of these neurons had strong anxiolytic effects on several anxiety-related behavioural paradigms, indicating that orexin-responsive L6 neurons modulate emotional states and may be a substrate for anxiety regulation.
Efficacy of digital cognitive behavioral therapy for treating insomnia in adults aged 65 and older: a secondary analysis using individual participant data from three randomized controlled trials.
OBJECTIVES: Insomnia prevalence increases with age. Although cognitive behavioral therapy (CBT) for insomnia is the first-line treatment, limited accessibility leaves many older adults with few effective treatment options. This study assessed the efficacy of digital CBT (dCBT) for treating insomnia, anxiety, and depression symptoms in adults aged 65 and older. METHOD: Data from three published randomized controlled trials of dCBT for insomnia (Sleepio) versus controls were combined for those aged 65+ with insomnia disorder (N = 315). Insomnia, anxiety, and depression scores were standardized into z-scores for comparison. Mixed-effects models estimated the treatment effect on insomnia, depression, and anxiety outcomes at post-treatment (8-10 wk) and follow-up (24 wk). Chi-squared tests of Sleep Condition Indicator (SCI-8) scores evaluated post-treatment insomnia remission rates between groups. RESULTS: Compared with controls, dCBT generated significantly greater improvements at post-treatment and follow-up in insomnia (gs ≤ -1.88, ps < 0.001) and depression (gs ≤ -0.44, ps ≤ 0.001) and significantly greater improvements in anxiety at post-treatment (g = -0.33, p
Shift workers' experiences and views of sleep disturbance, fatigue and healthy behaviors: a systematic review and qualitative evidence synthesis.
OBJECTIVE: Shift work is common across most societies but poses significant risks to the health of shift workers. In part, this risk is due to the disruption of healthy sleep-wake schedules. This systematic review identified qualitative research on shift workers' experiences of sleep disturbance, fatigue and healthy behaviors. METHODS: We conducted a systematic search of four databases (CINAHL, EMBASE, MEDLINE, PsycINFO) and identified 28 eligible studies involving 1519 participants. We appraised the studies using an adapted Critical Appraisal Skills Programme (CASP) checklist, and confidence in the review findings was formally assessed using the Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) approach. Data were thematically synthesized. RESULTS: Three analytical themes were generated. 'Inevitability of fatigue and tiredness' outlines how shift workers experience a culture where they feel "peer pressure to soldier through" their shifts regardless of fatigue. 'Balancing sleep needs with competing responsibilities' highlights how shift workers struggle to balance the need for daytime sleep with family, leisure, and work responsibilities, often prioritizing family needs over their own sleep. 'Obstacles to engaging in healthy behaviors' describes how shift workers often know which actions would benefit their health and reduce fatigue but find it challenging to translate this knowledge into behavior due to fatiguing and stressful work environments. For the purposes of the GRADE-CERQual assessment, short summary statements were developed to describe 22 review findings: there was moderate or high confidence in all but one of these findings. CONCLUSION: This review suggests that sleep education alone is unlikely to be effective. Interventions should focus on helping shift workers self-regulate their behaviors, thoughts, and emotions to better manage sleep and fatigue.
When life-saving measures lead to trauma: Subcapsular hepatic hematoma after CPR.
Cardiopulmonary resuscitation (CPR) is a critical intervention for cardiac arrest but can result in significant internal injuries due to the force of chest compressions. Among these, subcapsular hepatic hematoma is a rare and serious complication. Here we present a 55-year-old male with a history of alcohol abuse presented with a severe ischemic stroke and subsequently required CPR due to pulseless ventricular tachycardia. Following resuscitation, the patient developed a subcapsular hepatic hematoma, likely caused by the trauma of chest compressions. The patient also had a complex clinical course involving hemorrhagic conversion of the stroke and the need for anticoagulation due to bilateral pulmonary emboli, which further complicated the management of the hepatic hematoma. The identification of the hematoma was achieved through contrast-enhanced CT imaging after the patient exhibited worsening abdominal discomfort and signs of internal bleeding. The management focused on balancing the need for anticoagulation with the risks of further bleeding from the hematoma. A multidisciplinary approach was essential, involving close monitoring, potential surgical intervention, and careful adjustment of anticoagulant therapy. This case emphasizes the importance of recognizing the potential for internal injuries following CPR, especially in patients requiring anticoagulation. Early detection through imaging and a coordinated, multidisciplinary approach are crucial in managing such complications and improving patient outcomes.