Disagreement concerning atopic dermatitis subtypes between an English prospective cohort (ALSPAC) and linked electronic health records.

BACKGROUND: Subtypes of atopic dermatitis (AD) have been derived from the Avon Longitudinal Study of Parents and Children (ALSPAC) based on presence and severity of symptoms reported in questionnaires (Severe-Frequent, Moderate-Frequent, Moderate-Declining, Mild-Intermittent, Unaffected/Rare). Good agreement between ALSPAC and linked electronic health records (EHRs) would increase trust in the clinical validity of these subtypes and allow inferring subtypes from EHRs alone, which would enable their study in large primary care databases. OBJECTIVES: 1. Explore if presence and number of AD records in EHRs agrees with AD symptom and severity reports from ALSPAC; 2. Explore if EHRs agree with ALSPAC-derived AD subtypes; 3. Construct models to classify ALSPAC-derived AD subtype using EHRs. METHODS: We used data from the ALSPAC prospective cohort study from 11 timepoints until age 14 years (1991-2008), linked to local general practice EHRs. We assessed how far ALSPAC questionnaire responses and derived subtypes agreed with AD as established in EHRs using different AD definitions (e.g., diagnosis and/or prescription) and other AD-related records. We classified AD subtypes using EHRs, fitting multinomial logistic regression models tuning hyperparameters and evaluating performance in the testing set (ROC AUC, accuracy, sensitivity, and specificity). RESULTS: 8,828 individuals out of a total 13,898 had both been assigned an AD subtype and had linked EHRs. The number of AD-related codes in EHRs generally increased with severity of AD subtype, however not all with the Severe-Frequent subtypes had AD in EHRs, and many with the Unaffected/Rare subtype did have AD in EHRs. When predicting ALSPAC AD subtype using EHRs, the best tuned model had ROC AUC of 0.65, sensitivity of 0.29 and specificity of 0.83 (both macro averaged); when different sets of predictors were used, individuals with missing EHR coverage excluded, and subtypes combined, sensitivity was not considerably improved. CONCLUSIONS: ALSPAC and EHRs disagreed not just on AD subtypes, but also on whether children had AD or not. Researchers should be aware that individuals considered as having AD in one source may not be considered as having AD in another.

Ethnic differences in depression and anxiety among adults with atopic eczema: Population-based matched cohort studies within UK primary care.

BACKGROUND: Evidence demonstrates that individuals with atopic eczema (eczema) have increased depression and anxiety; however, the role of ethnicity in these associations is poorly understood. We aimed to investigate whether associations between eczema and depression or anxiety differed between adults from white and minority ethnic groups in the UK. METHODS: We used UK Clinical Practice Research Datalink GOLD to conduct matched cohort studies of adults (≥18 years) with ethnicity recorded in primary care electronic health records (April 2006-January 2020). We matched (age, sex, practice) adults with eczema to up to five adults without. We used stratified Cox regression with an interaction between eczema and ethnicity, to estimate hazard ratios (HRs) for associations between eczema and incident depression and anxiety in individuals from white ethnic groups and a pooled minority ethnic group (adults from Black, South Asian, Mixed and Other groups). RESULTS: We identified separate cohorts for depression (215,073 with eczema matched to 646,539 without) and anxiety (242,598 with eczema matched to 774,113 without). After adjusting for matching variables and potential confounders (age, sex, practice, deprivation, calendar period), we found strong evidence (p < 0.01) of ethnic differences in associations between eczema and depression (minority ethnic groups: HR = 1.33, 95% CI = 1.22,1.45; white ethnic groups: HR = 1.15, 95% CI = 1.12,1.17) and anxiety (minority ethnic groups: HR = 1.41, 95% CI = 1.28,1.55; white ethnic groups: HR = 1.17, 95% CI = 1.14,1.19). CONCLUSIONS: Adults with eczema from minority ethnic groups appear to be at increased depression and anxiety risk compared with their white counterparts. Culturally adapted mental health promotion and prevention strategies should be considered in individuals with eczema from minority ethnic groups.

Atopic Dermatitis and Cardiovascular Risk in Pediatric Patients: A Systematic Review and Meta-Analysis.

Cardiovascular guidelines recommend early screening and preventative treatment for children with chronic inflammatory diseases. Atopic dermatitis (AD) is associated with cardiovascular risk in adults, but data in children are limited. We systematically searched for studies that examined the association between childhood AD and cardiovascular risk factors and outcomes. Data from 10 publications, including 577,148 individuals, revealed an association between AD and ischemic heart disease (n = 3, OR = 1.68, 95% confidence interval [CI] = 1.29-2.19) and diabetes (n = 4, OR = 1.31, 95% CI = 1.12-1.53), but this did not persist among studies that adjusted for potential confounders (n = 2, OR = 0.98, 95% CI = 0.35-2.75). Similarly, there was an association with lipid disorders but not across the entire population distribution (n = 7, OR = 1.24, 95% CI = 1.13-1.36, 95% prediction interval = 0.95-1.61). AD was not associated with hypertension (n = 5, OR = 1.15, 95% CI = 0.98-1.34, 95% prediction interval = 0.81-1.62) or stroke (n = 2, OR = 1.24, 95% CI = 0.94-1.62). Studies lacked detail on AD severity and important confounders such as body mass index, and the certainty of evidence was very low to low on the basis of GRADE (Grading of Recommendations, Assessment, Development and Evaluation) assessments. Currently, data do not support a clinically meaningful increase in cardiovascular risk for children with AD.

Association of Different Prescribing Patterns for Oral Corticosteroids With Fracture Preventive Care Among Older Adults in the UK and Ontario.

Importance: Identifying and mitigating modifiable gaps in fracture preventive care for people with relapsing-remitting conditions such as eczema, asthma, and chronic obstructive pulmonary disease who are prescribed high cumulative oral corticosteroid doses may decrease fracture-associated morbidity and mortality. Objective: To estimate the association between different oral corticosteroid prescribing patterns and appropriate fracture preventive care, including treatment with fracture preventive care medications, among older adults with high cumulative oral corticosteroid exposure. Design, Setting, and Participants: This cohort study included 65 195 participants with UK electronic medical record data from the Clinical Practice Research Datalink (January 2, 1998, to January 31, 2020) and 28 674 participants with Ontario, Canada, health administrative data from ICES (April 1, 2002, to September 30, 2020). Participants were adults 66 years or older with eczema, asthma, or chronic obstructive pulmonary disease receiving prescriptions for oral corticosteroids with cumulative prednisolone equivalent doses of 450 mg or higher within 6 months. Data were analyzed October 22, 2020, to September 6, 2022. Exposures: Participants with prescriptions crossing the 450-mg cumulative oral corticosteroid threshold in less than 90 days were classified as having high-intensity prescriptions, and participants crossing the threshold in 90 days or more as having low-intensity prescriptions. Multiple alternative exposure definitions were used in sensitivity analyses. Main Outcomes and Measures: The primary outcome was prescribed fracture preventive care. A secondary outcome was major osteoporotic fracture. Individuals were followed up from the date they crossed the cumulative oral corticosteroid threshold until their outcome or the end of follow-up (up to 1 year after index date). Rates were calculated for fracture preventive care and fractures, and hazard ratios (HRs) were estimated from Cox proportional hazards regression models comparing high- vs low-intensity oral corticosteroid prescriptions. Results: In both the UK cohort of 65 195 participants (mean [IQR] age, 75 [71-81] years; 32 981 [50.6%] male) and the Ontario cohort of 28 674 participants (mean [IQR] age, 73 [69-79] years; 17 071 [59.5%] male), individuals with high-intensity oral corticosteroid prescriptions had substantially higher rates of fracture preventive care than individuals with low-intensity prescriptions (UK: 134 vs 57 per 1000 person-years; crude HR, 2.34; 95% CI, 2.19-2.51, and Ontario: 73 vs 48 per 1000 person-years; crude HR, 1.49; 95% CI, 1.29-1.72). People with high- and low-intensity oral corticosteroid prescriptions had similar rates of major osteoporotic fractures (UK: crude rates, 14 vs 13 per 1000 person-years; crude HR, 1.07; 95% CI, 0.98-1.15 and Ontario: crude rates, 20 vs 23 per 1000 person-years; crude HR, 0.87; 95% CI, 0.79-0.96). Results from sensitivity analyses suggested that reaching a high cumulative oral corticosteroid dose within a shorter time, with fewer prescriptions, or with fewer or shorter gaps between prescriptions, increased fracture preventive care prescribing. Conclusions: The results of this cohort study suggest that older adults prescribed high cumulative oral corticosteroids across multiple prescriptions, or with many or long gaps between prescriptions, may be missing opportunities for fracture preventive care.

Common mental health disorders in adults with inflammatory skin conditions: nationwide population-based matched cohort studies in the UK.

BACKGROUND: Psoriasis and atopic eczema are common inflammatory skin diseases. Existing research has identified increased risks of common mental disorders (anxiety, depression) in people with eczema and psoriasis; however, explanations for the associations remain unclear. We aimed to establish the risk factors for mental illness in those with eczema or psoriasis and identify the population groups most at risk. METHODS: We used routinely collected data from the UK Clinical Practice Research Datalink (CPRD) GOLD. Adults registered with a general practice in CPRD (1997-2019) were eligible for inclusion. Individuals with eczema/psoriasis were matched (age, sex, practice) to up to five adults without eczema/psoriasis. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for hazards of anxiety or depression in people with eczema/psoriasis compared to people without. We adjusted for known confounders (deprivation, asthma [eczema], psoriatic arthritis [psoriasis], Charlson comorbidity index, calendar period) and potential mediators (harmful alcohol use, body mass index [BMI], smoking status, and, in eczema only, sleep quality [insomnia diagnoses, specific sleep problem medications] and high-dose oral glucocorticoids). RESULTS: We identified two cohorts with and without eczema (1,032,782, matched to 4,990,125 without), and with and without psoriasis (366,884, matched to 1,834,330 without). Sleep quality was imbalanced in the eczema cohorts, twice as many people with eczema had evidence of poor sleep at baseline than those without eczema, including over 20% of those with severe eczema. After adjusting for potential confounders and mediators, eczema and psoriasis were associated with anxiety (adjusted HR [95% CI]: eczema 1.14 [1.13-1.16], psoriasis 1.17 [1.15-1.19]) and depression (adjusted HR [95% CI]: eczema 1.11 [1.1-1.12], psoriasis 1.21 [1.19-1.22]). However, we found evidence that these increased hazards are unlikely to be constant over time and were especially high 1-year after study entry. CONCLUSIONS: Atopic eczema and psoriasis are associated with increased incidence of anxiety and depression in adults. These associations may be mediated through known modifiable risk factors, especially sleep quality in people with eczema. Our findings highlight potential opportunities for the prevention of anxiety and depression in people with eczema/psoriasis through treatment of modifiable risk factors and enhanced eczema/psoriasis management.

Severe Mental Illness Among Adults with Atopic Eczema or Psoriasis: Population-Based Matched Cohort Studies within UK Primary Care.

Background: Existing research exploring associations between atopic eczema (AE) or psoriasis, and severe mental illness (SMI - ie, schizophrenia, bipolar disorder, other psychoses) is limited, with longitudinal evidence particularly scarce. Therefore, temporal directions of associations are unclear. We aimed to investigate associations between AE or psoriasis and incident SMI among adults. Methods: We conducted matched cohort studies using primary care electronic health records (January 1997 to January 2020) from the UK Clinical Practice Research Datalink GOLD. We identified two cohorts: 1) adults (≥18 years) with and without AE and 2) adults with and without psoriasis. We matched (on age, sex, general practice) adults with AE or psoriasis with up to five adults without. We used Cox regression, stratified by matched set, to estimate hazard ratios (HRs) comparing incident SMI among adults with and without AE or psoriasis. Results: We identified 1,023,232 adults with AE and 4,908,059 without, and 363,210 with psoriasis and 1,801,875 without. After adjusting for matching variables (age, sex, general practice) and potential confounders (deprivation, calendar period) both AE and psoriasis were associated with at least a 17% increased hazard of SMI (AE: HR=1.17,95% CI=1.12-1.22; psoriasis: HR=1.26,95% CI=1.18-1.35). After additionally adjusting for potential mediators (comorbidity burden, harmful alcohol use, smoking status, body mass index, and, in AE only, sleep problems and high-dose glucocorticoids), associations with SMI did not persist for AE (HR=0.98,95% CI=0.93-1.04), and were attenuated for psoriasis (HR=1.14,95% CI=1.05-1.23). Conclusion: Our findings suggest adults with AE or psoriasis are at increased risk of SMI compared to matched comparators. After adjusting for potential mediators, associations with SMI did not persist for AE, and were attenuated for psoriasis, suggesting that the increased risk may be explained by mediating factors (eg, sleep problems). Our research highlights the importance of monitoring mental health in adults with AE or psoriasis.

Factors associated with depression, anxiety and severe mental illness among adults with atopic eczema or psoriasis: a systematic review and meta-analysis.

BACKGROUND: Evidence suggests an association between atopic eczema (AE) or psoriasis and mental illness; however, the factors associated with mental illness are unclear. OBJECTIVES: To synthesize and evaluate all available evidence on factors associated with depression, anxiety and severe mental illness (SMI) among adults with AE or psoriasis. METHODS: We searched electronic databases, grey literature databases and clinical trial registries from inception to February 2022 for studies of adults with AE or psoriasis. Eligible studies included randomized controlled trials (RCTs), cohort, cross-sectional or case-control studies where effect estimates of factors associated with depression, anxiety or SMI were reported. We did not apply language or geographical restrictions. We assessed risk of bias using the Quality in Prognosis Studies tool. We synthesized results narratively, and if at least two studies were sufficiently homogeneous, we pooled effect estimates in a random effects meta-analysis. RESULTS: We included 21 studies (11 observational, 10 RCTs). No observational studies in AE fulfilled our eligibility criteria. Observational studies in people with psoriasis mostly investigated factors associated with depression or anxiety - one cross-sectional study investigated factors associated with schizophrenia. Pooled effect estimates suggest that female sex and psoriatic arthritis were associated with depression [female sex: odds ratio (OR) 1.62, 95% confidence interval (CI) 1.09-2.40, 95% prediction intervals (PIs) 0.62-4.23, I2 = 24.90%, τ2 = 0.05; psoriatic arthritis: OR 2.26, 95% CI 1.56-3.25, 95% PI 0.21-24.23, I2 = 0.00%, τ2 = 0.00] and anxiety (female sex: OR 2.59, 95% CI 1.32-5.07, 95% PI 0.00-3956.27, I2 = 61.90%, τ2 = 0.22; psoriatic arthritis: OR 1.98, 95% CI 1.33-2.94, I2 = 0.00%, τ2 = 0.00). Moderate/severe psoriasis was associated with anxiety (OR 1.14, 95% CI 1.05-1.25, I2 0.00%, τ2 = 0.00), but not depression. Evidence from RCTs suggested that adults with AE or psoriasis given placebo had higher depression and anxiety scores compared with comparators given targeted treatment (e.g. biologic agents). CONCLUSIONS: Our review highlights limited existing research on factors associated with depression, anxiety and SMI in adults with AE or psoriasis. Observational evidence on factors associated with depression or anxiety in people with psoriasis was conflicting or from single studies, but some identified factors were consistent with those in the general population. Evidence on factors associated with SMIs in people with AE or psoriasis was particularly limited. Evidence from RCTs suggested that AE and psoriasis treated with placebo was associated with higher depression and anxiety scores compared with skin disease treated with targeted therapy; however, follow-up was limited. Therefore, long-term effects on mental health are unclear.

Novel multimorbidity clusters in people with eczema and asthma: a population-based cluster analysis.

Eczema and asthma are allergic diseases and two of the commonest chronic conditions in high-income countries. Their co-existence with other allergic conditions is common, but little research exists on wider multimorbidity with these conditions. We set out to identify and compare clusters of multimorbidity in people with eczema or asthma and people without. Using routinely-collected primary care data from the U.K. Clinical Research Practice Datalink GOLD, we identified adults ever having eczema (or asthma), and comparison groups never having eczema (or asthma). We derived clusters of multimorbidity from hierarchical cluster analysis of Jaccard distances between pairs of diagnostic categories estimated from mixed-effects logistic regressions. We analysed 434,422 individuals with eczema (58% female, median age 47 years) and 1,333,281 individuals without (55% female, 47 years), and 517,712 individuals with asthma (53% female, 44 years) and 1,601,210 individuals without (53% female, 45 years). Age at first morbidity, sex and having eczema/asthma affected the scope of multimorbidity, with women, older age and eczema/asthma being associated with larger morbidity clusters. Injuries, digestive, nervous system and mental health disorders were more commonly seen in eczema and asthma than control clusters. People with eczema and asthma of all ages and both sexes may experience greater multimorbidity than people without eczema and asthma, including conditions not previously recognised as contributing to their disease burden. This work highlights areas where there is a critical need for research addressing the burden and drivers of multimorbidity in order to inform strategies to reduce poor health outcomes.

Association between vitamin D and incident herpes zoster: a UK Biobank study.

BACKGROUND: Vitamin D has immunomodulatory effects, but any association with herpes zoster (HZ) is unclear. AIM: To explore the association between vitamin D status and risk of incident HZ in adults in the UK. DESIGN AND SETTING: A cohort study involving participants of UK Biobank (a database containing the health information from half a million individuals) across England, Wales, and Scotland, who had at least one vitamin D testing result with linked primary care electronic health records. METHOD: The primary exposure was vitamin D status, categorised as deficient (<25 nmol/L), insufficient (25-49 nmol/L), or sufficient (≥50 nmol/L). The secondary exposures were self-reported vitamin D supplementation at baseline assessment and vitamin D prescription records. The outcome was diagnosed incident HZ, identified from linked primary care or hospital inpatient records. Weibull regression was used, adjusting for potential confounders, including demographic factors, comorbidities, and immunosuppression. RESULTS: In total, 177 572 eligible participants were included in the analysis, with a mean follow-up time of 10.1 years (standard deviation 1.9 years). No evidence showed that low vitamin D was associated with a higher incidence of HZ, compared with people with sufficient vitamin D (deficient: adjusted hazard ratio [HR] 0.99, 95% confidence interval [CI] = 0.90 to 1.10; insufficient: HR 1.03, 95% CI = 0.96 to 1.10). No evidence was found that supplementing vitamin D or receiving vitamin D prescription was associated with HZ incidence (supplementation: HR 0.88, 95% CI = 0.67 to 1.16; prescription: HR 1.11, 95% CI = 0.91 to 1.34). CONCLUSION: No association of vitamin D status, supplementation, or prescription with incident HZ was observed. No evidence supported vitamin D supplementation as a strategy to prevent HZ.

Migrants' primary care utilisation before and during the COVID-19 pandemic in England: An interrupted time series analysis.

Background: How international migrants access and use primary care in England is poorly understood. We aimed to compare primary care consultation rates between international migrants and non-migrants in England before and during the COVID-19 pandemic (2015-2020). Methods: Using data from the Clinical Practice Research Datalink (CPRD) GOLD, we identified migrants using country-of-birth, visa-status or other codes indicating international migration. We linked CPRD to Office for National Statistics deprivation data and ran a controlled interrupted time series (ITS) using negative binomial regression to compare rates before and during the pandemic. Findings: In 262,644 individuals, pre-pandemic consultation rates per person-year were 4.35 (4.34-4.36) for migrants and 4.60 (4.59-4.60) for non-migrants (RR:0.94 [0.92-0.96]). Between 29 March and 26 December 2020, rates reduced to 3.54 (3.52-3.57) for migrants and 4.2 (4.17-4.23) for non-migrants (RR:0.84 [0.8-0.88]). The first year of the pandemic was associated with a widening of the gap in consultation rates between migrants and non-migrants to 0.89 (95% CI 0.84-0.94) times the ratio before the pandemic. This widening in ratios was greater for children, individuals whose first language was not English, and individuals of White British, White non-British and Black/African/Caribbean/Black British ethnicities. It was also greater in the case of telephone consultations, particularly in London. Interpretation: Migrants were less likely to use primary care than non-migrants before the pandemic and the first year of the pandemic exacerbated this difference. As GP practices retain remote and hybrid models of service delivery, they must improve services and ensure primary care is accessible and responsive to migrants' healthcare needs. Funding: This study was funded by the Medical Research Council (MC_PC 19070 and MR/V028375/1) and a Wellcome Clinical Research Career Development Fellowship (206602).

The association between vitamin D status and COVID-19 in England: A cohort study using UK Biobank.

BACKGROUND: Recent studies indicate that vitamin D supplementation may decrease respiratory tract infections, but the association between vitamin D and COVID-19 is still unclear. OBJECTIVE: To explore the association between vitamin D status and infections, hospitalisation, and mortality due to COVID-19. METHODS: We used UK Biobank, a nationwide cohort of 500,000 individuals aged between 40 and 69 years at recruitment between 2006 and 2010. We included people with at least one serum vitamin D test, living in England with linked primary care and inpatient records. The primary exposure was serum vitamin D status measured at recruitment, defined as deficiency at <25 nmol/L, insufficiency at 25-49 nmol/L and sufficiency at ≥ 50 nmol/L. Secondary exposures were self-reported or prescribed vitamin D supplements. The primary outcome was laboratory-confirmed or clinically diagnosed SARS-CoV-2 infections. The secondary outcomes included hospitalisation and mortality due to COVID-19. We used multivariable Cox regression models stratified by summertime months and non-summertime months, adjusting for demographic factors and underlying comorbidities. RESULTS: We included 307,512 participants (54.9% female, 55.9% over 70 years old) in our analysis. During summertime months, weak evidence existed that the vitamin D deficiency group had a lower hazard of being diagnosed with COVID-19 (hazard ratio [HR] = 0.86, 95% confidence interval [CI] = 0.77-0.95). During non-summertime, the vitamin D deficiency group had a higher hazard of COVID-19 compared with the vitamin D sufficient group (HR = 1.14, 95% CI = 1.01-1.30). No evidence was found that vitamin D deficiency or insufficiency was associated with either hospitalisation or mortality due to COVID-19 in any time strata. CONCLUSION: We found no evidence of an association between historical vitamin D status and hospitalisation or mortality due to COVID-19, along with inconsistent results for any association between vitamin D and diagnosis of COVID-19. However, studies using more recent vitamin D measurements and systematic COVID-19 testing are needed.

Rates of serious clinical outcomes in survivors of hospitalisation with COVID-19 in England: a descriptive cohort study within the OpenSAFELY platform.

Background: Patients surviving hospitalisation for COVID-19 are thought to be at high risk of cardiometabolic and pulmonary complications, but quantification of that risk is limited. We aimed to describe the overall burden of these complications in people after discharge from hospital with COVID-19.   Methods: Working on behalf of NHS England, we used linked primary care records, death certificate and hospital data from the OpenSAFELY platform. We constructed three cohorts: patients discharged following hospitalisation with COVID-19, patients discharged following pre-pandemic hospitalisation with pneumonia, and a frequency-matched cohort from the general population in 2019. We studied seven outcomes: deep vein thrombosis (DVT), pulmonary embolism (PE), ischaemic stroke, myocardial infarction (MI), heart failure, AKI and new type 2 diabetes mellitus (T2DM) diagnosis. Absolute rates were measured in each cohort and Fine and Gray models were used to estimate age/sex adjusted subdistribution hazard ratios comparing outcome risk between discharged COVID-19 patients and the two comparator cohorts. Results: Amongst the population of 77,347 patients discharged following hospitalisation with COVID-19, rates for the majority of outcomes peaked in the first month post-discharge, then declined over the following four months. Patients in the COVID-19 population had markedly higher risk of all outcomes compared to matched controls from the 2019 general population. Across the whole study period, the risk of outcomes was more similar when comparing patients discharged with COVID-19 to those discharged with pneumonia in 2019, although COVID-19 patients had higher risk of T2DM (15.2 versus 37.2 [rate per 1,000-person-years for COVID-19 versus pneumonia, respectively]; SHR, 1.46 [95% CI: 1.31 - 1.63]).  Conclusions: Risk of cardiometabolic and pulmonary adverse outcomes is markedly raised following discharge from hospitalisation with COVID-19 compared to the general population. However, excess risks were similar to those seen following discharge post-pneumonia. Overall, this suggests a large additional burden on healthcare resources.

Atopic Eczema-Associated Fracture Risk and Oral Corticosteroids: A Population-Based Cohort Study.

BACKGROUND: Evidence suggests adults with atopic eczema have increased fracture risk. However, it is unclear whether oral corticosteroids explain the association. OBJECTIVE: To assess to what extent oral corticosteroids mediate the relationship between atopic eczema and fractures. METHODS: We conducted a cohort study using English primary care (Clinical Practice Research Datalink) and hospital admissions (Hospital Episode Statistics) records (1998-2016) including adults (18 years old and older) with atopic eczema matched (age, sex, and general practice) with up to 5 adults without atopic eczema. We used Cox regression to estimate hazard ratios (HRs) for specific major osteoporotic fractures (hip, spine, pelvis, or wrist) and for any-site fracture comparing individuals with atopic eczema with those without, adjusting for 6 different definitions of time-updated oral corticosteroid use (ever any prescription, ever high-dose, and recent, cumulative, current, or peak dose). RESULTS: We identified 526,808 individuals with atopic eczema and 2,569,030 without. We saw evidence of an association between atopic eczema and major osteoporotic fractures (eg, spine HR 1.15, 99% CI 1.08-1.22; hip HR 1.11, 99% CI 1.08-1.15) that remained after additionally adjusting for oral corticosteroids (eg, cumulative corticosteroid dose: spine HR 1.09, 99% CI 1.03-1.16; hip HR 1.09, 99% CI 1.06-1.12). Fracture rates were higher in people with severe atopic eczema than in people without even after adjusting for oral corticosteroids (eg, spine HR [99% CI]: confounder-adjusted 2.31 [1.91-2.81]; additionally adjusted for cumulative dose 1.71 [1.40-2.09]). CONCLUSIONS: Our findings suggest that little of the association between atopic eczema and major osteoporotic fractures is explained by oral corticosteroid use.

Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals.

BACKGROUND: Causes of mortality are a crucial input for health systems for identifying appropriate interventions for child survival. We present an updated series of cause-specific mortality for neonates and children younger than 5 years from 2000 to 2019. METHODS: We updated cause-specific mortality estimates for neonates and children aged 1-59 months, stratified by level (low, moderate, or high) of mortality. We made a substantial change in the statistical methods used for previous estimates, transitioning to a Bayesian framework that includes a structure to account for unreported causes in verbal autopsy studies. We also used systematic covariate selection in the multinomial framework, gave more weight to nationally representative verbal autopsy studies using a random effects model, and included mortality due to tuberculosis. FINDINGS: In 2019, there were 5·30 million deaths (95% uncertainty range 4·92-5·68) among children younger than 5 years, primarily due to preterm birth complications (17·7%, 16·1-19·5), lower respiratory infections (13·9%, 12·0-15·1), intrapartum-related events (11·6%, 10·6-12·5), and diarrhoea (9·1%, 7·9-9·9), with 49·2% (47·3-51·9) due to infectious causes. Vaccine-preventable deaths, such as for lower respiratory infections, meningitis, and measles, constituted 21·7% (20·4-25·6) of under-5 deaths, and many other causes, such as diarrhoea, were preventable with low-cost interventions. Under-5 mortality has declined substantially since 2000, primarily because of a decrease in mortality due to lower respiratory infections, diarrhoea, preterm birth complications, intrapartum-related events, malaria, and measles. There is considerable variation in the extent and trends in cause-specific mortality across regions and for different strata of all-cause under-5 mortality. INTERPRETATION: Progress is needed to improve child health and end preventable deaths among children younger than 5 years. Countries should strategize how to reduce mortality among this age group using interventions that are relevant to their specific causes of death. FUNDING: Bill & Melinda Gates Foundation; WHO.

Changes in Mental Health Needs during COVID-19 in the Republic of Georgia: A Longitudinal Follow-up Study.

Background: To examine changes in COVID-19 stressors and symptoms of mental disorders in the Republic of Georgia. Methods: A longitudinal design was used. Following on from our study of May-June 2020, this follow-up study in January-March 2021 was conducted at: (i)an individual level with the same respondents involved in the May-June 2020 study (repeat responders/cohort); and (ii) at a population-wide level, using non-probabilistic sampling. Questionnaire sections covered: (i)demographic, socio-economic characteristics; (ii)level of burden caused by COVID-19-related stressors/concern; and (iii)symptoms of anxiety(GAD-7), depression(PHQ-9), PTSD(ITQ), adjustment disorder(ADNM8). Descriptive and multivariable regression analyses were conducted. Results: Among population-level survey respondents(N=1195), the probability of reporting mental ill health symptoms increased in 2021 compared to 2020 for PTSD(OR1.82), depression(OR1.40), adjustment disorder(OR 1.80), and marginally for anxiety(OR1.17). For the individual repeat respondents(N=455), the probability increased for depression(OR1.88) and adjustment disorder(OR2.56). The perceived burden of pandemic concern worsened in 2021 compared to 2020 for almost all stressors, particularly around access to health care, infecting others, and conflict in the home. PTSD was associated with an increased concern score from 2020 to 2021. Conclusion: Our study highlights the need to strengthen response strategies to address the elevated mental health needs related to COVID-19 in Georgia. It recommends increasing accessibility of early interventions and the need to modernise mental health services to strengthen access to care. It also calls for monitoring patterns of mental health disorders for better understanding and responses to mental health needs in Georgia.

Estimating proportion of days covered (PDC) using real-world online medicine suppliers' datasets.

BACKGROUND: The proportion of days covered (PDC) is used to estimate medication adherence by looking at the proportion of days in which a person has access to the medication, over a given period of interest. This study aimed to adapt the PDC algorithm to allow for plausible assumptions about prescription refill behaviour when applied to data from online pharmacy suppliers. METHODS: Three PDC algorithms, the conventional approach (PDC1) and two alternative approaches (PDC2 and PDC3), were used to estimate adherence in a real-world dataset from an online pharmacy. Each algorithm has different denominators and increasing levels of complexity. PDC1, the conventional approach, is the total number of days between first dispensation and a defined end date. PDC2 counts the days until the end of supply date. PDC3 removes from the denominator specifically defined large gaps between refills, which could indicate legitimate reasons for treatment discontinuation. The distribution of the three PDCs across four different follow-up lengths was compared. RESULTS: The dataset included people taking ACE inhibitors (n = 65,905), statins (n = 100,362), and/or thyroid hormones (n = 30,637). The proportion of people taking ACE inhibitors with PDC ≥ 0.8 was 50-74% for PDC1, 81-91% for PDC2, and 86-100% for PDC3 with values depending on drug and length of follow-up. Similar ranges were identified in people taking statins and thyroid hormones. CONCLUSION: These algorithms enable researchers and healthcare providers to assess pharmacy services and individual levels of adherence in real-world databases, particularly in settings where people may switch between different suppliers of medicines, meaning an individual supplier's data may show temporary but legitimate gaps in access to medication. Accurately identifying problems with adherence provides the foundation for opportunities to improve experience, adherence and outcomes and to reduce medicines wastage. Research with people taking medications and prescribers is required to validate the algorithms' assumptions.

Patterns of Atopic Eczema Disease Activity From Birth Through Midlife in 2 British Birth Cohorts.

IMPORTANCE: Atopic eczema is characterized by a heterogenous waxing and waning course, with variable age of onset and persistence of symptoms. Distinct patterns of disease activity such as early-onset/resolving and persistent disease have been identified throughout childhood; little is known about patterns into adulthood. OBJECTIVE: This study aimed to identify subtypes of atopic eczema based on patterns of disease activity through mid-adulthood, to examine whether early life risk factors and participant characteristics are associated with these subtypes, and to determine whether subtypes are associated with other atopic diseases and general health in mid-adulthood. DESIGN, SETTING, AND PARTICIPANTS: This study evaluated members of 2 population-based birth cohorts, the 1958 National Childhood Development Study (NCDS) and the 1970 British Cohort Study (BCS70). Participant data were collected over the period between 1958 and 2016. Data were analyzed over the period between 2018 and 2020. MAIN OUTCOMES AND MEASURES: Subtypes of atopic eczema were identified based on self-reported atopic eczema period prevalence at multiple occasions. These subtypes were the outcome in models of early life characteristics and an exposure variable in models of midlife health. RESULTS: Latent class analysis identified 4 subtypes of atopic eczema with distinct patterns of disease activity among 15 939 individuals from the NCDS (51.4% male, 75.4% White) and 14 966 individuals from the BCS70 (51.6% male, 78.8% White): rare/no (88% to 91%), decreasing (4%), increasing (2% to 6%), and persistently high (2% to 3%) probability of reporting prevalent atopic eczema with age. Sex at birth and early life factors, including social class, region of residence, tobacco smoke exposure, and breastfeeding, predicted differences between the 3 atopic eczema subtypes and the infrequent/no atopic eczema group, but only female sex differentiated the high and decreasing probability subtypes (odds ratio [OR], 1.99; 95% CI, 1.66-2.38). Individuals in the high subtype were most likely to experience asthma and rhinitis, and those in the increasing subtype were at higher risk of poor self-reported general (OR, 1.29; 95% CI, 1.09-1.53) and mental (OR 1.45; 95% CI, 1.23-1.72) health in midlife. CONCLUSIONS AND RELEVANCE: The findings of this cohort study suggest that extending the window of observation beyond childhood may reveal clear subtypes of atopic eczema based on patterns of disease activity. A newly identified subtype with increasing probability of activity in adulthood warrants additional attention given observed associations with poor self-reported health in midlife.

Major Depression and Survival in People With Cancer.

OBJECTIVE: The question of whether depression is associated with worse survival in people with cancer remains unanswered because of methodological criticism of the published research on the topic. We aimed to study the association in a large methodologically robust study. METHODS: We analyzed data on 20,582 patients with breast, colorectal, gynecological, lung, and prostate cancers who had attended cancer outpatient clinics in Scotland, United Kingdom. Patients had completed two-stage screening for major depression as part of their cancer care. These data on depression status were linked to demographic, cancer, and subsequent mortality data from national databases. We estimated the association of major depression with survival for each cancer using Cox regression. We adjusted for potential confounders and interactions between potentially time-varying confounders and the interval between cancer diagnosis and depression screening, and used multiple imputation for missing depression and confounder data. We pooled the cancer-specific results using fixed-effects meta-analysis. RESULTS: Major depression was associated with worse survival for all cancers, with similar adjusted hazard ratios (HRs): breast cancer (HR = 1.42, 95% confidence interval [CI] = 1.15-1.75), colorectal cancer (HR = 1.47, 95% CI = 1.11-1.94), gynecological cancer (HR = 1.36, 95% CI = 1.08-1.71), lung cancer (HR = 1.39, 95% CI = 1.24-1.56), and prostate cancer (HR = 1.76, 95% CI = 1.08-2.85). The pooled HR was 1.41 (95% CI = 1.29-1.54, p < .001, I2 = 0%). These findings were not materially different when we only considered the deaths (90%) that were attributed to cancer. CONCLUSIONS: Major depression is associated with worse survival in patients with common cancers. The mechanisms of this association and the clinical implications require further study.

Association Between Atopic Dermatitis and Educational Attainment in Denmark.

IMPORTANCE: Atopic dermatitis (AD) may affect academic performance through multiple pathways, including poor concentration associated with itching, sleep deprivation, or adverse effects of medications. Because educational attainment is associated with health and well-being, any association with a prevalent condition such as AD is of major importance. OBJECTIVE: To examine whether a childhood diagnosis of AD is associated with lower educational attainment. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used linked routine health care data from January 1, 1977, to June 30, 2017 (end of registry follow-up), in Denmark. The study population included all children born in Denmark on June 30, 1987, or earlier with an inpatient or outpatient hospital clinic diagnosis of AD recorded before their 13th birthday (baseline) and a comparison cohort of children from the general population matched by birth year and sex. A secondary analysis included exposure-discordant full siblings as a comparison cohort to account for familial factors. Data were analyzed from September 11, 2019, to January 21, 2021. EXPOSURES: Hospital-diagnosed AD. MAIN OUTCOMES AND MEASURES: Estimated probability or risk of not attaining specific educational levels (lower secondary, upper secondary, and higher) by 30 years of age among children with AD compared with children in the matched general population cohort. Corresponding risk ratios (RRs) were computed using Poisson regression that was conditioned on matched sets and adjusted for age. The sibling analysis was conditioned on family and adjusted for sex and age. RESULTS: The study included a total of 61 153 children, 5927 in the AD cohort (3341 male [56.4%]) and 55 226 from the general population (31 182 male [56.5%]). Compared with matched children from the general population, children with AD were at increased risk of not attaining lower secondary education (150 of 5927 [2.5%] vs 924 of 55 226 [1.7%]; adjusted RR, 1.50; 95% CI, 1.26-1.78) and upper secondary education (1141 of 5777 [19.8%] vs 8690 of 52 899 [16.4%]; RR, 1.16; 95% CI, 1.09-1.24), but not higher education (2406 of 4636 [51.9%] vs 18 785 of 35 408 [53.1%]; RR, 0.95; 95% CI, 0.91-1.00). The absolute differences in probability were less than 3.5%. The comparison of 3259 children with AD and 4046 of their full siblings yielded estimates that were less pronounced than those in the main analysis (adjusted RR for lower secondary education, 1.29 [95% CI, 0.92-1.82]; adjusted RR for upper secondary education, 1.05 [95% CI, 0.93-1.18]; adjusted RR for higher education, 0.94 [95% CI, 0.87-1.02]). CONCLUSIONS AND RELEVANCE: This population-based cohort study found that hospital-diagnosed AD was associated with reduced educational attainment, but the clinical importance was uncertain owing to small absolute differences and possible confounding by familial factors in this study. Future studies should examine for replicability in other populations and variation by AD phenotype.