Front Pediatr. 2023 Dec 4;11:1322360. doi: 10.3389/fped.2023.1322360. eCollection 2023.

ABSTRACT

BACKGROUND: Currently, there are no guidelines or consensus statements about the usage of inhaled mucoactive drugs in pediatric respiratory disease conditions from an Indian perspective.

OBJECTIVE: To develop a practical consensus document to help pediatricians in clinical decision-making when choosing an appropriate mucoactive drug for the management of specific respiratory disease conditions.

METHODS: A committee of nine experts with significant experience in pediatric respiratory disease conditions and a microbiological expert constituted the panel. An electronic search of the PubMed/MEDLINE, Cochrane Library, Scopus, and Embase databases was undertaken to identify relevant articles. Various combinations of keywords such as inhaled, nebulized, mucoactive, mucolytic, mucokinetic, expectorants, mucoregulators, mucociliary clearance, respiratory disorders, pediatric, cystic fibrosis (CF), non-CF bronchiectasis, acute wheezing, asthma, primary ciliary dyskinesia (PCD), critically ill, mechanical ventilation, tracheomalacia, tracheobronchomalacia, esophageal atresia (EA), tracheoesophageal fistula (TEF), acute bronchiolitis, sputum induction, guideline, and management were used. Twelve questions were drafted for discussion. A roundtable meeting of experts was conducted to arrive at a consensus. The level of evidence and class of recommendation were weighed and graded.

CONCLUSIONS: Inhaled mucoactive drugs (hypertonic saline, dry powder mannitol, and dornase alfa) can enhance mucociliary clearance in children with CF. Experts opined that hypertonic saline could be beneficial in non-CF bronchiectasis, acute bronchiolitis, and PCD. The current state of evidence is inadequate to support the use of inhaled mucoactive drugs in asthma, acute wheezing, tracheomalacia, tracheobronchomalacia, and EA with TEF.

PMID:38111626 | PMC:PMC10725989 | DOI:10.3389/fped.2023.1322360

Klin Padiatr. 2023 Dec 18. doi: 10.1055/a-2214-7217. Online ahead of print.

ABSTRACT

RATIONALE: Multiple-breath washout (MBW)-derived lung clearance index (LCI) detects lung disease in children with cystic fibrosis (CF). Correction of a cross-talk error in the software of the MBW device Exhalyzer D in a new software version has generated significant interest regarding its impact on previous MBW findings. Since LCI and chest magnetic resonance imaging (MRI) correlated before in CF children, this study aims to reassess previous MBW data after correction.

PATIENTS/METHODS: Reanalysis of the main findings from a previously published study comparing MBW and MRI in a pediatric CF cohort by reassessment of nitrogen (N2) MBW of 61 stable children with CF, 75 age-matched healthy controls (HC), and 15 CF children with pulmonary exacerbation (PEx) in the corrected software version.

RESULTS: The corrected LCI (N2LCIcor) decreased in the entire cohort (-17.0 (11.2)%), HC (-8.5 (8.2)%), stable CF children (-22.2 (11.1)%), and within the PEx group at baseline, at PEx and after antibiotic therapy (-21.5 (7.3)%; -22.5 (6.1)%; -21.4 (6.6)%; all P<0.01). N2LCIcor and N2LCIpre correlated with chest MRI scores in stable CF (r=0.70 to 0.84; all P<0.01) without a significant difference between N2LCIcor and N2LCIpre. Change in LCI from baseline to PEx and from PEx to after therapy decreased from N2LCIpre to N2LCIcor, but these changes remained significant (all P=0.001).

DISCUSSION/CONCLUSIONS: Our results indicate that N2LCIcor is significantly lower than N2LCIpre, but key results published in the original study demonstrating N2MBW and MRI as complementary methods for clinical surveillance in children with CF remain unaffected.

PMID:38109903 | DOI:10.1055/a-2214-7217

Elife. 2023 Dec 18;12:RP88659. doi: 10.7554/eLife.88659.

ABSTRACT

Malfunction of the CFTR protein results in cystic fibrosis, one of the most common hereditary diseases. CFTR functions as an anion channel, the gating of which is controlled by long-range allosteric communications. Allostery also has direct bearings on CF treatment: the most effective CFTR drugs modulate its activity allosterically. Herein, we integrated Gaussian network model, transfer entropy, and anisotropic normal mode-Langevin dynamics and investigated the allosteric communications network of CFTR. The results are in remarkable agreement with experimental observations and mutational analysis and provide extensive novel insight. We identified residues that serve as pivotal allosteric sources and transducers, many of which correspond to disease-causing mutations. We find that in the ATP-free form, dynamic fluctuations of the residues that comprise the ATP-binding sites facilitate the initial binding of the nucleotide. Subsequent binding of ATP then brings to the fore and focuses on dynamic fluctuations that were present in a latent and diffuse form in the absence of ATP. We demonstrate that drugs that potentiate CFTR's conductance do so not by directly acting on the gating residues, but rather by mimicking the allosteric signal sent by the ATP-binding sites. We have also uncovered a previously undiscovered allosteric 'hotspot' located proximal to the docking site of the phosphorylated regulatory (R) domain, thereby establishing a molecular foundation for its phosphorylation-dependent excitatory role. This study unveils the molecular underpinnings of allosteric connectivity within CFTR and highlights a novel allosteric 'hotspot' that could serve as a promising target for the development of novel therapeutic interventions.

PMID:38109179 | DOI:10.7554/eLife.88659

J Korean Soc Radiol. 2023 Nov;84(6):1257-1265. doi: 10.3348/jksr.2023.0074. Epub 2023 Nov 2.

ABSTRACT

Cystic fibrosis (CF) is a fatal hereditary disorder that primarily affects Caucasians and is rare in Asian populations, including Koreans. Diagnosing CF is often challenging and delayed owing to its rarity and its overlapping features with non-CF diseases, ultimately affecting the patient prognosis. Radiologists can provide initial clues for clinically unsuspected cases and play a crucial role in establishing an early childhood diagnosis. This pictorial essay reviews the clinical and imaging features of genetically confirmed CF in Korean children and increases awareness of this rare disease, thereby facilitating early diagnosis.

PMID:38107683 | PMC:PMC10721430 | DOI:10.3348/jksr.2023.0074

RSC Med Chem. 2023 Sep 25;14(12):2459-2472. doi: 10.1039/d3md00448a. eCollection 2023 Dec 13.

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) gets activated via the cAMP signaling pathway and is present in various secretory epithelial cells, including conjunctival and corneal epithelial cells. Activation of CFTR leads to fluid secretion in both mouse and human ocular surfaces. Dry eye disease is a significant health problem for which limited therapeutic options are available. In this review, on the one hand, small molecule CFTR activators with different chemical structures are summarized, and on the other hand, the pharmacological activity test and structural optimization of small molecule CFTR activators in the treatment of dry eye are outlined. The purpose of this review is to highlight the important role of CFTR activators in the treatment of dry eye disease and their potential as a new strategy for the treatment of dry eye disease.

PMID:38107177 | PMC:PMC10718525 | DOI:10.1039/d3md00448a

EClinicalMedicine. 2023 Oct 4;65:102237. doi: 10.1016/j.eclinm.2023.102237. eCollection 2023 Nov.

ABSTRACT

BACKGROUND: Zapnometinib is an oral, non-ATP-competitive, small-molecule inhibitor of MEK1/MEK2 with immunomodulatory and antiviral properties. We aimed to investigate the safety and efficacy of zapnometinib in patients with COVID-19.

METHODS: In this randomised, double-blind, placebo-controlled, multicentre, proof-of-concept, phase 2 trial, we recruited hospitalised adults with moderate or severe COVID-19 from 18 hospitals in Germany, India, Romania, South Africa, and Spain. Those requiring ICU admission or ventilator support at screening or randomisation were excluded. Patients were randomly assigned (1:1) to receive oral zapnometinib (900 mg on Day 1; 600 mg on Days 2-6) or matching placebo, on top of standard of care. Randomisation, stratified by baseline clinical severity status (CSS 3 or 4, measured on a 7-point ordinal scale), was done using Interactive Response Technology. Patients, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was CSS at Day 15 and was conducted on the full analysis set (FAS: all patients who were randomised to the study, received at least one dose of study medication and had at least one post-dose assessment of CSS, as randomised). Safety analyses were conducted on the safety analysis set (all study participants who received at least one dose of study medication, as treated). This study is registered at ClinicalTrials.gov (NCT04776044) and EudraCT (2020-004206-59).

FINDINGS: The trial was terminated early as the emergence of the Omicron variant impacted recruitment. Between 12th April 2021 and 9th August 2022, 104 of the planned 220 patients were enrolled and randomly assigned, 103 were treated, and 101 were included in the FAS (zapnometinib: n = 50; placebo: n = 51). The primary outcome was not significantly different between the two groups, but patients on zapnometinib had higher odds of improved CSS versus placebo (odds ratio [OR] 1.54 [95% CI 0.72-3.33]; p = 0.26). Predefined subgroup analyses identified trends for improved CSS in patients with severe disease at baseline (OR 2.57 [0.76-8.88]; p = 0.13) and non-Omicron variants (OR 2.36 [0.85-6.71]; p = 0.10); the p value of the CSS subgroup by Treatment interaction term in the model was p = 0.28. The frequency and intensity of adverse events was low and similar between arms. Twenty (39.2%) patients treated with zapnometinib experienced adverse events compared with eighteen (34.6%) patients treated with placebo. One patient receiving zapnometinib and two patients receiving placebo died during the study. None of the deaths were considered related to study medication.

INTERPRETATION: These results provide proof-of-concept for the innovative approach of targeting the Raf/MEK/ERK pathway in patients with hospitalised moderate/severe COVID-19. Further clinical studies will be required to evaluate the clinical benefit of zapnometinib in this and other indications.

FUNDING: Atriva Therapeutics GmbH and the Federal Ministry of Education and Research, Germany.

PMID:38106555 | PMC:PMC10725048 | DOI:10.1016/j.eclinm.2023.102237

bioRxiv. 2023 Dec 6:2023.12.05.570291. doi: 10.1101/2023.12.05.570291. Preprint.

ABSTRACT

Due to their frequent coexistence in many polymicrobial infections, including in patients with burn or chronic wounds or cystic fibrosis, recent studies have started to investigate the mechanistic details of the interaction between the opportunistic pathogens Pseudomonas aeruginosa and Staphylococcus aureus . P. aeruginosa rapidly outcompetes S. aureus under in vitro co-cultivation conditions, which is mediated by several of P. aeruginosa 's virulence factors. Here, we report that polyphosphate (polyP), an efficient stress defense system and virulence factor in P. aeruginosa , plays a role for the pathogen's ability to inhibit and kill S. aureus in a contact-independent manner. We show that P. aeruginosa cells characterized by low polyP level are less detrimental to S. aureus growth and survival while the gram-positive pathogen is significantly more compromised by the presence of P. aeruginosa cells that produce high level of polyP. We show that the polyP-dependent phenotype could be a direct effect by the biopolymer, as polyP is present in the spent media and causes significant damage to the S. aureus cell envelope. However, more likely is that polyP's effects are indirect through the regulation of one of P. aeruginosa's virulence factors, pyocyanin. We show that pyocyanin production in P. aeruginosa occurs polyP-dependent and harms S. aureus through membrane damage and the generation of reactive oxygen species, resulting in increased expression of antioxidant enzymes. In summary, our study adds a new component to the list of biomolecules that the gram-negative pathogen P. aeruginosa generates to compete with S. aureus for resources.

IMPORTANCE: How do interactions between microorganisms shape the course of polymicrobial infections? Previous studies have provided evidence that the two opportunistic pathogens P. aeruginosa and S. aureus generate molecules that modulate their interaction with potentially significant impact on disease outcomes. Our study identified the biopolymer polyP as a new effector molecule that impacts P. aeruginosa 's interaction with S. aureus . We show that P. aeruginosa kills S. aureus in a polyP-dependent manner, which occurs primarily through the polyP-dependent production of the P. aeruginosa virulence factor pyocyanin. Our findings add a new role for polyP to an already extensive list of functions. A more in-depth understanding of how polyP influences interspecies interactions is critical, as targeting polyP synthesis in bacteria such as P. aeruginosa may have a significant impact on other microorganisms and potentially result in dynamic changes in the microbial composition.

PMID:38106195 | PMC:PMC10723280 | DOI:10.1101/2023.12.05.570291

Front Pediatr. 2023 Dec 1;11:1289256. doi: 10.3389/fped.2023.1289256. eCollection 2023.

ABSTRACT

Treating Ewing's Sarcoma of the thorax (Askin's tumor) with antineoplastic therapy in a malnourished cystic fibrosis patient colonized with Pseudomonas aeruginosa and Staphylococcus aureus may carry a significant potential for complications. We present the case of a known cystic fibrosis patient, diagnosed with Askin's tumor 5 years ago. Despite facing severe neutropenia, exacerbations of cystic fibrosis with Pseudomonas aeruginosa infections, and challenges in maintaining adequate caloric intake during the oncological treatment, the patient's outcome has been favorable. Chemotherapy doses had to be adjusted, and continuous antibiotic treatment was introduced throughout the course of therapy to reduce the frequency and intensity of exacerbations. Approximately 5 years after the cancer diagnosis, with no signs of relapse, the patient was started on CFTR (Cystic fibrosis transmembrane conductance regulator) modulator treatment. This intervention has successfully corrected the weight deficit. The coincidence of Ewing's sarcoma of the chest wall and cystic fibrosis in a single patient is 2.857 × 10-5% and to the best of our knowledge, this scenario has not been documented before.

PMID:38105789 | PMC:PMC10722287 | DOI:10.3389/fped.2023.1289256

ChemMedChem. 2023 Dec 17:e202300391. doi: 10.1002/cmdc.202300391. Online ahead of print.

ABSTRACT

Cystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In the search of novel series of CFTR modulators, a library of mono and diacyl thioureas were prepared by sequential synthesis. When tested alone, the obtained compounds 5 and 6 poorly affected F508del-CFTR conductance but, in combination with Lumacaftor, selected derivatives showed the ability to increase the activity of the approved modulator. Analogue 6i displayed the most marked enhancing effect and acylthioureas 6d and 6f were also able to improve efficacy of Lumacaftor. All compounds proved to be non-cytotoxic against different cancer cell lines. Good pharmacokinetic properties were predicted for derivatives 5 and 6, thus supporting the value of these compounds for the development of novel modulators potentially useful for cystic fibrosis.

PMID:38105411 | DOI:10.1002/cmdc.202300391

Respir Med. 2023 Dec 15:107499. doi: 10.1016/j.rmed.2023.107499. Online ahead of print.

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, respiratory symptoms, inflammation of the airways, and systemic manifestations of the disease. Genetic susceptibility and environmental factors are important in the development of the disease, particularly exposure to cigarette smoke which is the most notable risk factor. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are the cause of cystic fibrosis (CF), which shares several pathophysiological pulmonary features with COPD, including airway obstruction, chronic airway inflammation and bacterial colonization; in addition, both diseases also present systemic defects leading to comorbidities such as pancreatic, gastrointestinal, and bone-related diseases. In patients with COPD, systemic CFTR dysfunction can be acquired by cigarette smoking, inflammation, and infection. This dysfunction is, on average, about half of that found in CF. Herein we review the literature focusing on acquired CFTR dysfunction and the potential role in the pathogenesis of comorbidities associated with COPD and chronic bronchitis.

PMID:38104786 | DOI:10.1016/j.rmed.2023.107499

Respir Res. 2023 Dec 16;24(1):317. doi: 10.1186/s12931-023-02630-z.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a genetic disorder causing poor mucociliary clearance in the airways and subsequent respiratory infection. The recently approved triple therapy Elexacaftor-Tezacaftor-Ivacaftor (ETI) has significantly improved lung function and decreased airway infection in persons with CF (pwCF). This improvement has been shown to occur rapidly, within the first few weeks of treatment. The effects of longer term ETI therapy on lung infection dynamics, however, remain mostly unknown.

RESULTS: Here, we applied 16S rRNA gene amplicon sequencing, untargeted metabolomics, and neutral models to high-resolution, longitudinally collected sputum samples from pwCF on ETI therapy (162 samples, 7 patients) and compared to similarly collected data set from pwCF not taking ETI (630 samples, 9 patients). Because ETI reduces sputum production, samples were collected in freezers provided in the subject's homes at least 3 months after first taking ETI, with those on ETI collecting a sample approximately weekly. The lung function (%ppFEV1) of those in our longitudinal cohort significantly improved after ETI (6.91, SD = 7.74), indicating our study cohort was responsive to ETI. The daily variation of alpha- and beta-diversity of both the microbiome and metabolome was higher for those on ETI, reflecting a more dynamic microbial community and chemical environment during treatment. Four of the seven subjects on ETI were persistently infected with Pseudomonas or Burkholderia in their sputum throughout the sampling period while the total bacterial load significantly decreased with time (R = - 0.42, p = 0.01) in only one subject. The microbiome and metabolome dynamics on ETI were personalized, where some subjects had a progressive change with time on therapy, whereas others had no association with time on treatment. To further classify the augmented variance of the CF microbiome under therapy, we fit the microbiome data to a Hubbell neutral dynamics model in a patient-stratified manner and found that the subjects on ETI had better fit to a neutral model.

CONCLUSION: This study shows that the longitudinal microbiology and chemistry in airway secretions from subjects on ETI has become more dynamic and neutral and that after the initial improvement in lung function, many are still persistently infected with CF pathogens.

PMID:38104128 | DOI:10.1186/s12931-023-02630-z

Respir Res. 2023 Dec 16;24(1):316. doi: 10.1186/s12931-023-02612-1.

ABSTRACT

INTRODUCTION: Over the last ten years an increasing prevalence and incidence of non-tuberculous mycobacteria (NTM) has been reported among patients with cystic fibrosis (CF) Viviani (J Cyst Fibros, 15(5):619-623, 2016). NTM pulmonary disease has been associated with negative clinical outcomes and often requires pharmacological treatment. Although specific guidelines help clinicians in the process of diagnosis and clinical management, the focus on the multidimensional assessment of concomitant problems is still scarce.

MAIN BODY: This review aims to identify the treatable traits of NTM pulmonary disease in people with CF and discuss the importance of a multidisciplinary approach in order to detect and manage all the clinical and behavioral aspects of the disease. The multidisciplinary complexity of NTM pulmonary disease in CF requires careful management of respiratory and extra-respiratory, including control of comorbidities, drug interactions and behavioral factors as adherence to therapies.

CONCLUSIONS: The treatable trait strategy can help to optimize clinical management through systematic assessment of all the aspects of the disease, providing a holistic treatment for such a multi-systemic and complex condition.

PMID:38104098 | DOI:10.1186/s12931-023-02612-1

J Cyst Fibros. 2023 Dec 15:S1569-1993(23)01728-9. doi: 10.1016/j.jcf.2023.12.004. Online ahead of print.

ABSTRACT

BACKGROUND: Gut dysbiosis is implicated in colorectal cancer (CRC) pathogenesis. Cystic fibrosis (CF) is associated with both gut dysbiosis and increased CRC risk. We therefore compared the faecal microbiota from individuals with CF to CRC and screening samples. We also assessed changes in CRC-associated taxa before and after triple CF transmembrane conductance regulator (CFTR) modulator therapy.

METHODS: Bacterial DNA amplification comprising V4 16S rRNA analysis was conducted on 84 baseline and 53 matched follow-up stool samples from adults with CF. These data were compared to an existing cohort of 430 CRC and 491 control gFOBT samples from the NHS Bowel Cancer Screening Programme. Data were also compared to 26 previously identified CRC-associated taxa from a published meta-analysis.

RESULTS: Faecal CF samples had a lower alpha diversity and clustered distinctly from both CRC and control samples, with no clear clinical variables explaining the variation. Compared to controls, CF samples had an increased relative abundance in 6 of the 20 enriched CRC-associated taxa and depletion of 2 of the 6 taxa which have been reported as reduced in CRC. Commencing triple modulator therapy had subtle influence on the relative abundance of CRC-associated microbiota (n = 23 paired CF samples).

CONCLUSIONS: CF stool samples were clearly dysbiotic, clustering distinctly from both CRC and control samples. Several bacterial shifts in CF samples resembled those observed in CRC. Studies assessing the impact of dietary or other interventions and the longer-term use of CFTR modulators on reducing this potentially pro-oncogenic milieu are needed.

PMID:38104000 | DOI:10.1016/j.jcf.2023.12.004

BMJ Case Rep. 2023 Dec 16;16(12):e257553. doi: 10.1136/bcr-2023-257553.

ABSTRACT

A late adolescent man diagnosed with cystic fibrosis and presenting with predominantly gastrointestinal symptoms, including chronic constipation, exocrine pancreatic insufficiency and gastro-oesophageal reflux disease, experienced recurrent episodes of nausea, vomiting and abdominal pain. CT of the abdomen unveiled the presence of chronic appendicitis, alongside constipation without evidence of distal intestinal obstruction syndrome. Endoscopic biopsies revealed small bowel eosinophilic infiltrates. Subsequently, the patient underwent an appendectomy, and a tailored regimen was established to address constipation, resulting in an initial alleviation of his symptoms. Three months later, a resurgence of symptoms occurred, coinciding with persistent intestinal eosinophilic infiltrates. A diagnosis of eosinophilic enteritis was rendered, and treatment commenced with an oral dosage of 40 mg of prednisone. Two weeks later, the patient experienced symptom resolution, corroborated by the findings of an endoscopic biopsy conducted 8 weeks later. During a follow-up examination 6 months later, the patient remained asymptomatic.

PMID:38103903 | DOI:10.1136/bcr-2023-257553

Trends Microbiol. 2023 Dec 14:S0966-842X(23)00337-2. doi: 10.1016/j.tim.2023.12.002. Online ahead of print.

ABSTRACT

Does genetic background contribute to populations following the same or divergent adaptive trajectories? A recent study by Filipow et al. evolved multiple genetically distinct Pseudomonas aeruginosa strains to an artificial cystic fibrosis lung sputum media. The strains adapted at different rates but converged on similar phenotypes despite their initial diversity.

PMID:38102036 | DOI:10.1016/j.tim.2023.12.002

J Cyst Fibros. 2023 Dec 14:S1569-1993(23)01725-3. doi: 10.1016/j.jcf.2023.12.001. Online ahead of print.

NO ABSTRACT

PMID:38101988 | DOI:10.1016/j.jcf.2023.12.001

J Control Release. 2023 Dec 13:S0168-3659(23)00796-4. doi: 10.1016/j.jconrel.2023.12.012. Online ahead of print.

ABSTRACT

In the past decade RNA-based therapies such as small interfering RNA (siRNA) and messenger RNA (mRNA) have emerged as new and ground-breaking therapeutic agents for the treatment and prevention of many conditions from viral infection to cancer. Most clinically approved RNA therapies are parenterally administered which impacts patient compliance and adds to healthcare costs. Pulmonary administration via inhalation is a non-invasive means to deliver RNA and offers an attractive alternative to injection. Nebulisation is a particularly appealing method due to the capacity to deliver large RNA doses during tidal breathing. In this review, we discuss the unique physiological barriers presented by the lung to efficient nebulised RNA delivery and approaches adopted to circumvent this problem. Additionally, the different types of nebulisers are evaluated from the perspective of their suitability for RNA delivery. Furthermore, we discuss recent preclinical studies involving nebulisation of RNA and analysis in in vitro and in vivo settings. Several studies have also demonstrated the importance of an effective delivery vector in RNA nebulisation therefore we assess the variety of lipid, polymeric and hybrid-based delivery systems utilised to date. We also consider the outlook for nebulised RNA medicinal products and the hurdles which must be overcome for successful clinical translation. In summary, nebulised RNA delivery has demonstrated promising potential for the treatment of several lung-related conditions such as asthma, COPD and cystic fibrosis, to which the mode of delivery is of crucial importance for clinical success.

PMID:38101753 | DOI:10.1016/j.jconrel.2023.12.012

Lancet Respir Med. 2023 Dec 12:S2213-2600(23)00473-3. doi: 10.1016/S2213-2600(23)00473-3. Online ahead of print.

NO ABSTRACT

PMID:38101436 | DOI:10.1016/S2213-2600(23)00473-3

Chron Respir Dis. 2023 Jan-Dec;20:14799731231222282. doi: 10.1177/14799731231222282.

ABSTRACT

BACKGROUND: Chronic lung diseases, such as chronic obstructive pulmonary disease or asthma, are associated with an increased risk of dementia. However, few data are available regarding the risk of dementia in individuals with bronchiectasis.

OBJECTIVES: To explore the association between bronchiectasis and the risk of incident dementia using a longitudinal population-based cohort.

METHODS: A total of 4,068,560 adults older than 50 years without previous dementia were enrolled from the Korean National Health Insurance Service database in 2009. They were followed up until the date of the diagnosis of dementia or December 31, 2020. The study exposure was the diagnosis of bronchiectasis, and the primary outcome was incident dementia comprising Alzheimer's disease and vascular dementia.

RESULTS: During the median follow-up duration of 9.3 years, the incidence of all-cause dementia was 1.6-fold higher in individuals with bronchiectasis than in those without bronchiectasis (15.0 vs. 9.3/1000 person-years, p < .001). In the multivariable Cox regression analysis, the risk of all dementia was significantly higher in individuals with bronchiectasis than in those without bronchiectasis (adjusted hazard ratio [aHR] 1.09, 95% confidence interval [CI] 1.04-1.14). In a subgroup analysis by dementia type, individuals with bronchiectasis had an increased risk of Alzheimer's disease compared to those without bronchiectasis (aHR 1.07, 95% CI 1.01-1.12); the risk of vascular dementia did not significantly differ between the two groups (aHR 1.05, 95% CI 0.90-1.21).

CONCLUSION: Bronchiectasis was associated with an increased risk of dementia, especially Alzheimer's disease.

PMID:38100725 | DOI:10.1177/14799731231222282

Water Res X. 2023 Sep 9;21:100201. doi: 10.1016/j.wroa.2023.100201. eCollection 2023 Dec 1.

ABSTRACT

The regrowth and subsequent exposure of opportunistic pathogens (OPs) whilst reopening buildings that have been locked down due to the stay-at-home restrictions to limit the spread of COVID-19, is a public health concern. To better understand such microbiological risks due to lowered occupancy and water demand in buildings, first and post-flush water samples (n = 48) were sampled from 24 drinking water outlets from eight university buildings in two campuses (urban and rural), with various end-user occupancies. Both campuses were served with chlorinated water originating from a single drinking water distribution system in South-East Queensland, situated 14 km apart, where the rural campus had lower chlorine residuals. Culture-dependent and culture-independent methods (such as flow cytometry, qPCR and 16S rRNA gene amplicon sequencing) were used concurrently to comprehensively characterise the OPs of interest (Legionella spp., Pseudomonas aeruginosa, and nontuberculous mycobacteria (NTM)) and the premise plumbing microbiome. Results showed that buildings with extended levels of stagnation had higher and diverse levels of microbial growth, as observed in taxonomic structure and composition of the microbial communities. NTM were ubiquitous in all the outlets sampled, regardless of campus or end-user occupancy of the buildings. qPCR and culture demonstrated prevalent and higher concentrations of NTM in buildings (averaging 3.25 log10[estimated genomic copies/mL]) with extended stagnation in the urban campus. Furthermore, flushing the outlets for 30 minutes restored residual and total chlorine, and subsequently decreased the levels of Legionella by a reduction of 1 log. However, this approach was insufficient to restore total and residual chlorine levels for the outlets in the rural campus, where both Legionella and NTM levels detected by qPCR remained unchanged, regardless of building occupancy. Our findings highlight that regular monitoring of operational parameters such as residual chlorine levels, and the implementation of water risk management plans are important for non-healthcare public buildings, as the levels of OPs in these environments are typically not assessed.

PMID:38098883 | PMC:PMC10719583 | DOI:10.1016/j.wroa.2023.100201