PLoS Medicine

Condividi contenuti PLOS Medicine: New Articles
A Peer-Reviewed Open-Access Journal
Aggiornato: 22 ore 19 min fa

Revisiting child and adolescent health in the context of the Sustainable Development Goals

Ve, 30/10/2020 - 22:00

by Zulfiqar A. Bhutta, Kathryn M. Yount, Quique Bassat, Artur A. Arikainen

Acute kidney injury associated with COVID-19: A retrospective cohort study

Ve, 30/10/2020 - 22:00

by Nitin V. Kolhe, Richard J. Fluck, Nicholas M. Selby, Maarten W. Taal

Background

Initial reports indicate a high incidence of acute kidney injury (AKI) in Coronavirus Disease 2019 (COVID-19), but more data are required to clarify if COVID-19 is an independent risk factor for AKI and how COVID-19–associated AKI may differ from AKI due to other causes. We therefore sought to study the relationship between COVID-19, AKI, and outcomes in a retrospective cohort of patients admitted to 2 acute hospitals in Derby, United Kingdom.

Methods and findings

We extracted electronic data from 4,759 hospitalised patients who were tested for COVID-19 between 5 March 2020 and 12 May 2020. The data were linked to electronic patient records and laboratory information management systems. The primary outcome was AKI, and secondary outcomes included in-hospital mortality, need for ventilatory support, intensive care unit (ICU) admission, and length of stay. As compared to the COVID-19–negative group (n = 3,374), COVID-19 patients (n = 1,161) were older (72.1 ± 16.1 versus 65.3 ± 20.4 years, p < 0.001), had a greater proportion of men (56.6% versus 44.9%, p < 0.001), greater proportion of Asian ethnicity (8.3% versus 4.0%, p < 0.001), and lower proportion of white ethnicity (75.5% versus 82.5%, p < 0.001). AKI developed in 304 (26.2%) COVID-19–positive patients (COVID-19 AKI) and 420 (12.4%) COVID-19–negative patients (AKI controls). COVID-19 patients aged 65 to 84 years (odds ratio [OR] 1.67, 95% confidence interval [CI] 1.11 to 2.50), needing mechanical ventilation (OR 8.74, 95% CI 5.27 to 14.77), having congestive cardiac failure (OR 1.72, 95% CI 1.18 to 2.50), chronic liver disease (OR 3.43, 95% CI 1.17 to 10.00), and chronic kidney disease (CKD) (OR 2.81, 95% CI 1.97 to 4.01) had higher odds for developing AKI. Mortality was higher in COVID-19 AKI versus COVID-19 patients without AKI (60.5% versus 27.4%, p < 0.001), and AKI was an independent predictor of mortality (OR 3.27, 95% CI 2.39 to 4.48). Compared with AKI controls, COVID-19 AKI was observed in a higher proportion of men (58.9% versus 51%, p = 0.04) and lower proportion with white ethnicity (74.7% versus 86.9%, p = 0.003); was more frequently associated with cerebrovascular disease (11.8% versus 6.0%, p = 0.006), chronic lung disease (28.0% versus 19.3%, p = 0.007), diabetes (24.7% versus 17.9%, p = 0.03), and CKD (34.2% versus 20.0%, p < 0.001); and was more likely to be hospital acquired (61.2% versus 46.4%, p < 0.001). Mortality was higher in the COVID-19 AKI as compared to the control AKI group (60.5% versus 27.6%, p < 0.001). In multivariable analysis, AKI patients aged 65 to 84 years, (OR 3.08, 95% CI 1.77 to 5.35) and ≥85 years of age (OR 3.54, 95% CI 1.87 to 6.70), peak AKI stage 2 (OR 1.74, 95% CI 1.05 to 2.90), AKI stage 3 (OR 2.01, 95% CI 1.13 to 3.57), and COVID-19 (OR 3.80, 95% CI 2.62 to 5.51) had higher odds of death. Limitations of the study include retrospective design, lack of urinalysis data, and low ethnic diversity of the region.

Conclusions

We observed a high incidence of AKI in patients with COVID-19 that was associated with a 3-fold higher odds of death than COVID-19 without AKI and a 4-fold higher odds of death than AKI due to other causes. These data indicate that patients with COVID-19 should be monitored for the development of AKI and measures taken to prevent this.

Trial registration

ClinicalTrials.gov NCT04407156

Primary healthcare expansion and mortality in Brazil’s urban poor: A cohort analysis of 1.2 million adults

Ve, 30/10/2020 - 22:00

by Thomas Hone, Valeria Saraceni, Claudia Medina Coeli, Anete Trajman, Davide Rasella, Christopher Millett, Betina Durovni

Background

Expanding delivery of primary healthcare to urban poor populations is a priority in many low- and middle-income countries. This remains a key challenge in Brazil despite expansion of the country’s internationally recognized Family Health Strategy (FHS) over the past two decades. This study evaluates the impact of an ambitious program to rapidly expand FHS coverage in the city of Rio de Janeiro, Brazil, since 2008.

Methods and findings

A cohort of 1,241,351 low-income adults (observed January 2010–December 2016; total person-years 6,498,607) with linked FHS utilization and mortality records was analyzed using flexible parametric survival models. Time-to-death from all-causes and selected causes were estimated for FHS users and nonusers. Models employed inverse probability treatment weighting and regression adjustment (IPTW-RA).The cohort was 61% female (751,895) and had a mean age of 36 years (standard deviation 16.4). Only 18,721 individuals (1.5%) had higher education, whereas 102,899 (8%) had no formal education. Two thirds of individuals (827,250; 67%) were in receipt of conditional cash transfers (Bolsa Família). A total of 34,091 deaths were analyzed, of which 8,765 (26%) were due to cardiovascular disease; 5,777 (17%) were due to neoplasms; 5,683 (17%) were due to external causes; 3,152 (9%) were due to respiratory diseases; and 3,115 (9%) were due to infectious and parasitic diseases. One third of the cohort (467,155; 37.6%) used FHS services. In IPTW-RA survival analysis, an average FHS user had a 44% lower hazard of all-cause mortality (HR: 0.56, 95% CI 0.54–0.59, p < 0.001) and a 5-year risk reduction of 8.3 per 1,000 (95% CI 7.8–8.9, p < 0.001) compared with a non-FHS user. There were greater reductions in the risk of death for FHS users who were black (HR 0.50, 95% CI 0.46–0.54, p < 0.001) or pardo (HR 0.57, 95% CI 0.54–0.60, p < 0.001) compared with white (HR 0.59, 95% CI 0.56–0.63, p < 0.001); had lower educational attainment (HR 0.50, 95% CI 0.46–0.55, p < 0.001) for those with no education compared to no significant association for those with higher education (p = 0.758); or were in receipt of conditional cash transfers (Bolsa Família) (HR 0.51, 95% CI 0.49–0.54, p < 0.001) compared with nonrecipients (HR 0.63, 95% CI 0.60–0.67, p < 0.001).Key limitations in this study are potential unobserved confounding through selection into the program and linkage errors, although analytical approaches have minimized the potential for bias.

Conclusions

FHS utilization in urban poor populations in Brazil was associated with a lower risk of death, with greater reductions among more deprived race/ethnic and socioeconomic groups. Increased investment in primary healthcare is likely to improve health and reduce health inequalities in urban poor populations globally.

Metabolically healthy obesity, transition to unhealthy metabolic status, and vascular disease in Chinese adults: A cohort study

Ve, 30/10/2020 - 22:00

by Meng Gao, Jun Lv, Canqing Yu, Yu Guo, Zheng Bian, Ruotong Yang, Huaidong Du, Ling Yang, Yiping Chen, Zhongxiao Li, Xi Zhang, Junshi Chen, Lu Qi, Zhengming Chen, Tao Huang, Liming Li, for the China Kadoorie Biobank (CKB) Collaborative Group

Background

Metabolically healthy obesity (MHO) and its transition to unhealthy metabolic status have been associated with risk of cardiovascular disease (CVD) in Western populations. However, it is unclear to what extent metabolic health changes over time and whether such transition affects risks of subtypes of CVD in Chinese adults. We aimed to examine the association of metabolic health status and its transition with risks of subtypes of vascular disease across body mass index (BMI) categories.

Methods and findings

The China Kadoorie Biobank was conducted during 25 June 2004 to 15 July 2008 in 5 urban (Harbin, Qingdao, Suzhou, Liuzhou, and Haikou) and 5 rural (Henan, Gansu, Sichuan, Zhejiang, and Hunan) regions across China. BMI and metabolic health information were collected. We classified participants into BMI categories: normal weight (BMI 18.5–23.9 kg/m²), overweight (BMI 24.0–27.9 kg/m²), and obese (BMI ≥ 28 kg/m²). Metabolic health was defined as meeting less than 2 of the following 4 criteria (elevated waist circumference, hypertension, elevated plasma glucose level, and dyslipidemia). The changes in obesity and metabolic health status were defined from baseline to the second resurvey with combination of overweight and obesity. Among the 458,246 participants with complete information and no history of CVD and cancer, the mean age at baseline was 50.9 (SD 10.4) years, and 40.8% were men, and 29.0% were current smokers. During a median 10.0 years of follow-up, 52,251 major vascular events (MVEs), including 7,326 major coronary events (MCEs), 37,992 ischemic heart disease (IHD), and 42,951 strokes were recorded. Compared with metabolically healthy normal weight (MHN), baseline MHO was associated with higher hazard ratios (HRs) for all types of CVD; however, almost 40% of those participants transitioned to metabolically unhealthy status. Stable metabolically unhealthy overweight or obesity (MUOO) (HR 2.22, 95% confidence interval [CI] 2.00–2.47, p < 0.001) and transition from metabolically healthy to unhealthy status (HR 1.53, 1.34–1.75, p < 0.001) were associated with higher risk for MVE, compared with stable healthy normal weight. Similar patterns were observed for MCE, IHD, and stroke. Limitations of the analysis included lack of measurement of lipid components, fasting plasma glucose, and visceral fat, and there might be possible misclassification.

Conclusions

Among Chinese adults, MHO individuals have increased risks of MVE. Obesity remains a risk factor for CVD independent of major metabolic factors. Our data further suggest that metabolic health is a transient state for a large proportion of Chinese adults, with the highest vascular risk among those remained MUOO.

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium

Ve, 30/10/2020 - 22:00

by Signe Hässler, Delphine Bachelet, Julianne Duhaze, Natacha Szely, Aude Gleizes, Salima Hacein-Bey Abina, Orhan Aktas, Michael Auer, Jerôme Avouac, Mary Birchler, Yoram Bouhnik, Olivier Brocq, Dorothea Buck-Martin, Guillaume Cadiot, Franck Carbonnel, Yehuda Chowers, Manuel Comabella, Tobias Derfuss, Niek De Vries, Naoimh Donnellan, Abiba Doukani, Michael Guger, Hans-Peter Hartung, Eva Kubala Havrdova, Bernhard Hemmer, Tom Huizinga, Kathleen Ingenhoven, Poul Erik Hyldgaard-Jensen, Elizabeth C. Jury, Michael Khalil, Bernd Kieseier, Anna Laurén, Raija Lindberg, Amy Loercher, Enrico Maggi, Jessica Manson, Claudia Mauri, Badreddine Mohand Oumoussa, Xavier Montalban, Maria Nachury, Petra Nytrova, Christophe Richez, Malin Ryner, Finn Sellebjerg, Claudia Sievers, Dan Sikkema, Martin Soubrier, Sophie Tourdot, Caroline Trang, Alessandra Vultaggio, Clemens Warnke, Sebastian Spindeldreher, Pierre Dönnes, Timothy P. Hickling, Agnès Hincelin Mery, Matthieu Allez, Florian Deisenhammer, Anna Fogdell-Hahn, Xavier Mariette, Marc Pallardy, Philippe Broët, ABIRISK consortium

Background

Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited.

Methods and findings

The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn’s disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253–0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437–0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616–4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319–3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923–5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139–6.764], p < 1 × 10−5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106–4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings.

Conclusion

In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.

The intersection of genomics and big data with public health: Opportunities for precision public health

Gi, 29/10/2020 - 22:00

by Muin J. Khoury, Gregory L. Armstrong, Rebecca E. Bunnell, Juliana Cyril, Michael F. Iademarco

Muin Khoury and co-authors discuss anticipated contributions of genomics and other forms of large-scale data in public health.

Quantifying <i>Plasmodium falciparum</i> infections clustering within households to inform household-based intervention strategies for malaria control programs: An observational study and meta-analysis from 41 malaria-endemic countries

Gi, 29/10/2020 - 22:00

by Gillian Stresman, Charlie Whittaker, Hannah C. Slater, Teun Bousema, Jackie Cook

Background

Reactive malaria strategies are predicated on the assumption that individuals infected with malaria are clustered within households or neighbourhoods. Despite the widespread programmatic implementation of reactive strategies, little empirical evidence exists as to whether such strategies are appropriate and, if so, how they should be most effectively implemented.

Methods and findings

We collated 2 different datasets to assess clustering of malaria infections within households: (i) demographic health survey (DHS) data, integrating household information and patent malaria infection, recent fever, and recent treatment status in children; and (ii) data from cross-sectional and reactive detection studies containing information on the household and malaria infection status (patent and subpatent) of all-aged individuals. Both datasets were used to assess the odds of infections clustering within index households, where index households were defined based on whether they contained infections detectable through one of 3 programmatic strategies: (a) Reactive Case Detection (RACD) classifed by confirmed clinical cases, (b) Mass Screen and Treat (MSAT) classifed by febrile, symptomatic infections, and (c) Mass Test and Treat (MTAT) classifed by infections detectable using routine diagnostics. Data included 59,050 infections in 208,140 children under 7 years old (median age = 2 years, minimum = 2, maximum = 7) by microscopy/rapid diagnostic test (RDT) from 57 DHSs conducted between November 2006 and December 2018 from 23 African countries. Data representing 11,349 infections across all ages (median age = 22 years, minimum = 0.5, maximum = 100) detected by molecular tools in 132,590 individuals in 43 studies published between April 2006 and May 2019 in 20 African, American, Asian, and Middle Eastern countries were obtained from the published literature. Extensive clustering was observed—overall, there was a 20.40 greater (95% credible interval [CrI] 0.35–20.45; P < 0.001) odds of patent infections (according to the DHS data) and 5.13 greater odds (95% CI 3.85–6.84; P < 0.001) of molecularly detected infections (from the published literature) detected within households in which a programmatically detectable infection resides. The strongest degree of clustering identified by polymerase chain reaction (PCR)/ loop mediated isothermal amplification (LAMP) was observed using the MTAT strategy (odds ratio [OR] = 6.79, 95% CI 4.42–10.43) but was not significantly different when compared to MSAT (OR = 5.2, 95% CI 3.22–8.37; P-difference = 0.883) and RACD (OR = 4.08, 95% CI 2.55–6.53; P-difference = 0.29). Across both datasets, clustering became more prominent when transmission was low. However, limitations to our analysis include not accounting for any malaria control interventions in place, malaria seasonality, or the likely heterogeneity of transmission within study sites. Clustering may thus have been underestimated.

Conclusions

In areas where malaria transmission is peri-domestic, there are programmatic options for identifying households where residual infections are likely to be found. Combining these detection strategies with presumptively treating residents of index households over a sustained time period could contribute to malaria elimination efforts.

Defining remission of type 2 diabetes in research studies: A systematic scoping review

Me, 28/10/2020 - 22:00

by Mireille Captieux, Regina Prigge, Sarah Wild, Bruce Guthrie

Background

Remission has been identified as a top priority by people with type 2 diabetes. Remission is commonly used as an outcome in research studies; however, a widely accepted definition of remission of type 2 diabetes is lacking. A report on defining remission was published (but not formally endorsed) in Diabetes Care, an American Diabetes Association (ADA) journal. This Diabetes Care report remains widely used. It was the first to suggest 3 components necessary to define the presence of remission: (1) absence of glucose-lowering therapy (GLT); (2) normoglycaemia; and (3) for duration ≥1 year. Our aim is to systematically review how remission of type 2 diabetes has been defined by observational and interventional studies since publication of the 2009 report.

Methods and findings

Four databases (MEDLINE, EMBASE, Cochrane Library, and CINAHL) were searched for studies published from 1 September 2009 to 18 July 2020 involving at least 100 participants with type 2 diabetes in their remission analysis, which examined an outcome of type 2 diabetes remission in adults ≥18 years and which had been published in English since 2009. Remission definitions were extracted and categorised by glucose-lowering therapy, glycaemic thresholds, and duration. A total of 8,966 titles/abstracts were screened, and 178 studies (165 observational and 13 interventional) from 33 countries were included. These contributed 266 definitions, of which 96 were unique. The 2009 report was referenced in 121 (45%) definitions. In total, 247 (93%) definitions required the absence of GLT, and 232 (87%) definitions specified numeric glycaemic thresholds. The most frequently used threshold was HbA1c<42 mmol/mol (6.0%) in 47 (20%) definitions. Time was frequently omitted. In this study, a total of 104 (39%) definitions defined time as a duration. The main limitations of this systematic review lie in the restriction to published studies written in English with sample sizes of over 100. Grey literature was not included in the search.

Conclusions

We found that there is substantial heterogeneity in the definition of type 2 diabetes remission in research studies published since 2009, at least partly reflecting ambiguity in the 2009 report. This complicates interpretation of previous research on remission of type 2 diabetes and the implications for people with type 2 diabetes. Any new consensus definition of remission should include unambiguous glycaemic thresholds and emphasise duration. Until an international consensus is reached, studies describing remission should clearly define all 3 components of remission.

Systematic review registration

PROSPERO CRD42019144619

The diagnostic performance of CA125 for the detection of ovarian and non-ovarian cancer in primary care: A population-based cohort study

Me, 28/10/2020 - 22:00

by Garth Funston, Willie Hamilton, Gary Abel, Emma J. Crosbie, Brian Rous, Fiona M. Walter

Background

The serum biomarker cancer antigen 125 (CA125) is widely used as an investigation for possible ovarian cancer in symptomatic women presenting to primary care. However, its diagnostic performance in this setting is unknown. We evaluated the performance of CA125 in primary care for the detection of ovarian and non-ovarian cancers.

Methods and findings

We studied women in the United Kingdom Clinical Practice Research Datalink with a CA125 test performed between 1 May 2011–31 December 2014. Ovarian and non-ovarian cancers diagnosed in the year following CA125 testing were identified from the cancer registry. Women were categorized by age: <50 years and ≥50 years. Conventional measures of test diagnostic accuracy, including sensitivity, specificity, and positive predictive value, were calculated for the standard CA125 cut-off (≥35 U/ml). The probability of a woman having cancer at each CA125 level between 1–1,000 U/ml was estimated using logistic regression. Cancer probability was also estimated on the basis of CA125 level and age in years using logistic regression. We identified CA125 levels equating to a 3% estimated cancer probability: the “risk threshold” at which the UK National Institute for Health and Care Excellence advocates urgent specialist cancer investigation.A total of 50,780 women underwent CA125 testing; 456 (0.9%) were diagnosed with ovarian cancer and 1,321 (2.6%) with non-ovarian cancer. Of women with a CA125 level ≥35 U/ml, 3.4% aged <50 years and 15.2% aged ≥50 years had ovarian cancer. Of women with a CA125 level ≥35 U/ml who were aged ≥50 years and who did not have ovarian cancer, 20.4% were diagnosed with a non-ovarian cancer. A CA125 value of 53 U/ml equated to a 3% probability of ovarian cancer overall. This varied by age, with a value of 104 U/ml in 40-year-old women and 32 U/ml in 70-year-old women equating to a 3% probability. The main limitations of our study were that we were unable to determine why CA125 tests were performed and that our findings are based solely on UK primary care data, so caution is need in extrapolating them to other healthcare settings.

Conclusions

CA125 is a useful test for ovarian cancer detection in primary care, particularly in women ≥50 years old. Clinicians should also consider non-ovarian cancers in women with high CA125 levels, especially if ovarian cancer has been excluded, in order to prevent diagnostic delay. Our results enable clinicians and patients to determine the estimated probability of ovarian cancer and all cancers at any CA125 level and age, which can be used to guide individual decisions on the need for further investigation or referral.

Medicalization of female genital cutting in Malaysia: A mixed methods study

Ma, 27/10/2020 - 22:00

by Abdul Rashid, Yufu Iguchi, Siti Nur Afiqah

Background

Despite the clear stand taken by the United Nations (UN) and other international bodies in ensuring that female genital cutting (FGC) is not performed by health professionals, the rate of medicalization has not reduced. The current study aimed to determine the extent of medicalization of FGC among doctors in Malaysia, who the doctors were who practiced it, how and what was practiced, and the motivations for the practice.

Methods and findings

This mixed method (qualitative and quantitative) study was conducted from 2018 to 2019 using a self-administered questionnaire among Muslim medical doctors from 2 main medical associations with a large number of Muslim members from all over Malaysia who attended their annual conference. For those doctors who did not attend the conference, the questionnaire was posted to them. Association A had 510 members, 64 male Muslim doctors and 333 female Muslim doctors. Association B only had Muslim doctors; 3,088 were female, and 1,323 were male. In total, 894 questionnaires were distributed either by hand or by post, and 366 completed questionnaires were received back. For the qualitative part of the study, a snowball sampling method was used, and 24 in-depth interviews were conducted using a semi-structured questionnaire, until data reached saturation. Quantitative data were analysed using SPSS version 18 (IBM, Armonk, NY). A chi-squared test and binary logistic regression were performed. The qualitative data were transcribed manually, organized, coded, and recoded using NVivo version 12. The clustered codes were elicited as common themes. Most of the respondents were women, had medical degrees from Malaysia, and had a postgraduate degree in Family Medicine. The median age was 42. Most were working with the Ministry of Health (MoH) Malaysia, and in a clinic located in an urban location. The prevalence of Muslim doctors practising FGC was 20.5% (95% CI 16.6–24.9). The main reason cited for practising FGC was religious obligation. Qualitative findings too showed that religion was a strong motivating factor for the practice and its continuation, besides culture and harm reduction. Although most Muslim doctors performed type IV FGC, there were a substantial number performing type I. Respondents who were women (adjusted odds ratio [aOR] 4.4, 95% CI 1.9–10.0. P ≤ 0.001), who owned a clinic (aOR 30.7, 95% CI 12.0–78.4. P ≤ 0.001) or jointly owned a clinic (aOR 7.61, 95% CI 3.2–18.1. P ≤ 0.001), who thought that FGC was legal in Malaysia (aOR 2.09, 95% CI 1.02–4.3. P = 0.04), and who were encouraged in religion (aOR 2.25, 95% CI 3.2–18.1. P = 0.036) and thought that FGC should continue (aOR 3.54, 95% CI 1.25–10.04. P = 0.017) were more likely to practice FGC. The main limitations of the study were the small sample size and low response rate.

Conclusions

In this study, we found that many of the Muslim doctors were unaware of the legal and international stand against FGC, and many wanted the practice to continue. It is a concern that type IV FGC carried out by traditional midwives may be supplanted and exacerbated by type I FGC performed by doctors, calling for strong and urgent action by the Malaysian medical authorities.

Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against vaccine serotype pneumococcal pneumonia in adults: A case-control test-negative design study

Ve, 23/10/2020 - 22:00

by Hannah Lawrence, Harry Pick, Vadsala Baskaran, Priya Daniel, Chamira Rodrigo, Deborah Ashton, Rochelle C. Edwards-Pritchard, Carmen Sheppard, Seyi D. Eletu, David Litt, Norman K. Fry, Samuel Rose, Caroline Trotter, Tricia M. McKeever, Wei Shen Lim

Background

Vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPV23) is available in the United Kingdom to adults aged 65 years or older and those in defined clinical risk groups. We evaluated the vaccine effectiveness (VE) of PPV23 against vaccine-type pneumococcal pneumonia in a cohort of adults hospitalised with community-acquired pneumonia (CAP).

Methods and findings

Using a case-control test-negative design, a secondary analysis of data was conducted from a prospective cohort study of adults (aged ≥16 years) with CAP hospitalised at 2 university teaching hospitals in Nottingham, England, from September 2013 to August 2018. The exposure of interest was PPV23 vaccination at any time point prior to the index admission. A case was defined as PPV23 serotype-specific pneumococcal pneumonia and a control as non-PPV23 serotype pneumococcal pneumonia or nonpneumococcal pneumonia. Pneumococcal serotypes were identified from urine samples using a multiplex immunoassay or from positive blood cultures. Multivariable logistic regression was used to derive adjusted odds of case status between vaccinated and unvaccinated individuals; VE estimates were calculated as (1 − odds ratio) × 100%. Of 2,357 patients, there were 717 PPV23 cases (48% vaccinated) and 1,640 controls (54.5% vaccinated). The adjusted VE (aVE) estimate against PPV23 serotype disease was 24% (95% CI 5%–40%, p = 0.02). Estimates were similar in analyses restricted to vaccine-eligible patients (n = 1,768, aVE 23%, 95% CI 1%–40%) and patients aged ≥65 years (n = 1,407, aVE 20%, 95% CI −5% to 40%), but not in patients aged ≥75 years (n = 905, aVE 5%, 95% CI −37% to 35%). The aVE estimate in relation to PPV23/non-13-valent pneumococcal conjugate vaccine (PCV13) serotype pneumonia (n = 417 cases, 43.7% vaccinated) was 29% (95% CI 6%–46%). Key limitations of this study are that, due to high vaccination rates, there was a lack of power to reject the null hypothesis of no vaccine effect, and that the study was not large enough to allow robust subgroup analysis in the older age groups.

Conclusions

In the setting of an established national childhood PCV13 vaccination programme, PPV23 vaccination of clinical at-risk patient groups and adults aged ≥65 years provided moderate long-term protection against hospitalisation with PPV23 serotype pneumonia. These findings suggest that PPV23 vaccination may continue to have an important role in adult pneumococcal vaccine policy, including the possibility of revaccination of older adults.

Tuberculosis, human rights, and law reform: Addressing the lack of progress in the global tuberculosis response

Ve, 23/10/2020 - 22:00

by Matthew M. Kavanagh, Lawrence O. Gostin, John Stephens

Mathew Kavanagh and co-authors discuss law reform in the global tuberculosis response.

Predictive value of pulse oximetry for mortality in infants and children presenting to primary care with clinical pneumonia in rural Malawi: A data linkage study

Ve, 23/10/2020 - 22:00

by Tim Colbourn, Carina King, James Beard, Tambosi Phiri, Malizani Mdala, Beatiwel Zadutsa, Charles Makwenda, Anthony Costello, Norman Lufesi, Charles Mwansambo, Bejoy Nambiar, Shubhada Hooli, Neil French, Naor Bar Zeev, Shamim Ahmad Qazi, Yasir Bin Nisar, Eric D. McCollum

Background

The mortality impact of pulse oximetry use during infant and childhood pneumonia management at the primary healthcare level in low-income countries is unknown. We sought to determine mortality outcomes of infants and children diagnosed and referred using clinical guidelines with or without pulse oximetry in Malawi.

Methods and findings

We conducted a data linkage study of prospective health facility and community case and mortality data. We matched prospectively collected community health worker (CHW) and health centre (HC) outpatient data to prospectively collected hospital and community-based mortality surveillance outcome data, including episodes followed up to and deaths within 30 days of pneumonia diagnosis amongst children 0–59 months old. All data were collected in Lilongwe and Mchinji districts, Malawi, from January 2012 to June 2014. We determined differences in mortality rates using <90% and <93% oxygen saturation (SpO2) thresholds and World Health Organization (WHO) and Malawi clinical guidelines for referral. We used unadjusted and adjusted (for age, sex, respiratory rate, and, in analyses of HC data only, Weight for Age Z-score [WAZ]) regression to account for interaction between SpO2 threshold (pulse oximetry) and clinical guidelines, clustering by child, and CHW or HC catchment area. We matched CHW and HC outpatient data to hospital inpatient records to explore roles of pulse oximetry and clinical guidelines on hospital attendance after referral. From 7,358 CHW and 6,546 HC pneumonia episodes, we linked 417 CHW and 695 HC pneumonia episodes to 30-day mortality outcomes: 16 (3.8%) CHW and 13 (1.9%) HC patients died. SpO2 thresholds of <90% and <93% identified 1 (6%) of the 16 CHW deaths that were unidentified by integrated community case management (iCCM) WHO referral protocol and 3 (23%) and 4 (31%) of the 13 HC deaths, respectively, that were unidentified by the integrated management of childhood illness (IMCI) WHO protocol. Malawi IMCI referral protocol, which differs from WHO protocol at the HC level and includes chest indrawing, identified all but one of these deaths. SpO2 < 90% predicted death independently of WHO danger signs compared with SpO2 ≥ 90%: HC Risk Ratio (RR), 9.37 (95% CI: 2.17–40.4, p = 0.003); CHW RR, 6.85 (1.15–40.9, p = 0.035). SpO2 < 93% was also predictive versus SpO2 ≥ 93% at HC level: RR, 6.68 (1.52–29.4, p = 0.012). Hospital referrals and outpatient episodes with referral decision indications were associated with mortality. A substantial proportion of those referred were not found admitted in the inpatients within 7 days of referral advice. All 12 deaths in 73 hospitalised children occurred within 24 hours of arrival in the hospital, which highlights delay in appropriate care seeking. The main limitation of our study was our ability to only match 6% of CHW episodes and 11% of HC episodes to mortality outcome data.

Conclusions

Pulse oximetry identified fatal pneumonia episodes at HCs in Malawi that would otherwise have been missed by WHO referral guidelines alone. Our findings suggest that pulse oximetry could be beneficial in supplementing clinical signs to identify children with pneumonia at high risk of mortality in the outpatient setting in health centres for referral to a hospital for appropriate management.

Correction: Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study

Me, 21/10/2020 - 22:00

by Uma V. Mahajan, Vijay R. Varma, Michael E. Griswold, Chad T. Blackshear, Yang An, Anup M. Oommen, Sudhir Varma, Juan C. Troncoso, Olga Pletnikova, Richard O’Brien, Timothy J. Hohman, Cristina Legido-Quigley, Madhav Thambisetty

Variation in racial/ethnic disparities in COVID-19 mortality by age in the United States: A cross-sectional study

Ma, 20/10/2020 - 22:00

by Mary T. Bassett, Jarvis T. Chen, Nancy Krieger

Background

In the United States, non-Hispanic Black (NHB), Hispanic, and non-Hispanic American Indian/Alaska Native (NHAIAN) populations experience excess COVID-19 mortality, compared to the non-Hispanic White (NHW) population, but racial/ethnic differences in age at death are not known. The release of national COVID-19 death data by racial/ethnic group now permits analysis of age-specific mortality rates for these groups and the non-Hispanic Asian or Pacific Islander (NHAPI) population. Our objectives were to examine variation in age-specific COVID-19 mortality rates by racial/ethnicity and to calculate the impact of this mortality using years of potential life lost (YPLL).

Methods and findings

This cross-sectional study used the recently publicly available data on US COVID-19 deaths with reported race/ethnicity, for the time period February 1, 2020, to July 22, 2020. Population data were drawn from the US Census. As of July 22, 2020, the number of COVID-19 deaths equaled 68,377 for NHW, 29,476 for NHB, 23,256 for Hispanic, 1,143 for NHAIAN, and 6,468 for NHAPI populations; the corresponding population sizes were 186.4 million, 40.6 million, 2.6 million, 19.5 million, and 57.7 million. Age-standardized rate ratios relative to NHW were 3.6 (95% CI 3.5, 3.8; p < 0.001) for NHB, 2.8 (95% CI 2.7, 3.0; p < 0.001) for Hispanic, 2.2 (95% CI 1.8, 2.6; p < 0.001) for NHAIAN, and 1.6 (95% CI 1.4, 1.7; p < 0.001) for NHAP populations. By contrast, NHB rate ratios relative to NHW were 7.1 (95% CI 5.8, 8.7; p < 0.001) for persons aged 25–34 years, 9.0 (95% CI 7.9, 10.2; p < 0.001) for persons aged 35–44 years, and 7.4 (95% CI 6.9, 7.9; p < 0.001) for persons aged 45–54 years. Even at older ages, NHB rate ratios were between 2.0 and 5.7. Similarly, rate ratios for the Hispanic versus NHW population were 7.0 (95% CI 5.8, 8.7; p < 0.001), 8.8 (95% CI 7.8, 9.9; p < 0.001), and 7.0 (95% CI 6.6, 7.5; p < 0.001) for the corresponding age strata above, with remaining rate ratios ranging from 1.4 to 5.0. Rate ratios for NHAIAN were similarly high through age 74 years. Among NHAPI persons, rate ratios ranged from 2.0 to 2.8 for persons aged 25–74 years and were 1.6 and 1.2 for persons aged 75–84 and 85+ years, respectively. As a consequence, more YPLL before age 65 were experienced by the NHB and Hispanic populations than the NHW population—despite the fact that the NHW population is larger—with a ratio of 4.6:1 and 3.2:1, respectively, for NHB and Hispanic persons. Study limitations include likely lag time in receipt of completed death certificates received by the Centers for Disease Control and Prevention for transmission to NCHS, with consequent lag in capturing the total number of deaths compared to data reported on state dashboards.

Conclusions

In this study, we observed racial variation in age-specific mortality rates not fully captured with examination of age-standardized rates alone. These findings suggest the importance of examining age-specific mortality rates and underscores how age standardization can obscure extreme variations within age strata. To avoid overlooking such variation, data that permit age-specific analyses should be routinely publicly available.

Differential association of air pollution exposure with neonatal and postneonatal mortality in England and Wales: A cohort study

Ma, 20/10/2020 - 22:00

by Sarah J. Kotecha, W. John Watkins, John Lowe, Jonathan Grigg, Sailesh Kotecha

Background

Many but not all studies suggest an association between air pollution exposure and infant mortality. We sought to investigate whether pollution exposure is differentially associated with all-cause neonatal or postneonatal mortality, or specific causes of infant mortality.

Methods and findings

We separately investigated the associations of exposure to particulate matter with aerodynamic diameter ≤ 10 μm (PM10), nitrogen dioxide (NO2), and sulphur dioxide (SO2) with all-cause infant, neonatal, and postneonatal mortality, and with specific causes of infant deaths in 7,984,366 live births between 2001 and 2012 in England and Wales. Overall, 51.3% of the live births were male, and there were 36,485 infant deaths (25,110 neonatal deaths and 11,375 postneonatal deaths). We adjusted for the following major confounders: deprivation, birthweight, maternal age, sex, and multiple birth. Adjusted odds ratios (95% CI; p-value) for infant deaths were significantly increased for NO2, PM10, and SO2 (1.066 [1.027, 1.107; p = 0.001], 1.044 [1.007, 1.082; p = 0.017], and 1.190 [1.146, 1.235; p < 0.001], respectively) when highest and lowest pollutant quintiles were compared; however, neonatal mortality was significantly associated with SO2 (1.207 [1.154, 1.262; p < 0.001]) but not significantly associated with NO2 and PM10 (1.044 [0.998, 1.092; p = 0.059] and 1.008 [0.966, 1.052; p = 0.702], respectively). Postneonatal mortality was significantly associated with all pollutants: NO2, 1.108 (1.038, 1.182; p < 0.001); PM10, 1.117 (1.050, 1.188; p < 0.001); and SO2, 1.147 (1.076, 1.224; p < 0.001). Whilst all were similarly associated with endocrine causes of infant deaths (NO2, 2.167 [1.539, 3.052; p < 0.001]; PM10, 1.433 [1.066, 1.926; p = 0.017]; and SO2, 1.558 [1.147, 2.116; p = 0.005]), they were differentially associated with other specific causes: NO2 and PM10 were associated with an increase in infant deaths from congenital malformations of the nervous (NO2, 1.525 [1.179, 1.974; p = 0.001]; PM10, 1.457 [1.150, 1.846; p = 0.002]) and gastrointestinal systems (NO2, 1.214 [1.006, 1.466; p = 0.043]; PM10, 1.312 [1.096, 1.571; p = 0.003]), and NO2 was also associated with deaths from malformations of the respiratory system (1.306 [1.019, 1.675; p = 0.035]). In contrast, SO2 was associated with an increase in infant deaths from perinatal causes (1.214 [1.156, 1.275; p < 0.001]) and from malformations of the circulatory system (1.172 [1.011, 1.358; p = 0.035]). A limitation of this study was that we were not able to study associations of air pollution exposure and infant mortality during the different trimesters of pregnancy. In addition, we were not able to control for all confounding factors such as maternal smoking.

Conclusions

In this study, we found that NO2, PM10, and SO2 were differentially associated with all-cause mortality and with specific causes of infant, neonatal, and postneonatal mortality.

Rapid Epidemiological Analysis of Comorbidities and Treatments as risk factors for COVID-19 in Scotland (REACT-SCOT): A population-based case-control study

Ma, 20/10/2020 - 22:00

by Paul M. McKeigue, Amanda Weir, Jen Bishop, Stuart J. McGurnaghan, Sharon Kennedy, David McAllister, Chris Robertson, Rachael Wood, Nazir Lone, Janet Murray, Thomas M. Caparrotta, Alison Smith-Palmer, David Goldberg, Jim McMenamin, Colin Ramsay, Sharon Hutchinson, Helen M. Colhoun, on behalf of Public Health Scotland COVID-19 Health Protection Study Group

Background

The objectives of this study were to identify risk factors for severe coronavirus disease 2019 (COVID-19) and to lay the basis for risk stratification based on demographic data and health records.

Methods and findings

The design was a matched case-control study. Severe COVID-19 was defined as either a positive nucleic acid test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the national database followed by entry to a critical care unit or death within 28 days or a death certificate with COVID-19 as underlying cause. Up to 10 controls per case matched for sex, age, and primary care practice were selected from the national population register. For this analysis—based on ascertainment of positive test results up to 6 June 2020, entry to critical care up to 14 June 2020, and deaths registered up to 14 June 2020—there were 36,948 controls and 4,272 cases, of which 1,894 (44%) were care home residents. All diagnostic codes from the past 5 years of hospitalisation records and all drug codes from prescriptions dispensed during the past 240 days were extracted. Rate ratios for severe COVID-19 were estimated by conditional logistic regression. In a logistic regression using the age-sex distribution of the national population, the odds ratios for severe disease were 2.87 for a 10-year increase in age and 1.63 for male sex. In the case-control analysis, the strongest risk factor was residence in a care home, with rate ratio 21.4 (95% CI 19.1–23.9, p = 8 × 10−644). Univariate rate ratios for conditions listed by public health agencies as conferring high risk were 2.75 (95% CI 1.96–3.88, p = 6 × 10−9) for type 1 diabetes, 1.60 (95% CI 1.48–1.74, p = 8 × 10−30) for type 2 diabetes, 1.49 (95% CI 1.37–1.61, p = 3 × 10−21) for ischemic heart disease, 2.23 (95% CI 2.08–2.39, p = 4 × 10−109) for other heart disease, 1.96 (95% CI 1.83–2.10, p = 2 × 10−78) for chronic lower respiratory tract disease, 4.06 (95% CI 3.15–5.23, p = 3 × 10−27) for chronic kidney disease, 5.4 (95% CI 4.9–5.8, p = 1 × 10−354) for neurological disease, 3.61 (95% CI 2.60–5.00, p = 2 × 10−14) for chronic liver disease, and 2.66 (95% CI 1.86–3.79, p = 7 × 10−8) for immune deficiency or suppression. Seventy-eight percent of cases and 52% of controls had at least one listed condition (51% of cases and 11% of controls under age 40). Severe disease was associated with encashment of at least one prescription in the past 9 months and with at least one hospital admission in the past 5 years (rate ratios 3.10 [95% CI 2.59–3.71] and 2.75 [95% CI 2.53–2.99], respectively) even after adjusting for the listed conditions. In those without listed conditions, significant associations with severe disease were seen across many hospital diagnoses and drug categories. Age and sex provided 2.58 bits of information for discrimination. A model based on demographic variables, listed conditions, hospital diagnoses, and prescriptions provided an additional 1.07 bits (C-statistic 0.804). A limitation of this study is that records from primary care were not available.

Conclusions

We have shown that, along with older age and male sex, severe COVID-19 is strongly associated with past medical history across all age groups. Many comorbidities beyond the risk conditions designated by public health agencies contribute to this. A risk classifier that uses all the information available in health records, rather than only a limited set of conditions, will more accurately discriminate between low-risk and high-risk individuals who may require shielding until the epidemic is over.

The impact of delayed treatment of uncomplicated <i>P</i>. <i>falciparum</i> malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis

Lu, 19/10/2020 - 22:00

by Andria Mousa, Abdullah Al-Taiar, Nicholas M. Anstey, Cyril Badaut, Bridget E. Barber, Quique Bassat, Joseph D. Challenger, Aubrey J. Cunnington, Dibyadyuti Datta, Chris Drakeley, Azra C. Ghani, Victor R. Gordeuk, Matthew J. Grigg, Pierre Hugo, Chandy C. John, Alfredo Mayor, Florence Migot-Nabias, Robert O. Opoka, Geoffrey Pasvol, Claire Rees, Hugh Reyburn, Eleanor M. Riley, Binal N. Shah, Antonio Sitoe, Colin J. Sutherland, Philip E. Thuma, Stefan A. Unger, Firmine Viwami, Michael Walther, Christopher J. M. Whitty, Timothy William, Lucy C. Okell

Background

Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as ‘test-and-treat’ policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM.

Methods and findings

A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case–control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle–Ottawa scale, and all studies were ranked as ‘Good’, scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07–1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92–4.06; p < 0.001) for a delay of 2–3 days and 5.46 (95% CI: 3.49–8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24–4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70–9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify.

Conclusions

Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment.

The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis

Ve, 16/10/2020 - 22:00

by Ju-Sheng Zheng, Jian’an Luan, Eleni Sofianopoulou, Stephen J. Sharp, Felix R. Day, Fumiaki Imamura, Thomas E. Gundersen, Luca A. Lotta, Ivonne Sluijs, Isobel D. Stewart, Rupal L. Shah, Yvonne T. van der Schouw, Eleanor Wheeler, Eva Ardanaz, Heiner Boeing, Miren Dorronsoro, Christina C. Dahm, Niki Dimou, Douae El-Fatouhi, Paul W. Franks, Guy Fagherazzi, Sara Grioni, José María Huerta, Alicia K. Heath, Louise Hansen, Mazda Jenab, Paula Jakszyn, Rudolf Kaaks, Tilman Kühn, Kay-Tee Khaw, Nasser Laouali, Giovanna Masala, Peter M. Nilsson, Kim Overvad, Anja Olsen, Salvatore Panico, J. Ramón Quirós, Olov Rolandsson, Miguel Rodríguez-Barranco, Carlotta Sacerdote, Annemieke M. W. Spijkerman, Tammy Y. N. Tong, Rosario Tumino, Konstantinos K. Tsilidis, John Danesh, Elio Riboli, Adam S. Butterworth, Claudia Langenberg, Nita G. Forouhi, Nicholas J. Wareham

Background

Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis.

Methods and findings

We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]–InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1–standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities.

Conclusions

Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D.