Miopatías RYR1 en la infancia: correlación fenotipo-genotipo e incidencia / RYR1 myopathies in childhood: phenotype-genotype correlation and incidence

Introducción: Las miopatías relacionadas con el receptor de rianodina de tipo 1 (RYR1-RM) constituyen la categoría más frecuente de miopatías congénitas. La introducción de técnicas genéticas ha cambiado el paradigma diagnóstico y sugiere la prioridad de estudios moleculares sobre biopsias. Este estudio busca explorar las características clinicoepidemiológicas de pacientes con variantes del gen RYR1 en un hospital pediátrico de tercer nivel con el objetivo de ampliar la comprensión de la correlación genotipo-fenotipo en las RYR1-RM. Pacientes y métodos: Estudio observacional, descriptivo y transversal, de pacientes menores de 14 años con síntomas miopáticos y variantes potencialmente patógenas del gen RYR1 entre enero de 2013 y diciembre de 2023, considerando variables como sexo, edad, desarrollo motor, variantes genéticas, patrón de herencia y otras manifestaciones. Todas las variables fueron tabuladas frente a la variante genética. Resultados: De los nueve pacientes incluidos, la incidencia estimada fue de aproximadamente 1/10.000 nacidos vivos. La mediana en el momento del diagnóstico fue de 6 años, con una variabilidad fenotípica significativa. Se observaron síntomas comunes, como debilidad y retraso del desarrollo motor. Las variantes genéticas afectaron al gen RYR1 de manera diversa, y hubo cinco variantes previamente no descritas. La biopsia muscular se realizó en cinco pacientes, en dos de ellos de tipo miopatía central core; en uno, multiminicore; en uno, desproporción congénita de fibras; y en otro, de patrón inespecífico. Conclusiones: Las RYR1-MR de nuestra serie ofrecieron variabilidad fenotípica y de afectación, con una incidencia en nuestra área de en torno a 1/10.000 recién nacidos. La mayoría de los casos fueron varones, de variantes missense dominantes. Aportamos cinco variantes genéticas no descritas con anterioridad.(AU)

Introduction: Ryanodine receptor type 1-related myopathies (RYR1-RM) represent the most prevalent category of congenital myopathies. The introduction of genetic techniques has shifted the diagnostic paradigm, suggesting the prioritization of molecular studies over biopsies. This study aims to explore the clinical and epidemiological characteristics of patients with RYR1 gene variants in a tertiary pediatric hospital, intending to enhance the understanding of the genotype-phenotype correlation in RYR1-RM. Patients and methods: An observational, descriptive, and cross-sectional study was conducted on patients under 14 years old with myopathic symptoms and potentially pathogenic RYR1 gene variants from January 2013 to December 2023. Variables such as gender, age, motor development, genetic variants, inheritance pattern, and other manifestations were considered. All variables were tabulated against the genetic variant. Results: Of the nine included patients, the estimated incidence was approximately 1 in 10,000 live births. The median age at diagnosis was six years, with significant phenotypic variability. Common symptoms such as weakness and delayed motor development were observed. Genetic variants affected the RYR1 gene diversely, including five previously undescribed variants. Muscle biopsy was performed in five patients, revealing central core myopathy in two, multiminicore in one, congenital fiber-type disproportion in one, and a nonspecific pattern in another.(AU)

A practical guide to estimating treatment effects in patients with rheumatic diseases using real-world data.

OBJECTIVE: Randomized controlled trials are considered the gold standard in study methodology. However, due to their study design and inclusion criteria, these studies may not capture the heterogeneity of real-world patient populations. In contrast, the lack of randomization and the presence of both measured and unmeasured confounding factors could bias the estimated treatment effect when using observational data. While causal inference methods allow for the estimation of treatment effects, their mathematical complexity may hinder their application in clinical research. METHODS: We present a practical, nontechnical guide using a common statistical package (Stata) and a motivational simulated dataset that mirrors real-world observational data from patients with rheumatic diseases. We demonstrate regression analysis, regression adjustment, inverse-probability weighting, propensity score (PS) matching and two robust estimation methods. RESULTS: Although the methods applied to control for confounding factors produced similar results, the commonly used one-to-one PS matching method could yield biased results if not thoroughly assessed. CONCLUSION: The guide we propose aims to facilitate the use of readily available methods in a common statistical package. It may contribute to robust and transparent epidemiological and statistical methods, thereby enhancing effectiveness research using observational data in rheumatology.

Changed sleep according to weighted blanket adherence in a 16-week sleep intervention among children with attention-deficit/hyperactivity disorder.

STUDY OBJECTIVES: To examine differences in sample characteristics and longitudinal sleep outcomes according to weighted blanket adherence. METHODS: Children with attention-deficit/hyperactivity disorder (ADHD) (n =94), mean age 9.0 (sd 2.2, range 6-14) participated in a 16-week sleep intervention with weighted blankets (WB). Children were classified as WB adherent (use of WB ≥ 4 nights/week) or non-adherent (use of WB ≤ 3 nights/week). Changes in objectively measured sleep by actigraphy, parent-reported sleep problems (Children's Sleep Habits Questionnaire (CSHQ)) and child-reported Insomnia Severity Index (ISI) were evaluated according to adherence with mixed effect models. Gender, age, and ADHD subtype were examined as potential moderators. RESULTS: Children adherent to WBs (48/94) showed an early response in sleep outcomes and an acceptance of the WB after four weeks of use as well as a decrease in parent- (CSHQ) (-5.73, P = .000) and child-reported sleep problems (ISI) (-4.29, P = .005) after 16 weeks. The improvement in sleep was larger among WB adherent vs. non-adherent (between-group difference: CSHQ: -2.09, P = .038; ISI: -2.58, P =.007). Total sleep time was stable for children adherent to WB but decreased for non-adherent (between-group difference: +16.90, P = .019). CONCLUSIONS: An early response in sleep and acceptance of the WB predicted later adherence to WBs. Improvements in sleep were more likely among WB adherents vs. non-adherents. Children with ADHD may thus benefit from using WBs to handle their sleep problems.

Nitrogen dioxide exposure, attentional function, and working memory in children from 4 to 8 years: Periods of susceptibility from pregnancy to childhood.

BACKGROUND: Air pollution exposure during pregnancy and childhood has been linked to executive function impairment in children, however, very few studies have assessed these two exposure periods jointly to identify susceptible periods of exposure. We sought to identify potential periods of susceptibility of nitrogen dioxide (NO2) exposure from conception to childhood on attentional function and working memory in school-aged children. METHODS: Within the Spanish INMA Project, we estimated residential daily NO2 exposures during pregnancy and up to 6 years of childhood using land use regression models (n = 1,703). We assessed attentional function at 4-6 years and 6-8 years, using the Conners Kiddie Continuous Performance Test and the Attention Network Test, respectively, and working memory at 6-8 years, using the N-back task. We used distributed lag non-linear models to assess the periods of susceptibility of each outcome, adjusting for potential confounders and correcting for multiple testing. We also stratified all models by sex. RESULTS: Higher exposure to NO2 between 1.3 and 1.6 years of age was associated with higher hit reaction time standard error (HRT-SE) (0.14 ms (95 % CI 0.05; 0.22) per 10 µg/m3 increase in NO2) and between 1.5 and 2.2 years of age with more omission errors (1.02 (95 % CI 1.01; 1.03) of the attentional function test at 4-6 years. Higher exposure to NO2 between 0.3 and 2.2 years was associated with higher HRT-SE (10.61 ms (95 % CI 3.46; 17.75) at 6-8 years only in boys. We found no associations between exposure to NO2 and working memory at 6-8 years. CONCLUSION: Our findings suggest that NO2 exposure during the first two years of life is associated with poorer attentional function in children from 4 to 8 years of age, especially in boys. These findings highlight the importance of exploring long-term effects of traffic-related air pollution exposure in older age groups.

Social Activities and Risk of Dementia in Community-Dwelling Older People: Gender-Specific Findings From a Prospective Cohort Study.

OBJECTIVES: This study examines the gender-specific associations between a wide range of social activities and dementia risk. METHODS: A prospective cohort study was conducted involving community-dwelling older Australians (≥70 years) without significant cognitive impairment at enrolment. During the first year of enrolment, we assessed 25 self-reported social activities covering various aspects, including support from relatives and friends, community participation, social interactions with surroundings, and loneliness. Dementia diagnosis followed DSM-IV criteria, adjudicated by an international expert panel. To estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between social activities and dementia, we performed Cox proportional hazards models, adjusting for age, educational attainment, baseline global cognition, and depressive symptoms. RESULTS: Among 9,936 participants who completed all social activity questionnaires (median [IQR] age: 73.4 [71.6-77.1] years; 47.4% men), dementia was diagnosed in 3.8% of men (n = 181/4,705) and 2.6% of women (n = 138/5,231) over a median 6.4 years (IQR: 5.3-7.6, range: 0.2-10.1) follow-up. Gender-specific relationships emerged: caregiving for a person with illness/disability in women (HR: 0.65, 95% CI: 0.42-0.99), and having ≥9 relatives feeling close to call for help in men (HR: 0.56, 95% CI: 0.33-0.96; reference <9 relatives) were associated with reduced dementia risk. Unexpectedly, in women, having ≥5 friends with whom they felt comfortable discussing private matters were associated with a greater dementia risk (HR: 1.69, 95% CI: 1.10-2.59; reference ≤2 friends). Imputed models further identified that babysitting/childminding was associated with lower dementia risk in men (HR: 0.75, 95% CI: 0.56-0.99). No other social activities showed significant associations with dementia. DISCUSSION: This study provides evidence of social activities influencing dementia risk. Further investigations are required to uncover the mechanisms driving these observed relationships.

Identifying atopic dermatitis risk loci in 1,094,060 individuals with sub analysis of disease severity and onset.

Atopic dermatitis (AD) is a common inflammatory skin disease highly attributable to genetic factors. Here, we report results from a genome-wide meta-analysis of AD in 37,541 cases and 1,056,519 controls with data from the FinnGen project, the Estonian Biobank, the UK Biobank, the EAGLE Consortium, and the BioBank Japan. We detected 77 independent AD-associated loci of which 10 were to our knowledge previously unreported. The associated loci showed enrichment in various immune regulatory processes. We further performed subgroup analyses of mild and severe AD, and of early and late-onset AD, with data from the FinnGen project. 55 of the 79 tested variants in the associated loci showed larger effect estimates for severe than mild AD as determined through administered treatment. The age of onset, as determined by the first hospital visit with AD diagnosis, was lower in patients with particular AD-risk alleles. Our findings add to the knowledge of the genetic background of AD and may underlay the development of new therapeutic strategies.

Association between glycemic status and the risk of gastric cancer in pre-and postmenopausal women: A nationwide cohort study.

PURPOSE: This study aimed to assess the correlation between glycemic status (prediabetes and type 2 diabetes mellitus) and the risk of gastric cancer according to menopausal status. METHODS: A total of 982,559 pre/peri-menopausal and 1,445,419 postmenopausal women aged ≥ 40, who underwent the Korean national health screening in 2009, were included and followed up until 2018. Hazard ratio (HR) and 95% confidence interval (CI) were calculated for development of gastric cancers according to hyperglycemic status in both groups using Cox proportional hazards models. RESULTS: Over a mean follow-up period of 8.3 years, 3,259 (0.33%) pre/peri-menopausal women and 13,245 (0.92%) postmenopausal women were diagnosed with gastric cancer. In postmenopausal women, only diabetes mellitus conferred a higher risk of gastric cancer compared to normal glycemic status (HR, 1.15; 95% CI, 1.09-1.20), with an increasing trend of gastric cancers from prediabetes to diabetes (P for trend < 0.001) observed regardless of menopausal status. Obesity, smoking, and heavy alcohol consumption was associated with increased gastric cancer risk mainly in the postmenopausal period. CONCLUSIONS: The risk of gastric cancer escalates with deteriorating glycemic status in a dose-response manner. Diabetes mellitus is linked with an elevated risk of gastric cancer in postmenopausal women.

Effects of short- and long-term exposures to multiple air pollutants on depression among the labor force: A nationwide longitudinal study in China.

BACKGROUND: Depression prevalence had surged within the labor force population in recent years. While a link between air pollution and depression was evident, there was a notable scarcity of research focusing on the workforce. METHODS: This nationwide longitudinal study analyzed 27,457 workers aged 15-64. We estimated monthly mean concentrations of fine particulate matter (PM2.5), its primary components, and Ozone (O3) at participants' residences using spatiotemporal models. To assess the relationship between short- (1 to 3 months) and long-term (1 to 2 years) exposure to various air pollutants and depressive symptoms and occurrences, we employed linear mixed effects models and mixed effects logistic regression. We considered potential occupational moderators, such as employment relationship, labor contracts, overtime compensation, and total annual income. RESULTS: We found significant increases in depression risks within the workforce linked to both short- and long-term air pollution exposure. A 10 µg/m3 rise in 2-year average PM2.5, black carbon (BC), and O3 concentrations correlated with increments in depressive scores of 0.009, 0.173, and 0.010, and a higher likelihood of depression prevalence by 0.5 %, 12.6 %, and 0.7 %. The impacts of air pollutants and depression were more prominent in people without labor contracts, overtime compensation, and lower total incomes. CONCLUSION: Exposures to air pollutants could increase the risk of depression in labor force population. The mitigating effects of higher income, benefits, and job security against depression underscore the need for focused mental health interventions.

In-vitro and in silco analysis and antitumor studies of novel Cu(II) and V(V) complexes of N-p-Tolylbenzohydroxamic acid.

Copper(L2Cu) and vanadium(L2VOCl) complexes of N-p-tolylbenzohydroxamic acid (LH) ligand have been investigated for DNA binding efficacy by multiple analytical, spectral, and computational techniques. The results revealed that complexes as groove binders as evidenced by UV absorption. Fluorescence studies including displacement assay using classical intercalator ethidium bromide as fluorescent probe also confirmed as groove binders. The viscometric analysis too supports the inferences as strong groove binders for both the complexes. Molecular docking too exposed DNA as a target to the complexes which precisely binds L2Cu, in the minor groove region while L2VOCl in major groove region. Molecular dynamic simulation performed on L2Cu complex revealing the interaction of complex with DNA within 20 ns time. The complex stacked into the nitrogen bases of oligonucleotides and the bonding features were intrinsically preserved for longer simulation times. In-vitro cytotoxicity study was undertaken employing MTT assay against the breast cancer cell line (MCF-7). Potential cytotoxic activities were observed for L2Cu and L2VOCl complexes with IC50 values of showing 71 % and 74 % of inhibition respectively.

Determinants of normal haemoglobin concentration among under-five children in Sub-Saharan Africa: a Positive deviance inquiry using cross-sectional study design.

BACKGROUND: Low haemoglobin level in children is linked with short-term and long-term consequences including developmental delay. Globally, over half of the children under the age of five years had low haemoglobin concentration. However, there is limited research on the prevalence and determinants of normal haemoglobin concentration among under-five children in sub-Saharan Africa. OBJECTIVE: To assess determinants of normal haemoglobin concentration among under-five children in SSA. DESIGN: Cross-sectional study design using a positive deviance approach SETTING: 33 SSA countries. PARTICIPANTS: 129 408 children aged 6-59 months PRIMARY AND SECONDARY OUTCOME MEASURES: A multilevel Poisson regression model with robust variance was fitted to identify determinants of normal haemoglobin concentration. An adjusted prevalence ratio with a 95% CI was reported to declare the statistical significance. RESULT: The pooled prevalence of normal haemoglobin concentration among under-five children in SSA was 34.9% (95% CI: 34.6% to 35.1%). High maternal education, middle and rich household wealth, female child, frequent antenatal care visits, non-anaemic mothers, taking anthelmintic drugs and normal nutritional status were associated with increased odds of normal haemoglobin concentration. On the other hand, higher birth order, having fever and diarrhoea, rural residence were associated with lower odds of normal haemoglobin levels. CONCLUSION: According to our finding, only four out of 10 under-five children in SSA had a normal haemoglobin level. This finding proved that anaemia among children in SSA remains a serious public health concern. Therefore, improving maternal education, provision of drugs for an intestinal parasite and early detection and treatment of maternal anaemia, febrile illness and diarrhoeal disease is important.

Identifying prehospital trauma patients from ambulance patient care records; comparing two methods using linked data in New South Wales, Australia.

BACKGROUND: Linked datasets for trauma system monitoring should ideally follow patients from the prehospital scene to hospital admission and post-discharge. Having a well-defined cohort when using administrative datasets is essential because they must capture the representative population. Unlike hospital electronic health records (EHR), ambulance patient-care records lack access to sources beyond immediate clinical notes. Relying on a limited set of variables to define a study population might result in missed patient inclusion. We aimed to compare two methods of identifying prehospital trauma patients: one using only those documented under a trauma protocol and another incorporating additional data elements from ambulance patient care records. METHODS: We analyzed data from six routinely collected administrative datasets from 2015 to 2018, including ambulance patient-care records, aeromedical data, emergency department visits, hospitalizations, rehabilitation outcomes, and death records. Three prehospital trauma cohorts were created: an Extended-T-protocol cohort (patients transported under a trauma protocol and/or patients with prespecified criteria from structured data fields), T-protocol cohort (only patients documented as transported under a trauma protocol) and non-T-protocol (extended-T-protocol population not in the T-protocol cohort). Patient-encounter characteristics, mortality, clinical and post-hospital discharge outcomes were compared. A conservative p-value of 0.01 was considered significant RESULTS: Of 1 038 263 patient-encounters included in the extended-T-population 814 729 (78.5 %) were transported, with 438 893 (53.9 %) documented as a T-protocol patient. Half (49.6 %) of the non-T-protocol sub-cohort had an International Classification of Disease 10th edition injury or external cause code, indicating 79644 missed patients when a T-protocol-only definition was used. The non-T-protocol sub-cohort also identified additional patients with intubation, prehospital blood transfusion and positive eFAST. A higher proportion of non-T protocol patients than T-protocol patients were admitted to the ICU (4.6% vs 3.6 %), ventilated (1.8% vs 1.3 %), received in-hospital transfusion (7.9 vs 6.8 %) or died (1.8% vs 1.3 %). Urgent trauma surgery was similar between groups (1.3% vs 1.4 %). CONCLUSION: The extended-T-population definition identified 50 % more admitted patients with an ICD-10-AM code consistent with an injury, including patients with severe trauma. Developing an EHR phenotype incorporating multiple data fields of ambulance-transported trauma patients for use with linked data may avoid missing these patients.

Nerve Conduction Studies of the Larynx: Porcine Model and Human Application.

OBJECTIVE: There is a paucity of information in the literature about how electromyography (EMG) with nerve conduction studies (NCS) can be utilized in the field of neurolaryngology. The goal of this study was two-part: (1) to identify the NCS test parameters that best reflect underlying neurolaryngeal pathophysiology in a porcine model, and (2) to determine if comparable NCS parameters can be used to assess clinical laryngeal denervation injuries in patients. METHODS: Yukatan minipigs underwent general anesthesia with EMG and recurrent laryngeal NCS assessment. Recurrent laryngeal nerve (RLN) transection injury and uninjured RLN cases were included to determine NCS neuropathologic and normative findings, respectively. Our porcine analytic model was then applied to a clinical scenario of seven patients with RLN injury. RESULTS: The porcine model was able to differentiate and characterize normative and neuropathologic NCS changes. Clinical outcomes suggest that RLN NCS can be performed clinically and is overall well tolerated by in patients. Findings may serve as a useful tool to differentiate normal nerve function, neuropraxia, axonotmesis, and irreversible RLN injuries. CONCLUSION: This novel study is the first to demonstrate the feasibility and applicability of EMG with NCS in the evaluation of vocal fold function in a porcine model in addition to the clinical setting. Further studies are needed to better understand the clinical utility and predictive value in recovery of vocal fold paralysis.

The 5 C model and Mpox vaccination behavior in Germany: a cross-sectional survey.

BACKGROUND: Due to the authorization of the Mpox vaccines, we aimed to identify determinants of the intention to get vaccinated, actively trying to receive vaccination, and for successfully receiving a vaccination in Germany employing the 5 C model of vaccination readiness. METHODS: Data stem from a cross-sectional online survey that was available online from August 13, 2022 to August 31, 2022. To assess the influence of the 5 C Model on vaccination behavior, we conducted a multinomial logistic regression. RESULTS: 3,338 participants responded to the survey, with 487 already vaccinated and 2,066 intending to receive a vaccination. Confidence and collective responsibility were positively associated with intention to get vaccinated, while complacency was negatively correlated. A higher score on the calculation scale increased the odds of intention to receive vaccination but not with actively having tried to receive a vaccination. Fewer perceived constraints were associated with higher odds to be vaccinated. Patients in practices that focus on HIV treatment were more likely to intend to get vaccinated, to have tried to get vaccinated and to be vaccinated, regardless of indication. While level of education had no impact, having an indication to get vaccinated was a strong predictor of vaccination behavior in all groups. CONCLUSION: Future vaccination campaigns should aim to reduce specific constraints of the target group and make vaccines widely available in primary care institutions beyond HIV-focused practices.

Pregnancy period and early-life risk factors for inflammatory bowel disease: a Northern Finland birth cohort 1966 study.

BACKGROUND: The pathogenesis of inflammatory bowel disease (IBD) has not been fully elucidated. The aim of this study was to analyze the pregnancy period, perinatal period, and infancy period risk factors for IBD in a well-characterized birth cohort from Northern Finland. METHODS: The Northern Finland Birth Cohort 1966 (NFBC1966) population comprises mothers living in the two northernmost provinces of Finland, Oulu, and Lapland, with dates of delivery between Jan 1st and Dec 31st, 1966 (12 055 mothers, 12 058 live-born children, 96.3% of all births during 1966). IBD patients were identified using hospital registries (from 1966 to 2020) and Social Insurance Institution (SII) registry reimbursement data for IBD drugs (from 1978 to 2016). The data were analyzed by Fisher's exact test and logistic regression. RESULTS: In total, 6972 individuals provided informed consent for the use of combined SII and hospital registry data. Of those, 154 (2.1%) had IBD (113 [1.6%] had ulcerative colitis (UC), and 41 (0.6%) had Crohn's disease (CD)). According to multivariate analysis, maternal smoking > 10 cigarettes/day during pregnancy was associated with a nearly 6-fold increased risk of CD in the offspring (OR 5.78, 95% CI 1.70-17.3). Breastfeeding (OR = 0.18, 95% CI 0.08-0.44) and iron supplementation during the first year of life (OR = 0.43, 95% CI 0.21-0.89) were negatively associated with CD. CONCLUSIONS: Smoking during pregnancy was associated with the risk of CD while Breastfeeding and oral iron supplementation at infancy were negatively associated with the risk of CD later in life.

Risk of depression in persons with Alzheimer's disease: A national cohort study.

INTRODUCTION: Depression is a risk factor and possible prodromal symptom of Alzheimer's disease (AD), but little is known about subsequent risk of developing depression in persons with AD. METHODS: National matched cohort study was conducted of all 129,410 persons diagnosed with AD and 390,088 with all-cause dementia during 1998-2017 in Sweden, and 3,900,880 age- and sex-matched controls without dementia, who had no prior depression. Cox regression was used to compute hazard ratios (HRs) for major depression through 2018. RESULTS: Cumulative incidence of major depression was 13% in persons with AD and 3% in controls. Adjusting for sociodemographic factors and comorbidities, risk of major depression was greater than two-fold higher in women with AD (HR, 2.21; 95% confidence interval [CI], 2.11-2.32) or men with AD (2.68; 2.52-2.85), compared with controls. Similar results were found for all-cause dementia. DISCUSSION: Persons diagnosed with AD or related dementias need close follow-up for timely detection and treatment of depression. Highlights: In a large cohort, women and men with AD had >2-fold subsequent risk of depression.Risks were highest in the first year (>3-fold) but remained elevated ≥3 years later.Risk of depression was highest in persons aged ≥85 years at AD diagnosis.Persons with AD need close follow-up for detection and treatment of depression.

On-time denosumab dosing recovered rapidly during the COVID-19 pandemic, yet remains suboptimal.

Timely administration of denosumab every 6 mo is critical in osteoporosis treatment to avoid multiple vertebral fracture risk upon denosumab discontinuation or delay. This study aimed to estimate the immediate and prolonged impact of the COVID-19 pandemic on the timing of denosumab doses. We identified older adults (≥66 yr) residing in the community who were due to receive denosumab between January 2016 and December 2020 using Ontario Drug Benefit data. We completed an interrupted time-series analysis to estimate the impact of the COVID-19 pandemic (March 2020) on the monthly proportion of on-time denosumab doses (183 +/-30 d). Analyses were stratified by user type: patients due for their second dose (novice users), third or fourth dose (intermediate users), or ≥5th dose (established users). In additional analyses, we considered patients living in nursing homes, switching to other osteoporosis drugs, and reported trends until February 2022. We studied 148 554 patients (90.9% female, mean [SD] age 79.6 [8.0] yr) receiving 648 221 denosumab doses. The average pre-pandemic proportion of on-time therapy was steady in the community, yet differed by user type: 64.9% novice users, 72.3% intermediate users, and 78.0% established users. We identified an immediate overall decline in the proportion of on-time doses across all user types at the start of the pandemic: -17.8% (95% CI, -19.6, -16.0). In nursing homes, the pre-pandemic proportion of on-time therapy was similar across user types (average 83.5%), with a small decline at the start of the pandemic: -3.2% (95% CI, -5.0, -1.2). On-time therapy returned to pre-pandemic levels by October 2020 and was not impacted by therapy switching. Although on-time dosing remains stable as of February 2022, approximately one-fourth of patients in the community do not receive denosumab on-time. In conclusion, although pandemic disruptions to denosumab dosing were temporary, levels of on-time therapy remain suboptimal.

Validity of Prescription-Defined and Hospital-Diagnosed Hypertension Compared with Self-Reported Hypertension in Denmark.

Purpose: Hypertension is an important risk factor in cardio-epidemiological research, but data quality remains a concern. We validated different registry-based definitions of hypertension. Patients and Methods: The cohort included all first-time responders of the Danish National Health Surveys (2010, 2013, or 2017). Prescription-defined hypertension was defined as ≥1 or ≥2 filled prescriptions of antihypertensive specific drugs in ≥1 or ≥2 different antihypertensive drug classes within 90, 180, or 365 days before survey response. Hospital-diagnosed hypertension was defined from hypertension diagnoses within five years before the survey response. Considering self-reported hypertension as the reference, we calculated the positive predictive value (PPV), the negative predictive value (NVP), the sensitivity, and the specificity of prescription-defined and hospital-diagnosed hypertension. Results: Among 442,490 survey responders, 127,247 (29%) had self-reported hypertension. For prescription-defined hypertension with 365-day lookback, the PPV was highest for ≥2 prescriptions in ≥2 drug classes (94%) and lowest for ≥1 prescription in ≥1 drug class (85%). The NPV was highest for ≥1 prescription in ≥2 drug classes (94%) and lowest for ≥1 prescription in ≥2 drug classes (80%). The sensitivity was highest for ≥1 prescription in ≥1 drug class (79%) and lowest for ≥2 prescriptions in ≥2 drug classes (30%). The specificity was ≥94% for all algorithms. The PPV and specificity did not change noteworthy with length of lookback period, whereas the NPV and the sensitivity generally were higher for longer lookback. The algorithm ≥1 prescription in ≥2 drug classes with 365-day lookback was among the best balanced across all measures of validity (PPV=88%, NPV=94%, sensitivity=75%, specificity=96%). For hospital-diagnosed hypertension, the PPV was 90%, the NPV was 76%, the sensitivity was 22%, and the specificity was 99%. Conclusion: Compared with self-reported hypertension, the algorithms for prescription-defined and hospital-diagnosed hypertension had high predictive values and specificity, but low sensitivity.

Application of causal inference methods in individual-participant data meta-analyses in medicine: addressing data handling and reporting gaps with new proposed reporting guidelines.

Observational data provide invaluable real-world information in medicine, but certain methodological considerations are required to derive causal estimates. In this systematic review, we evaluated the methodology and reporting quality of individual-level patient data meta-analyses (IPD-MAs) conducted with non-randomized exposures, published in 2009, 2014, and 2019 that sought to estimate a causal relationship in medicine. We screened over 16,000 titles and abstracts, reviewed 45 full-text articles out of the 167 deemed potentially eligible, and included 29 into the analysis. Unfortunately, we found that causal methodologies were rarely implemented, and reporting was generally poor across studies. Specifically, only three of the 29 articles used quasi-experimental methods, and no study used G-methods to adjust for time-varying confounding. To address these issues, we propose stronger collaborations between physicians and methodologists to ensure that causal methodologies are properly implemented in IPD-MAs. In addition, we put forward a suggested checklist of reporting guidelines for IPD-MAs that utilize causal methods. This checklist could improve reporting thereby potentially enhancing the quality and trustworthiness of IPD-MAs, which can be considered one of the most valuable sources of evidence for health policy.

Protocol for a systematic review and meta-analysis on Janus kinase inhibitors in the management of vitiligo.

BACKGROUND: Vitiligo is a disease that affects people of all skin shades and can impact their quality of life. Reliable evidence on the effectiveness and adverse events associated with the recent use of Janus kinase (JAK) inhibitors to treat vitiligo is needed. This protocol for a systematic review and meta-analysis seeks to collect evidence from both randomized controlled trials (RCTs) and observational studies to determine the effectiveness and patient-centered outcomes concerning treatment with JAK inhibitors. METHODS: We will conduct a systematic review of the literature for RCTs and observational studies that used upadacitinib, ritlecitinib, brepocitinib, ifidancitinib, cerdulatinib, deglocitinib, baricitinib, tofacitinib, and ruxolitinib JAK inhibitors as treatments for vitiligo compared to placebo, no treatment, or combination therapies. We will systematically search from inception in Epistemonikos, MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, EMBASE, ClinicalTrials.gov, PsycINFO, Allied and Complementary Medicine Database, Latin American and Caribbean Health Sciences Literature, Web of Science Core Collection, relevant preprint servers, and the gray literature. Ethics approval was not sought as the protocol and systematic review will not involve human participants, but rather summarized and anonymous data from studies. Primary outcomes include quality of life, percentage repigmentation, decreased vitiligo within 1 year or more, lasting repigmentation after a 2-year follow-up, cosmetic acceptability of repigmentation and tolerability or burden of treatment, and adverse events. Secondary outcomes are patient and study characteristics. We will include full-text articles, preprints, and clinical trial data in any language and all geographic regions. For data sources unavailable in English, we will obtain translations from global collaborators via the Cochrane Engage network. We will exclude articles for which sufficient information cannot be obtained from the authors of articles and systematic reviews. At least two investigators will independently assess articles for inclusion and extract data; reliability will be assessed before subsequent selection and data extraction of remaining studies. The risk of bias and certainty of evidence with Grading of Recommendations Assessment, Development, and Evaluation guidelines will be assessed independently by at least two investigators. We will estimate treatment effects by random-effects meta-analyses and assess heterogeneity using I2. Data that cannot be included in the meta-analysis will be reported narratively using themes. DISCUSSION: The proposed systematic review and meta-analysis describe the methods for summarizing and synthesizing the evidence on the effectiveness and patient-centered outcomes concerning the treatment of vitiligo with JAK inhibitors that were recently approved for this indication. To disseminate further the results of our systematic review, we plan to present them at international conferences and meetings. Our findings will provide robust evidence to facilitate decision-making at the policy or practitioner level. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023383920.

Prevalence and perceptions of flavour capsule cigarettes among adults who smoke in Brazil, Japan, Republic of Korea, Malaysia and Mexico: findings from the ITC surveys.

INTRODUCTION: The global market of flavour capsule cigarettes (FCCs) has grown significantly over the past decade; however, prevalence data exist for only a few countries. This study examined prevalence and perceptions of FCCs among adults who smoke across five countries. METHODS: Cross-sectional data among adults who smoked cigarettes came from the International Tobacco Control Policy Evaluation Project Surveys-Brazil (2016/2017), Japan (2021), Republic of Korea (2021), Malaysia (2020) and Mexico (2021). FCCs use was measured based on reporting one's usual/current brand or favourite variety has flavour capsule(s). Perceptions of the harmfulness of one's usual brand versus other brands were compared between those who used capsules versus no capsules. Adjusted logistic regression models examined correlates of FCC use. RESULTS: There were substantial differences in the prevalence of FCC use among adults who smoke across the five countries: Mexico (50.3% in 2021), Republic of Korea (31.8% in 2021), Malaysia (26.5% in 2020), Japan (21.6% in 2021) and Brazil (6.7% in 2016/2017). Correlates of FCC use varied across countries. Capsule use was positively associated with being female in Japan and Mexico, younger age in Japan, Republic of Korea and Malaysia, high education in Brazil, Japan and Mexico, non-daily smoking in Republic of Korea, and having plans to quit in Japan and Republic of Korea. There was no consistent pattern of consumer perceptions of brand harmfulness. CONCLUSION: Our study documented the high prevalence of FCCs in some countries, pointing to the need to develop and implement regulatory strategies to control these attractive products.