BMJ Open Respir Res. 2025 Mar 26;12(1):e003044. doi: 10.1136/bmjresp-2024-003044.

ABSTRACT

BACKGROUND: Respiratory virus infections are a major cause of morbidity in early life. During the SARS-CoV-2 pandemic, non-pharmaceutical interventions (NPIs) lead to worldwide changes in respiratory virus epidemiology. However, evidence regarding virus circulation in the outpatient setting remains largely unknown. The aim of this study is to longitudinally assess respiratory viruses in healthy infants before and during the SARS-CoV-2 pandemic in Switzerland.

METHODS: In this prospective observational birth cohort study, we followed 34 infants throughout the first year of life before and during the SARS-CoV-2 pandemic. We analysed 648 biweekly nasal swabs for nine different respiratory viruses by Multiplex-PCR and assessed respiratory symptoms, COVID-19 infections of family members and childcare status in weekly interviews. 712 nasal swabs from 32 infants analysed before the pandemic and published previously served as control group.

RESULTS: During the period with strict NPIs (pandemic I), most common respiratory viruses were not detected, with a rebound (driven by Adenovirus and Parainfluenza virus) after most NPIs were relaxed (pandemic II): prepandemic: 27%, pandemic I: 19%, pandemic II: 33%; historic: 36% of collected swabs per period, p<0.001. Human rhinovirus (HRV) prevalence persisted during NPIs presence, mainly in the form of asymptomatic HRV detection: prepandemic=24%, pandemic I=19%, pandemic II=25%, historic: 25%, p=0.3. SARS-CoV-2 detection (asymptomatic and symptomatic) was low, and only present after NPIs were relaxed: pandemic II=2.4%. No severe COVID-19 infections were reported.

DISCUSSION: In our cohort, infants did not contribute largely to spread of SARS-CoV-2. The role of persisting asymptomatic HRV prevalence is still unclear, but it might help to maintain population immunity to prevent more severe infections. Our results underscore the importance of capturing asymptomatic viruses via longitudinal community-based data assessment to better understand virus transmission.

PMID:40139841 | DOI:10.1136/bmjresp-2024-003044

Biochemistry. 2025 Mar 26. doi: 10.1021/acs.biochem.4c00780. Online ahead of print.

ABSTRACT

Lumacaftor and Ivacaftor are two FDA-approved medications currently used to treat cystic fibrosis (CF), a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel located in epithelial cell membranes; however, the detailed mechanism(s) of their action remains to be elucidated. Both drugs, termed modulators, bind CFTR at a protein-lipid interface, yet Lumacaftor acts at the endoplasmic reticulum (ER), while Ivacaftor acts at the plasma membrane (PM). A major difference among biological membranes is their level of cholesterol (viz., the ER, 5% cholesterol; the Golgi apparatus, 12.5%; and the PM, 30%). Therefore, we investigated the ability of each molecule to interact with membranes of the corresponding cholesterol content to determine if lipid cholesterol content provides a physical basis for their observed localized activity. Using differential scanning calorimetry and a terbium-based liposome disruption assay, we show that both Lumacaftor (a corrector) and Ivacaftor (a potentiator) penetrate/diffuse through membranes containing high cholesterol concentrations, such as in Golgi and the PM. The results further suggest that (1) Lumacaftor resides within membranes containing 5% cholesterol, supporting the proposition that Lumacaftor acts as a corrector of the CFTR channel at the ER level where the nascent protein is in its initial folding stage; and (2) Ivacaftor is well-suited to penetrate the PM and reach its binding pocket on CFTR. Our findings provide evidence that membrane cholesterol levels significantly modulate CFTR corrector/potentiator activity and consequently may affect sensitivity to clinical therapeutics in CF patients.

PMID:40138627 | DOI:10.1021/acs.biochem.4c00780

Pathogens. 2025 Mar 12;14(3):271. doi: 10.3390/pathogens14030271.

ABSTRACT

The Achromobacter genus comprises 22 species and various genogroups. Some species with higher virulence or antibiotic resistance are more likely to cause chronic infections in people with cystic fibrosis (CF). Current identification methods often fail to accurately distinguish between the species or result in misidentifications due to biochemical similarities. This study aims to develop an accurate qPCR protocol for species-level identification that is applicable in clinical diagnostic laboratories. Whole-genome sequencing of clinical isolates from different Achromobacter species identified species-specific single-nucleotide polymorphisms (SNPs) in two 16S gene regions. Based on these SNPs, two sets of primers and qPCR probes were designed to generate unique identification profiles. Thermal profiles were optimized, and qPCR was performed on serial bacterial DNA dilutions to determine the detection limit (LOD). Four probes successfully identified three species: A. xylosoxidans, A. dolens, and A. insuavis. Two additional probes were designed for novel genotypes unrelated to publicly available sequences. The LOD ranged from 0.005 pg/µL to 1 pg/µL. Combined probes achieved 100% sensitivity, with specificity ranging from 97.95% to 100%. This qPCR protocol enables accurate species identification, overcoming the limitations of current methods, and represents a reliable tool for clinical diagnostics.

PMID:40137756 | DOI:10.3390/pathogens14030271

Respirol Case Rep. 2025 Mar 24;13(3):e70146. doi: 10.1002/rcr2.70146. eCollection 2025 Mar.

ABSTRACT

Hepatotoxicity due to Elexacaftor/Tezacaftor/Ivacaftor (ETI) use has been well documented. There are no dose adjustments or increased-frequency monitoring algorithms recommended for people who experience elevated transaminases without cirrhosis, only suggested treatment interruption or withdrawal depending on the severity of the derangement. Here we describe a patient with non-cirrhotic hepatic steatosis who experienced persistently elevated liver function tests due to modulator therapy but demonstrated a remarkable response to a notably low dose of ETI.

PMID:40134928 | PMC:PMC11932953 | DOI:10.1002/rcr2.70146

J Fungi (Basel). 2025 Mar 9;11(3):210. doi: 10.3390/jof11030210.

ABSTRACT

Cystic fibrosis is a severe, inherited, life-limiting disorder, and over half of those living with CF are children. Persistent airway infection and inflammation, resulting in progressive lung function decline, is the hallmark of this disorder. Aspergillus colonization and infection is a well-known complication in people with CF and can evolve in a range of Aspergillus disease phenotypes, including Aspergillus bronchitis, fungal sensitization, and allergic bronchopulmonary aspergillosis (ABPA). Management strategies for children with CF are primarily aimed at preventing lung damage and lung function decline caused by bacterial infections. The role of Aspergillus infections is less understood, especially during childhood, and therefore evidence-based diagnostic and treatment guidelines are lacking. This narrative review summarizes our current understanding of the impact of Aspergillus on the airways of children and young people with CF.

PMID:40137248 | DOI:10.3390/jof11030210

Cells. 2025 Mar 19;14(6):459. doi: 10.3390/cells14060459.

ABSTRACT

Polycystic kidney disease (PKD) is the most common hereditary disorder that disrupts renal function and frequently progresses to end-stage renal disease. Recent advances have elucidated the critical role of primary cilia and ciliary ion channels, including transient receptor potential (TRP) channels, cystic fibrosis transmembrane conductance regulator (CFTR), and polycystin channels, in the pathogenesis of PKD. While some channels primarily function as chloride conductance channels (e.g., CFTR), others primarily regulate calcium (Ca+2) homeostasis. These ion channels are essential for cellular signaling and maintaining the normal kidney architecture. Dysregulation of these pathways due to genetic mutations in PKD1 and PKD2 leads to disrupted Ca+2 and cAMP signaling, aberrant fluid secretion, and uncontrolled cellular proliferation, resulting in tubular cystogenesis. Understanding the molecular mechanisms underlying these dysfunctions has opened the door for innovative therapeutic strategies, including TRPV4 activators, CFTR inhibitors, and calcimimetics, to mitigate cyst growth and preserve renal function. This review summarizes the current knowledge on the roles of ciliary ion channels in PKD pathophysiology, highlights therapeutic interventions targeting these channels, and identifies future research directions for improving patient outcomes.

PMID:40136708 | DOI:10.3390/cells14060459

Cells. 2025 Mar 9;14(6):400. doi: 10.3390/cells14060400.

ABSTRACT

Pulmonary homeostasis can be agitated either by external environmental insults or endogenous factors produced during respiratory/pulmonary diseases. The lungs counter these insults by initiating mechanisms of inflammation as a localized, non-specific first-line defense response. Cytokines are small signaling glycoprotein molecules that control the immune response. They are formed by numerous categories of cell types and induce the movement, growth, differentiation, and death of cells. During respiratory diseases, multiple proinflammatory cytokines play a crucial role in orchestrating chronic inflammation and structural changes in the respiratory tract by recruiting inflammatory cells and maintaining the release of growth factors to maintain inflammation. The issue aggravates when the inflammatory response is exaggerated and/or cytokine production becomes dysregulated. In such instances, unresolving and chronic inflammatory reactions and cytokine production accelerate airway remodeling and maladaptive outcomes. Pro-inflammatory cytokines generate these deleterious consequences through interactions with receptors, which in turn initiate a signal in the cell, triggering a response. The cytokine profile and inflammatory cascade seen in different pulmonary diseases vary and have become fundamental targets for advancement in new therapeutic strategies for lung diseases. There are considerable therapeutic approaches that target cytokine-mediated inflammation in pulmonary diseases; however, blocking specific cytokines may not contribute to clinical benefit. Alternatively, broad-spectrum anti-inflammatory approaches are more likely to be clinically effective. Herein, this comprehensive review of the literature identifies various cytokines (e.g., interleukins, chemokines, and growth factors) involved in pulmonary inflammation and the pathogenesis of respiratory diseases (e.g., asthma, chronic obstructive pulmonary, lung cancer, pneumonia, and pulmonary fibrosis) and investigates targeted therapeutic treatment approaches.

PMID:40136649 | DOI:10.3390/cells14060400

Rev Paul Pediatr. 2025 Mar 24;43:e2024155. doi: 10.1590/1984-0462/2025/43/2024155. eCollection 2025.

ABSTRACT

OBJECTIVE: Determine the immediate effect of forced expiration technique (FET) on the respiratory mechanics of children and adolescents with cystic fibrosis (CF). As a secondary objective, the effect of cough induced by FET was evaluated by comparing respiratory mechanics and lung function between those who coughed and those who did not during the FET.

METHODS: A before-after clinical trial was conducted with children and adolescents with CF aged six to 15 years. Respiratory mechanics parameters were assessed using the impulse oscillometry system (IOS) in three stages: basal IOS, post-huff IOS, and final post-diaphragmatic breathing exercises (DBE) IOS. For the intervention, FET was requested with five low-volume followed by three high-volume huffs, and finally ten DBE repetitions. Coughing occurred randomly and was not previously requested. To investigate whether FET-induced coughing alters oscillometric parameters, the participants were divided into two groups: those who presented with cough (CG) during the protocol and those who did not (NCG).

RESULTS: Forty-three children and adolescents with CF participated in the study (51.2% female), with an average age of 10.44±2.64 years, where forced expiratory value - FEV1=78.51±23.28%, and body mass index - BMI=17.18±2.24 kg/m2. The huffing sequence increased all oscillometric parameters, while DBE repetitions led to an increase in these parameters, without a complete return to baseline values. In terms of coughing, there was no significant difference between the NCG and CG in any of the parameters studied.

CONCLUSIONS: It was observed that, during the FET, diaphragmatic breathing exercises can attenuate the effort exerted by the forced expiratory maneuver on the airways.

PMID:40136119 | DOI:10.1590/1984-0462/2025/43/2024155

J Bacteriol. 2025 Mar 26:e0002925. doi: 10.1128/jb.00029-25. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen that uses several mechanisms to survive in the iron-limiting host environment. The innate immune protein calprotectin (CP) sequesters ferrous iron [Fe(II)], among other divalent transition metal ions, to limit its availability to pathogens. CP levels are increased in individuals with cystic fibrosis (CF), a hereditary disease that leads to chronic pulmonary infection by P. aeruginosa. We previously showed that aerobic CP treatment of P. aeruginosa induces a multi-metal starvation response that alters expression of several virulence properties. However, the CF lung is a hypoxic environment due to the growth of P. aeruginosa in dense biofilms. Here, we report that anaerobic CP treatment of P. aeruginosa induces many processes associated with an aerobic iron starvation response, including decreased phenazine production and increased expression of the PrrF small regulatory RNAs (sRNAs). However, the iron starvation response elicited by CP in anaerobic conditions shows characteristics that are distinct from responses observed in aerobic growth, including a lack of siderophore production and increased induction of genes for the FeoAB Fe(II) and Phu heme uptake systems. Also distinct from aerobic conditions, CP treatment induces expression of genes for predicted manganese transporters MntH1 and MntH2 during anaerobic growth while eliciting a less robust zinc starvation response compared to aerobic conditions. Induction of mntH2 is dependent on the PrrF sRNAs, suggesting a novel example of metal regulatory cross-talk. Thus, anaerobic CP treatment results in a multi-metal starvation response with key distinctions from aerobic conditions, revealing differences in P. aeruginosa metal homeostasis during anaerobic growth.IMPORTANCEIron is critical for most microbial pathogens, and the innate immune system sequesters this metal to limit microbial growth. Pathogens must overcome iron sequestration to survive during infection. For many pathogens, iron homeostasis has primarily been studied in aerobic conditions. Nevertheless, some host environments are hypoxic, including chronic lung infection sites in individuals with cystic fibrosis (CF). Here, we use the innate immune protein calprotectin, which sequesters divalent metal ions including Fe(II), to study the anaerobic iron starvation response of a common CF lung pathogen, Pseudomonas aeruginosa. We report several distinctions of this response during anaerobiosis, highlighting the importance of carefully considering the host environment when investigating the role of nutritional immunity in host-pathogen interactions.

PMID:40135923 | DOI:10.1128/jb.00029-25

J Bacteriol. 2025 Mar 26:e0011623. doi: 10.1128/jb.00116-23. Online ahead of print.

ABSTRACT

Staphylococcus aureus asymptomatically colonizes the nasal cavity and pharynx of up to 60% of the human population and, as an opportunistic pathogen, can breach its normal habitat, resulting in life-threatening infections. S. aureus infections are of additional concern for populations with impaired immune function such as those with cystic fibrosis (CF) or chronic granulomatous disease. Multi-drug resistance is increasingly common in S. aureus infections, creating an urgent need for new antimicrobials or compounds that improve efficacy of currently available antibiotics. S. aureus biofilms, such as those found in the lungs of people with CF and in soft tissue infections, are notoriously recalcitrant to antimicrobial treatment due to the characteristic metabolic differences associated with a sessile mode of growth. In this work, we show that another CF pathogen, Burkholderia cenocepacia, produces one or more secreted compounds that can prevent S. aureus biofilm formation and inhibit existing S. aureus biofilms. The B. cenocepacia-mediated antagonistic activity is restricted to S. aureus species and perhaps some other staphylococci; however, this inhibition does not necessarily extend to other Gram-positive species. This inhibitory activity is due to death of S. aureus through a contact-independent mechanism, potentially mediated through the siderophore pyochelin and perhaps additional compounds. This works paves the way to better understanding of interactions between these two bacterial pathogens.IMPORTANCEStaphylococcus aureus is a major nosocomial pathogen responsible for infecting thousands of people each year. Some strains are becoming increasingly resistant to antimicrobials, and consequently new treatments must be sought. This paper describes the characterization of one or more compounds capable of inhibiting S. aureus biofilm formation and may potentially lead to development of a new therapeutic.

PMID:40135855 | DOI:10.1128/jb.00116-23

J Cyst Fibros. 2025 Mar 24:S1569-1993(25)00077-3. doi: 10.1016/j.jcf.2025.03.009. Online ahead of print.

ABSTRACT

BACKGROUND: We aimed to build a cohort of Maternal-Cystic Fibrosis (CF) fetal dyads treated in utero with Variant Specific Therapy (VST), to assess the efficacy on Meconium Ileus (MI) and potential adverse effects of treatment.

METHODS: Dyads were included if the foetus had a genetic diagnosis of CF and carried at least one variant responsive to VST. Standardized assessment included pre-VST Magnetic Resonance Imaging (MRI), repeated ultrasound (US), and VST drug concentrations in cord blood, maternal and infant plasma.

RESULTS: We enrolled 13 dyads. One withdrew from the study. VST therapies (Elexacaftor (ELX)/Tezacaftor (TEZ)/Ivacaftor(IVA) (ETI) n = 11, ivacaftor (IVA) n = 1) were administered to the pregnant women between 19 and 36 weeks' of gestation for a median[IQR] of 35[55] days, either as a curative indication of MI (n = 8) or as a tertiary prevention of fetal CF-related intestinal symptoms (n = 4). One foetus experienced increased bowel dilatation after ETI introduction. MRI revealed intestinal atresia. One dyad received only 2 doses. In the other 6 cases, resolution of MI was observed within 14[10] days of ETI. Fetal development and neonatal tolerance were excellent. Fecal elastase at birth was always below 200 ng/g even in the ETI breast-fed infant. Cord-to-maternal concentration yielded median ratios of 0.40 for ELX, 0.54 for IVA and 1.59 for TEZ.

CONCLUSION: ETI administration from the third trimester of pregnancy enables MI resolution. Trans-placental transfer is high. Fetal tolerance at ETI initiation needs to be monitored by a standardized assessment.

PMID:40133101 | DOI:10.1016/j.jcf.2025.03.009

BMJ Open. 2025 Mar 25;15(3):e091357. doi: 10.1136/bmjopen-2024-091357.

ABSTRACT

INTRODUCTION: Target trial emulation is a framework for evaluating the effects of treatments using observational data. The trial emulation approach involves specifying key elements of a protocol for a target trial (a randomised controlled trial designed to address the question of interest) and then describing how best to emulate the trial using observational data. Recent years have seen an uptake of target trial emulation in several disease areas, although there are limited examples in cystic fibrosis (CF). This protocol describes a study which aims to assess the applicability of target trial emulation in CF. We aim to emulate an existing trial in CF and assess to what extent the results from the trial can be replicated using registry data.

METHODS AND ANALYSIS: The target trial is a published randomised controlled trial which found evidence for beneficial effects of azithromycin use on lung function in young adults with CF. Two emulated trials are planned: one using data from the UK CF Registry and one using data from the US CF Registry. The inclusion and exclusion criteria, treatment and outcome definitions, follow-up period, and estimand of interest are all designed to match the published trial as closely as possible. The analysis step of the trial emulations will use causal inference methods to control for confounding. Results obtained in the emulated trials using registry data will be compared with those from the target trial.

ETHICS AND DISSEMINATION: Ethical approval has been granted by the London School of Hygiene and Tropical Medicine Ethics Committee (Ref: 29609). This study has also been approved by the UK CF Registry Research Committee and the North Star Review Board. The results of this study will be published in a peer-reviewed journal and presented at relevant scientific conferences.

PMID:40132841 | DOI:10.1136/bmjopen-2024-091357

Respir Med. 2025 Mar 23:108052. doi: 10.1016/j.rmed.2025.108052. Online ahead of print.

ABSTRACT

PURPOSE: Nontuberculous mycobacterial pulmonary disease (NTMPD) is a chronic, often progressive condition associated with a significant symptom burden and increased mortality. Goals of NTMPD treatment include microbiological eradication, symptom reduction, improved quality of life (QoL), and preventing disease progression. Antibiotics are used to reduce microbial burden and cultures of sputum are used to guide treatment. However, it is unclear whether achieving culture-negative status (often called "culture conversion") is associated with improved clinical outcomes. Studies use a variety of measures including symptom burden, radiological status, lung function, six-minute walk test distance, QoL assessments, and mortality to evaluate clinical outcomes related to changes in how patients feel, function, and survive. There is strong interest in more clearly understanding which clinical benefits may be associated with culture conversion. As NTMPD can cause sustained structural lung damage and declines in long-term pulmonary function, it is important to have clear evidence if prevention of these morbidities is associated with culture conversion.

METHODS: This targeted literature review summarizes the published evidence regarding associations between sputum culture conversion and clinical outcomes in patients with NTMPD. Identified studies used varying definitions of culture conversion and treatment success, making interpretation of outcomes across studies challenging.

RESULTS: Although some studies suggest an association between culture conversion and aspects of clinical improvement, overall, there are currently few high-quality studies supporting a link.

CONCLUSION: Further clarification of the relationship between culture conversion and clinical outcomes would be helpful in improving clinical monitoring and therapeutic decision-making during the treatment of patients with NTMPD.

PMID:40132751 | DOI:10.1016/j.rmed.2025.108052

Am J Respir Crit Care Med. 2025 Mar 25. doi: 10.1164/rccm.202503-0579ED. Online ahead of print.

NO ABSTRACT

PMID:40132170 | DOI:10.1164/rccm.202503-0579ED

JCI Insight. 2025 Mar 25:e191098. doi: 10.1172/jci.insight.191098. Online ahead of print.

ABSTRACT

Type 2 inflammatory diseases are common in cystic fibrosis (CF) including asthma, sinusitis, and allergic bronchopulmonary aspergillosis. CD4+ T helper 2 (Th2) cells promote these diseases through secretion of IL-4, IL-5, and IL-13. Whether the cystic fibrosis transmembrane conductance regulator (CFTR), the mutated protein in CF, has a direct effect on Th2 development is unknown. Using murine models of CFTR deficiency and human CD4+ T cells, we show CD4+ T cells expressed Cftr transcript and CFTR protein following activation. Loss of T cell CFTR expression increased Th2 cytokine production compared to control cells. Mice with CFTR-deficient T cells developed increased allergic airway disease to Alternaria alternata extract compared to control mice. Culture of CFTR-deficient Th2 cells demonstrated increased IL-4Rα expression and increased sensitivity to IL-4 with greater induction of GATA3 and IL-13 compared to control Th2 cell cultures. The CFTR potentiator ivacaftor reduced allergic inflammation and type 2 cytokine secretion in bronchoalveolar lavage of "humanized" CFTR mice following Alternaria alternata extract challenge and decreased Th2 development in human T cell culture. Together, these data support a direct role of CFTR in regulating T cell sensitivity to IL-4 and demonstrate a potential CFTR-specific therapeutic strategy for Th2 cell-mediated allergic disease.

PMID:40131363 | DOI:10.1172/jci.insight.191098

Curr Res Microb Sci. 2025 Feb 28;8:100367. doi: 10.1016/j.crmicr.2025.100367. eCollection 2025.

ABSTRACT

Antimicrobial peptides (AMPs) offer a promising alternative to control airway infections with multi-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), which commonly infects patients with cystic fibrosis (CF). However, the behavior of AMPs in the CF context has yet to be fully elucidated. CF airways produce large amounts of proteases and viscous mucus (sputum), which may affect the efficacy of AMPs. The present work aimed to determine whether CF conditions affect the bactericidal efficacy of CAMA, a promising AMP known to kill clinical MRSA strains efficiently. Using a killing assay, we quantified CAMA bactericidal activity on a CF clinical MRSA strain in the presence of several compounds of CF airways, including sputum and bronchial epithelial cells (BECs). Our results indicate that CF sputum impairs the bactericidal efficacy of CAMA. Similar results were observed when CAMA was incubated with an artificial sputum medium (ASM). When used separately, sputum components (DNA, lipids, and mucins) reproduced the inhibitory effects of ASM. Additionally, the bactericidal efficacy of CAMA was also slightly altered when planktonic S. aureus strains were co-cultured with CF BECs. However, CAMA was not active against S. aureus cultured on BEC in biofilm mode, characteristic of chronic infections in CF patients. These findings suggest that although CAMA represents a promising tool to treat MRSA strains, the CF environment may impair the efficacy of this AMP. Identifying strategies to protect AMPs from the deleterious effects of CF sputum is a key priority.

PMID:40129463 | PMC:PMC11931299 | DOI:10.1016/j.crmicr.2025.100367

United European Gastroenterol J. 2025 Mar 25. doi: 10.1002/ueg2.70012. Online ahead of print.

ABSTRACT

Malabsorption is a complex and multifaceted condition characterised by the defective passage of nutrients into the blood and lymphatic streams. Several congenital or acquired disorders may cause either selective or global malabsorption in both children and adults, such as cystic fibrosis, exocrine pancreatic insufficiency (EPI), coeliac disease (CD) and other enteropathies, lactase deficiency, small intestinal bacterial overgrowth (SIBO), autoimmune atrophic gastritis, Crohn's disease, and gastric or small bowel resections. Early recognition of malabsorption is key for tailoring a proper diagnostic work-up for identifying the cause of malabsorption. A patient's medical and pharmacological history is essential for identifying risk factors. Several examinations such as endoscopy with small intestinal biopsies, non-invasive functional tests and radiological imaging are useful in diagnosing malabsorption. Because of its high prevalence, CD should always be looked for in cases of malabsorption with no other obvious explanations and in high-risk individuals. Nutritional support is key in the management of patients with malabsorption; different options are available, including oral supplements, enteral or parenteral nutrition. In patients with short bowel syndrome, teduglutide proved effective in reducing the need for parenteral nutrition, thus improving the quality of life of these patients. Primary care physicians play a central role in the early detection of malabsorption and should be involved in multidisciplinary teams for improving the overall management of these patients. In this European consensus, involving ten scientific societies and several experts, we have dissected all the issues around malabsorption, including the definitions and diagnostic testing (Part 1), high-risk categories and special populations, nutritional assessment and management, and primary care perspective (Part 2).

PMID:40129317 | DOI:10.1002/ueg2.70012

Orphanet J Rare Dis. 2025 Mar 24;20(1):142. doi: 10.1186/s13023-025-03661-z.

ABSTRACT

BACKGROUND: Hereditary bronchiectasis refers to a subset of bronchiectasis related to genetic mutations, presenting with common clinical features. Historically, diagnosing this condition has been difficult due to the inaccessibility of diagnostic services coupled with a lack of awareness of the syndrome. We hypothesize that whole exome sequencing (WES) in patients with supporting clinical features, combined with non-genetic testing methods, will enhance the diagnosis of hereditary bronchiectasis.

RESULTS: In total, 87 patients with clinical features suggestive of hereditary bronchiectasis, such as diffuse bronchiectasis (≥ 2 lobes) combined with early onset symptoms, recurrent otitis media, rhinosinusitis, infertility, organ laterality defects or a family history of bronchiectasis, were included in this study. Among them, 49.4% (43/87) were diagnosed with hereditary bronchiectasis, including 15 patients with cystic fibrosis, 27 patients with primary ciliary dyskinesia, and 1 patient with immunodeficiency-21. The combined use of WES and non-genetic testing methods significantly improved the diagnostic rate of hereditary bronchiectasis compared to non-genetic testing alone (47.1% vs. 25.3%, P = 0.005). Re-analysis of negative commercial genetic tests led to two additional diagnoses, though this increase was not statistically significant (47.1% vs. 49.4%, P = 0.879).

CONCLUSIONS: We have described the supporting clinical features of patients with hereditary bronchiectasis. Clinicians should recommend WES for patients exhibiting these characteristics, in combination with accessible non-genetic testing methods, to maximize diagnostic accuracy. For patients with negative initial genetic test results, re-analysis of WES data may facilitate obtaining a new diagnosis.

PMID:40128832 | DOI:10.1186/s13023-025-03661-z

Function (Oxf). 2025 Mar 24:zqaf016. doi: 10.1093/function/zqaf016. Online ahead of print.

ABSTRACT

Extracellular ATP is a signaling molecule that acts as a paracrine and autocrine modulator of cell function. Here we characterized the role of luminal ATP in the regulation of epithelial principal cells (PCs) in the epididymis, an understudied organ that plays crucial roles in male reproduction. We previously showed that ATP secretion by PCs is part of a complex communication system that ensures the establishment of an optimal luminal acidic environment in the epididymis. However, the molecular mechanisms regulating ATP release and the role of ATP-mediated signaling in PCs acidifying functions are not fully understood. In other cell types, Pannexin 1 (PANX-1) has been associated with ATP-induced ATP release through interaction with the purinergic P2 × 7 receptor. Here, we show that PANX-1 and P2 × 7 are located in the apical membrane of PCs in the mouse epididymis. Functional analysis using the immortalized epididymal PCs cell line (DC2) and the mouse epididymis perfused in vivo showed that: 1) PANX-1 and P2 × 7 participate in ATP release by DC2 cells, together with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR); 2) Several ATP-activated P2Y and P2X purinergic receptors are expressed in DC2 cells; 3) The non-hydrolysable ATP analogue ATPγS induces a dose-dependent increase in intracellular Ca2+ concentration in DC2 cells, a process that is mainly mediated by P2 × 7; and 4) Perfusion of the epididymal lumen in vivo with ATPγS induces the internalization of apical sodium-hydrogen exchanger 3 (NHE3) in PCs. Altogether, this study shows that luminal ATP, regulated by CFTR, PANX-1 and P2 × 7, modulates sodium-proton exchange in PCs in an autocrine-manner through activation of purinergic receptor-mediated intracellular calcium signaling.

PMID:40128095 | DOI:10.1093/function/zqaf016

J Clin Endocrinol Metab. 2025 Mar 24:dgaf165. doi: 10.1210/clinem/dgaf165. Online ahead of print.

NO ABSTRACT

PMID:40126533 | DOI:10.1210/clinem/dgaf165