Gastroschisis prevalence patterns in 27 surveillance programs from 24 countries, International Clearinghouse for Birth Defects Surveillance and Research, 1980-2017.

BACKGROUND: Gastroschisis is a serious birth defect with midgut prolapse into the amniotic cavity. The objectives of this study were to evaluate the prevalence and time trends of gastroschisis among programs in the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), focusing on regional variations and maternal age changes in the population. METHODS: We analyzed data on births from 1980 to 2017 from 27 ICBDSR member programs, representing 24 countries and three regions (Europe+ (includes Iran) , Latin America, North America). Cases were identified using diagnostic codes (i.e., 756.7, 756.71, or Q79.3). We excluded cases of amniotic band syndrome, limb-body wall defect, and ruptured omphalocele. Programs provided annual counts for gastroschisis cases (live births, stillbirths, and legally permitted pregnancy terminations for fetal anomalies) and source population (live births, stillbirths), by maternal age. RESULTS: Overall, gastroschisis occurred in 1 of every 3268 births (3.06 per 10,000 births; 95% confidence intervals [CI]: 3.01, 3.11), with marked regional variation. European+ prevalence was 1.49 (95%CI: 1.44, 1.55), Latin American 3.80 (95%CI: 3.69, 3.92) and North American 4.32 (95%CI: 4.22, 4.42). A statistically significant increasing time trend was observed among six European+ , four Latin American, and four North American programs. Women <20 years of age had the highest prevalence in all programs except the Slovak Republic. CONCLUSIONS: Gastroschisis prevalence increased over time in 61% of participating programs, and the highest increase in prevalence was observed among the youngest women. Additional inquiry will help to assess the impact of the changing maternal age proportions in the birth population on gastroschisis prevalence.

Comparing binary efficacy outcomes for systemic immunomodulatory treatments for atopic dermatitis in a living systematic review and network meta-analysis.

BACKGROUND: Systemic treatments for atopic dermatitis (AD) are evaluated primarily in placebo-controlled trials with binary efficacy outcomes. In a living systematic review and network meta-analysis (NMA), we previously analysed continuous efficacy measures. OBJECTIVES: To compare binary efficacy outcomes of systemic treatments for AD. METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Latin American and Caribbean Health Science Information (LILACS) database, Global Resource for Eczema Trials (GREAT) database and trial registries up to 1 March 2023. We included randomized trials examining ≥ 8 weeks of treatment with systemic immunomodulatory medications for moderate-to-severe AD. We screened titles, abstracts and full texts and abstracted data independently, in duplicate. Outcomes included the proportion of patients achieving at least 50%, 75% and 90% improvements in Eczema Area and Severity Index (EASI 50, EASI 75 and EASI 90, respectively) and Investigator Global Assessment (IGA) success. We performed random-effects Bayesian NMAs to calculate odds ratios (OR) and 95% credible intervals (CrIs) between each intervention for each outcome. RESULTS: Eighty-three trials with 22 122 participants were included in the systematic review. In analyses limited to trials of 8-16 weeks' duration with predominantly adult populations, abrocitinib 200 mg daily (OR 1.5, 95% CrI 1.1-2.2) and upadacitinib 15 mg daily (OR 1.7, 95% CrI 0.9-3.3) and 30 mg daily (OR 2.5, 95% CrI 1.3-5.0) were associated with higher odds of achieving EASI 50 vs. dupilumab. Abrocitinib 100 mg daily (OR 0.7, 95% CrI 0.5-1.0), baricitinib 2 mg daily (OR 0.4, 95% CrI 0.3-0.5) and 4 mg daily (OR 0.5, 95% CrI 0.3-0.7), and tralokinumab (OR 0.4, 95% CrI 0.3-0.6) were associated with lower odds of achieving EASI 50 vs. dupilumab. Results were similar for EASI 75, EASI 90 and IGA success. CONCLUSIONS: Supporting results for continuous outcome measures, upadacitinib 30 mg daily and abrocitinib 200 mg daily are the most efficacious with regard to binary efficacy endpoints up to 16 weeks in adults with moderate-to-severe AD, followed by upadacitinib 15 mg daily, dupilumab and abrocitinib 100 mg daily. Dupilumab and both doses of upadacitinib and abrocitinib are more efficacious than baricitinib 4 and 2 mg daily and tralokinumab.

Prevalence of chronic pain or analgesic use in children and young people and its long-term impact on substance misuse, mental illness, and prescription opioid use: a retrospective longitudinal cohort study.

Background: Epidemiological studies suggest chronic and recurrent pain affects around a quarter of children, while 8% report intense and frequent pain. The long-term implications of chronic pain in childhood are uncertain. Using electronic health records (EHRs) we used both disease codes and medicines prescription records to investigate the scale of chronic pain and long-term analgesic use in children and young people (CYP), and if chronic pain and/or use of analgesic medicines at an early age is associated with substance misuse, use of prescription opioids, and poor mental health in adulthood. Methods: We conducted a cohort study using data from IQVIA Medical Research Data UK. We identified individuals aged 2-24 with exposure to either a diagnostic code indicating chronic pain (diagnosis-exposed), repeat prescription for medicines commonly used to treat pain (prescription-exposed), or both. Follow-up began at 25, and the unexposed population acted as comparators. We calculated hazard ratios (HR) for mental health and substance misuse outcomes, and rate ratios (RR) for opioid prescriptions in adulthood. Additionally, we investigated which diagnoses, if any, were over-represented in the prescription-exposed subgroup. Findings: The cohort constituted 853,625 individuals; 146,431 had one or more of the exposures of interest (diagnosis-exposed = 115,101, prescription-exposed = 20,298, both-exposed = 11,032), leaving 707,194 as comparators. Median age at index exposure was 18.7 years (IQR 14.7-22.3). On average during follow-up, the pooled exposed group had, respectively, a 31% and 17% higher risk of adverse mental health and substance misuse outcomes (adjusted HR [95% CI] of 1.31 [1.29-1.32] and 1.17 [1.11-1.24]). Exposed individuals also received prescription opioids at double the rate of unexposed individuals on average during follow-up (adjusted RR 2.01 [95% CI 1.95-2.10]). Outcomes varied between exposure subgroups, with prescription- and both-exposure tending to have worse outcomes. Unlike these two subgroups, in the diagnosis-exposed subgroup we did not detect a greater risk of substance misuse. Interpretation: Chronic pain in CYP is associated with increased prescription opioid use and adverse mental health outcomes in adulthood, as is repeat prescription for analgesic medicines, but only the latter is also associated with substance misuse in adulthood. It is essential to avoid the harms of under-treating pain in CYP while giving due consideration to the risks posed by analgesic medicines. Early recognition of chronic pain in CYP and utilising non-pharmacological management options may help minimise overprescribing, and long-term reliance on dependence-forming-drugs. Funding: AL is an NIHR funded academic clinical fellow, and was supported by funding from UCLH Charities while carrying out this work. RS and DS are part of the Advanced Pain Discovery Platform and were supported by a UKRI and Versus Arthritis grant (MR/W002566/1) as part of the Consortium Against Pain Inequality. AW was supported by the Wellcome Trust (220558/Z/20/Z).

Optimising prediction of mortality, stroke, and major bleeding for patients with atrial fibrillation: validation of the GARFIELD-AF tool in UK primary care electronic records.

BACKGROUND: The GARFIELD-AF tool is a novel risk tool that simultaneously assesses the risk of all-cause mortality, stroke or systemic embolism, and major bleeding in patients with atrial fibrillation (AF). AIM: To validate the GARFIELD-AF tool using UK primary care electronic records. DESIGN AND SETTING: A retrospective cohort study using the Clinical Practice Research Datalink (CPRD) linked with Hospital Episode Statistics data and Office for National Statistics mortality data. METHOD: Discrimination was evaluated using the area under the curve (AUC) and calibration was evaluated using calibration-in-the-large regression and calibration plots. RESULTS: A total of 486 818 patients aged ≥18 years with incident diagnosis of non-valvular AF between 2 January 1998 and 31 July 2020 were included; 50.6% (n = 246 425/486 818) received anticoagulation at diagnosis The GARFIELD- AF models outperformed the CHA2DS2VASc and HAS-BLED scores in discrimination ability of death, stroke, and major bleeding at all the time points. The AUC for events at 1 year for the 2017 models were: death 0.747 (95% confidence interval [CI] = 0.744 to 0.751) versus 0.635 (95% CI = 0.631 to 0.639) for CHA2DS2VASc; stroke 0.666 (95% CI = 0.663 to 0.669) versus 0.625 (95% CI = 0.622 to 0.628) for CHA2DS2VASc; and major bleeding 0.602 (95% CI = 0.598 to 0.606) versus 0.558 (95% CI = 0.554 to 0.562) for HAS- BLED. Calibration between predicted and Kaplan- Meier observed events was inadequate with the GARFIELD-AF models. CONCLUSION: The GARFIELD-AF models were superior to the CHA2DS2VASc score for discriminating stroke and death and superior to the HAS-BLED score for discriminating major bleeding. The models consistently underpredicted the level of risk, suggesting that a recalibration is needed to optimise its use in the UK population.

Fixed dose combination drugs for cardiovascular disease in a prolonged humanitarian crisis in Lebanon: an implementation study.

OBJECTIVES: This pre-post implementation study evaluated the introduction of fixed dose combination (FDC) medications for atherosclerotic cardiovascular disease (ASCVD) secondary prevention into routine care in a humanitarian setting. SETTING: Two Médecins sans Frontières (MSF) primary care clinics serving Syrian refugee and host populations in north Lebanon. PARTICIPANTS: Consenting patients ≥18 years with existing ASCVD requiring secondary prevention medication were eligible for study enrolment. Those with FDC contraindication(s) or planning to move were excluded. Of 521 enrolled patients, 460 (88.3%) were retained at 6 months, and 418 (80.2%) switched to FDC. Of these, 84% remained on FDC (n=351), 8.1% (n=34) discontinued and 7.9% (n=33) were lost to follow-up by month 12. INTERVENTIONS: Eligible patients, enrolled February-May 2019, were switched to Trinomia FDC (atorvastatin 20 mg, aspirin 100 mg, ramipril 2.5/5/10 mg) after 6 months' usual care. During the study, the COVID-19 pandemic, an economic crisis and clinic closures occurred. OUTCOME MEASURES: Descriptive and regression analyses compared key outcomes at 6 and 12 months: medication adherence, non-high density lipoprotein cholesterol (non-HDL-C) and systolic blood pressure (SBP) control. We performed per-protocol, intention-to-treat and secondary analyses of non-switchers. RESULTS: Among 385 switchers remaining at 12 months, total adherence improved 23%, from 63% (95% CI 58 to 68) at month 6, to 86% (95% CI 82 to 90) at month 12; mean non-HDL-C levels dropped 0.28 mmol/L (95% CI -0.38 to -0.18; p<0.0001), from 2.39 (95% CI 2.26 to 2.51) to 2.11 mmol/L (95% CI 2.00 to 2.22); mean SBP dropped 2.89 mm Hg (95% CI -4.49 to -1.28; p=0.0005) from 132.7 (95% CI 130.8 to 134.6) to 129.7 mm Hg (95% CI 127.9 to 131.5). Non-switchers had smaller improvements in adherence and clinical outcomes. CONCLUSION: Implementing an ASCVD secondary prevention FDC improved adherence and CVD risk factors in MSF clinics in Lebanon, with potential for wider implementation by humanitarian actors and host health systems.

Randomized double-blind placebo-controlled clinical trial to evaluate the effect of a mixture of probiotic strains on symptom severity and use of corticosteroids in children and adolescents with atopic dermatitis.

BACKGROUND: The intestinal microbiota is altered in patients with atopic dermatitis (AD) when compared with those of the healthy population. Some interventions with specific probiotic preparations already demonstrate a change in composition of this microbiota accompanied by improvement in the disease. OBJECTIVES: This research work was designed to evaluate clinical efficacy of the probiotic preparation, and to measure the effect of the intervention on the total dose of corticosteroids administered to subjects. METHODS: This double-blind, randomized, placebo-controlled clinical trial including 70 participants with AD aged 4-17 years was designed to evaluate the clinical effect, compared with placebo, of a probiotic mixture of Bifidobacterium lactis, Bifidobacterium longum and Lactobacillus casei at a total daily consumption of 1 × 109 colony-forming units per capsule, over 12 weeks. After randomization and exclusion, 35 patients were allocated to probiotic and 35 to placebo. Clinical variables analysed were SCORAD (SCORing of Atopic Dermatitis) and Investigator Global Assessment (IGA) indices; effect on the amount of topical corticosteroids used; and assessment of safety. RESULTS: Mean SCORAD index at 12 weeks showed a statistically significant difference of -5.43 (95% confidence interval -10.65 to -0.21) between probiotic (SCORAD 13.52) and placebo groups (SCORAD 18.96); P = 0.04. Comparison between groups showed a statistically significant difference in the number of patients with IGA score improvement over the 12-week intervention: 29 of 32 (90.5%) in the probiotic group vs. 17 of 30 (56.7%) in the placebo group (P < 0.002). A comparison between groups of the proportions of days using corticosteroids and the total dose (g) of corticosteroids between baseline and end of study showed no significant difference, but between weeks 6 and 12 there was a statistically significant reduction in the probiotic group when compared with the placebo group in both variables. Numbers of adverse events were similar in both groups of treatment. CONCLUSIONS: The probiotic mix used in this clinical trial demonstrated efficacy on the change in activity index of AD compared with placebo. Furthermore, the total number of days and total amount of topical corticosteroids required by participants in the probiotic group showed a significant reduction compared with placebo between 6 and 12 weeks.

The effects of systemic immunomodulatory treatments on COVID-19 outcomes in patients with atopic dermatitis: Results from the global SECURE-AD registry.

BACKGROUND: Limited data are available on the effects of systemic immunomodulatory treatments on COVID-19 outcomes in patients with atopic dermatitis (AD). OBJECTIVE: To investigate COVID-19 outcomes in patients with AD treated with or without systemic immunomodulatory treatments, using a global registry platform. METHODS: Clinicians were encouraged to report cases of COVID-19 in their patients with AD in the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Atopic Dermatitis (SECURE-AD) registry. Data entered from 1 April 2020 to 31 October 2021 were analysed using multivariable logistic regression. The primary outcome was hospitalization from COVID-19, according to AD treatment groups. RESULTS: 442 AD patients (mean age 35.9 years, 51.8% male) from 27 countries with strongly suspected or confirmed COVID-19 were included in analyses. 428 (96.8%) patients were treated with a single systemic therapy (n = 297 [67.2%]) or topical therapy only (n = 131 [29.6%]). Most patients treated with systemic therapies received dupilumab (n = 216). Fourteen patients (3.2%) received a combination of systemic therapies. Twenty-six patients (5.9%) were hospitalized. No deaths were reported. Patients treated with topical treatments had significantly higher odds of hospitalization, compared with those treated with dupilumab monotherapy (odds ratio (OR) 4.65 [95%CI 1.71-14.78]), including after adjustment for confounding variables (adjusted OR (aOR) 4.99 [95%CI 1.4-20.84]). Combination systemic therapy which did not include systemic corticosteroids was associated with increased odds of hospitalization, compared with single agent non-steroidal immunosuppressive systemic treatment (OR 8.09 [95%CI 0.4-59.96], aOR 37.57 [95%CI 1.05-871.11]). Hospitalization was most likely in patients treated with combination systemic therapy which included systemic corticosteroids (OR 40.43 [95%CI 8.16-207.49], aOR 45.75 [95%CI 4.54-616.22]). CONCLUSIONS: Overall, the risk of COVID-19 complications appears low in patients with AD, even when treated with systemic immunomodulatory agents. Dupilumab monotherapy was associated with lower hospitalization than other therapies. Combination systemic treatment, particularly combinations including systemic corticosteroids, was associated with the highest risk of severe COVID-19.

Comparison of real-world treatment outcomes of systemic immunomodulating therapy in atopic dermatitis patients with dark and light skin types.

Background: Few data exist on differences in treatment effectiveness and safety in atopic dermatitis patients of different skin types. Objective: To investigate treatment outcomes of dupilumab, methotrexate, and ciclosporin, and morphological phenotypes in atopic dermatitis patients, stratified by Fitzpatrick skin type. Methods: In an observational prospective cohort study, pooling data from the Dutch TREAT (TREatment of ATopic eczema) NL (treatregister.nl) and UK-Irish A-STAR (Atopic eczema Systemic TherApy Register; astar-register.org) registries, data on morphological phenotypes and treatment outcomes were investigated. Results: A total of 235 patients were included (light skin types [LST]: Fitzpatrick skin type 1-3, n = 156 [Ethnicity, White: 94.2%]; dark skin types [DST]: skin type 4-6, n = 68 [Black African/Afro-Caribbean: 25%, South-Asian: 26.5%, and Hispanics: 0%]). DST were younger (19.5 vs 29.0 years; P < .001), more often had follicular eczema (22.1% vs 2.6%; P < .001), higher baseline Eczema Area and Severity Index (EASI) scores (20.1 vs 14.9; P = .009), less allergic contact dermatitis (30.9% vs 47.4%; P = .03), and less previous phototherapy use (39.7% vs 59.0%; P = .008). When comparing DST and LST corrected for covariates including baseline EASI, DST showed greater mean EASI reduction between baseline and 6 months with only dupilumab (16.7 vs 9.7; adjusted P = .032). No differences were found for adverse events for any treatments (P > .05). Limitations: Unblinded, non-randomized. Conclusion: Atopic dermatitis differs in several characteristics between LST and DST. Skin type may influence treatment effectiveness of dupilumab.

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 practice coding of chronic kidney disease (CKD) in primary care and subsequent hospitalisations and death: a cohort analysis using national audit data.

OBJECTIVE: To examine the association between practice percentage coding of chronic kidney disease (CKD) in primary care with risk of subsequent hospitalisations and death. DESIGN: Retrospective cohort study using linked electronic healthcare records. SETTING: 637 general practitioner (GP) practices in England. PARTICIPANTS: 167 208 patients with CKD stages 3-5 identified by 2 measures of estimated glomerular filtration rate <60 mL/min/1.73 m2, separated by at least 90 days, excluding those with coded initiation of renal replacement therapy. MAIN OUTCOME MEASURES: Hospitalisations with cardiovascular (CV) events, heart failure (HF), acute kidney injury (AKI) and all-cause mortality RESULTS: Participants were followed for (median) 3.8 years for hospital outcomes and 4.3 years for deaths. Rates of hospitalisations with CV events and HF were lower in practices with higher percentage CKD coding. Trends of a small reduction in AKI but no substantial change in rate of deaths were also observed as CKD coding increased. Compared with patients in the median performing practice (74% coded), patients in practices coding 55% of CKD cases had a higher rate of CV hospitalisations (HR 1.061 (95% CI 1.015 to 1.109)) and HF hospitalisations (HR 1.097 (95% CI 1.013 to 1.187)) and patients in practices coding 88% of CKD cases had a reduced rate of CV hospitalisations (HR 0.957 (95% CI 0.920 to 0.996)) and HF hospitalisations (HR 0.918 (95% CI 0.855 to 0.985)). We estimate that 9.0% of CV hospitalisations and 16.0% of HF hospitalisations could be prevented by improving practice CKD coding from 55% to 88%. Prescription of antihypertensives was the most dominant predictor of a reduction in hospitalisation rates for patients with CKD, followed by albuminuria testing and use of statins. CONCLUSIONS: Higher levels of CKD coding by GP practices were associated with lower rates of CV and HF events, which may be driven by increased use of antihypertensives and regular albuminuria testing, although residual confounding cannot be ruled out.

Prevalencia y factores sociodemográficos asociados a la ambliopía en población preescolar / Prevalence and sociodemographic factors associated with amblyopia in preschool children

Objetivo: estimar la prevalencia de la ambliopía y su tratamiento en niños de preescolar de la provincia de Alicante (España) durante un periodo de larga duración, así como la influencia de diferentes factores sociodemográficos. Material y método: estudio observacional descriptivo transversal (2002-2015) mediante protocolo de detección de ambliopía validado (sensibilidad 89,3%; especificidad 93,1%) en niños escolarizados de 4 a 6 años. La variable principal fue la clasificación, de los 140 102 niños examinados, según el resultado de las pruebas (“normales”, “sospechosos de patología” o en “tratamiento previo”) y las variables explicativas: edad, sexo, curso escolar, tipo de gestión del colegio y su ubicación. Resultados: la prevalencia de niños con sospecha de ambliopía osciló significativamente, entre los cursos escolares, desde 8,54% hasta 23,9% (p = 0,00000). Los niños de 6 años presentaron valores de sospecha de ambliopía notablemente más altos (16,68%; p = 0,00000) y los niños matriculados en colegios privados, los más bajos (8,05%; p = 0,00000). La probabilidad de que un niño “no-normal” estuviera ya tratado aumentaba con la edad (OR 2,06; p <0,001) y con el hecho de asistir a un colegio privado (OR 1,56; p = 0,001). Conclusiones: la prevalencia de la sospecha de ambliopía fue alta en el área de estudio, siendo los niños de mayor edad y los niños pertenecientes al grupo de nivel socioeconómico más bajo los de mayor riesgo. Los programas de cribado escolar para la detección temprana de la ambliopía son recomendados para aumentar y equiparar la probabilidad de acceso al tratamiento, reduciendo así la prevalencia y la gravedad de la ambliopía en niños (AU)

Objective: to estimate the prevalence of amblyopia and its treatment in preschool children in the province of Alicante over a long time period, and assess the influence of different sociodemographic factors.Methods: cross-sectional descriptive observational study (2002-2015) using a validated amblyopia detection protocol (sensitivity, 89.3%; specificity, 93.1%) in preschool children aged 4 to 6 years. The primary outcome was the classification of the 140 102 examined children based on the test results ('normal', 'suspected amblyopia' or 'in treatment') and the explanatory variables: age, sex, school year, private/public ownership of school and school location.Results: the prevalence of children with suspected amblyopia varied significantly between school years, ranging from 8.54% to 23.9% (p=0.00000). The prevalence of suspected amblyopia was significantly higher in children aged 6 years (16.68%; p=0.00000) and lowest in those attending private schools (8.05%; p=0.00000). The probability that a child with abnormal results was already in treatment increased with age (OR 2.06; p<0.001) and with enrolment in a private school (OR 1.56; p=0.001).Conclusions: the prevalence of suspected amblyopia was high in the study area, with a higher risk in older children and children in to the lowest socioeconomic status group. School-based screening programs for early detection of amblyopia are recommended to increase and equalize access to treatment, thereby reducing the prevalence and severity of amblyopia in children. (AU)

A systematic review of statistical methodology used to evaluate progression of chronic kidney disease using electronic healthcare records.

BACKGROUND: Electronic healthcare records (EHRs) are a useful resource to study chronic kidney disease (CKD) progression prior to starting dialysis, but pose methodological challenges as kidney function tests are not done on everybody, nor are tests evenly spaced. We sought to review previous research of CKD progression using renal function tests in EHRs, investigating methodology used and investigators' recognition of data quality issues. METHODS AND FINDINGS: We searched for studies investigating CKD progression using EHRs in 4 databases (Medline, Embase, Global Health and Web of Science) available as of August 2021. Of 80 articles eligible for review, 59 (74%) were published in the last 5.5 years, mostly using EHRs from the UK, USA and East Asian countries. 33 articles (41%) studied rates of change in eGFR, 23 (29%) studied changes in eGFR from baseline and 15 (19%) studied progression to binary eGFR thresholds. Sample completeness data was available in 44 studies (55%) with analysis populations including less than 75% of the target population in 26 studies (33%). Losses to follow-up went unreported in 62 studies (78%) and 11 studies (14%) defined their cohort based on complete data during follow up. Methods capable of handling data quality issues and other methodological challenges were used in a minority of studies. CONCLUSIONS: Studies based on renal function tests in EHRs may have overstated reliability of findings in the presence of informative missingness. Future renal research requires more explicit statements of data completeness and consideration of i) selection bias and representativeness of sample to the intended target population, ii) ascertainment bias where follow-up depends on risk, and iii) the impact of competing mortality. We recommend that renal progression studies should use statistical methods that take into account variability in renal function, informative censoring and population heterogeneity as appropriate to the study question.

Hidden heterogeneity: Uncovering patterns of adherence in microbicide trials for HIV prevention.

BACKGROUND: Interpretation of clinical trial results testing vaginal microbicide gels for HIV prevention depends on participant adherence. Prior to the era of antiretrovirals, microbicide trials collected adherence data via self-report, and trials typically reported trial population adherence as overall averages in primary results manuscripts. This study first sought to determine if different patterns of adherence from three trials of vaginal microbicide gels could be identified, using self-reported data and if so, how those patterns compare across trials. The second objective was to explore which individual-level factors were associated with different adherence patterns. METHODS: Data from the following three clinical trials of vaginal microbicides were used for this study: HIV Prevention Trials Network (HPTN) 035 testing PRO 2000 and Buffergel, the Microbicides Development Programme (MDP) 301 testing PRO 2000, and the Population Council's Carraguard study, testing Carraguard gel. Latent Class Analysis (LCA) was used to identify longitudinal patterns of adherence using self-reported data about gel use. Multinomial multivariable logistic regression was used to estimate relative risk-ratios for factors which were independently associated with different latent adherence trajectories within each trial, and compared across trials. RESULTS: Included in this analysis are 2,282 women from HPTN 035 (age 17-56 years), 6238 women from MDP 301 (age 16-75 years), and 6039 women from Carraguard (age 16-73 years). Using LCA, 3-4 different patterns of gel adherence were identified in each trial; these patterns were similar across the trials. Factors associated with adherence patterns were identified in all trials. Older age was associated with the adherence trajectory that consistently reported gel use in three trials. Participant-reported negative reaction of partners to the gel was associated with trajectories that reported less consistent adherence in two trials. A greater number of baseline-reported sex partners or sex acts was associated with trajectories which reported less consistent adherence in some trials. Trial site location was associated with membership of trajectories in all trials. CONCLUSION: LCA was able to identify patterns of microbicide gel adherence in clinical trials that used self-reported data. Key factors associated with patterns of adherence in this study were participant age, clinical trial site location, and partner reaction to the study gel. These findings, in particular, age and perceived partner reaction to the method, are consistent with results from other clinical trials and programmatic rollout of biomedical HIV prevention methods for women in Africa. This study contributes to the body of evidence that women need more support to navigate power dynamics within their relationships with men so that they can successfully use HIV prevention methods.

Manual Therapy Intervention in Men With Chronic Pelvic Pain Syndrome or Chronic Prostatitis: An Exploratory Prospective Case-Series.

Purpose Chronic pelvic pain syndrome (CPPS) is permanent pelvic pain of unknown etiology. Current theories suggest a multifactorial origin for CPPS, including urinary pathologies, psychosocial factors, prostate inflammation, infection, central sensitization of the nervous system, and muscular contractures or fibrosis. As there are no defined treatment protocols for CPPS, a multimodal approach is recommended. The objective of this study was to evaluate the impact of a manual therapy treatment protocol on pain, urinary symptoms, and overall quality of life. Materials and Methods Twenty-three men aged 47.36 ± 10.11 years were recruited consecutively by urologists practicing at two hospitals. All men presented prostatic tenderness with no other positive clinical history, urine cultures, or echography studies. Patients underwent six manual therapy sessions (three during the first week and three every two weeks after that) performed by a single osteopath or physiotherapist. The intervention protocol addressed the treatment of muscle structures, fascial mechanics, vascularization, innervation, emotional factors, and the need for information. The questionnaires used to evaluate outcomes included the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), the International Prostate Symptoms Score (IPSS), and a Visual Analog Scale (VAS) for pain, and the Hospital Anxiety and Depression Scale (HADS). Data were evaluated using Chi-squared or paired difference tests by an external researcher. Results The mean NIH-CPSI scores recorded for our study cohort decreased by 7.69 points (30.92%; p<0.0005; 95% CI 4.02-10.52). IPSS measurements decreased by 3.20 points (22.18%; p=0.009; 95% CI 1.00-6.09), although the item addressing quality of life decreased by 1.67 points only (31.99%; p<0.0005; 95% CI 0.94-2.33). The VAS score also decreased by 2.20 points (38.6%; p<0.0005; 95% CI 1.45-2.73). Changes in HADS scores were not statistically significant. Conclusions Based on patient responses, this case series revealed that manual therapy improved urinary symptoms, pain, and quality of life.

Systemic Immunomodulatory Treatments for Atopic Dermatitis: Update of a Living Systematic Review and Network Meta-analysis.

Importance: Systemic treatments for atopic dermatitis are being evaluated primarily in placebo-controlled trials; network meta-analysis can provide relative efficacy and safety estimates for treatments that have not been compared head to head. Objective: To compare reported measures of efficacy and assessments of safety in clinical trials of systemic treatments for atopic dermatitis in a living systematic review and network meta-analysis. Data Sources: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of EczemA Trials database, and trial registries were searched through June 15, 2021. Study Selection: Randomized clinical trials examining 8 or more weeks of treatment with systemic immunomodulatory medications for moderate-to-severe atopic dermatitis were included after screening titles, abstracts, and papers in duplicate. Data Extraction and Synthesis: Data were abstracted in duplicate. Bayesian network meta-analyses and assessed Grading of Recommendations Assessment, Development and Evaluation certainty of evidence were performed. The updated analysis was completed from June to December 2021. Main Outcomes and Measures: Outcomes include change in Eczema Area and Severity Index (EASI), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), and Peak Pruritus Numeric Rating Scales (PP-NRS). Results: Since October 2019, 21 new studies were added, for a total of 60 trials with 16 579 patients. Up to 16 weeks of treatment in adults, abrocitinib, 200 mg daily (mean difference [MD], 2.2; 95% credible interval [CrI], 0.2-4.0; high certainty) and upadacitinib, 30 mg daily (MD, 2.7; 95% CrI, 0.6-4.7; high certainty) were associated with reduced EASI slightly more than dupilumab, 600 mg then 300 mg every 2 weeks. Abrocitinib, 100 mg daily (MD, -2.1; 95% CrI, -4.1 to -0.3; high certainty), baricitinib, 4 mg daily (MD, -3.2; 95% CrI, -5.7 to -0.8; high certainty), baricitinib, 2 mg daily (MD, -5.2; 95% CrI, -7.5 to -2.9; high certainty) and tralokinumab, 600 mg then 300 mg every 2 weeks (MD, -3.5; 95% CrI, -5.8 to -1.3; high certainty) were associated with reduced EASI slightly less than dupilumab. There was little or no difference between upadacitinib, 15 mg daily, and dupilumab (MD, 0.2; 95% CrI, -1.9 to 2.2; high certainty). The pattern of results was similar for POEM, DLQI, and PP-NRS. Conclusions and Relevance: In this systematic review and meta-analysis, abrocitinib, 200 mg; and upadacitinib, 30 mg daily, were associated with slightly better scores than dupilumab, and upadacitinib, 15 mg daily, was associated with similar scores to dupilumab. Abrocitinib, 100 mg daily, baricitinib, 4 mg and 2 mg daily, and tralokinumab, 300 mg, every 2 weeks were associated with slightly worse scores.

Beneficial Impact of Pork Dry-Cured Ham Consumption on Blood Pressure and Cardiometabolic Markers in Individuals with Cardiovascular Risk.

BACKGROUND: Evidence suggests that bioactive peptides reduce hypertension and affect certain metabolic pathways. METHODS: Fifty-four volunteers with stage 1 prehypertension and/or hypercholesterolemia and/or basal glucose >100 mg/dL were recruited and randomized to pork dry-cured ham (n = 35) or cooked ham (placebo group; n = 19) for 28 days. After a wash-out period, meat products were changed for 28 additional days. Bioactive peptides composition and enzyme inhibitory activities of both products were characterized. Treatment comparisons for the main effects were made using a two (treatment) × two (times) repeated measures minus the effect of cooked ham (placebo). RESULTS: 24 h mean systolic and diastolic pressures decreased up to 2.4 mmHg in the dry-cured ham period (treatment effect, p = 0.0382 y p = 0.0233, respectively) as well as the number of systolic pressure measures > 135 mmHg (treatment effect, p = 0.0070). Total cholesterol levels also decreased significantly after dry-cured ham intake (p = 0.049). No significant differences were observed between the two treatments for basal glucose, HOMA-IR index and insulin levels (p > 0.05). However, a significant rise of ghrelin levels was observed (treatment effect, p = 0.0350), while leptin plasma values slightly decreased (treatment effect, p = 0.0628). CONCLUSIONS: This study suggested the beneficial effects of regular dry-cured ham consumption on the improvement of systolic/diastolic blood pressures and facilitated the maintenance of metabolic pathways, which may be beneficial in the primary prevention of cardiovascular disease.

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.

High sensitivity troponin and COVID-19 outcomes.

BACKGROUND: Recent reports have demonstrated high troponin levels in patients affected with COVID-19. In the present study, we aimed to determine the association between admission and peak troponin levels and COVID-19 outcomes. METHODS: This was an observational multi-ethnic multi-centre study in a UK cohort of 434 patients admitted and diagnosed COVID-19 positive, across six hospitals in London, UK during the second half of March 2020. RESULTS: Myocardial injury, defined as positive troponin during admission was observed in 288 (66.4%) patients. Age (OR: 1.68 [1.49-1.88], p < .001), hypertension (OR: 1.81 [1.10-2.99], p = .020) and moderate chronic kidney disease (OR: 9.12 [95% CI: 4.24-19.64], p < .001) independently predicted myocardial injury. After adjustment, patients with positive peak troponin were more likely to need non-invasive and mechanical ventilation (OR: 2.40 [95% CI: 1.27-4.56], p = .007, and OR: 6.81 [95% CI: 3.40-13.62], p < .001, respectively) and urgent renal replacement therapy (OR: 4.14 [95% CI: 1.34-12.78], p = .013). With regards to events, and after adjustment, positive peak troponin levels were independently associated with acute kidney injury (OR: 6.76 [95% CI: 3.40-13.47], p < .001), venous thromboembolism (OR: 11.99 [95% CI: 3.20-44.88], p < .001), development of atrial fibrillation (OR: 10.66 [95% CI: 1.33-85.32], p = .026) and death during admission (OR: 2.40 [95% CI: 1.34-4.29], p = .003). Similar associations were observed for admission troponin. In addition, median length of stay in days was shorter for patients with negative troponin levels: 8 (5-13) negative, 14 (7-23) low-positive levels and 16 (10-23) high-positive (p < .001). CONCLUSIONS: Admission and peak troponin appear to be predictors for cardiovascular and non-cardiovascular events and outcomes in COVID-19 patients, and their utilisation may have an impact on patient management.

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.