Bronchiectasis is a common but neglected respiratory condition, particularly in resource-poor countries such as Bangladesh. Cystic fibrosis (CF), a recognized cause of bronchiectasis in children, especially among Caucasians, is increasingly reported in adults of Asian descent. However, CF remains under-recognized in Bangladesh, and no prior data exist on its prevalence in adults. This study aimed to determine the prevalence of CF in adult bronchiectasis patients and to assess their lung function characteristics using spirometry in Bangladesh. This cross-sectional study was conducted in the Department of Respiratory Medicine at Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, from June 2023 to November 2024. A total of 130 adults with bronchiectasis were enrolled in accordance with the inclusion and exclusion criteria. CF diagnosis was established using pilocarpine iontophoresis sweat chloride testing, and lung function severity was assessed by spirometry. Statistical analyses were performed using SPSS version 25. Among 130 participants, 12 were diagnosed with CF, representing 9.2% of patients. Obstructive airway abnormality was the predominant pattern among CF patients (75.0%), with half presenting in the mild category. A moderate negative correlation was observed between forced expiratory volume in 1 s (FEV1 % predicted) and sweat chloride concentration (Cl-) (Spearman's rho = *-0.477, p = 0.117). Approximately one in ten adult bronchiectasis patients in Bangladesh were found to have CF, and most had mild airway obstruction. These findings highlight that CF, traditionally regarded as a childhood disease, should also be considered in adult bronchiectasis, particularly in South Asian populations where it remains underdiagnosed.

Cystic fibrosis (CF) is a genetic disease that causes lung inflammation. Although new treatments have improved the quality of life of people with CF, inflammation remains a problem. Alveolar macrophages have been shown to be important mediators of CF lung inflammation although the interactions between macrophages and other immune cells in CF are poorly understood. To identify and compare the cellular composition between CF and healthy airspace macrophages and monocytes, healthy control and CF subjects underwent bronchoscopy and single-cell RNA sequencing was performed on the BAL fluid. Unbiased clustering identified 12 macrophage subtypes. We found up-regulation of macrophages expressing CDKN1A and LDLR, both of which are known to alter cholesterol metabolism and promote inflammation. Pathway analysis revealed important interactions between macrophages and monocytes in CF that likely contribute to overall inflammation and adaptation of recruited monocytes to the CF lung. Some of the top pathways identified were related to inflammation and lipid metabolism, which may contribute to persistent inflammation in CF. Our results may identify novel potential therapeutic targets to treat CF lung inflammation.

Speech-in-noise difficulties in aminoglycoside ototoxicity reflects combined afferent and efferent dysfunction.

Cystic fibrosis (CF) is a rare, multisystem genetic disease requiring early diagnosis and lifelong multidisciplinary follow-up. In many middle-income countries, including Colombia, national CF registries are absent, and epidemiological information largely relies on administrative health data. Although such data do not reflect true clinical prevalence, they enable systematic monitoring of service-based prevalence and diagnostic practice patterns, offering critical insights for health system planning. We conducted a nationwide, observational study using the Colombian Individual Registry of Provision of Health Services (RIPS) from 2015 to 2024. Children and adolescents aged 0-19 years with CF diagnoses (ICD-10 E84.0-E84.9) were identified. Annual crude and age-standardized administrative prevalence rates were estimated using national population projections. Diagnostic test utilization (spirometry, chest CT, pancreatic elastase, genetic testing) was quantified per 100 encounters. Temporal trends were analyzed using LOESS smoothing with 95% confidence intervals. The age-standardized national administrative prevalence of CF-related healthcare encounters was 5.64 per 100,000. Administrative prevalence was highest in children aged 0-4 years and declined progressively with age. The contributory insurance regime showed the highest service-based prevalence, suggesting disparities in diagnostic access. Temporal patterns revealed a peak in 2018-2019 followed by a decline after 2020, coinciding with COVID-19-related disruptions in pediatric care. Diagnostic utilization was markedly low: spirometry was performed in fewer than 6 tests per 100 encounters annually, chest CT use was sporadic, and genetic testing was minimal before 2018, increasing slightly thereafter. Administrative prevalence of CF in Colombia has remained stable over a decade but is accompanied by underutilization of essential diagnostic procedures and inequities across insurance groups. Strengthening diagnostic capacity, standardizing monitoring practices, and improving early detection are urgent priorities. This study provides a scalable framework for CF surveillance in countries lacking national registries.

Cystic fibrosis (CF) is an autosomal recessive disease caused by variants in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Delivery of a functional CFTR transgene to airway epithelial cells (AEC) offers the potential to provide durable restoration of normal CFTR function. Adeno-associated virus (AAV) vectors are the leading platform for the delivery of in vivo gene therapy; however, wild-type AAV vectors exhibit a limited capacity to transduce airway cells and evade pre-existing human neutralizing antibodies (NAb). We therefore employed a directed evolution platform to invent a novel AAV capsid (A101) with the capacity to efficiently transduce AECs, including in the presence of NAbs, following aerosolized administration to nonhuman primates (NHP). We then engineered 4D-710, a gene therapy comprising the A101 vector and a CFTR transgene with a partial deletion in the regulatory domain (CFTRΔR) to facilitate vector packaging. 4D-710 exhibited efficient transduction of human bronchial epithelial (HBE) cell air-liquid interface (ALI) cultures in vitro and robust functional activity in CF HBE ALI cultures. Aerosolized administration of 4D-710 to NHPs was well tolerated and resulted in dose-dependent transgene expression and increased CFTR protein in diverse AEC types compared with vehicle controls. No significant differences in CFTRΔR mRNA levels were observed in lung samples from NHPs with pre-existing serum anticapsid NAbs compared with NAb-negative NHPs. These findings demonstrate the tolerability and feasibility of A101-mediated transgene delivery and expression in primate airways. A clinical trial evaluating aerosol delivery of 4D-710 in adults with CF (NCT05248230) is underway.

Cystic fibrosis (CF) is a monogenic disorder leading to pulmonary disease, pancreatic insufficiency and cystic fibrosis-related diabetes (CFRD). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now being investigated in people with cystic fibrosis (pwCF) and CFRD. To date, their therapeutic potential has been almost exclusively studied in case reports or case series. These agents improved glycated haemoglobin (HbA1c) and continuous glucose monitoring (CGM) parameters. Benefits were also observed in weight reduction, particularly for subjects on cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI). However, discordant results have also been reported. Moreover, GLP-1RAs have improved pulmonary function, even following lung transplantation. Importantly, the dual glucagon-like peptide1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide has also yielded favourable outcomes. Finally, preliminary evidence suggests potential inhibition of bone resorption, pointing to a therapeutic perspective in cystic fibrosis-related bone disease (CFBD). However, potential adverse events should not be ignored. These include risk of acute pancreatitis, nausea/vomiting, nutritional depletion, bowel dysmotility and distal intestinal obstruction syndrome, as well as others. Adverse events should be addressed with caution, and dose adjustments may be useful. Large prospective multicentre studies are now required to validate these outcomes and to suggest implications for clinical practice.

Cardiovascular disease-associated admissions in patients with Cystic Fibrosis: A 7-Year U.S. National Inpatient Sample Analysis.

When viruses meet cystic fibrosis: Insights into host-pathogen dynamics.

A 50-year-old woman with cystic fibrosis (CF) and lung transplantation developed persistent deep abscesses due to multidrug-resistant (MDR) Burkholderia cenocepacia, unresponsive to multiple antibiotics and surgeries. Combination therapy with sulbactam-durlobactam (SUL-DUR) and cefiderocol (FDC) along with surgical interventions led to clinical and radiographic stability. This report of a successful sulbactam-durlobactam and cefiderocol treatment highlights this targeted β-lactam-β-lactamase inhibitor combination as an option for refractory B. cepacia complex (BCC) infections.

New Lungs, Old Foes: The Challenges of Resistant Infections Pre - and Post-Transplant in a Patient with Cystic Fibrosis

Ceftazidime is an effective antipseudomonal antibiotic, used commonly in cystic fibrosis. Continuous 24-hour intravenous infusion allows children to receive daily treatment at home. However, the instability of 24-h ceftazidime infusions and production of toxic pyridine has led to recommendations not to use them. We aimed to determine a suitable target temperature to limit degradation of ceftazidime in 24-h infusions and assess effectiveness of simple temperature control. For in vitro experiments, infusers with 6g ceftazidime in 0.9% saline were incubated at 4ºC, 25ºC and 33ºC and sampled over 24h to measure ceftazidime and pyridine concentrations using high-performance liquid chromatography. For carried infuser experiments, to simulate 24-h home infusions, children carried two insulated carry bags containing ceftazidime 2g, 6g or 12g infusers with zero, 1 or 2 ice-packs for 24h. Samples were analysed for ceftazidime and pyridine concentrations. Results for in vitro experiments showed that after 24h, ceftazidime remained stable (>90% original concentration) at 4ºC and 25ºC but not 33ºC (decreased to 84%). Pyridine increased over 24h at 4ºC, 25ºC and 33ºC by 50%, 550% and 1,040% respectively. For carried infuser experiments, at a controlled temperature of 17-25ºC, ceftazidime concentration remained >90% for all infusers except 12g with no ice-pack. Pyridine production in infusers with one or two ice-packs were reduced by 44-57% compared to no ice-pack. In conclusion, adding an ice-pack to a ceftazidime infuser in an insulated carry bag halves the pyridine produced. This indicates that a temperature-controlled daily 24-h continuous intravenous infusion of ceftazidime can replace the recommended twice daily 12-h infusions, allowing patients to receive ceftazidime treatment at home.

Refractory Antibody-Mediated Rejection in a Lung Transplant Recipient with Cystic Fibrosis: A Challenging Case

Small-molecule discovery and drug development are increasingly being pursued in academic settings, expanding beyond their traditional confinement to the pharmaceutical industry. The initial steps in drug discovery typically include identification and validation of a target, screening of chemical libraries to identify modulators of target activity, and subsequent prioritization and optimization of lead compounds using in vitro systems and animal models, with emphasis on compound potency, selectivity, and pharmacological properties. This review focuses on early-stage discovery of small molecules that target plasma membrane transporters on epithelial cells, including absorptive and secretory epithelia in kidney, gastrointestinal tract, lung, and eye. Of the estimated 500 distinct epithelial plasma membrane transporters, fewer than a dozen are the targets of approved drugs, most of which have been in clinical use for decades. We discuss the logistics and challenges associated with small-molecule discovery in an academic setting. Specific epithelial cell targets are considered, including chloride channels, solute-coupled transporters, urea transporters, and aquaporins, with therapeutic implications spanning constipation and secretory diarrheas, cystic fibrosis, dry eye disease, edema, hypertension, and kidney stones. We conclude by identifying unmet needs and outlining opportunities to enable next-generation pharmacological modulation of epithelial transport processes.

Advances in DNA technology are revolutionizing the landscape of illness prevention, providing new opportunities to combat hereditary abnormalities and chronic diseases before they manifest. CRISPR-Cas9 gene editing, epigenetic alterations, somatic cell genome editing, and RNA-based therapies are all significant advancements in this field. These techniques enable precise changes to DNA and gene expression, potentially preventing a wide range of illnesses at their genetic origins. The following discussion delves into the transformative potential of these technologies. CRISPR-Cas9 is notable for its precision in fixing defective genes, offering promise for avoiding diseases, such as cystic fibrosis and sickle cell anemia. Epigenetic modifications caused by environmental factors are also opening up new avenues for preventing chronic illnesses and malignancies. Furthermore, somatic cell genome editing is a potential, ethically viable strategy as it targets non-reproductive cells, preventing heritable genetic alterations. Along with these developments, RNA-based therapies are emerging as a new avenue for disease prevention. This paper will explore each of these advancements, their applications, and the ethical and technical challenges involved.

Lung transplant remains the ultimate life-saving therapy for people with progressive end-stage lung disease. It is important to highlight the evolution of the field in the United States, as its development has had varying impacts on the different lung transplant candidate groups. This review seeks to synthesize current evidence on the evolution of transplantation across various patient groups, reflecting advances in medical therapies, the implementation of the new composite allocation score (CAS) and trends in lung transplant candidate groups over the years. The proportion of waitlisted candidate with chronic obstructive pulmonary disease (COPD, group A) and cystic fibrosis (group C) has declined, reflecting the impact of novel therapeutics and advanced procedural interventions. In contrast, restrictive lung disease patients (group D) now account for most lung transplant recipients, which is likely reflective of our increased use of extracorporeal membrane oxygen (ECMO) for bridging and transplant centers expanded eligibility. Pulmonary hypertension patients (group B) continue to face high waitlist mortality despite the change to the new allocation scoring system. Advancements in medical therapies and the new composite allocation scoring system has altered both the timing and outcomes for various transplant candidate groups. It is important that we continue to study these findings to optimize patient outcomes and organ allocation.

The COVID-19 pandemic further emphasized the global demand for heparin and its expanding clinical relevance, indicating that even one of the oldest drugs in medicine continues to reveal new therapeutic horizons. Traditionally recognized for its anticoagulant and antithrombotic activities, heparin is increasingly being explored for its versatile therapeutic potential in the treatment of a range of pulmonary diseases, including respiratory infections (e.g. COVID-19), Acute Respiratory Distress Syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. In all of these diseases, inhaled unfractionated heparin (UFH) therapy has been investigated in a number of clinical trials that have demonstrated promise for this drug when administered directly to the lungs. However, using heparin by this "off label" route of administration, poses a number of technical challenges: the physicochemical properties of heparin at therapeutic doses often results in highly viscous formulations, causing device blockage and drug sorption during nebulization. These limitations underscore the need for innovative formulation strategies to improve aerosol flow, reduce dosing inefficiencies, and enable reliable pulmonary administration. Advancing heparin formulations for delivery to the lung could therefore unlock significant benefits for a wide spectrum of respiratory disorders, marking a new chapter in the long medical history of this drug as discussed below.

Alpha-1-antitrypsin (A1AT) is a multifunctional, clinically important, high-value therapeutic glycoprotein that can be used for the treatment of many diseases, such as A1AT deficiency, diabetes, graft-versus-host disease, cystic fibrosis, and various viral infections. Currently, the only U.S. food and drug administration-approved treatment for A1AT disorders is intravenous augmentation therapy with human plasma-derived A1AT (pdA1AT). In addition to its limited supply, this approach poses a risk of infection transmission, since it uses therapeutic A1AT harvested from donors. To address these issues, we sought to generate recombinant human A1AT (rhA1AT) that is comparable to its plasma-derived counterpart using glycoengineered Chinese Hamster Ovary (geCHO-L) cells. By perturbing nine key genes that are part of the CHO glycosylation machinery and expressing the human ST6GAL1 and A1AT genes, we obtained stable, high producing geCHO-L lines that produced rhA1AT having a highly similar glycoprofile to pdA1AT. Additionally, the rhA1AT demonstrated in vitro activity and in vivo half-life comparable to commercial pdA1AT. Thus, we anticipate that this platform will help produce human-like recombinant plasma proteins, thereby providing a more sustainable and reliable source of therapeutics that are cost-effective and better-controlled regarding purity, clinical safety, and quality.

Fetal Transplacental Therapy to Mitigate Consequences of Cystic Fibrosis.

Pre-Transplant Risk Factors and Associations with Post-Transplant Outcomes for People with Cystic Fibrosis in a Multicenter Cohort

TRXR2, a thioredoxin reductase-encoding gene, contributes to protection against the oxidative stress and virulence in Scedosporium apiospermum.