A living WHO guideline on drugs to prevent covid-19.

CLINICAL QUESTION: What is the role of drugs in preventing covid-19? WHY DOES THIS MATTER?: There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. The first version of this living guideline focuses on the evidence for hydroxychloroquine. Subsequent updates will cover other drugs being investigated for their role in the prevention of covid-19. RECOMMENDATION: The guideline development panel made a strong recommendation against the use of hydroxychloroquine for individuals who do not have covid-19 (high certainty). HOW THIS GUIDELINE WAS CREATED: This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development panel of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. UNDERSTANDING THE NEW RECOMMENDATION: The linked systematic review and network meta-analysis (6 trials and 6059 participants) found that hydroxychloroquine had a small or no effect on mortality and admission to hospital (high certainty evidence). There was a small or no effect on laboratory confirmed SARS-CoV-2 infection (moderate certainty evidence) but probably increased adverse events leading to discontinuation (moderate certainty evidence). The panel judged that almost all people would not consider this drug worthwhile. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation. The panel considers that this drug is no longer a research priority and that resources should rather be oriented to evaluate other more promising drugs to prevent covid-19. UPDATES: This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline. READERS NOTE: This is the first version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19. When citing this article, please consider adding the update number and date of access for clarity.

TIDieR-Placebo: A guide and checklist for reporting placebo and sham controls.

BACKGROUND: Placebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their delivery have been shown to affect study outcomes, placebo and sham controls are rarely reported and often not matched to those of the active comparator. This can influence how beneficial or harmful the active intervention appears to be. Without adequate descriptions of placebo or sham controls, it is difficult to interpret results about the benefits and harms of active interventions within placebo-controlled trials. To overcome this problem, we developed a checklist and guide for reporting placebo or sham interventions. METHODS AND FINDINGS: We developed an initial list of items for the checklist by surveying experts in placebo research (n = 14). Because of the diverse contexts in which placebo or sham treatments are used in clinical research, we consulted experts in trials of drugs, surgery, physiotherapy, acupuncture, and psychological interventions. We then used a multistage online Delphi process with 53 participants to determine which items were deemed to be essential. We next convened a group of experts and stakeholders (n = 16). Our main output was a modification of the existing Template for Intervention Description and Replication (TIDieR) checklist; this allows the key features of both active interventions and placebo or sham controls to be concisely summarised by researchers. The main differences between TIDieR-Placebo and the original TIDieR are the explicit requirement to describe the setting (i.e., features of the physical environment that go beyond geographic location), the need to report whether blinding was successful (when this was measured), and the need to present the description of placebo components alongside those of the active comparator. CONCLUSIONS: We encourage TIDieR-Placebo to be used alongside TIDieR to assist the reporting of placebo or sham components and the trials in which they are used.

Anticholinergic burden in middle-aged women and recurrent falls in later life: findings from the Aberdeen prospective osteoporosis screening study (APOSS).

BACKGROUND: Anticholinergic burden (ACB) is a recognised risk factor for falls in older people; however, whether ACB in middle age predicts falls in later life is unknown. METHODS: We examined this association in the middle-aged women of the Aberdeen Prospective Osteoporosis Screening Study (APOSS). ACB was calculated at the second health visit (1997-1999, study baseline) using the Anticholinergic Cognitive Burden Scale. Outcomes were incidence of 1 fall and recurrent falls (⩾2 falls) during the 12 months prior to follow up 2007-2011. Multinomial logistic regression analyses adjusted for potential confounders including demographics, comorbidities and falls history. RESULTS: A total of 2125 women {mean age (standard deviation [SD]): 54.7 (2.2) years at baseline and 66.0 (2.2) years at follow up} were included. Prevalence of baseline ACB score of 0, 1 and ⩾2 was 87.1%, 7.3% and 5.6%, respectively. Compared with no ACB, ACB ⩾2 was associated with recurrent falls in the previous 12 months [adjusted odds ratio (OR): 2.34, 95% confidence interval (CI): 1.31, 4.19] at an average of 11 years after initial exposure. No such association was found for an ACB score of 1. CONCLUSIONS: These findings highlight the potential negative effects of anticholinergic medications in middle age. While cautious use of anticholinergic medications is advisable, further longitudinal research should be conducted to confirm these findings before any specific clinical recommendations can be made.

A high anticholinergic burden is associated with a history of falls in the previous year in middle-aged women: findings from the Aberdeen Prospective Osteoporosis Screening Study.

PURPOSE: To examine the cross-sectional association between anticholinergic medication burden (ACB) and a history of falls, bone mineral density, and low trauma fractures in middle-aged women aged under 65 years from the Aberdeen Prospective Osteoporosis Screening Study. METHODS: ACB (0 = none, 1 = possible, ≥2 = definite) was calculated from medication use for 3883 Caucasian women [mean age (SD) = 54.3 (2.3) years] attending the second Aberdeen Prospective Osteoporosis Screening Study visit (1997-2000). Outcomes were examined using logistic regression. Model adjustments were selected a priori based on expert opinion. RESULTS: Of 3883 participants, 3293 scored ACB = 0, 328 scored ACB = 1, and 262 scored ACB ≥2. High ACB burden (≥2) was associated with increased odds (ACB = 0 reference) for falls (fully adjusted odds ratio [95% confidence intervals] = 1.81 [1.25-2.62]; P = 0.002) and having low bone mineral density (lowest quintile-20%) at Ward's triangle (3.22 [1.30-7.99]; P = 0.01). A history of falls over the year prior to the study visit in participants with ACB score ≥2 was 32 per 100. For ACB categories 1 and 0, a history of falls per 100 was 21 and 22, respectively. CONCLUSIONS: The risk of falling associated with ACB observed in older age may also extend to middle-aged women.

25-Hydroxyvitamin D Threshold for the Effects of Vitamin D Supplements on Bone Density: Secondary Analysis of a Randomized Controlled Trial.

Most trials of vitamin D supplementation have shown no benefits on bone mineral density (BMD), although severe vitamin D deficiency causes osteomalacia, which is associated with profound BMD deficits. Recently, the ViDA-BMD study from New Zealand demonstrated a threshold of baseline 25-hydroxyvitamin D (25OHD; 30 nmol/L) below which vitamin D supplementation did benefit BMD. We have now reexamined data from a similar trial in Aberdeen to determine whether a baseline 25OHD threshold of 30 nmol/L is also observed in that database. The Aberdeen study recruited 305 postmenopausal women in late winter and randomized them to receive placebo, vitamin D 400 IU/d, or vitamin D 1000 IU/d over 1 year. As previously reported, BMD loss at the hip was reduced by vitamin D 1000 IU/d only, and there was no significant treatment effect of either dose at the lumbar spine. In the present analysis, when the trial participants were grouped according to whether their baseline 25OHD was ≤30 nmol/L or above this threshold, significant treatment effects were apparent at both the spine and hip in those with baseline 25OHD ≤30 nmol/L, but no significant effects were apparent in those with baseline 25OHD above this level. There was evidence of a similar threshold for effects on parathyroid hormone, but no groups showed changes in bone turnover markers during the study. It is concluded that vitamin D supplements only increase bone density in adults with nadir 25OHD ≤30 nmol/L. This moves us further toward a trial-based definition of vitamin D deficiency in adults with adequate calcium intakes and suggests that supplement use should be targeted accordingly. Future trials of vitamin D supplementation should focus on individuals with 25OHD concentrations in this range. © 2018 American Society for Bone and Mineral Research.

An application of partial least squares for identifying dietary patterns in bone health.

In a large cohort of older women, a mechanism-driven statistical technique for assessing dietary patterns that considers a potential nutrient pathway found two dietary patterns associated with lumbar spine and femoral neck bone mineral density. A "healthy" dietary pattern was observed to be beneficial for bone mineral density. INTRODUCTION: Dietary patterns represent a broader, more realistic representation of how foods are consumed, compared to individual food or nutrient analyses. Partial least-squares (PLS) is a data-reduction technique for identifying dietary patterns that maximizes correlation between foods and nutrients hypothesized to be on the path to disease, is more hypothesis-driven than previous methods, and has not been applied to the study of dietary patterns in relation to bone health. METHODS: Women from the Aberdeen Prospective Osteoporosis Screening Study (2007-2011, n = 2129, age = 66 years (2.2)) provided dietary intake using a food frequency questionnaire; 37 food groups were created. We applied PLS to the 37 food groups and 9 chosen response variables (calcium, potassium, vitamin C, vitamin D, protein, alcohol, magnesium, phosphorus, zinc) to identify dietary patterns associated with bone mineral density (BMD) cross-sectionally. Multivariable regression was used to assess the relationship between the retained dietary patterns and BMD at the lumbar spine and femoral neck, adjusting for age, body mass index, physical activity level, smoking, and national deprivation category. RESULTS: Five dietary patterns were identified, explaining 25% of the variation in food groups and 77% in the response variables. Two dietary patterns were positively associated with lumbar spine (per unit increase in factor 2: 0.012 g/cm2 [95% CI: 0.006, 0.01]; factor 4: 0.007 g/cm2 [95% CI: 0.00001, 0.01]) and femoral neck (factor 2: 0.006 g/cm2 [95% CI: 0.002, 0.01]; factor 4: 0.008 g/cm2 [95% CI: 0.003, 0.01)]) BMD. Dietary pattern 2 was characterized by high intakes of milk, vegetables, fruit and vegetable juices, and wine, and low intakes of processed meats, cheese, biscuits, cakes, puddings, confectionary, sweetened fizzy drinks and spirits while dietary pattern 4 was characterized by high intakes of fruits, red and white meats, and wine, and low intakes of vegetables and sweet spreads. CONCLUSION: Our findings using a robust statistical technique provided important support to initiatives focusing on what constitutes a healthy diet and its implications.

National Osteoporosis Society vitamin D guideline summary.

The National Osteoporosis Society (NOS) published its document, Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management, in 2013 as a practical clinical guideline on the management of vitamin D deficiency in adult patients with, or at risk of developing, bone disease. There has been no clear consensus in the UK on vitamin D deficiency its assessment and treatment, and clinical practice is inconsistent. This guideline is aimed at clinicians, including doctors, nurses and dieticians. It recommends the measurement of serum 25 (OH) vitamin D (25OHD) to estimate vitamin D status in the following clinical scenarios: bone diseases that may be improved with vitamin D treatment; bone diseases, prior to specific treatment where correcting vitamin D deficiency is appropriate; musculoskeletal symptoms that could be attributed to vitamin D deficiency. The guideline also states that routine vitamin D testing is unnecessary where vitamin D supplementation with an oral antiresorptive treatment is already planned and sets the following serum 25OHD thresholds: <30 nmol/l is deficient; 30-50 nmol/l may be inadequate in some people; >50 nmol/l is sufficient for almost the whole population. For treatment, oral vitamin D3 is recommended with fixed loading doses of oral vitamin D3 followed by regular maintenance therapy when rapid correction of vitamin D deficiency is required, although loading doses are not necessary where correction of deficiency is less urgent or when co-prescribing with an oral antiresorptive agent. For monitoring, serum calcium (adjusted for albumin) should be checked 1 month after completing a loading regimen, or after starting vitamin D supplementation, in case primary hyperparathyroidism has been unmasked. However, routine monitoring of serum 25OHD is generally unnecessary but may be appropriate in patients with symptomatic vitamin D deficiency or malabsorption and where poor compliance with medication is suspected. The guideline focuses on bone health as, although there are numerous putative effects of vitamin D on immunity modulation, cancer prevention and the risks of cardiovascular disease and multiple sclerosis, there remains considerable debate about the evaluation of extraskeletal factors and optimal vitamin D status in these circumstances.

Seasonal variation in 25(OH)D at Aberdeen (57°N) and bone health indicators--could holidays in the sun and cod liver oil supplements alleviate deficiency?

Vitamin D has been linked with many health outcomes. The aim of this longitudinal study, was to assess predictors of seasonal variation of 25-hydroxy-vitamin D (25(OH)D) (including use of supplements and holidays in sunny destinations) at a northerly latitude in the UK (57°N) in relation to bone health indicators. 365 healthy postmenopausal women (mean age 62.0 y (SD 1.4)) had 25(OH)D measurements by immunoassay, serum C-telopeptide (CTX), estimates of sunlight exposure (badges of polysulphone film), information regarding holidays in sunny destinations, and diet (from food diaries, including use of supplements such as cod liver oil (CLO)) at fixed 3-monthly intervals over 15 months (subject retention 88%) with an additional 25(OH)D assessment in spring 2008. Bone mineral density (BMD) at the lumbar spine (LS) and dual hip was measured in autumn 2006 and spring 2007 (Lunar I-DXA). Deficiency prevalence (25(OH)D<25 nmol/L) was reduced in women who went on holiday to sunny destinations 3 months prior to their visit, compared to women who did not go on holidays [5.4% vs. 24.6% in Spring (p<0.001) and 3.8% vs. 25.6% in Winter (p = 0.001), respectively]. Similarly deficiency was lower amongst those who took CLO supplements compared to women that did not consume these supplements [2.0% vs. 23.7% in Spring (p = 0.001) and 4.5% vs. 24.8% in winter (p = 0.005), respectively]. There was no seasonal variation in CTX; 25(OH)D predicted a small proportion (1.8% variation) of LS BMD in spring 2007 [unstandardized ß (SE): 0.039 (0.016), p = 0.017]. Seasonal variation of 25(OH)D had little effect on BMD and no effect on CTX. It appears that small increments in vitamin D (e.g. those that can be achieved by cod liver oil supplements of 5 µg/day) are sufficient to ensure that 25(OH)D is above 25 nmol/L for most people throughout the year. Similarly, holidays in sunny destinations show benefit.

Contributions of sunlight and diet to vitamin D status.

Vitamin D is made in the skin using ultraviolet radiation of specific low wavelength, 290-315 nm (UVB). For many parts of the world there is a period when there is insufficient intensity of UVB to make vitamin D, which is reflected by a clear seasonal variation in vitamin D status. Sun avoidance practices, melanin in pigmented skin, and sun protection creams (sunscreen), if used properly, can dramatically reduce vitamin D synthesis. Few foods naturally contain vitamin D, although some countries fortify foods with vitamin D. Regulatory mechanisms in the skin mean there is no danger of vitamin D toxicity through sunlight synthesis. Although oral vitamin D is potentially toxic with high-dose supplements, there is a wide safety margin. Long-term safety data covering a range of potential adverse outcomes are limited.

Do lifestyle choices explain the effect of alcohol on bone mineral density in women around menopause?

BACKGROUND: Moderate alcohol consumption has been shown to be positively associated with increased bone mineral density (BMD). However, other lifestyle choices have also been shown to have an effect on bone health. OBJECTIVE: The objective was to examine the association between alcohol intake and BMD in women around menopause in the United Kingdom and to determine whether any association is independent of other lifestyle choices. DESIGN: A cross-sectional study design was used to examine the relation between alcohol intake and BMD in a cohort of 3218 women aged 50-62 y from the Aberdeen Prospective Osteoporosis Screening Study. Women were grouped into clusters according to their lifestyle choices. ANCOVA was used to examine the effect of categorized alcohol intake on BMD adjusted for cluster of lifestyle and other baseline covariates. The ANCOVA was repeated for different types of alcoholic beverage (eg, beer, liquor, and wine) separately. RESULTS: Three lifestyle clusters were identified and were based on different levels of the following 3 factors: smoking pack-years, fruit and vegetable intakes, and physical activity. In the lifestyle-adjusted models, women who consumed >1 drink/d of alcohol had a significantly greater femoral neck BMD (P = 0.008) and lumbar spine BMD (P = 0.007) than did those who never consumed alcohol. For separate alcoholic drinks, only beer had a positive significant effect on lumbar spine BMD after adjustment for lifestyle (P = 0.005). CONCLUSION: Moderate alcohol intake appears to be positively associated with BMD independently of the type of lifestyle led by women around menopause.

Dietary silicon interacts with oestrogen to influence bone health: evidence from the Aberdeen Prospective Osteoporosis Screening Study.

BACKGROUND: Silicon (Si), as Si(OH)(4), is derived mainly from plant-based foods. Dietary Si is associated with bone mineral density (BMD) in premenopausal but not postmenopausal women. OBJECTIVE: To examine the association between Si intake and markers of bone health in middle-aged women and to test for interaction with oestrogen status. METHODS: Femoral neck (FN) and lumbar spine (LS) BMD, urinary markers of bone resorption (free pyridinoline and deoxypyridinoline cross-links relative to creatinine, fPYD/Cr and fDPD/Cr) and serum markers of bone formation (N-terminal propeptide of type 1 collagen, P1NP) were measured in a cohort of 3198 women aged 50-62 years (n=1170 current HRT users, n=1018 never used HRT). Dietary Si, bioavailable Si and dietary confounders were estimated by food frequency questionnaire. RESULTS: Mean FN BMD was 2% lower (p<0.005) in the lowest quartile (Q1) compared to the top quartile of energy-adjusted Si intake (Q4) (mean (SD) Q1, 16 (4.0) mg/d; Q4, 31.5 (7.3) mg/d). Energy-adjusted Si intake was associated with FN BMD for oestrogen-replete women only (late premenopausal women (r=+0.21, p=0.03); women on HRT [r=+0.09, p<0.001]). There was an interaction between oestrogen status and quartile of energy-adjusted Si intake on FN BMD, which was significant after adjustment for confounders (F=3.3, p=0.020), and stronger for bioavailable Si (F=5.0. p=0.002). Quartile of energy-adjusted dietary Si intake was negatively associated with fDPD/Cr and fPYD/Cr (p<0.001) and positively with P1NP (p<0.05). CONCLUSIONS: This study suggests that oestrogen status is important for Si metabolism in bone health. Further work is required to elucidate the mechanism.

Vitamin D deficiency and disease risk among aboriginal Arctic populations.

Aboriginal populations living above the Arctic Circle are at particularly high risk of vitamin D deficiency due to limited ultraviolet B exposure (related to geographic latitude) and inadequate dietary intake (recently related to decreased traditional food consumption). Major changes in diet and lifestyle over the past 50 years in these populations have coincided with increased prevalence rates of rickets, cancer, diabetes, and obesity, each of which may be associated with vitamin D inadequacy. This review examines the risk factors for vitamin D inadequacy, the associations between vitamin D and disease risk at high geographic latitudes, and the recommendations for improving vitamin D status particularly among aboriginal Arctic populations. Traditional foods, such as fatty fish and marine mammals, are rich sources of vitamin D and should continue to be promoted to improve dietary vitamin D intake. Supplementation protocols may also be necessary to ensure adequate vitamin D status in the Arctic.

Associations between dietary flavonoid intakes and bone health in a Scottish population.

Flavonoids are bioactive polyphenols found particularly in fruit and vegetables, but little is known about their role in bone health in humans. The aim of this observational study was to investigate whether dietary flavonoid intake was associated with bone mineral density (BMD) and bone resorption in a large group of perimenopausal Scottish women. Over 3000 women completed a food frequency questionnaire as part of an osteoporosis screening study. The diets were analyzed for flavonoid intake using a food composition database. BMD was measured at the femoral neck (FN) and lumbar spine (LS) by dual-energy X-ray absorptiometry (DXA). Free pyridinoline (PYD) and deoxypyridinoline (DPD) were measured by high-performance liquid chromatography (HPLC) in second early morning fasted urine samples. The mean flavonoid intake of the diet was 307 ±199 mg/d. The catechin family contributed the most to flavonoid intakes (55%), and the flavones the least (<1%). Associations were found between energy-adjusted total flavonoid intakes and BMD at the FN and LS (FN r = 0.054, LS r = 0.036, p ≤ .05). Annual percent change in BMD was associated with intakes of procyanidins and catechins (p ≤ .05), and flavanones were negatively associated with bone-resorption markers (PYD r = -0.049, DPD r = -0.057, p ≤ .001). These associations were still seen after adjusting for confounders. It is concluded that dietary flavonoid intakes are associated with BMD, supporting the evidence from animal and cellular studies.

Diet, lifestyle and chronic widespread pain: results from the 1958 British Birth Cohort Study.

OBJECTIVES: To examine the relationship between diet and lifestyle, and chronic widespread pain (CWP). If persons with CWP have dietary and lifestyle habits consistent with an increased risk of cancer or cardiovascular disease, it may partially explain evidence in the literature suggesting an association between CWP and these diseases. METHODS: The 1958 British Birth Cohort Study comprises individuals born in England, Scotland and Wales in the United Kingdom during one week in March 1958. At 45 years of age, pain was recorded using a self-completion questionnaire. CWP was classified using the American College of Rheumatology definition for fibromyalgia. Data were collected on diet and lifestyle at 33 and 42 years of age. RESULTS: A total of 8572 participants provided pain data at 45 years of age, of whom 12% reported CWP. Women with CWP, compared with those without, reported an unhealthy diet (ie, fruit/vegetable consumption less than once per week [OR 2.0; 95% CI 1.3 to 3.1], and fatty food [OR 1.7; 95% CI 1.1 to 2.7] and chips (french fries) [OR 1.5; 95% CI 1.0 to 2.4] at least once per day) that may have predisposed them to other chronic diseases such as cancer and cardiovascular disease. Women with CWP were also more likely to be unemployed (adjusted OR 1.4; 95% CI 1.1 to 1.8), to have had high physical exertion at work (adjusted OR 1.6; 95% CI 1.2 to 2.2) and elevated body mass index (overweight - adjusted OR 1.5, 95% CI 1.2 to 1.9; obese - adjusted OR 1.8, 95% CI 1.3 to 2.5). Similar relationships between lifestyle (but not diet) and the risk of CWP were identified in men. CONCLUSIONS: The findings for smoking, body mass index and (for women) diet offer support for the hypothesis that lifestyle factors may partially explain the association between CWP and cancer or cardiovascular disease. Prospective studies are necessary to confirm this relationship.