Epigenome-wide Association Analysis of Mitochondrial Heteroplasmy Provides Insight into Molecular Mechanisms of Disease.

The relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA (nDNA) methylation (CpGs) remains to be studied. We conducted an epigenome-wide association analysis of heteroplasmy burden scores across 10,986 participants (mean age 77, 63% women, and 54% non-White races/ethnicities) from seven population-based observational cohorts. We identified 412 CpGs (FDR p < 0.

One-Year Effect of Elexacaftor/Tezacaftor/Ivacaftor Therapy on HbA1c Levels and Insulin Requirement in Patients with Insulin-Dependent Cystic Fibrosis-Related Diabetes: A Retrospective Observational Study.

Introduction: The impact of ETI therapy on pulmonary function and nutritional status has been widely studied; the literature on the possible outcomes on glycemic control and insulin requirement in patients affected by CFRD is controversial.

Aim: The main objective of our study was to evaluate HbA1c levels in patients with cystic fibrosis-related diabetes (CFRD) after one year of therapy with elexacaftor/tezacaftor/ivacaftor (ETI). The secondary objective was to study the changes in the total daily insulin dose (TDD), pulmonary function and metabolism in this population.

Isolated Radial Nerve Palsy in a Newborn Due to a Congenital Myofibroma: A Rare Case of Peripheral Nerve Injury.

Isolated musculoskeletal infantile myofibroma is a rare tumor of pediatric age. The majority of cases are seen in children under two years old, but it can occur at any age as a painless enlarging mass that involves bone, skin, or soft tissue, typically accompanied by compression symptoms. Perineural involvement is extremely rare in myofibromas.

Impact of the expanded label for elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis with no F508del variant in the USA.

Background: Elexacaftor/tezacaftor/ivacaftor (ETI), which is approved for people with cystic fibrosis (pwCF) with a F508del variant, was further approved based on data in the USA for those carrying at least one of 177 rare (cystic fibrosis transmembrane conductance regulator) variants.

Methods: PwCF, aged ≥6 years, carrying no F508del variant but with at least one of these 177 rare variants, were identified within the US Cystic Fibrosis Foundation Patient Registry (CFFPR) between 2020 and 2022. The evolution of forced expiratory volume in 1 s (FEV) percentage predicted and rates of pulmonary exacerbations were analysed over the first year following ETI initiation, using a linear regression with generalised estimating equations and a negative binomial model, respectively.

Differential times of submission and approval of CFTR modulators for the treatment of Cystic Fibrosis in the United States and the European Union.

Background: The objective of this study was to assess the differential times of submission and approval of CFTR modulators in the United States (US) and the European Union (EU).

Methods: By collecting publicly available data from the websites of the Food and Drug Administration and the European Medicines Agency, we quantified differential times in submission, review duration, and approvals of initial marketing authorization and variation of indications of CFTR modulators in the US and the EU by December 31, 2023.

Results: Applications regarding marketing of 4 CFTR modulators were submitted 103 (SD ±143) days later in the EU than in the US: 31 (SD ±39) days later for initial approval, and 124 (SD ±155) days for supplemental indications.

Cystic fibrosis.

Cystic fibrosis is a rare genetic disease caused by mutations in CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). The discovery of CFTR in 1989 has enabled the unravelling of disease mechanisms and, more recently, the development of CFTR-directed therapeutics that target the underlying molecular defect. The CFTR protein functions as an ion channel that is crucial for correct ion and fluid transport across epithelial cells lining the airways and other organs.

Hypothalamic-pituitary-ovarian axis suppression is common among women during US Army Basic Combat Training.

Objective: Less than half of servicewomen report loss of menses during initial military training. However, self-reported menstrual status may not accurately reflect hypothalamic-pituitary-ovarian (HPO) axis suppression and may underestimate reproductive health consequences of military training. Our aim was to characterise HPO axis function during US Army Basic Combat Training (BCT) in non-hormonal contraceptive-using women and explore potential contributors to HPO axis suppression.

Optical Absorption in Tilted Geometries as an Indirect Measurement of Longitudinal Plasma Waves in Layered Cuprates.

Electromagnetic waves propagating in a layered superconductor with arbitrary momentum, with respect to the main crystallographic directions, exhibit an unavoidable mixing between longitudinal and transverse degrees of freedom. Here we show that this basic physical mechanism explains the emergence of a well-defined absorption peak in the in-plane optical conductivity when light propagates at small tilting angles relative to the stacking direction in layered cuprates. More specifically, we show that this peak, often interpreted as a spurious leakage of the -axis Josephson plasmon, is instead a signature of the true longitudinal plasma mode occurring at larger momenta.

Myofunctional Speech Therapy for Facial Rejuvenation and Orofacial Function Improvement: A Systematic Review.

This review aims to reveal the effectiveness of myofunctional speech therapy on facial rejuvenation and/or improvement of orofacial function. A systematic review of four medical electronic databases (Medline, Google Scholar, SciELO, and LILACS) was conducted between January and March 2023. The research question was defined using the PICO model: Population (P): adult subjects with signs of physiological aging of facial skin.

Retention rate of abatacept in rheumatoid arthritis patients in a real-life setting: results from a monocentric cohort.

Objective: Data from trials demonstrated that abatacept (ABA) has a good safety and efficacy profile in treating rheumatoid arthritis. We have studied the retention rate of ABA in a real-life cohort of patients with rheumatoid arthritis.

Methods: This is a monocentric, retrospective study including patients with rheumatoid arthritis classified by the American College of Rheumatology/European League Against Rheumatism 2010 criteria who started treatment with ABA.

Deriving lessons learned from monitoring adaptation activities in projects under the EU mission on adaptation.

Actions to strengthen climate resilience are gaining more traction. In order to ensure effective adaptation, it is important to monitor the outcomes and impacts of these actions. However, there are numerous challenges and a multitude of approaches when it comes to monitoring adaptation to climate change.

Standards for the care of people with cystic fibrosis (CF); Planning for a longer life.

This is the final of four papers updating standards for the care of people with CF. That this paper "Planning a longer life" was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy.

When Waldenström macroglobulinemia hits the kidney: Description of a case series and management of a "rare in rare" scenario.

Background: Renal injury related to Waldenström macroglobulinemia (WM) occurs in approximately 3% of patients. Kidney biopsy is crucial to discriminate between distinct histopathological entities such as glomerular (amyloidotic and non-amyloidotic), tubulo-interstitial and non-paraprotein mediated renal damage. In this context, disease characterization, management, relationship between renal, and hematological response have been poorly explored.

ECFS standards of care on CFTR-related disorders: Identification and care of the disorders.

This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided.

Neutrophil Extracellular Traps and Thrombolysis Resistance: New Insights for Targeting Therapies.

Background: Thrombosis is linked to neutrophil release of neutrophil extracellular traps (NETs). NETs are proposed as a mechanism of resistance to thrombolysis. This study intends to analyze the composition of thrombi retrieved after mechanical thrombectomy, estimate the age and organization of thrombi, and evaluate associations with the use of thrombolysis, antiplatelets, and heparin.

ECFS standards of care on CFTR-related disorders: Towards a comprehensive program for affected individuals.

After three publications defining an updated guidance on the diagnostic criteria for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (pwCFTR-RDs), establishing its relationship to CFTR-dysfunction and describing the individual disorders, this fourth and last paper in the series addresses some critical challenges facing health care providers and pwCFTR-RD. Topics included are: 1) benefits and obstacles to collect data from pwCFTR-RD are discussed, together with the opportunity to integrate them into established CF-registries; 2) the potential of infants designated CRMS/CFSPID to develop a CFTR-RD and how to communicate this information; 3) a description of the challenges in genetic counseling, with particular regard to phenotypic variability, unknown long-term evolution, CFTR testing and pregnancy termination 4) a proposal for the assessment of potential barriers to the implementation and dissemination of the produced documents to health care professionals involved in the care of pwCFTR-RD and a process to monitor the implementation of the CFTR-RD recommendations; 5) clinical trials investigating the efficacy of CFTR modulators in CFTR-RD and how endpoints and outcomes might be adapted to the heterogeneity of these disorders.

Short-term effects of positive expiratory pressure mask on ventilation inhomogeneity in children with cystic fibrosis: A randomized, sham-controlled crossover study.

Background: Can physiotherapy with a positive expiratory pressure (PEP) mask improve peripheral ventilation inhomogeneity, a typical feature of children with cystic fibrosis (cwCF)? To answer this question, we used the nitrogen multiple-breath washout (NMBW) test to measure diffusion-convection-dependent inhomogeneity arising within the intracinar compartment (S*VT).

Methods: For this randomized, sham-controlled crossover trial, two NMBW tests were performed near the hospital discharge date: one before and the other after PEP mask therapy (1 min of breathing through a flow-dependent PEP device attached to a face mask, followed by three huffs and one cough repeated 10 times) by either a standard (10-15 cmH0) or a sham (<5 cmH0) procedure on two consecutive mornings. Deception entailed misinforming the subjects about the nature of the study; also the NMBW operators were blinded to treatment allocation.

Mitochondrial DNA copy number reduction via knockout remodels the nuclear epigenome and transcriptome.

Mitochondrial DNA copy number (mtDNA-CN) is associated with several age-related chronic diseases and is a predictor of all-cause mortality. Here, we examine site-specific differential nuclear DNA (nDNA) methylation and differential gene expression resulting from reduction of mtDNA-CN to uncover shared genes and biological pathways mediating the effect of mtDNA-CN on disease. Epigenome and transcriptome profiles were generated for three independent human embryonic kidney (HEK293T) cell lines harbouring a mitochondrial transcription factor A () heterozygous knockout generated via CRISPR-Cas9, and matched control lines.

Simultaneous assessment of mitochondrial DNA copy number and nuclear epigenetic age towards predictive models of development and aging.

Objective: Mitochondrial dysfunction and nuclear epigenetic alterations, two hallmarks of aging, are associated with aberrant development and complex disease risk. Here, we report a method for the simultaneous assessment of mitochondrial DNA copy number (mtDNA-CN) and DNA methylation age (DNAm age) from the same DNA extraction using quantitative polymerase chain reaction (qPCR) and array data, respectively.

Result: We present methods for the concurrent estimation of mtDNA-CN and DNAm age from the same DNA samples.

[Cystic fibrosis carrier screening: a Health technology assessment.].

This project of Health technology assessment was aimed at defining the impacts of offering a cystic fibrosis (CF) carrier screening to the general population, compared to the current situation, where the test is offered to individuals at high-risk to give birth to a child with CF. Results revealed: i) a lack of robust and updated data; ii) a return on investment up to six years from the screening's introduction, despite important economic and organizational efforts; iii) a general positive attitude of healthcare professionals, people with CF, families and general population; iv) possible issues related to the social impact.