Light exposure during sleep impairs cardiometabolic function

This study tested the hypothesis that acute exposure to light during nighttime sleep adversely affects next-morning glucose homeostasis and whether this effect occurs via reduced sleep quality, melatonin suppression, or sympathetic nervous system (SNS) activation during sleep. A total of 20 young adults participated in this parallel-group study design. The room light condition (n = 10) included one night of sleep in dim light (<3 lx) followed by one night of sleep with overhead room lighting (100 lx). The dim light condition (n = 10) included two consecutive nights of sleep in dim light. Measures of insulin resistance (morning homeostatic model assessment of insulin resistance, 30-min insulin area under the curve [AUC] from a 2-h oral glucose tolerance test) were higher in the room light versus dim light condition. Melatonin levels were similar in both conditions. In the room light condition, participants spent proportionately more time in stage N2 and less in slow wave and rapid eye movement sleep. Heart rate was higher and heart rate variability lower (higher sympathovagal balance) during sleep in the room light versus the dim light condition. Importantly, the higher sympathovagal balance during sleep was associated with higher 30-min insulin AUC, consistent with increased insulin resistance the following morning. These results demonstrate that a single night of exposure to room light during sleep can impair glucose homeostasis, potentially via increased SNS activation. Attention to avoiding exposure to light at night during sleep may be beneficial for cardiometabolic health.

Exposure to artificial light during the night is widespread globally, particularly in industrialized countries (1–3). Given that light and dark exposure patterns play a key role in the timing of many behaviors and physiological functions (4), exposure to light in the evening and night has been posited to be deleterious for human health and well-being (1, 5–10). Impacts of light exposure during sleep are not as well studied as other kinds of nighttime light exposure. However, a recent cross-sectional observation study noted that, compared to no light exposure during sleep, any self-reported artificial light exposure in the bedroom during sleep (small nightlight in room, light from outside room, or television/light in room) was associated with obesity in women (11). Furthermore, the incidence of obesity was highest in those who reported sleeping with a television or light on in the bedroom (11). These findings suggest that light in the bedroom during nighttime sleep may negatively influence metabolic regulation.Emerging evidence indicates that light exposure plays a role in human metabolic regulation, with evening light exposure having unfavorable effects on metabolic functions including decreased glucose tolerance and decreased insulin sensitivity (12, 13). In line with these data, we have previously shown that blue-enriched light exposure in the morning and evening alters glucose metabolism, with an increase in insulin resistance compared to dim light exposure (14). In addition, evidence indicates that nighttime indoor light exposure during the habitual sleep period while awake (15), and during sleep itself (16), likely has deleterious metabolic effects. A recent study prospectively measured light exposure in the bedroom during nighttime sleep and showed that higher levels of bedroom light exposure were associated with a higher incidence of type 2 diabetes in an elderly population (16). However, the exact mechanisms by which light exposure, particularly during nighttime sleep, impacts metabolic regulation are not well understood.A proposed pathway to explain the relationship between nighttime light exposure and altered metabolic function is via changes in sleep. Robust evidence from epidemiological and experimental studies indicates that nighttime light exposure, either from outdoor or indoor sources, has negative impacts on subjective and objective sleep quality as indicated by actigraphy or polysomnography (PSG) measures of reduced total sleep time (TST), sleep efficiency (SE), increased wake after sleep onset (WASO), reduced amount of slow wave sleep (SWS), or increased arousal index (AI) (17–20). Given the well-established contribution of sleep disruptions to metabolic dysfunction (21), it is plausible that nighttime light exposure alters glucose metabolism due to disturbances to sleep. However, nighttime light exposure also appears to have a direct effect on glucose regulation that is independent of sleep loss, as shown by a study that subjected healthy male individuals to sleep deprivation in the dark or to sleep deprivation with nighttime light exposure (22). This study showed that a full night of sleep deprivation with nighttime light exposure increased postprandial levels of insulin and glucagon-like peptide-1, increased insulin resistance, and reduced nighttime melatonin; these changes were not observed under conditions of sleep deprivation in darkness.A second proposed mechanism to explain the impairment of glucose metabolism from nighttime light exposure is via light-induced changes to the endogenous circadian system, including suppression and phase shifting of the melatonin rhythm (23). It is well established that light exposure suppresses melatonin secretion (24, 25), and several studies have implicated suppression of nighttime melatonin with incidence of diabetes (26) and insulin resistance (27). The association between altered melatonin levels and changes in glucose regulation may be explained by evidence that melatonin plays a role in the secretion and action of insulin (28–30). In particular, lower melatonin levels resulting from light exposure during the nighttime sleep period, in a fasting condition, have been suggested to alter melatonin’s facilitation of pancreatic β-cell recovery (31). Moreover, evidence shows that light exposure, even of moderate intensity, during the nighttime sleep period can produce a phase shift of the internal circadian system (32, 33). Given the established role of the circadian system in the control of glucose metabolism, light exposure during the nighttime sleep period could facilitate the misalignment between the central clock and peripheral clocks in metabolic tissues, with consequent negative impact on glucose homeostasis (34).A third potential mechanism is the effect of light exposure on autonomic nervous system (ANS) activity. Light exposure has an arousing effect on the sympathetic autonomic system as revealed by the increase in cortisol or heart rate (HR) associated with light exposure mainly during the morning and/or nighttime hours as compared to evening hours (35–37). Beyond the direct excitatory effect exerted by light exposure on sympathetic activity (35), alterations of the ANS characterized by a shift toward an increased sympathetic drive have also been suggested to mediate the negative effects of sleep disruption on many physiological systems such as glucose metabolism (38). Thus, it is plausible that light-induced autonomic activation, either directly and/or mediated by sleep disruption, significantly contributes to the observed relationship between nighttime light exposure and altered glucose metabolism. Notably, sympathetic overactivity has been shown to precede the development of insulin resistance and prediabetes and contribute to the development of obesity and metabolic syndrome (39–41).Prior studies have reported that light exposure during sleep increases HR and decreases HR variability (HRV), consistent with increased sympathetic activation (42–44). These studies either examined bright light (1,000 lx) over the entire sleep period (42) or lower light levels (50 lx or dawn simulation) early or late in the sleep period (43, 44). However, the effect of a single night of moderate room light exposure across the entire nighttime sleep period on autonomic activation and its impact on metabolic function has never been fully investigated.In the present study, we tested the hypothesis that room light exposure (100 lx) during habitual nighttime sleep is associated with increased insulin resistance as measured by the homeostatic model of insulin resistance (HOMA-IR), the Matsuda insulin sensitivity index, and impaired response to an oral glucose tolerance test (OGTT) the next morning. In addition, we hypothesized potential mechanisms of light-induced metabolic changes, such as reduced sleep quality, suppression of melatonin level, and elevated sympathetic activation (HR and HRV) during the sleep period.     

HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models

Germline mutations that activate genes in the canonical RAS/MAPK signaling pathway are responsible for rare human developmental disorders known as RASopathies. Here, we analyzed the molecular determinants of Costello syndrome (CS) using a mouse model expressing HRAS p.G12S, patient skin fibroblasts, hiPSC-derived human cardiomyocytes, a HRAS p.G12V zebrafish model, and human fibroblasts expressing lentiviral constructs carrying HRAS p.G12S or HRAS p.G12A mutations. The findings revealed alteration of mitochondrial proteostasis and defective oxidative phosphorylation in the heart and skeletal muscle of CS mice that were also found in the cell models of the disease. The underpinning mechanisms involved the inhibition of the AMPK signaling pathway by mutant forms of HRAS, leading to alteration of mitochondrial proteostasis and bioenergetics. Pharmacological activation of mitochondrial bioenergetics and quality control restored organelle function in HRAS p.G12A and p.G12S cell models, reduced left ventricle hypertrophy in CS mice, and diminished the occurrence of developmental defects in the CS zebrafish model. Collectively, these findings highlight the importance of mitochondrial proteostasis and bioenergetics in the pathophysiology of RASopathies and suggest that patients with CS may benefit from treatment with mitochondrial modulators.     

An evaluation of a national mass media campaign to raise public awareness of possible lung cancer symptoms in England in 2016 and 2017

Background A two-phase ‘respiratory symptoms’ mass media campaign was conducted in 2016 and 2017 in England raising awareness of cough and worsening shortness of breath as symptoms warranting a general practitioner (GP) visit.Method A prospectively planned pre–post evaluation was done using routinely collected data on 15 metrics, including GP attendance, GP referral, emergency presentations, cancers diagnosed (five metrics), cancer stage, investigations (two metrics), outpatient attendances, inpatient admissions, major lung resections and 1-year survival. The primary analysis compared 2015 with 2017. Trends in metrics over the whole period were also considered. The effects of the campaign on awareness of lung cancer symptoms were evaluated using bespoke surveys.Results There were small favourable statistically significant and clinically important changes over 2 years in 11 of the 15 metrics measured, including a 2.11% (95% confidence interval 1.02–3.20, p < 0.001) improvement in the percentage of lung cancers diagnosed at an early stage. However, these changes were not accompanied by increases in GP attendances. Furthermore, the time trends showed a gradual change in the metrics rather than steep changes occurring during or after the campaigns.Conclusion There were small positive changes in most metrics relating to lung cancer diagnosis after this campaign. However, the pattern over time challenges whether the improvements are wholly attributable to the campaign. Given the importance of education on cancer in its own right, raising awareness of symptoms should remain important. However further research is needed to maximise the effect on health outcomes.Subject terms: Translational research, Epidemiology     

SUDEP classification: Discordances between forensic investigators and epileptologists

We compared sudden unexpected death in epilepsy (SUDEP) diagnosis rates between North American SUDEP Registry (NASR) epileptologists and original death investigators, to determine degree and causes of discordance. In 220 SUDEP cases with post-mortem examination, we recorded the epileptologist adjudications and medical examiner- and coroner- (ME/C) listed causes of death (CODs). COD diagnosis concordance decreased with NASR’s uncertainty in the SUDEP diagnosis: highest for Definite SUDEP (84%, n = 158), lower in Definite Plus (50%, n = 36), and lowest in Possible (0%, n = 18). Rates of psychiatric comorbidity, substance abuse, and toxicology findings for drugs of abuse were all higher in discordant cases than concordant cases. Possible SUDEP cases, an understudied group, were significantly older, and had higher rates of cardiac, drug, or toxicology findings than more certain SUDEP cases. With a potentially contributing or competing COD, ME/Cs favored non–epilepsy-related diagnoses, suggesting a bias toward listing CODs with structural or toxicological findings; SUDEP has no pathognomonic features. A history of epilepsy should always be listed on death certificates and autopsy reports. Even without an alternate COD, ME/Cs infrequently classified COD as “SUDEP.” Improved collaboration and communication between epilepsy and ME/C communities improve diagnostic accuracy, as well as bereavement and research opportunities.     

SARS-CoV-2 Vaccine Responses in Individuals with Antibody Deficiency: Findings from the COV-AD Study

Background

Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood.

Objectives

COVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination.

Methods

Individuals on immunoglobulin replacement therapy or with an IgG less than 4 g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs.

Results

A total of 5.6% (n?=?320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n?=?168) compared with 100% of healthy controls (n?=?205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs. 48.0%, p?=?0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs. 2.39, p?=?0.0003). T cell responses post vaccination was demonstrable in 46.2% of participants and were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine.

Conclusion

SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection.

     

Consumption of animal source foods,especially fish,is associated with better nutritional status among women of reproductive age in rural Bangladesh

In rural Bangladesh, intake of nutrient-rich foods, such as animal source foods (ASFs), is generally suboptimal. Diets low in nutrients and lacking in diversity put women of reproductive age (WRA) at risk of malnutrition as well as adverse birth outcomes. The objective of this study was to assess the relationship between maternal dietary diversity, consumption of specific food groups and markers of nutritional status, including underweight [body mass index (BMI) < 18.5 kg/m²], overweight (BMI ≥ 23 kg/m²) and anaemia (haemoglobin < 120 g/dl) among WRA in Bangladesh. This analysis used data from the third round of a longitudinal observational study, collected from February through May of 2017. Dietary data were collected with a questionnaire, and Women's Dietary Diversity Score (WDDS) was calculated. Associations between WDDS, food group consumption and markers of nutritional status were assessed with separate adjusted logistic regression models. Among WRA, the prevalence of underweight, overweight and anaemia was 13.38%, 40.94% and 39.99%, respectively. Women who consumed dark green leafy vegetables (DGLV) or eggs were less likely to be anaemic or underweight, respectively, and women who consumed ASFs, particularly fish, were less likely to be underweight compared with women who did not consume these foods. WDDS did not show any consistent relationship with WRA outcomes. Interventions that focus on promoting optimal nutritional status among WRA in Bangladesh should emphasise increasing consumption of specific nutrient-rich foods, including ASFs, DGLV and eggs, rather than solely focusing on improving diet diversity in general.