NIHR Southampton Biomedical Research Centre

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: =0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments - including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances - are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification.

Importance: In communities with high rates of coronavirus disease 2019, reports have emerged of children with an unusual syndrome of fever and inflammation. Objectives: To describe the clinical and laboratory characteristics of hospitalized children who met criteria for the pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS) and compare these characteristics with other pediatric inflammatory disorders. Design, Setting, and Participants: Case series of 58 children from 8 hospitals in England admitted between March 23 and May 16, 2020, with persistent fever and laboratory evidence of inflammation meeting published definitions for PIMS-TS. The final date of follow-up was May 22, 2020. Clinical and laboratory characteristics were abstracted by medical record review, and were compared with clinical characteristics of patients with Kawasaki disease (KD) (n = 1132), KD shock syndrome (n = 45), and toxic shock syndrome (n = 37) who had been admitted to hospitals in Europe and the US from 2002 to 2019. Exposures: Signs and symptoms and laboratory and imaging findings of children who met definitional criteria for PIMS-TS from the UK, the US, and World Health Organization. Main Outcomes and Measures: Clinical, laboratory, and imaging characteristics of children meeting definitional criteria for PIMS-TS, and comparison with the characteristics of other pediatric inflammatory disorders. Results: Fifty-eight children (median age, 9 years [interquartile range {IQR}, 5.7-14]; 20 girls [34%]) were identified who met the criteria for PIMS-TS. Results from SARS-CoV-2 polymerase chain reaction tests were positive in 15 of 58 patients (26%) and SARS-CoV-2 IgG test results were positive in 40 of 46 (87%). In total, 45 of 58 patients (78%) had evidence of current or prior SARS-CoV-2 infection. All children presented with fever and nonspecific symptoms, including vomiting (26/58 [45%]), abdominal pain (31/58 [53%]), and diarrhea (30/58 [52%]). Rash was present in 30 of 58 (52%), and conjunctival injection in 26 of 58 (45%) cases. Laboratory evaluation was consistent with marked inflammation, for example, C-reactive protein (229 mg/L [IQR, 156-338], assessed in 58 of 58) and ferritin (610 μg/L [IQR, 359-1280], assessed in 53 of 58). Of the 58 children, 29 developed shock (with biochemical evidence of myocardial dysfunction) and required inotropic support and fluid resuscitation (including 23/29 [79%] who received mechanical ventilation); 13 met the American Heart Association definition of KD, and 23 had fever and inflammation without features of shock or KD. Eight patients (14%) developed coronary artery dilatation or aneurysm. Comparison of PIMS-TS with KD and with KD shock syndrome showed differences in clinical and laboratory features, including older age (median age, 9 years [IQR, 5.7-14] vs 2.7 years [IQR, 1.4-4.7] and 3.8 years [IQR, 0.2-18], respectively), and greater elevation of inflammatory markers such as C-reactive protein (median, 229 mg/L [IQR 156-338] vs 67 mg/L [IQR, 40-150 mg/L] and 193 mg/L [IQR, 83-237], respectively). Conclusions and Relevance: In this case series of hospitalized children who met criteria for PIMS-TS, there was a wide spectrum of presenting signs and symptoms and disease severity, ranging from fever and inflammation to myocardial injury, shock, and development of coronary artery aneurysms. The comparison with patients with KD and KD shock syndrome provides insights into this syndrome, and suggests this disorder differs from other pediatric inflammatory entities.

Inappropriate, excessive or uncontrolled inflammation contributes to a range of human diseases. Inflammation involves a multitude of cell types, chemical mediators and interactions. The present article will describe nutritional and metabolic aspects of omega-6 (n-6) and omega-3 (n-3) fatty acids and explain the roles of bioactive members of those fatty acid families in inflammatory processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are capable of partly inhibiting many aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid and production of pro-inflammatory cytokines. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid, and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of EPA and DHA include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor κB so reducing expression of inflammatory genes and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor γ. Animal experiments demonstrate benefit from EPA and DHA in a range of models of inflammatory conditions. Human trials demonstrate benefit of oral n-3 fatty acids in rheumatoid arthritis and in stabilizing advanced atherosclerotic plaques. Intravenous n-3 fatty acids may have benefits in critically ill patients through reduced inflammation. The anti-inflammatory and inflammation resolving actions of EPA, DHA and their derivatives are of clinical relevance.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Extensive experimental animal studies and epidemiological observations have shown that environmental influences during early development affect the risk of later pathophysiological processes associated with chronic, especially noncommunicable, disease (NCD). This field is recognized as the developmental origins of health and disease (DOHaD). We discuss the extent to which DOHaD represents the result of the physiological processes of developmental plasticity, which may have potential adverse consequences in terms of NCD risk later, or whether it is the manifestation of pathophysiological processes acting in early life but only becoming apparent as disease later. We argue that the evidence suggests the former, through the operation of conditioning processes induced across the normal range of developmental environments, and we summarize current knowledge of the physiological processes involved. The adaptive pathway to later risk accords with current concepts in evolutionary developmental biology, especially those concerning parental effects. Outside the normal range, effects on development can result in nonadaptive processes, and we review their underlying mechanisms and consequences. New concepts concerning the underlying epigenetic and other mechanisms involved in both disruptive and nondisruptive pathways to disease are reviewed, including the evidence for transgenerational passage of risk from both maternal and paternal lines. These concepts have wider implications for understanding the causes and possible prevention of NCDs such as type 2 diabetes and cardiovascular disease, for broader social policy and for the increasing attention paid in public health to the lifecourse approach to NCD prevention.

A variety of fatty acids exists in the diet of humans, in the bloodstream of humans, and in cells and tissues of humans. Fatty acids are energy sources and membrane constituents. They have biological activities that act to influence cell and tissue metabolism, function, and responsiveness to hormonal and other signals. The biological activities may be grouped as regulation of membrane structure and function; regulation of intracellular signaling pathways, transcription factor activity, and gene expression; and regulation of the production of bioactive lipid mediators. Through these effects, fatty acids influence health, well-being, and disease risk. The effects of saturated, cis monounsaturated, ω-6 and ω-3 polyunsaturated, and trans fatty acids are discussed. Although traditionally most interest in the health impact of fatty acids related to cardiovascular disease, it is now clear that fatty acids influence a range of other diseases, including metabolic diseases such as type 2 diabetes, inflammatory diseases, and cancer. Scientists, regulators, and communicators have described the biological effects and the health impacts of fatty acids according to fatty acid class. However, it is now obvious that within any fatty acid class, different members have different actions and effects. Thus, it would seem more appropriate to describe biological effects and health impacts of individual named fatty acids, although it is recognized that this would be a challenge when communicating outside of an academic environment (eg, to consumers).

The definition of what constitutes a healthy diet is continually shifting to reflect the evolving understanding of the roles that different foods, essential nutrients, and other food components play in health and disease. A large and growing body of evidence supports that intake of certain types of nutrients, specific food groups, or overarching dietary patterns positively influences health and promotes the prevention of common non-communicable diseases (NCDs). Greater consumption of health-promoting foods and limited intake of unhealthier options are intrinsic to the eating habits of certain regional diets such as the Mediterranean diet or have been constructed as part of dietary patterns designed to reduce disease risk, such as the Dietary Approaches to Stop Hypertension (DASH) or Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets. In comparison with a more traditional Western diet, these healthier alternatives are higher in plant-based foods, including fresh fruits and vegetables, whole grains, legumes, seeds, and nuts and lower in animal-based foods, particularly fatty and processed meats. To better understand the current concept of a "healthy diet," this review describes the features and supporting clinical and epidemiologic data for diets that have been shown to prevent disease and/or positively influence health. In total, evidence from epidemiological studies and clinical trials indicates that these types of dietary patterns reduce risks of NCDs including cardiovascular disease and cancer.

BACKGROUND: Context is a problem in research on health behaviour change, knowledge translation, practice implementation and health improvement. This is because many intervention and evaluation designs seek to eliminate contextual confounders, when these represent the normal conditions into which interventions must be integrated if they are to be workable in practice. DISCUSSION: We present an ecological model of the ways that participants in implementation and health improvement processes interact with contexts. The paper addresses the problem of context as it affects processes of implementation, scaling up and diffusion of interventions. We extend our earlier work to develop Normalisation Process Theory and show how these processes involve interactions between mechanisms of resource mobilisation, collective action and negotiations with context. These mechanisms are adaptive. They contribute to self-organisation in complex adaptive systems. CONCLUSION: Implementation includes the translational efforts that take healthcare interventions beyond the closed systems of evaluation studies into the open systems of 'real world' contexts. The outcome of these processes depends on interactions and negotiations between their participants and contexts. In these negotiations, the plasticity of intervention components, the degree of participants' discretion over resource mobilisation and actors' contributions, and the elasticity of contexts, all play important parts. Understanding these processes in terms of feedback loops, adaptive mechanisms and the practical compromises that stem from them enables us to see the mechanisms specified by NPT as core elements of self-organisation in complex systems.

Oxidative stress and inflammation have been recognized as important contributors to the risk of chronic non-communicable diseases. Polyunsaturated fatty acids (PUFAs) may regulate the antioxidant signaling pathway and modulate inflammatory processes. They also influence hepatic lipid metabolism and physiological responses of other organs, including the heart. Longitudinal prospective cohort studies demonstrate that there is an association between moderate intake of the omega-6 PUFA linoleic acid and lower risk of cardiovascular diseases (CVDs), most likely as a result of lower blood cholesterol concentration. Current evidence suggests that increasing intake of arachidonic acid (up to 1500 mg/day) has no adverse effect on platelet aggregation and blood clotting, immune function and markers of inflammation, but may benefit muscle and cognitive performance. Many studies show that higher intakes of omega-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with a lower incidence of chronic diseases characterized by elevated inflammation, including CVDs. This is because of the multiple molecular and cellular actions of EPA and DHA. Intervention trials using EPA + DHA indicate benefit on CVD mortality and a significant inverse linear dose-response relationship has been found between EPA + DHA intake and CVD outcomes. In addition to their antioxidant and anti-inflammatory roles, omega-3 fatty acids are considered to regulate platelet homeostasis and lower risk of thrombosis, which together indicate their potential use in COVID-19 therapy.

Public health practices including handwashing and vaccinations help reduce the spread and impact of infections. Nevertheless, the global burden of infection is high, and additional measures are necessary. Acute respiratory tract infections, for example, were responsible for approximately 2.38 million deaths worldwide in 2016. The role nutrition plays in supporting the immune system is well-established. A wealth of mechanistic and clinical data show that vitamins, including vitamins A, B6, B12, C, D, E, and folate; trace elements, including zinc, iron, selenium, magnesium, and copper; and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid play important and complementary roles in supporting the immune system. Inadequate intake and status of these nutrients are widespread, leading to a decrease in resistance to infections and as a consequence an increase in disease burden. Against this background the following conclusions are made: (1) supplementation with the above micronutrients and omega-3 fatty acids is a safe, effective, and low-cost strategy to help support optimal immune function; (2) supplementation above the Recommended Dietary Allowance (RDA), but within recommended upper safety limits, for specific nutrients such as vitamins C and D is warranted; and (3) public health officials are encouraged to include nutritional strategies in their recommendations to improve public health.

The importance of chronic low-grade inflammation in the pathology of numerous age-related chronic conditions is now clear. An unresolved inflammatory response is likely to be involved from the early stages of disease development. The present position paper is the most recent in a series produced by the International Life Sciences Institute's European Branch (ILSI Europe). It is co-authored by the speakers from a 2013 workshop led by the Obesity and Diabetes Task Force entitled 'Low-grade inflammation, a high-grade challenge: biomarkers and modulation by dietary strategies'. The latest research in the areas of acute and chronic inflammation and cardiometabolic, gut and cognitive health is presented along with the cellular and molecular mechanisms underlying inflammation-health/disease associations. The evidence relating diet composition and early-life nutrition to inflammatory status is reviewed. Human epidemiological and intervention data are thus far heavily reliant on the measurement of inflammatory markers in the circulation, and in particular cytokines in the fasting state, which are recognised as an insensitive and highly variable index of tissue inflammation. Potential novel kinetic and integrated approaches to capture inflammatory status in humans are discussed. Such approaches are likely to provide a more discriminating means of quantifying inflammation-health/disease associations, and the ability of diet to positively modulate inflammation and provide the much needed evidence to develop research portfolios that will inform new product development and associated health claims.

ABSTRACT Background Coronavirus disease 2019 (COVID-19) is associated with diffuse lung damage. Corticosteroids may modulate immune-mediated lung injury and reducing progression to respiratory failure and death. Methods The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, adaptive, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual care alone. The primary outcome was 28-day mortality. Results 2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age-adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P&lt;0.001). The proportional and absolute mortality rate reductions varied significantly depending on level of respiratory support at randomization (test for trend p&lt;0.001): Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p&lt;0.001), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14). Conclusions In patients hospitalized with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support. Trial registrations The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov ( NCT04381936 ). Funding Medical Research Council and National Institute for Health Research (Grant ref: MC_PC_19056).

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

BACKGROUND: In older adults, diminished balance is associated with reduced physical functioning and an increased risk of falling. This is an update of a Cochrane review first published in 2007. OBJECTIVES: To examine the effects of exercise interventions on balance in older people, aged 60 and over, living in the community or in institutional care. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, CENTRAL (The Cochrane Library 2011, Issue 1), MEDLINE and EMBASE (to February 2011). SELECTION CRITERIA: Randomised controlled studies testing the effects of exercise interventions on balance in older people. The primary outcomes of the review were clinical measures of balance. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently assessed risk of bias and extracted data from studies. Data were pooled where appropriate. MAIN RESULTS: This update included 94 studies (62 new) with 9,917 participants. Most participants were women living in their own home.Most trials were judged at unclear risk of selection bias, generally reflecting inadequate reporting of the randomisation methods, but at high risk of performance bias relating to lack of participant blinding, which is largely unavoidable for these trials. Most studies only reported outcome up to the end of the exercise programme.There were eight categories of exercise programmes. These are listed below together with primary measures of balance for which there was some evidence of a statistically significant effect at the end of the exercise programme. Some trials tested more than one type of exercise. Crucially, the evidence for each outcome was generally from only a few of the trials for each exercise category. 1. Gait, balance, co-ordination and functional tasks (19 studies of which 10 provided primary outcome data): Timed Up & Go test (mean difference (MD) -0.82 s; 95% CI -1.56 to -0.08 s, 114 participants, 4 studies); walking speed (standardised mean difference (SMD) 0.43; 95% CI 0.11 to 0.75, 156 participants, 4 studies), and the Berg Balance Scale (MD 3.48 points; 95% CI 2.01 to 4.95 points, 145 participants, 4 studies).2. Strengthening exercise (including resistance or power training) (21 studies of which 11 provided primary outcome data): Timed Up & Go Test (MD -4.30 s; 95% CI -7.60 to -1.00 s, 71 participants, 3 studies); standing on one leg for as long as possible with eyes closed (MD 1.64 s; 95% CI 0.97 to 2.31 s, 120 participants, 3 studies); and walking speed (SMD 0.25; 95% CI 0.05 to 0.46, 375 participants, 8 studies).3. 3D (3 dimensional) exercise (including Tai Chi, qi gong, dance, yoga) (15 studies of which seven provided primary outcome data): Timed Up & Go Test (MD -1.30 s; 95% CI -2.40 to -0.20 s, 44 participants, 1 study); standing on one leg for as long as possible with eyes open (MD 9.60 s; 95% CI 6.64 to 12.56 s, 47 participants, 1 study), and with eyes closed (MD 2.21 s; 95% CI 0.69 to 3.73 s, 48 participants, 1 study); and the Berg Balance Scale (MD 1.06 points; 95% CI 0.37 to 1.76 points, 150 participants, 2 studies).4. General physical activity (walking) (seven studies of which five provided primary outcome data). 5. General physical activity (cycling) (one study which provided data for walking speed). 6. Computerised balance training using visual feedback (two studies, neither of which provided primary outcome data). 7. Vibration platform used as intervention (three studies of which one provided primary outcome data).8. Multiple exercise types (combinations of the above) (43 studies of which 29 provided data for one or more primary outcomes): Timed Up & Go Test (MD -1.63 s; 95% CI -2.28 to -0.98 s, 635 participants, 12 studies); standing on one leg for as long as possible with eyes open (MD 5.03 s; 95% CI 1.19 to 8.87 s, 545 participants, 9 studies), and with eyes closed ((MD 1.60 s; 95% CI -0.01 to 3.20 s, 176 participants, 2 studies); walking speed (SMD 0.04; 95% CI -0.10 to 0.17, 818 participants, 15 studies); and the Berg Balance Scale ((MD 1.84 points; 95% CI 0.71 to 2.97 points, 80 participants, 2 studies).Few adverse events were reported but most studies did not monitor or report adverse events.In general, the more effective programmes ran three times a week for three months and involved dynamic exercise in standing. AUTHORS' CONCLUSIONS: There is weak evidence that some types of exercise (gait, balance, co-ordination and functional tasks; strengthening exercise; 3D exercise and multiple exercise types) are moderately effective, immediately post intervention, in improving clinical balance outcomes in older people. Such interventions are probably safe. There is either no or insufficient evidence to draw any conclusions for general physical activity (walking or cycling) and exercise involving computerised balance programmes or vibration plates. Further high methodological quality research using core outcome measures and adequate surveillance is required.

OBJECTIVE: Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans. RESEARCH DESIGN AND METHODS: Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5' from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ≥5% and a 5-95% range ≥10%, we related methylation status to maternal pregnancy diet and to child's adiposity at age 9 years. Replication was sought in a second independent cohort. RESULTS: In cohort 1, retinoid X receptor-α (RXRA) chr9:136355885+ and endothelial nitric oxide synthase (eNOS) chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient [β] 17% per SD change in methylation [95% CI 4-31], P = 0.009, n = 64, and β = 20% [9-32], P < 0.001, n = 66, respectively) and %fat mass (β = 10% [1-19], P = 0.023, n = 64 and β =12% [4-20], P = 0.002, n = 66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (β = 6% [2-10] and β = 4% [1-7], respectively, both P = 0.002, n = 239). CONCLUSIONS: Our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease.

"I broke down and cried today. I cried of exhaustion, of defeat. Because after 4 years of being an ER nurse, I suddenly feel like I know nothing" (Sydni Lane, USA, Instagram and Facebook). (Fick , 2020) “It's an experience I would compare to a world war” Roberta Re, Italy. (Giuffrida, 2020) “we're on our knees here, and it's really difficult and we're all trying the best we can and we don't feel… we feel like we could be doing more, and I know we can't … we're staying away from our families and we're putting ourselves in danger to try and save other people's loved ones, it feels like a losing battle but it's not, we've all got hope and we're all trying to do what we can.” (Shirley Watts, UK ICU Nurse, BBC news 04 April 2020) As the coronavirus disease 2019 (COVID-19) pandemic takes hold, nurses are on the front line of health and social care in the most extreme of circumstances. We reflect during a moment in time (week three of lockdown in the UK and week 5/6 across Europe) to highlight the issues facing nurses at this unprecedented time. At the bedside 24 hr a day seven days a week, in similar outbreaks, nurses have had the highest levels of occupational stress and resulting distress compared with other groups (Cheong & Lee, 2004; Maunder et al., 2006; Nickell et al., 2004). Nurses are already a high-risk group, with the suicide rate among nurses 23% higher than the national average (ONS, 2017). Despite this, the RCN (Royal College of Nursing in the UK) has reported that nurses feel “repeatedly” ignored by their employers when they raise concerns about their mental health (Mitchell, 2019). A focus on personal responsibility for psychological health and well-being and an overemphasis on nurses being “resilient” in the face of under-staffing and often intense emotional work is consistently challenged by nurses and nurse academics (Traynor, 2018). Treating resilience as an individual trait is seen to “let organisations off the hook” (Traynor, 2018), yet has often been the focus of organisational strategies to date. This does not work at the best of times and certainly is not appropriate now in these most difficult of circumstances. Here, we discuss the stressors and challenges and present evidence-informed guidance to address the physical and psychological needs of nurses during the COVID-19 pandemic. We stress the importance of peer and team support to enable positive recovery after acutely stressful and emotionally draining experiences, and outline what managers, organisations and leaders can do to support nurses at this most critical of times. The high prevalence of COVID-19 in the general population of many countries, its novelty and highly infectious nature, and the associated morbidity and mortality rates are placing an unprecedented demand on health and social care services worldwide. In addition to the admission to hospital of high numbers of critically ill patients, care demands on nurses and care assistants have also increased in the community, in care homes and in learning disability and mental health services. These demands must be met by an already-depleted workforce (+44,000 RN vacancies in the UK pre-COVID-19) and one that is further depleted at this time due to infection, self-isolation and family responsibilities in the face of the crisis. The nature of care itself and new ways of working are potentially highly stressful for staff. Nurses are not only experiencing an increase in the volume and intensity of their work, but are having to accommodate new protocols and a very “new normal.” For instance, many mental health services have transformed almost overnight from providing face-to-face care and treatment to a predominately virtual service of telephone or video consultations. In many other areas, nurses are adjusting to providing end-of-life care more frequently and often in the face of more rapid deterioration than they are used to. Isolation rules mean the presence of family at the bedside is rarely possible. Nurses are therefore frequently standing in for family members and facilitating remote access for loved ones. Established nurse–patient ratios are under strain. In ITU in the UK, for instance, staff-patient ratios of one-to-one are changing to ratios of one ITU nurse to six or more patients, with the shortfall being made up by staff without ITU experience. To boost the nursing workforce, many countries have also fast-tracked their final-year nursing students to join the nursing register early and have encouraged retired colleagues back to practice (Jackson et al., 2020). Many nurses have been redeployed, working in new specialities or in higher acuity areas. All of these factors are likely to be adding stress for existing staff, with additional implications for the well-being of new members of the team. Evidence from studies on COVID-19 and other infectious respiratory disease outbreaks reflects high concern among nurses for personal or family health in the face of direct contact with a potentially deadly virus and the stress of balancing this concern with the ethical obligations of continuing to provide care (Jiang, 2020; Khalid, Khalid, Qabajah, Barnard, & Qushmaq, 2016; Kim & Choi, 2016; Nickell et al., 2004). Other stressors evident from research to date include concerns about shortages of staff and of personal protective equipment (PPE), navigating an unfamiliar setting or system of care and lack of organisational support (Kim, 2018; O'Boyle, Robertson, & Secor-Turner, 2006; Shih et al., 2009). Additionally psychological conflicts between healthcare workers' responsibility to care for the ill and their right to protect themselves from a potentially lethal virus were reported (Chen, Wu, Yang, & Yen, 2005). Our own anecdotal sources in the UK and Europe endorse these findings for COVID-19 as (at time of writing) we approach the peak of the pandemic, but also raise the possibility of other stressors including moral distress resulting from treatment decisions based on finite resources, the lack of access to antigen or antibody testing for most front-line staff, and the discomfort and fatigue resulting from long shifts spent wearing full PPE. On social media, nurses speak of crippling tiredness after long shifts with sore faces after so many hours in masks, as well as communication barriers with colleagues and patients when wearing full PPE; nurses often cannot hear patients, and patients can struggle too; not being able to see nurses' faces or hear what is said. Nurses also speak of the difficult ethical and moral judgements that are being taken in hospitals; care homes and the community throughout the world. They tell of experiencing stigma in the wider community, being perceived as a threat to the safety of others and as “disease-carriers.” As the number of COVID-19 patients grow, there will be increasingly stringent rules about who can be offered ventilation, with one doctor suggesting “soon many of our own staff would not meet the criteria” (Anon & The Guardian, 2020). Reflecting on the Italian College of Anaesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI) COVID-19 guidelines for the criteria that doctors and nurses should follow, the moral philosopher Yascha Mounk reflects: “If you are an overworked nurse battling a novel disease under the most desperate circumstances, and you simply cannot treat everyone, however hard you try, whose life should you save?” (Mounk, 2020). Nurses are likely to experience moral and ethical conflict with the potential for stress and moral distress or moral injury (Bridges et al., 2013; Greenberg, Docherty, Gnanapragasam, & Wessely, 2020; Morley, Ives, Bradbury-Jones, & Irvine, 2019). These stressors are present across settings in health and social care, and relevant to all members of the nursing team, including care assistants and temporary members of the team drafted in from their studies or from retirement. There is also an emerging narrative of guilt and some of potential shaming among nurses and students who are unable to contribute to direct patient care due to their own high risk and vulnerability to coronavirus. Nurses and their unions are speaking up about the lack of testing for front-line staff and the variation in access to PPE. Nationally and internationally it appears there is wide variation in access to PPE and the Royal College of Nursing in the UK and its counterparts across the world have been campaigning for adequate PPE for nurses suggesting the nursing voice has been side-lined in the relevant debates (Ford, 2020). In many countries, the focus has been on acute and intensive care; however, nurses in the community and mental health and learning disability settings may also have inadequate access to PPE. The UK priorities for PPE distribution and testing are being interpreted as further discrimination against nurses who do not work in acute physical health settings, leading to further anger that some lives appear to matter less. A failure to protect nursing staff adequately is causing anger and frustration, making nurses feel unsafe at work, while they are risking their own health and fearful of transmission to their families. Unless nurses feel well supported by their organisations and governments, that anger may linger after the crisis potentially causing some to leave the profession. It would be difficult as a nurse not to have strong emotional reactions to the COVID-19 virus and its impact on one's work (fear, anger, frustration, worries). Such fear and anxieties are normal, as are the intense feelings evoked when nurses feel unable to care for patients as they would have otherwise. Nurses and healthcare or nursing assistants, in acute, community mental health and social care settings are having to make extremely difficult decisions from one moment to the next. They are having to be very creative about new ways of working with very ill patients with mental health needs or learning disabilities or dementia. Legal frameworks to support the continuation of care at times of mental health crises such as (in the UK) potential temporary amendments to the Mental Health Act 1983 and the Coronavirus Act 2020 which enforce isolation; place further strain on therapeutic relationships and the delicate balance between nursing care and restrictive practice. In situations where compliance with social distancing and isolation with COVID-19 is low on the list of priorities for people in receipt of care, nurses are having to weigh up human rights, safeguarding and infectious disease protocols all of which may potentially conflict. There are some good signs that health systems are recognising how important it is to support healthcare staff. In the UK, NHS staff have been given free access to more than 1,500 specialists, online therapy and group counselling sessions and will receive practical and financial assistance as well as specialist bereavement and psychological support. Volunteers from charities including Hospice UK, the Samaritans and Shout are staffing phone and text helplines. The NHS is also offering free access to support from Apps such as Headspace, UnMind and Big Health for healthcare staff and their families to include guided meditation and tools to battle anxiety and help with sleep problems. This is a good start, but these services rely on the individual seeking help, and this may well not be sufficient. Investment in a range of supportive measures that do not just place the onus on the individual is almost certainly necessary. Supporting nurses practically and psychologically is essential to preserving their health in the short and long term, particularly when occupational stress levels are so high. Ensuring psychological well-being requires a layered response, with different components at different times, comprising strategies aimed at prevention through to treatment, and strategies/actions at different levels, from organisational and team/ward responses to those aimed at individual self-care and peer support. Response to the specific unprecedented challenge of COVID-19 will also need a flexible strategy as needs and requirements are likely to change over the course of the pandemic response. Furthermore, nurses working outside acute hospitals, working autonomously or in dispersed teams across large geographical areas can find accessing support challenging. Having reviewed the literature and gathered intervention resources from a variety of sources, it is evident that there is much to learn from other similar crisis situations such as SARS, MERS and Ebola. The evidence base in this area is considered weak, and most research is observational or has focussed on early interventions after major incidents and once the crisis has passed (Billings et al., 2020). From a nursing perspective, few studies consider nursing outside of hospital walls. In Figure 1, we present strategies and interventions aimed at supporting nurses' psychological well-being during the COVID-19 crisis. This guidance is led by best-available evidence, underpinned by theory (see Figure 1), expert opinion and models used in the military, as well as experiences from other countries and other infectious disease outbreaks (Watson, 2020; Watson, Brymer, & Bonanno, 2011; Watson et al., 2013). Below, we highlight physiological and safety needs; peer support; team support; and the roles and needs of managers and leaders as well as long-term recovery support needs. While at work and outside of work, nurses should prioritise their own well-being as much as possible, paying attention to meeting their essential needs for drinks, food, rest and sleep, and building in rest and comfort breaks (Cole-King & Dykes, 2020). At times of crisis, human physiological and safety needs come to the forefront—adequate food, shelter, rest, sleep and safety needs for example (Kenrick, Griskevicius, Neuberg, & Schaller, 2010). Recent interviews with medical staff (including nurses) treating COVID-19 in a hospital in Hunan Province support this (Chen et al., 2020). A detailed psychological intervention package (online course to deal with psychological problems; a psychological assistance hotline; and group interventions) encountered obstacles, as staff were reluctant to participate. Staff reported not needing a psychologist at this time, as they were concerned with more immediate worries including not wanting their families to worry; more rest without protective and support and with anxiety and The psychological intervention measures were therefore to include a place to and of their work to with families to to psychological problems; and access to staff for psychological the rest areas to to staff and and provide support (Chen et al., 2020). In countries with the threat of the from the there are from nurses for adequate PPE; and access to the right for psychological support with the wider evidence base that early with more intense for example psychological can be & & Wessely, 2009). on the work of Watson (Watson, 2020; Watson et al., we know that to the healthcare work is by stress may be the to it and stigma can be an to for often do not prioritise good care of recognising it may on or they fear the team without after nurses cannot after health are to after others and not are therefore likely to need others and to to of For week a of a of for a nursing team who had not had a for more than Figure for strategies and interventions for individual and peer support. the pandemic, nurses may be working with people who are not their team therefore need to support other and find ways to help new members feel and as as (see Figure with more colleagues can help support colleagues who have from have been or are final-year students who are in the numbers or in some countries have been early et al., needs to be so that the people are not support and should be so that is not seen as an for organisations they are not providing adequate psychological or other support. All members of the and access to support during and after the In the for Care (Bridges et al., 2018), nurses and healthcare assistants the of nursing teams in to in on This other that the of for members to learning and social support for nurses difficult work with Staff in the an to meet to in on well-being the safety and other evidence at the and of shifts can also help to social support for other (see Figure In times, there is evidence that group such as can team and increase for colleagues and patients et al., 2018). to psychological safety in our that staff by members should not be staff should have had the to and a difficult or experience to protect staff from et al., 2009). as to all in the and face to may not be the at the of the pandemic. The of Care in the UK is therefore their in to in has the of but in a virtual to be in existing teams across the with by of and for a time of an with present 2020). These sessions are being in practice and in and other teams in the few and we to with our students at the of these will A from studies of members of the is that team and leaders and their is highly with mental with a reported in mental health between who perceived themselves as having a good or et al., There is therefore much managers and leaders can do to support nurses in their teams and organisations (see Figure for strategies and guidelines also and communication is as well as and access to physiological and safety needs (Billings et al., 2020; & Dykes, 2020). It is also important that nurses support for so that they have the to support others and are able to good to decisions and access to a are particularly important for where they can through the difficult decisions they are having to make in to COVID-19 They will need their healthcare and to on during the pandemic. or seeking a for peer support is therefore Evidence it is important not to what are and anxieties in such and situations and stress and that needs change over time (Billings et al., 2020). to highly or resilience and do not long-term psychological Greenberg, & Wessely, 2005). some will in most these without the need for interventions Wessely, & is evidence of staff experiencing stress after infectious disease outbreaks for example et al., that does not mean all staff will experience mental health it will be important to the psychological needs of the nursing workforce the of the pandemic, so that in teams and across organisations as well as across we can learn and make nurses have access to adequate support in the recovery to a of nurses with psychological or in the of the acute staff may be on some may have staff colleagues have or family members there has been time to and some may have or guilt (Cole-King & Dykes, 2020; et al., It is important that interventions do and are to individual at and groups should be early or detailed could an and psychological is now with A of research has the of the of as a in of long-term for a of psychological may in et al., et al., 2009). to treatment for those staff who of mental health such as therapy and and which are to be in et al., may be may be for this, and it will be important that there is of access and that this is to nurses as well as other members of the healthcare team. to this unprecedented some resilience is but nurses need their their the and the to support with and and front-line staff throughout Europe is to and some nurses at the of and of such as and other There are also of teams in and in and intensive care to but a this is not nurses also need to feel their needs are for and that they are with adequate PPE equipment in all settings where health and social care are being They need access to rest good peer and team support and leaders that will to care for well after the pandemic is As who have nurse well-being for it is to see the increased focus on healthcare staff yet that it takes a pandemic to its critical staff will need but resilience must be seen as an individual it is a and organisational Evidence from the the resilience of the team appears to be to the between team members than the psychological or of et al., The resilience is now as staff can feel it is to staff are and psychologically lack of resources or ethical and emotional challenges as in nurses can feel it is their they have not the adequately or been This is not this be an to the and emotional strain that nurses on of and not only through this crisis but after it is all health care is back to support for nurses' well-being will critically While COVID-19 particularly high stress on there is very in the guidance that not relevant to staff well-being and when the pandemic is we to the guidelines being used to support for nurses and nursing the We are to our colleagues for their support in the of this to who had the for guidance and through the different levels of while being with are also due to the colleagues who on the and for evidence and

As humans age, the risk and severity of infections vary in line with immune competence according to how the immune system develops, matures, and declines. Several factors influence the immune system and its competence, including nutrition. A bidirectional relationship among nutrition, infection and immunity exists: changes in one component affect the others. For example, distinct immune features present during each life stage may affect the type, prevalence, and severity of infections, while poor nutrition can compromise immune function and increase infection risk. Various micronutrients are essential for immunocompetence, particularly vitamins A, C, D, E, B2, B6, and B12, folic acid, iron, selenium, and zinc. Micronutrient deficiencies are a recognized global public health issue, and poor nutritional status predisposes to certain infections. Immune function may be improved by restoring deficient micronutrients to recommended levels, thereby increasing resistance to infection and supporting faster recovery when infected. Diet alone may be insufficient and tailored micronutrient supplementation based on specific age-related needs necessary. This review looks at immune considerations specific to each life stage, the consequent risk of infection, micronutrient requirements and deficiencies exhibited over the life course, and the available evidence regarding the effects of micronutrient supplementation on immune function and infection.