BACKGROUND: SCN5A variants are associated with a spectrum of cardiac electrical disorders with clear phenotypes. However, they may also be associated with complex phenotypic traits like overlap syndromes, or pleiotropy, which have not been systematically described. Additionally, the involvement of SCN5A in dilated cardiomyopathies (DCM) remains controversial.
OBJECTIVE: We aimed to (1) evaluate the different phenotypes associated with pathogenic (P)/likely pathogenic (LP) SCN5A variants and (2) determine the prevalence of pleiotropy in a large multicentric cohort of P/LP SCN5A variant carriers.
METHODS: The DNA of 13,510 consecutive probands (9960 with cardiomyopathies) was sequenced using a custom panel of genes. Individuals carrying a heterozygous single P/LP SCN5A variant were selected and phenotyped.
RESULTS: The study included 170 P/LP variants found in 495 patients. Among them, 119 (70%) were exclusively associated with a single well-established phenotype: 91 with Brugada syndrome, 15 with type 3 long QT syndrome, six with progressive cardiac conduction disease, four with multifocal ectopic Purkinje-related premature contraction, and three with sick sinus syndrome. Thirty-two variants (19%) were associated with overlap syndromes and/or pleiotropy. The 19 remaining variants (11%) were associated with atypical or unclear phenotypes. Among those, eight were carried by eight patients presenting with DCM with a debatable causative genotype/phenotype link.
CONCLUSIONS: Most P/LP SCN5A variants were found in patients with primary electrical disorders, mainly Brugada syndrome. Nearly 20% were associated with overlap syndromes or pleiotropy, underscoring the need for comprehensive phenotypic evaluation. The concept of SCN5A variants causing DCM is extremely rare (8/9960), if not questionable.

UNASSIGNED: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. However, there is a lack of comprehensive data from low- and middle-income countries (LMICs) regarding factors influencing COPD outcomes, particularly in regions where biomass exposure is prevalent.
UNASSIGNED: The Factors Affecting Survival in Severe and Very Severe COPD Patients Admitted to Tertiary Centers of India (FAST) study aims to address this gap by evaluating factors impacting survival and exacerbation rates among COPD patients in LMICs like India, with a specific focus on biomass exposure, clinical phenotypes, and nutritional status in patients admitted to the Intensive Care Unit (ICU).
UNASSIGNED: The FAST study is an observational cohort study conducted in university teaching hospitals across India. The study aims to enroll 1000 COPD patients admitted to the ICU meeting specific inclusion criteria, with follow-up assessments conducted every 6 months over a 2-year period. Data collection includes demographic information, clinical manifestations, laboratory investigations, pulmonary function tests, medications, nutritional status, mental health, and health-related quality of life. Adjudication of exacerbations and mortality will also be undertaken. The FAST study seeks to provide crucial insights into COPD outcomes in LMICs, informing more precise management strategies and mitigating the burden of COPD in these settings. By evaluating factors such as biomass exposure, clinical phenotypes, and nutritional status, the study aims to address key knowledge gaps in COPD research.
UNASSIGNED: Arunachala S, Devapal S, Swamy DSN, Greeshma MV, Ul Hussain I, Siddaiah JB, et al. Factors Affecting Survival in Severe and Very Severe COPD after Admission in ICUs of Tertiary Care Centers of India (FAST COPD): Study Protocol for a Multicentric Cohort Study. Indian J Crit Care Med 2024;28(6):552-560.

UNASSIGNED: Adverse social determinants of health (SDoH) have been associated with cardiometabolic disease; however, disparities in cardiometabolic outcomes are rarely the result of a single risk factor.
UNASSIGNED: This study aimed to identify and characterize SDoH phenotypes based on patient-reported and neighborhood-level data from the institutional electronic medical record and evaluate the prevalence of diabetes, obesity, and other cardiometabolic diseases by phenotype status.
UNASSIGNED: Patient-reported SDoH were collected (January to December 2020) and neighborhood-level social vulnerability, neighborhood socioeconomic status, and rurality were linked via census tract to geocoded patient addresses. Diabetes status was coded in the electronic medical record using International Classification of Diseases codes; obesity was defined using measured BMI ≥30 kg/m2. Latent class analysis was used to identify clusters of SDoH (eg, phenotypes); we then examined differences in the prevalence of cardiometabolic conditions based on phenotype status using prevalence ratios (PRs).
UNASSIGNED: Complete data were available for analysis for 2380 patients (mean age 53, SD 16 years; n=1405, 59% female; n=1198, 50% non-White). Roughly 8% (n=179) reported housing insecurity, 30% (n=710) reported resource needs (food, health care, or utilities), and 49% (n=1158) lived in a high-vulnerability census tract. We identified 3 patient SDoH phenotypes: (1) high social risk, defined largely by self-reported SDoH (n=217, 9%); (2) adverse neighborhood SDoH (n=1353, 56%), defined largely by adverse neighborhood-level measures; and (3) low social risk (n=810, 34%), defined as low individual- and neighborhood-level risks. Patients with an adverse neighborhood SDoH phenotype had higher prevalence of diagnosed type 2 diabetes (PR 1.19, 95% CI 1.06-1.33), hypertension (PR 1.14, 95% CI 1.02-1.27), peripheral vascular disease (PR 1.46, 95% CI 1.09-1.97), and heart failure (PR 1.46, 95% CI 1.20-1.79).
UNASSIGNED: Patients with the adverse neighborhood SDoH phenotype had higher prevalence of poor cardiometabolic conditions compared to phenotypes determined by individual-level characteristics, suggesting that neighborhood environment plays a role, even if individual measures of socioeconomic status are not suboptimal.

UNASSIGNED: Patients with asthma and low levels of type 2 inflammatory biomarkers (T2 low) have limited effective treatment options. Such biomarkers include eg blood eosinophils (b-eos) and fractional exhaled nitric oxide (FeNO). The healthcare resource utilisation (HCRU) of severe uncontrolled T2 low asthma remains unexplored. Thus, this study aimed to estimate the HCRU of T2 low and non-T2 low severe uncontrolled asthma patients using real-world data in Finland.
UNASSIGNED: Adult patients with an asthma diagnosis during baseline (2012-2017) at the pulmonary department of Turku University Hospital were included and followed during 2018-2021, or until death. Total HCRU costs and respiratory-related HCRU costs were evaluated. The main drivers for the HCRU and costs were assessed with gamma and negative binomial regression models.
UNASSIGNED: Of the severe uncontrolled asthma patients with T2 status available, 40% (N=66) were identified with T2 low and 60% (N=103) with non-T2 low asthma. The average cumulative cost per patient was similar in patients with T2 low compared with non-T2 low, with all-cause costs cumulating in four years of follow-up to 37,524€ (95% CI: 27,160, 47,888) in T2 low compared to 34,712€ (25,484, 43,940) in non-T2 low. The corresponding average cumulative respiratory-related costs were 5178€ (3150, 7205) in T2 low compared to 5209€ (4104, 6313) in non-T2 low. Regression modelling identified no differences between the T2-status groups when assessing all-cause healthcare costs per patient-year (PPY). On the other hand, the regression modelling predicted more inpatient days PPY for severe uncontrolled patients with T2 low status compared to the patients with non-T2 low status.
UNASSIGNED: Patients with uncontrolled severe T2 low asthma use equal healthcare resources as corresponding non-T2 low patients. This study brought new insights into the HCRU of severe uncontrolled asthma patients per T2 status, which has not previously been investigated.

OBJECTIVE: Obstructive sleep apnea (OSA) is a complex, heterogeneous disease. Categorizing the disorder into phenotypes can help us better understand its pathology and guide us toward more personalized treatment approaches. Nevertheless, most of the previous cluster analysis (CA) studies in OSA predominantly included middle-aged to older men and may not adequately represent the heterogeneity of OSA phenotypes in women. Our aim is to identify these phenotypes in women using an extensive, exclusively female cohort.
METHODS: Cross-sectional study of 1886 women diagnosed with OSA (apnea-hypopnea index >5 events/h) by PSG (polysomnography) and RP (respiratory polygraphy) at a tertiary hospital Sleep Unit. A CA was performed including general data, clinical variables, comorbidities and sleep study results.
RESULTS: Four phenotypic subtypes were identified: Cluster 1 \"Middle-aged paucisymptomatic women without cardiovascular risk factors\" (507 patients, 27 %); Cluster 2 \"Older paucisymptomatic women with established cardiovascular disease and severe OSA\" (228 patients, 12 %); Cluster 3 \"Middle-aged women with \"classic\" symptoms and cardiovascular risk factors\" (892 patients, 47 %), and Cluster 4 ″Middle-aged women with mood disorders, nonrestorative sleep and cardiovascular risk factors\" (259 patients, 14 %).
CONCLUSIONS: Conducting a CA exclusively within a female cohort reveals a heterogeneous presentation of OSA in women, similar to what has been previously reported in the literature for men. The \"classical\" presentation is notably the most prevalent, while the \"atypical\" presentation, which was previously more frequently associated with women, is less prevalent. Additionally, paucisymptomatic presentations, with or without associated comorbidities, are also present.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells assume pivotal roles in numerous autoimmune inflammatory maladies. However, scant knowledge exists regarding their involvement in the pathological progression of oral lichen planus (OLP). The focus of our study was to explore whether MAIT cells were altered across distinct clinical types of OLP.
METHODS: The frequency, phenotype, and partial functions of MAIT cells were performed by flow cytometry, using peripheral blood from 18 adults with non-erosive OLP and 22 adults with erosive OLP compared with 15 healthy adults. We also studied the changes in MAIT cells in 15 OLP patients receiving and 10 not receiving corticosteroids. Surface proteins including CD4, CD8, CD69, CD103, CD38, HLA-DR, Tim-3, Programmed Death Molecule-1 (PD-1), and related factors released by MAIT cells such as Granzyme B (GzB), interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-17A, and IL-22 were detected.
RESULTS: Within non-erosive OLP patients, MAIT cells manifested an activated phenotype, evident in an elevated frequency of CD69+ CD38+ MAIT cells (p < 0.01). Conversely, erosive OLP patients displayed an activation and depletion phenotype in MAIT cells, typified by elevated CD69 (p < 0.01), CD103 (p < 0.05), and PD-1 expression (p < 0.01). Additionally, MAIT cells exhibited heightened cytokine production, encompassing GzB, IFN-γ, and IL-17A in erosive OLP patients. Notably, the proportion of CD103+ MAIT cells (p < 0.05) and GzB secretion (p < 0.01) by MAIT cells diminished, while the proportion of CD8+ MAIT cells (p < 0.05) rose in OLP patients with corticosteroid therapy.
CONCLUSIONS: MAIT cells exhibit increased pathogenicity and pro-inflammatory capabilities in OLP. Corticosteroid therapy influences the expression of certain phenotypes and functions of MAIT cells in the peripheral blood of OLP patients.

BACKGROUND: Viral wheezing is an important risk factor for asthma, which comprises several respiratory phenotypes. We sought to understand if the etiology of early-life wheezing illnesses relates to childhood respiratory and asthma phenotypes.
METHODS: Data were collected prospectively on 429 children in the Urban Environment and Childhood Asthma (URECA) birth cohort study through age 10 years. We identified wheezing illnesses and the corresponding viral etiology (PCR testing of nasal mucus) during the first 3 years of life. Six phenotypes of respiratory health were identified at 10 years of age based on trajectories of wheezing, allergic sensitization, and lung function. We compared the etiology of early wheezing illnesses to these wheezing respiratory phenotypes and the development of asthma.
RESULTS: In the first 3 years of life, at least one virus was detected in 324 (67%) of the 483 wheezing episodes documented in the study cohort. Using hierarchical partitioning we found that non-viral wheezing episodes accounted for the greatest variance in asthma diagnosed at both 7 and 10 years of age (8.0% and 5.8% respectively). Rhinovirus wheezing illnesses explained the most variance in respiratory phenotype outcome followed by non-viral wheezing episodes (4.9% and 3.9% respectively) at 10 years of age.
CONCLUSIONS: Within this high-risk urban-residing cohort in early life, non-viral wheezing episodes were frequently identified and associated with asthma development. Though rhinovirus wheezing illnesses had the greatest association with phenotype outcome, the specific etiology of wheezing episodes in early life provided limited information about subsequent wheezing phenotypes.

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The European and global dairy breeding industry has benefited enormously from collaboration and sharing of data. The new era of genomics has disrupted the information flow due to the requirement to protect commercial investments. New trait phenotypes, evaluation models, and breeding goals continue to evolve and will impact the way national and proprietary data are shared and presented to the dairy industry. The global nature of cattle breeding will, however, continue to require some form of collaboration, even under the new ways of working.

Down syndrome is the most frequently occurring genetic condition, with a substantial escalation in risk associated with advanced maternal age. The syndrome is characterized by a diverse range of phenotypes, affecting to some extent all levels of organization, and its progeroid nature - early manifestation of aspects of the senile phenotype. Despite extensive investigations, many aspects and mechanisms of the disease remain unexplored. The current review aims to provide an overview of the main causes and manifestations of Down syndrome, while also examining the phenomenon of accelerated aging and exploring potential therapeutic strategies.