Front Immunol. 2023 Nov 16;14:1242381. doi: 10.3389/fimmu.2023.1242381. eCollection 2023.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator (CFTR) gene. The most severe pathologies of CF occur in the lung, manifesting as chronic bacterial infection, persistent neutrophilic inflammation, and mucopurulent airway obstruction. Despite increasing knowledge of the CF primary defect and the resulting clinical sequelae, the relationship between the CFTR loss of function and the neutrophilic inflammation remains incompletely understood. Here, we report that loss of CFTR function in macrophages causes extended lung inflammation. After intratracheal inoculation with Pseudomonas aeruginosa, mice with a macrophage-specific Cftr-knockout (Mac-CF) were able to mount an effective host defense to clear the bacterial infection. However, three days post-inoculation, Mac-CF lungs demonstrated significantly more neutrophil infiltration and higher levels of inflammatory cytokines, suggesting that Mac-CF mice had a slower resolution of inflammation. Single-cell RNA sequencing revealed that absence of CFTR in the macrophages altered the cell transcriptional program, affecting the cell inflammatory and immune responses, antioxidant system, and mitochondrial respiration. Thus, loss of CFTR function in macrophages influences cell homeostasis, leading to a dysregulated cellular response to infection that may exacerbate CF lung disease.

PMID:38035088 | PMC:PMC10687418 | DOI:10.3389/fimmu.2023.1242381

Front Pharmacol. 2023 Nov 14;14:1331829. doi: 10.3389/fphar.2023.1331829. eCollection 2023.

NO ABSTRACT

PMID:38035017 | PMC:PMC10682817 | DOI:10.3389/fphar.2023.1331829

Heliyon. 2023 Nov 10;9(11):e22111. doi: 10.1016/j.heliyon.2023.e22111. eCollection 2023 Nov.

ABSTRACT

Gastroesophageal reflux (GER) occurs in most cystic fibrosis (CF) patients and is the primary source of bile aspiration in the airway tract of CF individuals. Aspirated bile is associated with the severity of lung diseases and chronic inflammation caused by Pseudomonas aeruginosa as the most common pathogen of CF respiratory tract infections. P. aeruginosa is equipped with several mechanisms to facilitate the infection process, including but not limited to the expression of virulence factors, biofilm formation, and antimicrobial resistance, all of which are under the strong regulation of quorum sensing (QS) mechanism. By increasing the expression of lasI, rhlI, and pqsA-E, bile exposure directly impacts the QS network. An increase in psl expression and pyocyanin production can promote biofilm formation. Along with the loss of flagella and reduced swarming motility, GER-derived bile can repress the expression of genes involved in creating an acute infection, such as expression of Type Three Secretion (T3SS), hydrogen cyanide (hcnABC), amidase (amiR), and phenazine (phzA-E). Inversely, to cause persistent infection, bile exposure can increase the Type Six Secretion System (T6SS) and efflux pump expression, which can trigger resistance to antibiotics such as colistin, polymyxin B, and erythromycin. This review will discuss the influence of aspirated bile on the pathogenesis, resistance, and persistence of P. aeruginosa in CF patients.

PMID:38034726 | PMC:PMC10685303 | DOI:10.1016/j.heliyon.2023.e22111

Ear Nose Throat J. 2023 Nov 30:1455613231214622. doi: 10.1177/01455613231214622. Online ahead of print.

ABSTRACT

Objectives: To summarize the current applications and potential uses of optical coherence tomography (OCT), a noninvasive imaging modality that uses near-infrared light to produce cross-sectional, high-resolution images of biologic tissues, for evaluating the sinonasal mucosa in patients. Methods: Original articles utilizing OCT to image the sinonasal mucosa in patients were identified from the PubMed, Embase, Cochrane Library, Web of Science, and Scopus databases using the search phrase: "Optical Coherence Tomography" AND (sinonasal OR intranasal OR sinus OR nose OR sinusitis OR rhinitis OR olfactory). Strength of evidence, quality of evidence, and risk of bias were measured using validated scales. Study results were qualitatively assessed. Results: Out of 1662 original records identified through database searching, 9 studies were included in the systematic review. Levels of evidence ranged from III to IV and quality of evidence ranged from moderate to very low. Endoscopic OCT systems as well as OCT systems integrated with surgical microscopes were described in the literature. Applications of OCT for imaging the sinonasal mucosa included identifying morphological patterns unique to individual diseases, detecting mucosal structural changes after medical therapies and procedures, and evaluating mucociliary clearance. Conclusions: Most studies investigating OCT imaging of the sinonasal mucosa featured small sample sizes and lacked control groups. While OCT imaging could be a useful adjunct for diagnosing sinonasal disorders and monitoring response to treatment in the future, additional high-quality studies are necessary to determine if the use of OCT imaging can lead to improved diagnostic accuracy and health outcomes for patients with sinonasal pathologies.

PMID:38032064 | DOI:10.1177/01455613231214622

Expert Rev Gastroenterol Hepatol. 2023 Nov 29. doi: 10.1080/17474124.2023.2289530. Online ahead of print.

ABSTRACT

INTRODUCTION: New evidence supports the benefits of bolus feeding for children receiving home enteral feeding (HEN). Current home methods of bolus feeding have certain limitations, particularly in mobile or restless patients. Therefore, innovative delivery methods have been introduced to provide more flexible methods of reducing feeding time and formula handling.

AREAS COVERED: This manuscript presents an expert review of the updates in HEN for children and the results of an online user experience questionnaire about an innovative new cap-based bolus feeding system. A literature bibliographic search was conducted on Medline via PubMed up to September 2023 to collect relevant studies. We presented recent evidence demonstrating a dramatic increase in HEN use among children requiring EN and its benefits on patients' nutritional status and quality of life. In addition, the article examined the clinical and social benefits of bolus feeding and current challenges in delivery methods. We described the benefits of the new system and its user experience.

EXPERT OPINION: The uses and indications for bolus feeding in HEN are increasing among children. However, there are still some unmet needs regarding traditional delivery methods. Innovative techniques can improve flexibility, reduce feeding time, and improve user experience and quality of life.

PMID:38030649 | DOI:10.1080/17474124.2023.2289530

J Cardiothorac Vasc Anesth. 2023 Nov 2:S1053-0770(23)00903-5. doi: 10.1053/j.jvca.2023.10.036. Online ahead of print.

ABSTRACT

Lung transplantation is the only therapy for patients with end-stage lung disease. In advanced lung diseases such as cystic fibrosis (CF), life expectancy increases, and it is important to recognize extrapulmonary comorbidities. Cardiovascular involvement, including pulmonary hypertension, right-heart failure, and myocardial dysfunction, are manifest in the late stages of CF disease. Besides right-heart failure, left-heart dysfunction seems to be underestimated. Therefore, an optimal anesthesia and surgical management risk evaluation in this high-risk patient population is mandatory, especially concerning the perioperative use of mechanical circulatory support. The use of an index case of an older patient with the diagnosis of cystic fibrosis demonstrates the importance of early risk stratification and strategy planning in a multidisciplinary team approach to guarantee successful lung transplantation.

PMID:38030425 | DOI:10.1053/j.jvca.2023.10.036

Respir Med Res. 2023 Nov 3;84:101061. doi: 10.1016/j.resmer.2023.101061. Online ahead of print.

NO ABSTRACT

PMID:38029649 | DOI:10.1016/j.resmer.2023.101061

Food Chem. 2023 Nov 25;439:138073. doi: 10.1016/j.foodchem.2023.138073. Online ahead of print.

ABSTRACT

This study introduces an efficient electrochemical method for rapidly identifying the pathogen Pseudomonas aeruginosa (P. aeruginosa), which poses threats to individuals with compromised immune systems and cystic fibrosis. Unlike conventional techniques such as polymerase chain reaction, which fails to detect modifications in the resistant properties of microbes due to environmental stress, our proposed electrochemical approach offers a promising alternative. The characterisation analyses, involving microscopic and spectroscopic methods, reveal that the nanocomposite exhibits a crystalline structure, specific atomic vibrational patterns, a cubic surface shape, and distinct elemental compositions. This sensor demonstrates exceptional detection capabilities for P. aeruginosa, with a linear range of 1-23 CFU mL-1 and a low detection limit of 4.0 × 10-3 CFU mL-1. This research not only explores novel electrochemical techniques and the CoFe2O4/AgNPs nanocomposite but also their practical implications in food science, highlighting their relevance across various food samples, water, and soil.

PMID:38029564 | DOI:10.1016/j.foodchem.2023.138073

Respirol Case Rep. 2023 Nov 17;11(12):e01235. doi: 10.1002/rcr2.1235. eCollection 2023 Dec.

ABSTRACT

N,N'-dimethyl-4,4'bipyridinium dichloride (Paraquat) is a potent herbicide used widely in agriculture. We report the effects of an ingestion of paraquat by a 28 year old male with cystic fibrosis and the diagnostic and management challenges this posed in both the acute and longer term setting. We describe the effects of direct paraquat toxicity on the lung tissue secondary to aspiration and review the long-term sequelae of paraquat, namely osteonecrosis. Our case is the first to describe osteonecrosis of the knee in the context of paraquat toxicity. Survival following ingestion remains poor with a high associated mortality. However, timely treatment with NAC and immunosuppression may impact on survival. In those patients who do survive the acute phase post ingestion, follow-up over years may be required to detect the long-term effects of paraquat on bone health.

PMID:38028563 | PMC:PMC10655628 | DOI:10.1002/rcr2.1235

Clin Case Rep. 2023 Nov 20;11(11):e8046. doi: 10.1002/ccr3.8046. eCollection 2023 Nov.

ABSTRACT

The introduction of newborn screening for cystic fibrosis (CF) increased diagnosis of cystic fibrosis screen positive inconclusive diagnosis (CFSPID). We described the case of a 12-month-old boy with CFSPID who, during summer, presented Pseudo-Bartter syndrome with no diagnostic criteria for CF.

PMID:38028053 | PMC:PMC10659916 | DOI:10.1002/ccr3.8046

Pulm Circ. 2023 Nov 21;13(4):e12308. doi: 10.1002/pul2.12308. eCollection 2023 Oct.

ABSTRACT

Relationships between obesity and outcomes in pulmonary arterial hypertension (PAH) are complex. Previous work suggested obesity, occurring alongside PAH, may be associated with better survival. In our work, we suggest obesity prior to PAH development is associated with worse survival. This may add a novel temporal element to the "obesity-paradox."

PMID:38027456 | PMC:PMC10663650 | DOI:10.1002/pul2.12308

Front Pediatr. 2023 Nov 1;11:1283823. doi: 10.3389/fped.2023.1283823. eCollection 2023.

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited renal disease characterized by the bilateral development of multiple cysts in the kidneys. Pain management is a clinically important issue, especially because approximately 60% of patients with ADPKD experience chronic pain related to hemorrhage from renal cysts, which significantly reduces their daily life. The cystic fibrosis transmembrane conductance regulator, the molecule responsible for cyst formation in ADPKD, is also the cause of cystic fibrosis. Since attention deficit hyperactivity disorder (ADHD) is known to occur frequently in conjunction with cystic fibrosis, ADPKD may be associated with ADHD. However, to our knowledge, no study has investigated 1) ADHD or autism spectrum disorder (ASD) as comorbidities with ADPKD, 2) the effects of ADHD medications on chronic pain in ADPKD, or 3) cerebral blood flow corresponding to guanfacine (GF) or methylphenidate (MP) treatment for chronic pain. We report the case of a 15-year-old girl with ADPKD, who had chronic back pain associated with ADPKD and had to withdraw from high school because the pain interfered with her daily life. Although she took antihypertensive medications to prevent bleeding, they did not provide adequate blood pressure control. The patient was referred to a child psychiatrist and diagnosed with ASD; however, the pain did not improve. Subsequently, she was referred to our pain center. The diagnosis of ADHD was confirmed and treatment with ADHD medications was initiated. Monotherapy with MP, atomoxetine, and GF resulted in hypertension and hypotension as side effects; however, a combination of MP 18 mg and GF 4 mg provided pain relief and moderate blood pressure control, and the patient was able to go on to college. During the course of treatment, there was an improvement in the distribution of cerebral blood flow in the prefrontal and insular cortices. Confirmation of an ADHD diagnosis comorbid with ASD enabled the use of ADHD medications. The combination of MP and GF improved chronic back pain and high blood pressure due to ADPKD and cerebral blood flow. Screening for ADHD is important in the treatment of ADPKD.

PMID:38027301 | PMC:PMC10646415 | DOI:10.3389/fped.2023.1283823

Mol Ther Methods Clin Dev. 2023 Oct 18;31:101140. doi: 10.1016/j.omtm.2023.101140. eCollection 2023 Dec 14.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. The 10th most common mutation, c.3178-2477C>T (3849+10kb C>T), involves a cryptic, intronic splice site. This mutation was corrected in CF primary cells homozygous for this mutation by delivering pairs of guide RNAs (gRNAs) with Cas9 protein in ribonucleoprotein (RNP) complexes that introduce double-strand breaks to flanking sites to excise the 3849+10kb C>T mutation, followed by DNA repair by the non-homologous end-joining pathway, which functions in all cells of the airway epithelium. RNP complexes were delivered to CF basal epithelial cell by a non-viral, receptor-targeted nanocomplex comprising a formulation of targeting peptides and lipids. Canonical CFTR mRNA splicing was, thus, restored leading to the restoration of CFTR protein expression with concomitant restoration of electrophysiological function in airway epithelial air-liquid interface cultures. Off-target editing was not detected by Sanger sequencing of in silico-selected genomic sites with the highest sequence similarities to the gRNAs, although more sensitive unbiased whole genome sequencing methods would be required for possible translational developments. This approach could potentially be used to correct aberrant splicing signals in several other CF mutations and other genetic disorders where deep-intronic mutations are pathogenic.

PMID:38027060 | PMC:PMC10661860 | DOI:10.1016/j.omtm.2023.101140

Front Pharmacol. 2023 Oct 25;14:1167407. doi: 10.3389/fphar.2023.1167407. eCollection 2023.

ABSTRACT

Background: Elexacaftor-tezacaftor-ivacaftor (ETI) is a novel, highly effective CFTR modulator combination proven to enhance lung function and body weight in people with cystic fibrosis (pwCF) carrying a F508del mutation. Recently, we revealed significant reductions in abdominal symptoms (AS) in German, British, and Irish pwCF after 24-26 weeks of ETI using the CFAbd-Score, the first patient-reported outcome measure (PROM) specifically developed and validated for pwCF following FDA guidelines. Notably, many pwCF reported marked changes in their AS during the first days of the new treatment. To capture these immediate effects, we developed the CFAbd-day2day, a CF-specific GI-diary, following FDA and COSMIN guidelines. Aim: To prospectively capture the immediate dynamics of AS using the CFAbd-day2day 14 days before and 14-28 days after ETI initiation. In addition, we aim to provide validation steps of the novel PROM concerning sensitivity to changes. Methods: To develop the CFAbd-day2day, focus groups (community voice = pwCF and their proxies and CF specialists from different fields) were repeatedly consulted. Before and during the new ETI therapy, pwCF prospectively scored AS on a daily basis with the CFAbd-day2day. Results: Altogether, 45 pwCF attended in five CF centers prospectively completed the CFAbd-day2day before (mean ± sd:14 ± 7 days) and after (mean ± sd: 28 ± 23 days) ETI initiation. On the one hand, cumulative scores significantly decreased during the 3-4-week time frame after ETI initiation, compared to 2 weeks prior to therapy. On the other hand, many patients who revealed a relatively stable level of AS before ETI reported changes during the first days of treatment with the highly effective CFTR modulators. Factors like pain and flatulence increased in up to 21% of patients during the first 14 days of therapy, but they improved during days 15-27. Conclusion: The CFAbd-day2day, specifically developed and in the process of validation to prospectively capture GI symptoms in pwCF, provides new substantial insights into the dynamics of AS in pwCF receiving a new treatment with ETI. This novel tool is also helpful in prospectively monitoring patients with specific GI problems. International implementation and further validation steps of the diary are ongoing.

PMID:38026920 | PMC:PMC10658783 | DOI:10.3389/fphar.2023.1167407

iScience. 2023 Oct 12;26(11):108180. doi: 10.1016/j.isci.2023.108180. eCollection 2023 Nov 17.

ABSTRACT

Mutation targeted therapy in cystic fibrosis (CF) is still not eligible for all CF subjects, especially for cases carrying rare variants such as the CFTR genotype W57G/A234D (c.169T>G/c.701C>A). We performed in silico analysis of the effects of these variants on protein stability, which we functionally characterized using colonoids and reprogrammed nasal epithelial cells. The effect of mutations on cystic fibrosis transmembrane conductance regulator (CFTR) protein was analyzed by western blotting, forskolin-induced swelling (FIS), and Ussing chamber analysis. We detected a residual CFTR function that increases following treatment with the CFTR modulators VX661±VX445±VX770, correlates among models, and is associated with increased CFTR protein levels following treatment with CFTR correctors. In vivo treatment with VX770 reduced sweat chloride concentration to non-CF levels, increased the number of CFTR-dependent sweat droplets, and induced a 6% absolute increase in predicted FEV1% after 27 weeks of treatment indicating the relevance of theratyping with patient-derived cells in CF.

PMID:38026150 | PMC:PMC10660498 | DOI:10.1016/j.isci.2023.108180

Cureus. 2023 Nov 9;15(11):e48564. doi: 10.7759/cureus.48564. eCollection 2023 Nov.

ABSTRACT

Background Cystic fibrosis (CF) is a genetic disorder with diverse symptoms. Understanding its genetic basis and prevalence is crucial for effective management and treatment. Objective The study aimed to provide comprehensive insights into the frequency of CF gene mutations, clinical presentations, and complications among the Pakistani population. Methodology A cohort comprising 892 patients, ranging in age from 18 to more than 40 years, was selected on the basis of clinical and genetic criteria for the diagnosis of CF. Polymerase chain reaction (PCR) was used to look for 34 variants in the CFTR gene in blood samples. Statistical analysis, which included figuring out the number of mutations, the average age of diagnosis, and the genetic diversity of the samples, was performed to analyze the percentage of patients with specific mutations, offering insights into the genetic diversity. Results In our comprehensive analysis of 892 patient samples, 77.47% (n=691) displayed consanguinity, indicating a family history. The prevailing symptoms included chronic cough (88.67%; n=791), recurrent respiratory infections (76.68%; n=684), and fatigue (73.76%; n=658). The major complications comprised pulmonary infections (22%; n=197), cystic fibrosis-related diabetes (21%; n=187), and malabsorption (20%: n=178). A paired t-test revealed a mean difference of 5.750 with a standard deviation of 9.147, a 95% confidence interval from -0.061 to 11.561, a t-value of 2.178 with 11 degrees of freedom, and a two-tailed p-value of 0.052, suggesting a potential trend towards significance. Nevertheless, the asymptotic significance values of 1.000 and 0.998 for both groups indicate no significant difference. Furthermore, the study identified 12 cystic fibrosis gene mutations, with F508del and N1303K being the most prevalent. Conclusion This research revealed significant consanguinity, confirmed typical CF symptoms, and identified common complications and prevalent CFTR gene mutations (with F508del and N1303K being the most common), providing insights for genetic guidance and treatment in the Pakistani community.

PMID:38024076 | PMC:PMC10653747 | DOI:10.7759/cureus.48564

Bioeng Transl Med. 2023 Aug 21;8(6):e10580. doi: 10.1002/btm2.10580. eCollection 2023 Nov.

ABSTRACT

Although mRNA lipid nanoparticles (LNPs) are highly effective as vaccines, their efficacy for pulmonary delivery has not yet fully been established. A major barrier to this therapeutic goal is their instability during aerosolization for local delivery. This imparts a shear force that degrades the mRNA cargo and therefore reduces cell transfection. In addition to remaining stable upon aerosolization, mRNA LNPs must also possess the aerodynamic properties to achieve deposition in clinically relevant areas of the lungs. We addressed these challenges by formulating mRNA LNPs with SM-102, the clinically approved ionizable lipid in the Spikevax COVID-19 vaccine. Our lead candidate, B-1, had the highest mRNA expression in both a physiologically relevant air-liquid interface (ALI) human lung cell model and in healthy mice lungs upon aerosolization. Further, B-1 showed selective transfection in vivo of lung epithelial cells compared to immune cells and endothelial cells. These results show that the formulation can target therapeutically relevant cells in pulmonary diseases such as cystic fibrosis. Morphological studies of B-1 revealed differences in the surface structure compared to LNPs with lower transfection efficiency. Importantly, the formulation maintained critical aerodynamic properties in simulated human airways upon next generation impaction. Finally, structure-function analysis of SM-102 revealed that small changes in the number of carbons can improve upon mRNA delivery in ALI human lung cells. Overall, our study expands the application of SM-102 and its analogs to aerosolized pulmonary delivery and identifies a potent lead candidate for future therapeutically active mRNA therapies.

PMID:38023707 | PMC:PMC10658486 | DOI:10.1002/btm2.10580

Case Rep Dermatol. 2023 Nov 16;15(1):217-224. doi: 10.1159/000533923. eCollection 2023 Jan-Dec.

ABSTRACT

Green nail syndrome (GNS) is a persistent greenish pigmentation of the nail plate, originally described in 1944 by Goldman and Fox, due to Pseudomonas aeruginosa infection. Recently, pulmonary co-infection of P. aeruginosa and Achromobacter spp. has been described in patients with cystic fibrosis. Achromobacter xylosoxidans is a multidrug-resistant (MDR) pathogen involved in lung and soft tissue skin infections. Both Achromobacter xylosoxidans and P. aeruginosa are mainly found in humid environments or in water. There are no recognized co-infections due to P. aeruginosa and A. xylosoxidans in the skin and appendages. We describe two cases of GNS, the first due to P. aeruginosa associated with Achromobacter xylosoxidans; the other due to MDR P. aeruginosa, both successfully treated with topical ozenoxacin 1% cream daily for 12 weeks. The clinical management of GNS can be confusing, especially when the bacterial culture result is inconsistent or when non-Pseudomonas bacteria are isolated. In our case, due to the co-infection of P. aeruginosa and Achromobacter spp., local treatment with ozenoxacin - the first nonfluorinated quinolone - could be a safe and effective treatment in case of MDR nail infections. Further studies are required to evaluate clinical isolation from nail infections and the co-presence of P. aeruginosa and A. xylosoxidans.

PMID:38023344 | PMC:PMC10653707 | DOI:10.1159/000533923

Med Mycol Case Rep. 2023 Nov 10;42:100617. doi: 10.1016/j.mmcr.2023.100617. eCollection 2023 Dec.

ABSTRACT

We report a patient with anorexia nervosa without bronchiectasis and cystic fibrosis who developed acute pneumonia caused by Exophiala dermatitidis (E. dermatitidis). The black fungus found in multiple sputum cultures was determined to be E. dermatitidis using mass spectrometry and identified using genetic analysis. Although the initiation of antifungal therapy was late, the pneumonia gradually improved with long-term treatment. This case highlights the need for early diagnosis and effective long-term treatment of the fungal etiologic agent.

PMID:38022890 | PMC:PMC10661607 | DOI:10.1016/j.mmcr.2023.100617

ERJ Open Res. 2023 Nov 27;9(6):00504-2023. doi: 10.1183/23120541.00504-2023. eCollection 2023 Nov.

ABSTRACT

Although the mechanisms are not known, this is a case of progressive interstitial lung involvement, with a NSIP radiological pattern, evolving in pulmonary fibrosis in a patient with von Hippel-Lindau syndrome, without extrapulmonary fibrosis. https://bit.ly/3QlNStu.

PMID:38020566 | PMC:PMC10680027 | DOI:10.1183/23120541.00504-2023