Trends in obstructive sleep apnea disease severity over nearly two decades: update on the VA San Diego experience.

Study Objectives: The Sleep Program at the VA San Diego Healthcare System (VASDHS) started a patient database over twenty years ago for its home sleep apnea testing (HSAT) program. An analysis of ten years of diagnostic HSAT data was reported on over 12 500 patients in 2014. Over this time period, severe obstructive sleep apnea (OSA) decreased in frequency. In contrast, mild OSA increased in frequency and was the most frequently reported severity in our analysis. In more recent times, the 2021 continuous positive airway pressure (CPAP) crisis created difficulties in dispersing CPAP therapies to individuals including Veterans with OSA, prompting our group to reexamine the HSAT database. Methods: A retrospective review was performed of the local clinical database of HSAT diagnostic testing of 8,928 sleep studies from 2018 to 2022. Results: The overall mean apnea-hypopnea index (AHI) decreased from 40.4/hour (2004) to 24.3/hour (2022) (p < .001). The two time periods were examined separately. For 2004-2013, it was found that the mean AHI in 2004 was not significantly different from the mean AHI in 2005, 2006, or 2007 but was significantly different from the mean AHI in each year from 2008 (mean AHI = 30.7/h) to 2013 (mean AHI = 26.1/hour). For 2019-2022, the mean AHI did not significantly differ between the 4 years. Conclusions: These findings have implications for OSA therapies. Additionally, the high prevalence of mild sleep apnea, which is typically associated with lesser adherence to PAP therapy, further highlights the importance of non-PAP alternatives to improve treatment effectiveness.

Interventions to Prevent Hospital Admissions in Long-Term Care Facilities: A Rapid Review of Economic Evidence.

OBJECTIVES: Hospital admissions can be hazardous for older adults, particularly those living in long-term care facilities. Preventing nonessential admissions can be beneficial for this population, as well as reducing demand on health services. This review summarizes the economic evidence surrounding effective interventions to reduce hospital attendances and admissions for people living in long-term care facilities. DESIGN: Rapid review of economic evidence. SETTING AND PARTICIPANTS: People living in long-term facilities. METHODS: We searched MEDLINE, CINAHL, Cochrane CENTRAL, PubMed, and Web of Science on September 20, 2022, and again on January 10, 2023. Full economic evaluations and cost analyses reporting on advanced care planning, goals of care setting, nurse practitioner input, palliative care, influenza vaccinations, and enhancing access to intravenous therapies were eligible. Data were extracted using a prepiloted data extraction form and critically appraised using either the Drummond-Jefferson checklist or an amended NIH Critical Appraisal Tool appended with questions from a critical appraisal checklist for cost analyses. Data were synthesized narratively. RESULTS: We included 7 studies: 3 full economic evaluations and 4 cost analyses. Because of lack of clarity on the underlying study design, we did not include one of the cost analyses in our synthesis. Advanced care planning, a palliative care program, and a high-dose influenza vaccination reported potential cost savings. Economic evidence for a multicomponent intervention and a nurse practitioner model was inconclusive. The overall quality of the evidence varied between studies. CONCLUSIONS AND IMPLICATIONS: A number of potentially cost-effective approaches to reduce demand on hospital services from long-term care facilities were identified. However, further economic evaluations are needed to overcome limitations of the current evidence base and offer more confident conclusions.

Oxygen consumption rate of flatworms under the influence of wake- and sleep-promoting neurotransmitters.

Flatworms are among the best studied animal models for regeneration; however, they also represent an emerging opportunity to investigate other biological processes as well. For instance, flatworms are nocturnal and sleep during the day, a state that is regulated by sleep/wake history and the action of the sleep-promoting neurotransmitter gamma-aminobutyric acid (or GABA). Sleep is widespread across the animal kingdom, where it serves many nonexclusive functions. Notably, sleep saves energy by reducing metabolic rate and by not doing something more energetically taxing. Whether the conservation of energy is apparent in sleeping flatworms is unclear. We measured the oxygen consumption rate (OCR) of flatworms dosed with either (1) GABA (n = 29) which makes flatworms inactive or (2) dopamine (n = 20) which stimulates flatworms to move, or (3) day and night neurotransmitter-free controls (n = 28 and 27, respectively). While OCR did not differ between the day and night, flatworms treated with GABA used less oxygen than those treated with dopamine, and less than the day-time control. Thus, GABA affected flatworm physiology, ostensibly by enforcing energy-conserving sleep. Evidence that dopamine increased metabolism was less strong. This work broadens our understanding of flatworm physiology and expands the phylogenetic applicability of energy conservation as a function of sleep.

Wild white-capped noddies keep a cool head in a heated situation.

Sunning, or sunbathing, is a behavior observed in diverse birds from at least 50 taxonomic families. While sunning, birds exhibit signs of heat stress, notably panting, indicating a risk of overheating. Given that even modest increases in brain temperature can impair brain function, sunning birds may have mechanisms that selectively cool the brain. Sunning birds could cool the brain using active physiological mechanisms (e.g., an ophthalmic rete or sleeping) or passive adaptations, such as light-colored plumage over the cranium. White-capped noddies are tropical seabirds that sunbathe in direct sunlight on cloudless days. Using infrared thermography on wild birds, we found that the white cap is 20 °C cooler than that of the black back while sunning. A deceased bird showed the same thermal profile, indicating that this difference arises from dichromatic coloration and not underlying physiology. Thus, the white cap may extend the duration of time noddies can sunbathe and keep the brain cool, near core body temperature, while allowing the rest of the body to heat up, perhaps to displace or kill parasites.

Which interventions are effective at decreasing or increasing emergency department attendances or hospital admissions from long-term care facilities? A systematic review.

OBJECTIVE: UK long-term care facility residents account for 185 000 emergency hospital admissions each year. Avoidance of unnecessary hospital transfers benefits residents, reduces demand on the healthcare systems but is difficult to implement. We synthesised evidence on interventions that influence unplanned hospital admissions or attendances by long-term care facility residents. METHODS: This is a systematic review of randomised controlled trials. PubMed, MEDLINE, EMBASE, ISI Web of Science, CINAHL and the Cochrane Library were searched from 2012 to 2022, building on a review published in 2013. We included randomised controlled trials that evaluated interventions that influence (decrease or increase) acute hospital admissions or attendances of long-term care facility residents. Risk of bias and evidence quality were assessed using Cochrane Risk Of Bias-2 and Grading of Recommendations Assessment, Development and Evaluation. RESULTS: Forty-three randomised studies were included in this review. A narrative synthesis was conducted and the weight of evidence described with vote counting. Advance care planning and goals of care setting appear to be effective at reducing hospitalisations from long-term care facilities. Other effective interventions, in order of increasing risk of bias, were: nurse practitioner/specialist input, palliative care intervention, influenza vaccination and enhancing access to intravenous therapies in long-term care facilities. CONCLUSIONS: Factors that affect hospitalisation and emergency department attendances of long-term care facility residents are complex. This review supports the already established use of advance care planning and influenza vaccination to reduce unscheduled hospital attendances. It is likely that more than one intervention will be needed to impact on healthcare usage across the long-term care facility population. The findings of this review are useful to identify effective interventions that can be combined, as well as highlighting interventions that either need evaluation or are not effective at decreasing healthcare usage. PROSPERO REGISTRATION NUMBER: CRD42020169604.

National Early Warning Scores Following Emergency Hospital Transfer: Implications for Care Home Residents.

OBJECTIVE: Care home residents have high rates of hospital admission. The UK National Early Warning Score (NEWS2) standardizes the secondary care response to acute illness. However, the ability of NEWS2 to predict adverse health outcomes specifically for care home residents is unknown. This study explored the relationship between NEWS2 on admission to hospital and resident outcome 7 days later. DESIGN: Repeated cross-sectional study. SETTING AND PARTICIPANTS: Data on UK care home residents admitted to 160 hospitals in two 24-hour periods (2019 and 2020). METHOD: Chi-squared and Kruskal-Wallis tests, and multinomial regression were used to explore the association between low (score ≤2), intermediate (3-4), high (5-6), and critically high (≥7) NEWS2 on admission and each of the following: discharge on day of admission, admission and discharge within 7 days, prolonged hospital admission (>7 days), and death. RESULTS: From 665 resident admissions across 160 hospital sites, NEWS2 was low for 54%, intermediate for 18%, high for 13%, and critically high for 16%. The 7-day outcome was 10% same-day discharge, 47% admitted and subsequently discharged, 34% remained inpatients, and 8% died. There is a significant association between NEWS2 and these outcomes (P < .001). Compared with those with low NEWS2, residents with high and critically high NEWS2 had 3.6 and 9.5 times increased risk of prolonged hospitalization [relative risk ratio (RRR) 3.56; 95% CI 1.02-12.37; RRR 9.47; CI 2.20-40.67], respectively. The risk of death was approximately 14 times higher for residents with high NEWS2 (RRR 13.62; CI 3.17-58.49) and 54 times higher (RRR 53.50; CI 11.03-259.54) for critically high NEWS2. CONCLUSION AND IMPLICATIONS: Higher NEWS2 measurements on admission are associated with an increased risk of hospitalization up to 7 days duration, prolonged admission, and mortality for care home residents. NEWS2 may have a role as an adjunct to acute care decision making for hospitalized residents.

In Chagas disease, transforming growth factor beta neutralization reduces Trypanosoma cruzi infection and improves cardiac performance.

Chronic Chagasic cardiomyopathy (CCC), a progressive inflammatory and fibrosing disease, is the most prominent clinical form of Chagas disease, a neglected tropical disease caused by Trypanosoma cruzi infection. During CCC, the parasite remains inside the cardiac cells, leading to tissue damage, involving extensive inflammatory response and irregular fibrosis. Among the fibrogenic factors is transforming growth factor-ß (TGF-ß), a key cytokine controlling extracellular matrix synthesis and degradation. TGF-ß is involved in CCC onset and progression, with increased serum levels and activation of its signaling pathways in the cardiac tissue, which crucially contributes to fibrosis. Inhibition of the TGF-ß signaling pathway attenuates T. cruzi infection and prevents cardiac damage in an experimental model of acute Chagas disease. The aim of this study was to investigate the effect of TGF-ß neutralization on T. cruzi infection in both in vitro and in vivo pre-clinical models, using the 1D11 monoclonal antibody. To this end, primary cultures of cardiac cells were infected with T. cruzi trypomastigote forms and treated with 1D11. For in vivo studies, 1D11 was administered in different schemes for acute and chronic phase models (Swiss mice infected with 104 parasites from the Y strain and C57BL/6 mice infected with 102 parasites from the Colombian strain, respectively). Here we show that the addition of 1D11 to cardiac cells greatly reduces cardiomyocyte invasion by T. cruzi and the number of parasites per infected cell. In both acute and chronic experimental models, T. cruzi infection altered the electrical conduction, decreasing the heart rate, increasing the PR interval and the P wave duration. The treatment with 1D11 reduced cardiac fibrosis and reversed electrical abnormalities improving cardiac performance. Taken together, these data further support the major role of the TGF-ß signaling pathways in T. cruzi-infection and their biological consequences on parasite/host interactions. The therapeutic effects of the 1D11 antibody are promising and suggest a new possibility to treat cardiac fibrosis in the chronic phase of Chagas' heart disease by TGF-ß neutralization.

NEWS2 and the older person.

The National Early Warning Score (NEWS), published in 2012, made no specific adjustments for older people. The updated NEWS2 (2017) incorporated new confusion as a category for consciousness. In this article, we consider the role of NEWS2 in detection of acute clinical deterioration in older people and how the score may be used to inform care, highlighting the additional aspects, such as care escalation decisions, that may ensue. We consider the evidence of NEWS and NEWS2 in assessment of the older person in different settings, including the potential benefits and limitations for care home residents. We suggest that NEWS2 may need adaptation for older people in future iterations, and that it should be used in conjunction with other clinical assessments, such as the Clinical Frailty Scale and the four 'A's test (4AT) for delirium.

NEWS2 in out-of-hospital settings, the ambulance and the emergency department.

As more healthcare is provided in non-hospital settings, it is essential to support clinicians in recognising early signs of clinical deterioration to enable prompt intervention and treatment.There are intuitive reasons why the use of the National Early Warning Score 2 (NEWS2) in out-of-hospital settings may enhance the community response to acute illness by using a common language across healthcare. An additional advantage of the use of NEWS2 in community settings is that it is not disease specific and requires no expensive technology or great expertise to take a full set of observations that can be an indicator of clinical acuity.However, concerns have been expressed as NEWS2 was developed in acute hospital settings that it may not be applicable in community settings; this review shares some of the practical ways that NEWS2 can support clinical practice along with the emerging published evidence.

Human iPSC-derived astrocytes generated from donors with globoid cell leukodystrophy display phenotypes associated with disease.

Globoid cell leukodystrophy (Krabbe disease) is a fatal neurodegenerative, demyelinating disease caused by dysfunctional activity of galactosylceramidase (GALC), leading to the accumulation of glycosphingolipids including psychosine. While oligodendrocytes have been extensively studied due to their high levels of GALC, the contribution of astrocytes to disease pathogenesis remains to be fully elucidated. In the current study, we generated induced pluripotent stem cells (iPSCs) from two donors with infantile onset Krabbe disease and differentiated them into cultures of astrocytes. Krabbe astrocytes recapitulated many key findings observed in humans and rodent models of the disease, including the accumulation of psychosine and elevated expression of the pro-inflammatory cytokine IL-6. Unexpectedly, Krabbe astrocytes had higher levels of glucosylceramide and ceramide, and displayed compensatory changes in genes encoding glycosphingolipid biosynthetic enzymes, suggesting a shunting away from the galactosylceramide and psychosine pathway. In co-culture, Krabbe astrocytes negatively impacted the survival of iPSC-derived human neurons while enhancing survival of iPSC-derived human microglia. Substrate reduction approaches targeting either glucosylceramide synthase or serine palmitoyltransferase to reduce the sphingolipids elevated in Krabbe astrocytes failed to rescue their detrimental impact on neuron survival. Our results suggest that astrocytes may contribute to the progression of Krabbe disease and warrant further exploration into their role as therapeutic targets.

Thermography for disease detection in livestock: A scoping review.

Infra-red thermography (IRT) offers potential opportunities as a tool for disease detection in livestock. Despite considerable research in this area, there are no common standards or protocols for managing IRT parameters in animal disease detection research. In this review, we investigate parameters that are essential to the progression of this tool and make recommendations for their use based on the literature found and the veterinary thermography guidelines from the American Academy of Thermology. We analyzed a defined set of 109 articles concerned with the use of IRT in livestock related to disease and from these articles, parameters for accurate IRT were identified and sorted into the fields of camera-, animal- or environment-related categories to assess the practices of each article in reporting parameters. This review demonstrates the inconsistencies in practice across peer-reviewed articles and reveals that some important parameters are completely unreported while others are incorrectly captured and/or under-represented in the literature. Further to this, our review highlights the lack of measured emissivity values for live animals in multiple species. We present guidelines for the standards of parameters that should be used and reported in future experiments and discuss potential opportunities and challenges associated with using IRT for disease detection in livestock.

A novel brain-penetrant oral UGT8 inhibitor decreases in vivo galactosphingolipid biosynthesis in murine Krabbe disease.

Krabbe disease is a rare, inherited neurodegenerative disease due to impaired lysosomal ß-galactosylceramidase (GALC) activity and formation of neurotoxic ß-galactosylsphingosine ('psychosine'). We investigated substrate reduction therapy with a novel brain-penetrant inhibitor of galactosylceramide biosynthesis, RA 5557, in twitcher mice that lack GALC activity and model Krabbe disease. This thienopyridine derivative selectively inhibits uridine diphosphate-galactose glycosyltransferase 8 (UGT8), the final step in the generation of galactosylceramides which are precursors of sulphatide and, in the pathological lysosome, the immediate source of psychosine. Administration of RA 5557, reduced pathologically elevated psychosine concentrations (72-86%) in the midbrain and cerebral cortex in twitcher mice: the inhibitor decreased galactosylceramides by about 70% in midbrain and cerebral cortex in mutant and wild type animals. Exposure to the inhibitor significantly decreased several characteristic inflammatory response markers without causing apparent toxicity to myelin-producing cells in wild type and mutant mice; transcript abundance of oligodendrocyte markers MBP (myelin basic protein) and murine UGT8 was unchanged. Administration of the inhibitor before conception and during several breeding cycles to mice did not impair fertility and gave rise to healthy offspring. Nevertheless, given the unchanged lifespan, it appears that GALC has critical functions in the nervous system beyond the hydrolysis of galactosylceramide and galactosylsphingosine. Our findings support further therapeutic exploration of orally active UGT8 inhibitors in Krabbe disease and related galactosphingolipid disorders. The potent thienopyridine derivative with effective target engagement here studied appears to have an acceptable safety profile in vivo; judicious dose optimization will be needed to ensure efficacious clinical translation.

Structural Bases of Zoonotic and Zooanthroponotic Transmission of SARS-CoV-2.

The emergence of multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the importance of possible animal-to-human (zoonotic) and human-to-animal (zooanthroponotic) transmission and potential spread within animal species. A range of animal species have been verified for SARS-CoV-2 susceptibility, either in vitro or in vivo. However, the molecular bases of such a broad host spectrum for the SARS-CoV-2 remains elusive. Here, we structurally and genetically analysed the interaction between the spike protein, with a particular focus on receptor binding domains (RBDs), of SARS-CoV-2 and its receptor angiotensin-converting enzyme 2 (ACE2) for all conceivably susceptible groups of animals to gauge the structural bases of the SARS-CoV-2 host spectrum. We describe our findings in the context of existing animal infection-based models to provide a foundation on the possible virus persistence in animals and their implications in the future eradication of COVID-19.

MUC5B mucin films under mechanical confinement: A combined neutron reflectometry and atomic force microscopy study.

HYPOTHESIS: Among other functions, mucins hydrate and protect biological interfaces from mechanical challenges. Mucins also attract interest as biocompatible coatings with excellent lubrication performance. Therefore, it is of high interest to understand the structural response of mucin films to mechanical challenges. We hypothesized that this could be done with Neutron Reflectometry using a novel sample environment where mechanical confinement is achieved by inflating a membrane against the films. EXPERIMENTS: Oral MUC5B mucin films were investigated by Force Microscopy/Spectroscopy and Neutron Reflectometry both at solid-liquid interfaces and under mechanical confinement. FINDINGS: NR indicated that MUC5B films were almost completely compressed and dehydrated when confined at 1 bar. This was supported by Force Microscopy/Spectroscopy investigations. Force Spectroscopy also indicated that MUC5B films could withstand mechanical confinement by means of steric interactions for pressures lower than âˆ¼ 0.5 bar i.e., mucins could protect interfaces from mechanical challenges of this magnitude while keeping them hydrated. To investigate mucin films under these pressures by means of the employed sample environment for NR, further technological developments are needed. The most critical would be identifying or developing more flexible membranes that would still meet certain requirements like chemical homogeneity and very low roughness.

Hydration Forces Dominate Surface Charge Dependent Lipid Bilayer Interactions under Physiological Conditions.

Lipid bilayer interactions are essential to a vast range of biological functions, such as intracellular transport mechanisms. Surface charging mediated by concentration dependent ion adsorption and desorption on lipid headgroups alters electric double layers as well as van der Waals and steric hydration forces of interacting bilayers. Here, we directly measure bilayer interactions during charge modulation in a symmetrically polarized electrochemical three-mirror interferometer surface forces apparatus. We quantify polarization and concentration dependent hydration and electric double layer forces due to cation adsorption/desorption. Our results demonstrate that exponential hydration layer interactions effectively describe surface potential dependent surface forces due to cation adsorption at high salt concentrations. Hence, electric double layers of lipid bilayers are exclusively dominated by inner Helmholtz charge regulation under physiological conditions. These results are important for rationalizing bilayer behavior under physiological conditions, where charge and concentration modulation may act as biological triggers for function and signaling.

National Early Warning Scores and COVID-19 deaths in care homes: an ecological time-series study.

OBJECTIVES: To investigate whether National Early Warning Scores (NEWS/NEWS2) could contribute to COVID-19 surveillance in care homes. SETTING: 460 care home units using the same software package to collect data on residents, from 46 local authority areas in England. PARTICIPANTS: 6464 care home residents with at least one NEWS recording. EXPOSURE MEASURE: 29 656 anonymised person-level NEWS from 29 December 2019 to 20 May 2020 with component physiological measures: systolic blood pressure, respiratory rate, pulse rate, temperature and oxygen saturation. Baseline values for each measure calculated using 80th and 20th centile scores before March 2020. OUTCOME MEASURE: Cross-correlation comparison of time series with Office for National Statistics weekly reported registered deaths of care home residents where COVID-19 was the underlying cause of death, and all other deaths (excluding COVID-19) up to 10 May 2020. RESULTS: Deaths due to COVID-19 were registered from 23 March 2020 in the local authority areas represented in the study. Between 23 March 2020 and 10 May 2020, there were 5753 deaths (1532 involving COVID-19 and 4221 other causes). We observed a rise in the proportion of above-baseline NEWS beginning 16 March 2020, followed 2 weeks later by an increase in registered deaths (cross-correlation of r=0.82, p<0.05 for a 2 week lag) in corresponding local authorities. The proportion of above-baseline oxygen saturation, respiratory rate and temperature measurements also increased approximately 2 weeks before peaks in deaths. CONCLUSIONS: NEWS could contribute to COVID-19 disease surveillance in care homes during the pandemic. Oxygen saturation, respiratory rate and temperature could be prioritised as they appear to signal rise in mortality almost as well as NEWS. This study reinforces the need to collate data from care homes, to monitor and protect residents' health. Further work using individual level outcome data is needed to evaluate the role of NEWS in the early detection of resident illness.

Mutually Beneficial Combination of Molecular Dynamics Computer Simulations and Scattering Experiments.

We showcase the combination of experimental neutron scattering data and molecular dynamics (MD) simulations for exemplary phospholipid membrane systems. Neutron and X-ray reflectometry and small-angle scattering measurements are determined by the scattering length density profile in real space, but it is not usually possible to retrieve this profile unambiguously from the data alone. MD simulations predict these density profiles, but they require experimental control. Both issues can be addressed simultaneously by cross-validating scattering data and MD results. The strengths and weaknesses of each technique are discussed in detail with the aim of optimizing the opportunities provided by this combination.

Experiences of a National Early Warning Score (NEWS) intervention in care homes during the COVID-19 pandemic: a qualitative interview study.

BACKGROUND: The COVID-19 pandemic has taken a heavy toll on the care home sector, with residents accounting for up to half of all deaths in Europe. The response to acute illness in care homes plays a particularly important role in the care of residents during a pandemic. Digital recording of a National Early Warning Score (NEWS), which involves the measurement of physical observations, started in care homes in one area of England in 2016. Implementation of a NEWS intervention (including equipment, training and support) was accelerated early in the pandemic, despite limited evidence for its use in the care home setting. OBJECTIVES: To understand how a NEWS intervention has been used in care homes in one area of North-East England during the COVID-19 pandemic, and how it has influenced resident care, from the perspective of stakeholders involved in care delivery and commissioning. METHODS: A qualitative interview study with care home (n=10) and National Health Service (n=7) staff. Data were analysed using thematic analysis. RESULTS: Use of the NEWS intervention in care homes in this area accelerated during the COVID-19 pandemic. Stakeholders felt that NEWS, and its associated education and support package, improved the response of care homes and healthcare professionals to deterioration in residents' health during the pandemic. Healthcare professionals valued the ability to remotely monitor resident observations, which facilitated triage and treatment decisions. Care home staff felt empowered by NEWS, providing a common clinical language to communicate concerns with external services, acting as an adjunct to staff intuition of resident deterioration. CONCLUSIONS: The NEWS intervention formed an important part of the care home response to COVID-19 in the study area. Positive staff perceptions now need to be supplemented with data on the impact on resident health and well-being, workload, and service utilisation, during the pandemic and beyond.

Low-Dose Vitamin D3 Supplementation Does Not Affect Natural Regulatory T Cell Population but Attenuates Seasonal Changes in T Cell-Produced IFN-γ: Results From the D-SIRe2 Randomized Controlled Trial.

Background: Seasonal variations have been reported for immune markers. However, the relative contributions of sunlight and vitamin D variability on such seasonal changes are unknown. Objective: This double-blind, randomized, placebo-controlled trial tested whether daily 400 IU vitamin D3 supplementation affected short-term (12 weeks) and long-term (43 weeks) natural regulatory T cell (nTreg) populations in healthy participants. Design: 62 subjects were randomized equally to vitamin D versus placebo in March and assessed at baseline, April (4w), June (12w), September (25w) and January (43w). Circulating nTregs, ex vivo proliferation, IL-10 and IFN-γ productions were measured. Vitamin D metabolites and sunlight exposure were also assessed. Results: Mean serum 25-hydroxyvitamin D (25(OH)D) increased from 35.8(SD 3.0) to 65.3(2.6) nmol/L in April and remained above 75 nmol/L with vitamin D supplementation, whereas it increased from 36.4(3.2) to 49.8(3.5) nmol/L in June to fall back to 39.6(3.5) nmol/L in January with placebo. Immune markers varied similarly between groups according to the season, but independently of 25(OH)D. For nTregs, the mean (%CD3+CD4+CD127lo cells (SEM)) nadir observed in March (2.9(0.1)%) peaked in September at 4.0(0.2)%. Mean T cell proliferation peaked in June (33156(1813) CPM) returning to the nadir in January (17965(978) CPM), while IL-10 peaked in June and reached its nadir in September (median (IQR) of 262(283) to (121(194) pg/ml, respectively). Vitamin D attenuated the seasonal increase in IFN-γ by ~28% with mean ng/ml (SEM) for placebo vs vitamin D, respectively, for April 12.5(1.4) vs 10.0(1.2) (p=0.02); June 13.9(1.3) vs 10.2(1.7) (p=0.02) and January 7.4(1.1) vs 6.0(1.1) (p=0.04). Conclusions: Daily low dose Vitamin D intake did not affect the nTregs population. There were seasonal variation in nTregs, proliferative response and cytokines, suggesting that environmental changes influence immune response, but the mechanism seems independent of vitamin D status. Vitamin D attenuated the seasonal change in T cell-produced IFN-γ, suggesting a decrease in effector response which could be associated with inflammation. Clinical Trial Registration: https://www.isrctn.com, identifier (ISRCTN 73114576).

Prevalence of loneliness amongst older people in high-income countries: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Loneliness is associated with increased rates of morbidity and mortality, and is a growing public health concern in later life. This study aimed to produce an evidence-based estimate of the prevalence of loneliness amongst older people (aged 60 years and above). STUDY DESIGN AND SETTING: Systematic review and random-effects meta-analysis of observational studies from high income countries 2008 to 2020, identified from searches of five electronic databases (Medline, EMBASE, PsychINFO, CINAHL, Proquest Social Sciences Premium Collection). Studies were included if they measured loneliness in an unselected population. RESULTS: Thirty-nine studies reported data on 120,000 older people from 29 countries. Thirty-one studies were suitable for meta-analysis. The pooled prevalence estimate of loneliness was 28.5% (95%CI: 23.9% - 33.2%). In twenty-nine studies reporting loneliness severity, the pooled prevalence was 25.9% (95%CI: 21.6% - 30.3%) for moderate loneliness and 7.9% (95%CI: 4.8% - 11.6%) for severe loneliness (z = -6.1, p < 0.001). Similar pooled prevalence estimates were observed for people aged 65-75 years (27.6%, 95%CI: 22.6% - 33.0%) and over 75 years (31.3%, 95%CI: 21.0% - 42.7%, z = 0.64, p = 0.52). Lower levels of loneliness were reported in studies from Northern Europe compared to South and Eastern Europe. CONCLUSIONS: Loneliness is common amongst older adults affecting approximately one in four in high income countries. There is no evidence of an increase in the prevalence of loneliness with age in the older population. The burden of loneliness is an important public health and social problem, despite severe loneliness being uncommon. PROSPERO REGISTRATION: CRD42017060472.