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)

Optimal control strategies for toxoplasmosis disease transmission dynamics via harmonic mean-type incident rate.

Toxoplasma infection in humans is considered due to direct contact with infected cats. Toxoplasma infection (an endemic disease) has the potential to affect various organs and systems (brain, eyes, heart, lungs, liver, and lymph nodes). Bilinear incidence rate and constant population (birth rate is equal to death rate) are used in the literature to explain the dynamics of Toxoplasmosis disease transmission in humans and cats. The goal of this study is to consider the mathematical model of Toxoplasma disease with harmonic mean type incident rate and also consider that the population of humans and cats is not equal (birth rate and the death rate are not equal). In examining Toxoplasma transmission dynamics in humans and cats, harmonic mean incidence rates are better than bilinear incidence rates. The disease dynamics are first schematically illustrated, and then the law of mass action is applied to obtain nonlinear ordinary differential equations (ODEs). Analysis of the boundedness, positivity, and equilibrium points of the system has been analyzed. The reproduction number is calculated using the next-generation matrix technique. The stability of disease-free and endemic equilibrium are analyzed. Sensitivity analysis is also done for reproduction number. Numerical simulation shows that the infection is spread in the population when the contact rate ß h and ß c increases while the infection is reduced when the recovery rate δ h increases. This study investigates the impact of various optimal control strategies, such as vaccinations for the control of disease and the awareness of disease awareness, on the management of disease.

Delayed epistaxis after endoscopic transnasal pituitary tumor resection: clinical characteristics, risk factors, treatment and prevention.

BACKGROUND: Delayed epistaxis after endoscopic transnasal pituitary tumor resection (ETPTR) is a critical complication, tending to cause aspiration or hemorrhagic shock. This study assessed clinical characteristics, risk factors, and provide treatment and prevention advice of this complication. METHODS: This was a retrospective monocentric analysis of 862 patients who underwent ETPTR. Statistical analyses of clinical data revealed the incidence, sources and onset time of delayed epistaxis. Univariate analysis and binary logistic regression were used to identify risk factors. RESULTS: The incidence of delayed epistaxis was 2.78% (24/862), with an average onset time of 20.71 ± 7.39 days. The bleeding sources were: posterior nasal septal artery branch of sphenopalatine artery (12/24), multiple inflammatory mucosae (8/24), sphenopalatine artery trunk (3/24) and sphenoid sinus bone (1/24). Univariate analysis and binary logistic regression analysis confirmed that hypertension, nasal septum deviation, chronic rhinosinusitis and growth hormone pituitary tumor subtype were independent risk factors for delayed epistaxis. Sex, age, history of diabetes, tumor size, tumor invasion and operation time were not associated with delayed epistaxis. All patients with delayed epistaxis were successfully managed through endoscopic transnasal hemostasis without recurrence. CONCLUSIONS: Delayed epistaxis after ETPTR tends to have specific onset periods and risk factors. Prevention of these characteristics may reduce the occurrence of delayed epistaxis. Endoscopic transnasal hemostasis is recommended as the preferred treatment for delayed epistaxis.

Malignancy is increased in patients with antineutrophil cytoplasmic antibody-associated vasculitis in China.

OBJECTIVE: It has been reported that in western countries malignancy risk was higher in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) compared with that in the general population. In the current study, we investigated the incidence, spectrum and risk factors of malignancy in Chinese AAV patients. METHODS: AAV patients diagnosed from 1995 to 2021 in Peking University First Hospital with a follow-up more than 12 months were recruited. Standardized incidence ratios (SIR) were calculated to describe the risk of malignancy, adjusted for sex, age and follow-up time. RESULTS: A total of 552 AAV patients were recruited, among which 23 patients had malignancies either preceding or concurrent with AAV diagnosis, and 43 of the remaining 529 patients developed malignancies within 4.3 ± 4.2 years post AAV diagnosis (SIR: 2.24; 95% CI: 1.68-2.99; p < 0.001). Among these 66 patients, twenty different sites of malignancy were observed, lung cancer being most frequent. To get exactly expected malignancies for the calculation of SIR, 529 patients without preceding or concurrent malignancies were included in the following analysis. Lung cancer was still the leading malignancy diagnosis (SIR: 5.01; 95% CI: 3.29-7.62), followed by malignancies in the kidney, bladder, ureter and prostate. Male gender (HR:2.84; 95%CI:1.36-5.96; p = 0.006) and older age (per year, HR:1.04; 95%CI:1.00-1.07; p = 0.038) were significantly associated with increased risk of malignancy. For patients with malignancy developed beyond 5 years after the diagnosis of AAV, a significantly higher malignancy risk was observed in those with a cumulative cyclophosphamide dose over 20.0 g (SIR: 11.54; 95% CI: 4.77-27.93; p < 0.001). Within the first 2 years after the diagnosis of AAV, the risk of malignancy was still significantly higher than that in the general population, but the cumulative cyclophosphamide dose was not significantly associated with malignancy occurrence in this subgroup of patients. CONCLUSIONS: Malignancy risk is higher in Chinese AAV patients than that in the general population, with a different malignancy spectrum from western countries. Both the use of cyclophosphamide and AAV per se might be associated with higher incidence of malignancy occurrence.

Epidemiological and clinical trends of visceral leishmaniasis in Portugal: retrospective analysis of cases diagnosed in public hospitals between 2010 and 2020.

BACKGROUND: Leishmania infantum is endemic in the Mediterranean region, presenting mostly as visceral leishmaniasis (VL). In Portugal, reporting of VL cases to public health authorities is mandatory, but significant underreporting is likely. This study aimed to describe the epidemiological and clinical aspects of the VL cases diagnosed in hospitals of the Portuguese National Health Service (NHS), between 2010 and 2020. METHODS: Collaboration was requested to every hospital of the Portuguese NHS in Mainland Portugal. Cases were screened through a search of diagnostic discharge codes or, if not available, by a search of positive laboratory results for Leishmania infection. Sociodemographic and clinical data was retrieved from medical records. Simultaneously, the National Health authority was contacted to request access to data of notified cases of VL between 2010 and 2020. Descriptive, hypothesis testing and multiple binary logistic regression models were performed. RESULTS: A total of 221 VL cases were identified. A significant increase in estimated national incidence was seen in the years after 2016 (P = 0.030). VL was predominantly diagnosed in people living with HIV (PLWH) and in children (representing around 60% of the new cases), but the outcome was generally poorer in non-HIV patients with associated immunosuppression, with significantly lower rates of clinical improvement at 7 (P = 0.003) and 30 days (P = 0.008) after treatment. Atypical presentations, with gastrointestinal and/or respiratory involvement, were seen in 8.5% of VL cases. Hemophagocytic lymphohistiocytosis was diagnosed in 40.0% of children under 5 years of age. Only 49.7% of incident VL cases were reported. Simultaneous involvement of the skin was confirmed in 5.9% of patients. CONCLUSIONS: VL presents a continuing threat in Portugal, especially to PLWH and children, and an increasing threat to other immunosuppressed groups. Recent increases in incidence should be closely monitored to allow prompt interventions. Programs to control the disease should focus on providing tools for earlier diagnosis and on reducing underreporting and promoting an integrated surveillance of human and animal disease. These data should be combined with asymptomatic infection and vector information, following a One Health approach.

An epidemiological analysis of TB trends in native and migrant populations, New Mexico, 1993-2021.

To analyze the epidemiological, demographic, clinical, laboratory, radiographic and treatment outcome trends in non-US-born individuals with TB in New Mexico.We retrospectively analyzed TB data from New Mexico TB surveillance system from (1993-2021), comparing variables between non-US-born and US-born individuals.Of the 1,512 TB cases, 876 (56.5%) were non-US-born and 653 (43.3%) were US-born. The incidence rate among non-US-born patients declined from 15.3/100,000 (1993) to 7.8/100,000 (2021) (54.6% reduction), while among US-born patients it declined from 3.3/100,000 (1993) to 0.5/100,000 (2021) (84.8% reduction). The majority of non-US-born individuals were from Mexico (n = 482, 73.5%). Non-US-born were typically younger adults (median age: 54 vs. 61), predominantly male (64.8% vs. 59.4%), less likely to consume excess alcohol and have extrapulmonary TB. However, they were more likely to exhibit resistance to standard TB drugs (P < 0.01). Non-US-born individuals were less likely to die (7.8% vs. 15.4%), but more likely to be lost to follow-up (P < 0.007). Treatment by providers outside the Department of Health was associated with noncompletion (OR 0.18, 95% CI 0.09-0.35; P < 0.001).These results highlight the need for a detailed understanding of the impact of migration on TB epidemiology and the development of tailored interventions to improve treatment outcomes..

Incidence of tuberculous infection in a TB-endemic city.

Current metrics for TB transmission include TB notifications, disease mortality, and prevalence surveys. These metrics are helpful to national TB programs to assess the burden of disease, but they do not directly measure incident infection in the community.To estimate incidence of Mycobacterium tuberculosis infection in Kampala, Uganda, we performed a prospective cohort study between 2014 and 2017 which enrolled of 1,275 adult residents without signs of tuberculous infection (tuberculin skin test [TST] <5 mm and no signs of TB disease) and followed them for conversion of TST at 1 year.During follow-up, 194 participants converted the TST and 158 converted by one year. The incidence density of TST conversion was 13.2 conversions/100 person-year (95% CI 11.6-15.1), which corresponds to an annual cumulative incidence of tuberculous infection of 12.4% (95% CI 10.7-14.3). Cumulative incidence was greater among older participants and among men. Among participants who reported prior exposure to TB cases, the cumulative risk was highest among those reporting exposure during follow-up.The high annual incidence of infection suggests that residents of Kampala have adequate contact for infection with undetected, infectious cases of TB as they go about their daily lives..

Skin health of community-living older people: a scoping review.

The population of older people is steadily increasing and the majority live at home. Although the home and community are the largest care settings worldwide, most of the evidence on dermatological care relates to secondary and tertiary care. The overall aims were to map the available evidence regarding the epidemiology and burden of the most frequent skin conditions and regarding effects of screening, risk assessment, diagnosis, prevention and treatment of the most frequent skin conditions in older people living in the community. A scoping review was conducted. MEDLINE, Embase and Epistemonikos were systematically searched for clinical practice guidelines, reviews and primary studies, as well as Grey Matters and EASY for grey literature published between January 2010 and March 2023. Records were screened and data of included studies extracted by two reviewers, independently. Results were summarised descriptively. In total, 97 publications were included. The vast majority described prevalence or incidence estimates. Ranges of age groups varied widely and unclear reporting was frequent. Sun-exposure and age-related skin conditions such as actinic keratoses, xerosis cutis, neoplasms and inflammatory diseases were the most frequent dermatoses identified, although melanoma and/or non-melanoma skin cancer were the skin conditions investigated most frequently. Evidence regarding the burden of skin conditions included self-reported skin symptoms and concerns, mortality, burden on the health system, and impact on quality of life. A minority of articles reported effects of screening, risk assessment, diagnosis, prevention and treatment, mainly regarding skin cancer. A high number of skin conditions and diseases affect older people living at home and in the community but evidence about the burden and effective prevention and treatment strategies is weak. Best practices of how to improve dermatological care in older people remain to be determined and there is a particular need for interventional studies to support and to improve skin health at home.

Medial malleolar osteotomy in the treatment of osteochondral lesions of the Talus - incidence and impact on functional outcome: a retrospective analysis based on data from the German Cartilage Register (KnorpelRegister DGOU).

BACKGROUND: There has long been discussion regarding the impact of medial malleolar osteotomies (MMO) as an adjunctive treatment for osteochondral lesions of the talus (OCLT). MMO may improve the visibility and accessibility of the talus, but they also pose a risk of periprocedural morbidity. There is a lack of research about the prevalence and consequences of MMO in the surgical treatment of OCLT. METHODS: This study retrospectively evaluated data from the German Cartilage Register (KnorpelRegister DGOU) from its implementation in 2015 to December 2020. The impact of MMO on patient-reported outcome measures (PROMs) was investigated. Wherever possible, subgroups were built and matched using a propensity score which matched a group undergoing OCLT without MMO. Matching included age, sex, weight, localization of the OCLT, the international cartilage repair society (ICRS) grading, surgical procedure and preoperative symptoms using the Foot and Ankle Ability Measure (FAAM) and the Activities of Daily Living Subscale (ADL). RESULTS: The prevalence of MMO in the operative treatment of OCLT was 15.9%. Most of the osteotomies were performed in OCL of the medial talar dome (76.8%) and in more serious lesions with an ICRS grade of III (29.1%) and IV (61.4%). More than half of the osteotomies (55.6%) were performed during revision surgery. A matched pair analysis of n = 44 patients who underwent AMIC® via arthrotomy and MMO vs. arthrotomy alone showed no significant differences in patient-reported outcome measures (PROMs, i.e. FAAM-ADL, and FAOS) at 6,12 and 24 months. CONCLUSIONS: MMO are mostly used in the treatment of severe (≥ ICRS grade 3) OCL of the medial talar dome and in revision surgery. Functional and patient-reported outcome measures are not significantly affected by MMO compared to arthrotomy alone. TRIAL REGISTRATION: The German Cartilage Register (KnorpelRegister DGOU) was initially registered at the German Clinical Trials Register ( https://www.drks.de , register number DRKS00005617, Date of registration 03.01.2014) and was later expanded by the ankle module.

The TEOGIC study project: a comprehensive characterization of early onset gastrointestinal cancer in the Northern area of Spain.

BACKGROUND: Gastrointestinal cancers represent one of the most prevalent diseases worldwide. Strikingly, the incidence of Early Onset Gastrointestinal Cancer (EOGIC) has been rising during the last decades and changes in lifestyle and environmental exposure seem to play a role. EOGIC has been defined as a different entity compared to on-average gastrointestinal cancer, with distinct clinical and molecular characteristics. Inherent to the particularities of younger age, there is an unmet need for a tailored approach for the management of these patients. The TEOGIC proposes a comprehensive study to characterize EOGIC patients in the northern of Spain. METHODS: Patients with histologically confirmed new diagnosis of colorectal, gastroesophageal and pancreatic adenocarcinoma will be considered for two cohorts: EOGIC (≤ 50 years old) and non-EOGIC (60-75 years old), with a ratio of 1:2. Two hundred and forty patients will be recruited in 4 Public Hospitals from northern Spain. After receiving unified informed consent, demographic and clinical data of the patients will be collected in a REDCap database. Lifestyle related data will be obtained in questionnaires assessing diet, physical activity and the general quality of life of the patients before diagnosis. Biological samples prior to any onco-specific treatment will be obtained for the analyses of circulating inflammatory proteins, gut microbiota, and the proteome of the tumor microenvironment. Histologic characteristics and routine biomarkers will be also collected. Thereafter, data will be integrated and analyzed to assess tumor specific, pan-tumor and sex-associated differential characteristics of EOGIC. DISCUSSION: The underlying risk factors and differential characteristics of EOGIC remain poorly studied, particularly in our geographical area. Although limited by the exploratory nature and the small sample size estimated to be recruited, TEOGIC represents the first attempt to comprehensively characterize these young patients, and thus attend to their special needs. Findings derived from this study could contribute to raise awareness and preventive behaviors in the population. In parallel, molecular studies could lead to the identification of potential novel non-invasive biomarkers and therapeutic targets that would help in the development of the tailored clinical management of these patients, focusing on screening programs for early diagnosis and precision medicine.

Complicaciones y descargas inapropiadas tras el implante de un desfibrilador subcutáneo en pacientes pediátricos / Complications and inappropriate shocks in pediatric patients receiving a subcutaneous implantable cardioverter defibrilator

Introducción y objetivos: La experiencia con el desfibrilador automático implantable subcutáneo (DAI-SC) en pacientes pediátricos aún es reducida. El objetivo de este estudio es determinar la incidencia de complicaciones en pacientes pediátricos de nuestro centro en función del tipo de DAI y del tamaño del paciente.MétodosSe incluyó a pacientes menores de 18 años que recibieron un DAI-SC desde 2016 y pacientes contemporáneos (desde 2014) que recibieron un DAI transvenoso (DAI-TV). El evento principal fue el combinado de complicaciones y descargas inapropiadas.ResultadosSe implantó un DAI-SC a 26 pacientes (edad, 14 [intervalo, 5-17] años; índice de masa corporal [IMC], 20,2). De ellos, 23 (88%) fueron implantes intermusculares y el resto, en subserrato, 24 (92%) con 2 incisiones. Se programaron 2 zonas en todos los pacientes: condicional a 230 (220-230) lpm y de choque a 250 lpm. El grupo de DAI-TV incluyó a 19 pacientes (edad, 11 [5-16] años; IMC, 19,2; el 79% monocamerales). La supervivencia libre del evento principal a 5 años fue el 80% de los pacientes con DAI-SC y el 63% del grupo con DAI-TV (p=0,54); la de descargas inapropiadas fue similar (el 85 frente al 89%; p=0,86), mientras que la de complicaciones fue mayor en el grupo de DAI-SC (el 96 frente al 57%; cloglog p=0.016). En el grupo de DAI-SC no hubo fallo de la terapia ni mayores complicaciones con un IMC ≤ 20.ConclusionesCon las técnicas de implante y programación actuales, el DAI-SC es eficaz y seguro en pacientes pediátricos, con similares descargas inapropiadas y menos complicaciones a corto y medio plazo que el DAI-TV. (AU)

Introduction and objectives: There is limited evidence regarding the use of subcutaneous implantable cardioverter-defibrillators (S-ICD) in pediatric patients. The aim of this study was to determine the incidence of complications in these patients at our center, according to the type of ICD and patient size.MethodsWe included all patients aged<18 years who received an S-ICD since 2016 at our center. As a control group, we also included contemporary patients (since 2014) who received a transvenous ICD (TV-ICD). The primary endpoint was a composite of complications and inappropriate shocks.ResultsA total of 26 patients received an S-ICD (median age, 14 [5-17] years; body mass index [BMI], 20.2 kg/m2). Implantation was intermuscular in 23 patients (88%) and subserratus in the remainder. Two incisions were used in 24 patients (92%). In all patients, 2 zones were programmed: a conditional zone set at 230 (220-230) bpm, and a shock zone set at 250 bpm. Nineteen patients received a TV-ICD (median age, 11 [range, 5-16] years; BMI, 19.2 kg/m2, 79% single-chamber). Survival free from the primary endpoint at 5 years was 80% in the S-ICD group and 63% in the TV-ICD group (P=.54). Survival free from inappropriate shocks was similar (85% vs 89%, P=.86), while survival free from complications was higher in the S-ICD group (96% vs 57%, cloglogP=.016). There were no therapy failures in the S-ICD group, and no increased complication rates were observed in patients with BMI ≤ 20 kg/m2.ConclusionsWith contemporary implantation techniques and programming, S-ICD is a safe and effective therapy in pediatric patients. The number of inappropriate shocks is similar to TV-ICD, with fewer short- and mid-term complications. (AU)

Determinants of chronic energy deficiency (CED) incidence in pregnant women: A cross-sectional study in Banyumas, Indonesia.

Chronic energy deficiency (CED) in pregnant women is a condition of energy and protein deficiency that lasts for years and causes problems in the mother and fetus. Due to its significant consequences, determining the determinants associated with CED incidence is of utmost importance. The aim of this study was to determine the determinants of the incidence of CED in pregnant women in Indonesia. A cross-sectional study was conducted on pregnant women in Banyumas, Central Java, Indonesia, in 2022. Plausible determinants included maternal age, pregnancy interval, parity, educational attainment, nutritional knowledge, employment, frequency of antenatal care (ANC), and nutritional intake. The Chi-squared test followed by multivariate logistic regression were used to determine the factors associated with the incidence of CED. Our data indicated that 32% of the pregnant women had CED. Univariate analysis found that maternal age (p=0.022), pregnancy interval (p=0.009), educational attainment (p=0.012), knowledge of nutrition and CED (p=0.023), frequency of utilization of ANC services (p=0.028), energy intake (p=0.002), protein intake (p=0.006), vitamin C intake (p=0.016), folate intake (p=0.011), and calcium intake (p=0.004) were significantly associated with CED incidence in the pregnant women. Multivariate analysis indicated that extreme maternal age (OR; 3.49; 95%CI: 1.10-11.05), low educational attainment (OR: 4.12; 95%CI: 1.37-12.33), short pregnancy interval (OR; 7.30; 95%CI: 1.84-28.99), low frequency of ANC (OR: 3.06; 95%CI: 1.01-9.19) and low protein intake (OR: 6.80; 95%CI: 1.62-28.59) were associated with CED incidence. This study underscores the importance of increasing nutritional intake, frequency of ANC, and pregnancy interval among pregnant women to reduce the risk of CED and its adverse health outcomes.

[Stroke and stroke prevention in cardiac and thoracic aortic surgery]. / Ictus e prevenzione dell'ictus in cardiochirurgia e in chirurgia dell'aorta toracica.

Perioperative stroke and neurological injuries in general are complications that can occur during and after cardiac surgery, particularly in aortic surgery that involves the aortic arch. The overall incidence of early and delayed stroke is about 1% according to recent meta-analyses. This incidence depends on interindividual risk factor profile and type of surgery. In order to reduce cerebrovascular complications during cardiac surgery, a number of preventative measures can be taken, including the evaluation of atherosclerotic plaques, the site of cannulation and neuroprotection strategies. During aortic arch surgery, main strategies for cerebral protection are represented by deep hypothermic circulatory arrest, retrograde and antegrade cerebral perfusion.

Higher infection risk for JAK inhibitors tofacitinib and baricitinib compared to subcutaneous biological DMARDs.

INTRODUCTION: Rheumatoid arthritis (RA) is usually treated with disease modifying antirheumatic drugs (DMARDs), including biological DMARDs (bDMARDs) and more recently, Janus kinase inhibitors (JAKi). Randomized trials suggest similar infection risks for JAKi and bDMARDs, but real-world data are scarce. METHODS: From a nationally representative prescription database, adult RA patients starting a new JAKi or bDMARD between August 1st, 2018, and January 31st, 2021, were included. Prescriptions of antibiotic, antiviral or antifungal medication were used as proxy for infections. Infection incidence rates (IR) were compared between JAKi and bDMARDs and infection risks were estimated using multilevel Poisson regression adjusted for follow-up time and potential confounders and stratified for age < 65 and ≥ 65 years. RESULTS: In 14,989 patients, we identified 20,050 treatment episodes with either JAKi or bDMARDs. The infection IR was significantly higher in JAKi (48/100 patient years) compared bDMARDs (35/100 patient years, adjusted incidence rate ratio (IRR) 1.22, 95% CI 1.12-1.33). More herpes zoster infections were seen in JAKi compared to bDMARDs (adjusted IRR 2.65, 95% CI 1.94-3.60). No significant differences in infection IRs were found comparing JAKi baricitinib and tofacitinib. In older patients, infection IRs were higher, but IRRs were similar between age groups. CONCLUSION: In comparison to bDMARDs, JAKi are associated with a slightly higher infection risk and a higher risk of herpes zoster specifically. In older patients, infection IRs are higher but similar infection risks for JAKi and bDMARDs are observed. No differences in infection risk between tofacitinib and baricitinib were found. Key Points • Compared to bDMARDs, JAKi are associated with a slightly higher infection risk for all ages • An increased risk of herpes zoster in patients who use JAK inhibitors was confirmed • No significant differences in infection incidence were found between tofacitinib and baricitinib.

Youth Experiencing Parental Death Due to Drug Poisoning and Firearm Violence in the US, 1999-2020.

Importance: Youth (those aged <18 years) parental death has been associated with negative health outcomes. Understanding the burden of parental death due to drug poisoning (herein, drugs) and firearms is essential for informing interventions. Objective: To estimate the incidence of youth parental death due to drugs, firearms, and all other causes. Design, Setting, and Participants: This cross-sectional observational study was conducted using vital registration, including all US decedents, and census data from January 1990 through December 2020. Data were analyzed from May 30, 2023, to March 28, 2024. Exposures: Parental death due to drug poisoning or firearms. Main Outcomes and Measures: A demographic matrix projection model was used to estimate the number and incidence of youth experiencing parental death, defined as the death of 1 or more parents, per 1000 population aged less than 18 years. Analyses evaluated parental deaths by drugs, firearms, and all other causes from 1999 through 2020 by race and ethnicity. Results: Between 1999 and 2020, there were 931 785 drug poisoning deaths and 736 779 firearm-related deaths with a mean (SD) age of 42.6 (16.3) years. Most deaths occurred among males (73.8%) and White decedents (70.8%) followed by Black (17.5%) and Hispanic (9.5%) decedents. An estimated 759 000 (95% CI, 722 000-800 000) youth experienced parental death due to drugs and an estimated 434 000 (95% CI, 409 000-460 000) youth experienced parental death due to firearms, accounting for 17% of all parental deaths. From 1999 to 2020, the estimated number of youth who experienced parental death increased 345% (95% CI, 334%-361%) due to drugs and 39% (95% CI, 37%-41%) due to firearms compared with 24% (95% CI, 23%-25%) due to all other causes. Black youth experienced a disproportionate burden of parental deaths, based primarily on firearm deaths among fathers. In 2020, drugs and firearms accounted for 23% of all parental deaths, double the proportion in 1999 (12%). Conclusions and Relevance: Results of this modeling study suggest that US youth are at high and increasing risk of experiencing parental death by drugs or firearms. Efforts to stem this problem should prioritize averting drug overdoses and firearm violence, especially among structurally marginalized groups.

Within-city spatial variations in PM2.5 magnetite nanoparticles and brain cancer incidence in Toronto and Montreal, Canada.

Magnetite nanoparticles are small, strongly magnetic iron oxide particles which are produced during high-temperature combustion and friction processes and form part of the outdoor air pollution mixture. These particles can translocate to the brain and have been found in human brain tissue. In this study, we estimated associations between within-city spatial variations in concentrations of magnetite nanoparticles in outdoor fine particulate matter (PM2.5) and brain cancer incidence. We performed a cohort study of 1.29 million participants in four cycles of the Canadian Census Health and Environment Cohort in Montreal and Toronto, Canada who were followed for malignant brain tumour (glioma) incidence. As a proxy for magnetite nanoparticle content, we measured the susceptibility of anhysteretic remanent magnetization (χARM) in PM2.5 samples (N = 124 in Montreal, N = 110 in Toronto), and values were assigned to residential locations. Stratified Cox proportional hazards models were used to estimate hazard ratios (per IQR change in volume-normalized χARM). ARM was not associated with brain tumour incidence (HR = 0.998, 95% CI 0.988, 1.009) after adjusting for relevant potential confounders. Although we found no evidence of an important relationship between within-city spatial variations in airborne magnetite nanoparticles and brain tumour incidence, further research is needed to evaluate this understudied exposure, and other measures of exposure to magnetite nanoparticles should be considered.

Physical frailty, genetic predisposition, and incident dementia: a large prospective cohort study.

Physical frailty and genetic factors are both risk factors for increased dementia; nevertheless, the joint effect remains unclear. This study aimed to investigated the long-term relationship between physical frailty, genetic risk, and dementia incidence. A total of 274,194 participants from the UK Biobank were included. We applied Cox proportional hazards regression models to estimate the association between physical frailty and genetic and dementia risks. Among the participants (146,574 females [53.45%]; mean age, 57.24 years), 3,353 (1.22%) new-onset dementia events were recorded. Compared to non-frailty, the hazard ratio (HR) for dementia incidence in prefrailty and frailty was 1.396 (95% confidence interval [CI], 1.294-1.506, P < 0.001) and 2.304 (95% CI, 2.030-2.616, P < 0.001), respectively. Compared to non-frailty and low polygenic risk score (PRS), the HR for dementia risk was 3.908 (95% CI, 3.051-5.006, P < 0.001) for frailty and high PRS. Furthermore, among the participants, slow walking speed (HR, 1.817; 95% CI, 1.640-2.014, P < 0.001), low physical activity (HR, 1.719; 95% CI, 1.545-1.912, P < 0.001), exhaustion (HR, 1.670; 95% CI, 1.502-1.856, P < 0.001), low grip strength (HR, 1.606; 95% CI, 1.479-1.744, P < 0.001), and weight loss (HR, 1.464; 95% CI, 1.328-1.615, P < 0.001) were independently associated with dementia risk compared to non-frailty. Particularly, precise modulation for different dementia genetic risk populations can also be identified due to differences in dementia risk resulting from the constitutive pattern of frailty in different genetic risk populations. In conclusion, both physical frailty and high genetic risk are significantly associated with higher dementia risk. Early intervention to modify frailty is beneficial for achieving primary and precise prevention of dementia, especially in those at high genetic risk.