J Clin Med. 2024 Dec 6;13(23):7428. doi: 10.3390/jcm13237428.

ABSTRACT

Interest in the transition of care for cystic fibrosis (CF) patients has grown significantly over time, driven by advancements in treatment that have extended life expectancy. As more CF patients survive into adulthood, the need for structured transition strategies has become a priority for healthcare systems worldwide. Transition programs for CF differ globally, reflecting varying resources and healthcare systems. In North America, the US CF Foundation has fostered adult care since the 1990s, with accreditation standards mandating adult programs and structured transition guidelines, exemplified by the CF RISE program for gradual responsibility shifts. Canada integrates US-inspired models, emphasizing national advocacy and outcomes evaluation. In Europe, approaches varies widely; the UK leads with structured programs like the Liverpool model and robust registry support, while France and Germany adopt multidisciplinary methods. In Australia and New Zealand, youth-centered policies prioritize early planning and access via telemedicine. In Asia, where CF is rare, transitions are less formalized, with some progress in countries like Japan and Turkey, though resource gaps and limited data tracking remain significant challenges. Despite varied approaches across countries, common barriers like resource limitations and psychological readiness continue to challenge successful transitions. Highlighting the importance of centralized, well-coordinated transition programs, recent initiatives have focused on the implementation of national and international CF registries to enhance health outcomes and quality of life. This narrative review provides a global perspective on transition strategies developed across various healthcare systems for CF patients, identifying best practices, common challenges, and outcomes related to the continuity of care.

PMID:39685886 | DOI:10.3390/jcm13237428

Int J Mol Sci. 2024 Dec 4;25(23):13038. doi: 10.3390/ijms252313038.

ABSTRACT

Neutrophil elastase (NE) has been reported to be a pro-inflammatory stimulus for macrophages. The aim of the present study was to determine the impact of NE exposure on the human macrophage proteome and evaluate its impact on pro-inflammatory signals. Human blood monocytes from healthy volunteers were differentiated to macrophages and then exposed to either 500 nM of NE or control vehicle for 2 h in triplicate. Label-free quantitative proteomics analysis identified 41 differentially expressed proteins in the NE versus control vehicle datasets. A total of 26 proteins were downregulated and of those, 21 were cell surface proteins. Importantly, four of the cell surface proteins were proteoglycans: neuropilin 1 (NRP1), syndecan 2 (SDC2), glypican 4 (GPC4), and CD99 antigen-like protein 2 (CD99L2) along with neuropilin 2 (NRP2), CD99 antigen (CD99), and endoglin (ENG) which are known interactors. Additional NE-targeted proteins related to macrophage function were also measured including CD40, CD48, SPINT1, ST14, and MSR1. Collectively, this study provides a comprehensive unbiased view of selective NE-targeted cell surface proteins in chronically inflamed lungs.

PMID:39684750 | DOI:10.3390/ijms252313038

Nutrients. 2024 Nov 27;16(23):4071. doi: 10.3390/nu16234071.

ABSTRACT

BACKGROUND/OBJECTIVES: Early life gut microbiota plays a pivotal role in shaping immunity, metabolism, and overall health outcomes. This is relevant in healthy infants but may be even more crucial in infants with chronic devastating diseases, such as cystic fibrosis (CF). While the introduction of solid foods in healthy infants modifies the composition of colonic microbiota, less knowledge is available on those with CF. The aim of this descriptive observational study was to assess the composition of fecal microbiota in six exclusively breast-fed infants with CF, and then explore the changes induced upon the introduction of different foods.

METHODS: two types of fecal samples were collected from each subject: one during the exclusive-breastfeeding period, and the other after incorporating each new food in the ad libitum diet. The microbiota composition was analyzed by 16S rRNA amplicon sequencing.

RESULTS: Wide heterogenicity in the composition at the phylum level (variable proportions of Actinobacteriota, Proteobacteria, and Firmicutes, and the absence of Bacteroidota in all subjects) was found, and different enterotypes were characterized in each subject by the main presence of one genus: Bifidobacterium in Subject 1 (relative abundance of 54.4%), Klebsiella in Subject 3 (49.1%), Veillonella in Subjects 4 and 5 (32.7% and 36.9%, respectively), and Clostridium in Subject 6 (48.9%). The transition to complementary feeding induced variable changes in microbiota composition, suggesting a subject-specific response and highlighting the importance of inter-individual variation.

CONCLUSIONS: Further studies are required to identify which foods contribute to shaping colonic microbiota in the most favorable way for patients with CF using a personalized approach.

PMID:39683464 | DOI:10.3390/nu16234071

J Rheumatol. 2024 Dec 15:jrheum.2024-0978. doi: 10.3899/jrheum.2024-0978. Online ahead of print.

NO ABSTRACT

PMID:39681377 | DOI:10.3899/jrheum.2024-0978

Microbes Infect. 2024 Dec 14:105465. doi: 10.1016/j.micinf.2024.105465. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive genetic disorder characterized by impairment of the CF transmembrane conductance regulator (CFTR) via gene mutation. CFTR is expressed at the cellular membrane of epithelial cells and functions as an anion pump which maintains water and salt ion homeostasis. In pulmonary airways of CF patients, pathogens such as P. aeruginosa and subsequent uncontrolled inflammation damage the human airway epithelial cells (HAECs) and can be life-threatening. We previously identified that inhibiting endogenous retroelement (ERE) reverse transcriptase can hamper the inflammatory response to bacterial flagella in THP-1 cells. Here, we investigate how ERE expression is sensitive to HAEC repair and toll-like receptor 5 (TLR5) activation, a primary mechanism by which inflammation impacts disease outcome. Our results demonstrate that several human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs) fluctuate throughout the various stages of repair and that TLR5 activation further influences ERE expression. By considering the impact of the most common CF mutation F508del/F508del on ERE expression in unwounded HAECs, we also found that two specific EREs, L1FLnI_2p23.1c and HERVH_10p12.33, were downregulated in CF-derived HAECs. Collectively, we show that ERE expression in HAECs is sensitive to certain modalities reflective of CF pathogenesis, and specific EREs may be indicative of CF disease state and pathogenesis.

PMID:39681187 | DOI:10.1016/j.micinf.2024.105465

J Clin Invest. 2024 Dec 16;134(24):e179563. doi: 10.1172/JCI179563.

ABSTRACT

The pathobiont Staphylococcus aureus (Sa) induces nonprotective antibody imprints that underlie ineffective staphylococcal vaccination. However, the mechanism by which Sa modifies antibody activity is not clear. Herein, we demonstrate that IL-10 is the decisive factor that abrogates antibody protection in mice. Sa-induced B10 cells drive antigen-specific vaccine suppression that affects both recalled and de novo developed B cells. Released IL-10 promotes STAT3 binding upstream of the gene encoding sialyltransferase ST3gal4 and increases its expression by B cells, leading to hyper-α2,3sialylation of antibodies and loss of protective activity. IL-10 enhances α2,3sialylation on cell-wall-associated IsdB, IsdA, and MntC antibodies along with suppression of the respective Sa vaccines. Consistent with mouse findings, human anti-Sa antibodies as well as anti-pseudomonal antibodies from cystic fibrosis subjects (high IL-10) are hypersialylated, compared with anti-Streptococcus pyogenes and pseudomonal antibodies from normal individuals. Overall, we demonstrate a pathobiont-centric mechanism that modulates antibody glycosylation through IL-10, leading to loss of staphylococcal vaccine efficacy.

PMID:39680460 | DOI:10.1172/JCI179563

Pediatr Pulmonol. 2024 Dec 16:e27442. doi: 10.1002/ppul.27442. Online ahead of print.

ABSTRACT

INTRODUCTION: Proper transfer of patients from pediatric to adult chest clinic has critical importance. In this study, we aimed to evaluate the follow-up data of the patients in the first 12 months after transfer.

METHODS: Cystic fibrosis (CF) patients previously transferred to adult chest clinics were included. Demographic and clinical data were retrospectively reviewed. The baseline visit was defined as the first visit at the adult center. One-year follow-up data were compared with the baseline data.

RESULTS: A total of 118 patients were included in the study (men/women: 70/48). The mean ages at the time of transfer and inclusion in the study inclusion were 26.5 (23-29) and 27.6 ( ± 6.4) years, respectively. There was a significant reduction in FEV1 (%) and FEV1/FVC ratio between baseline and 1-year follow-up visits (p < 0.001, p < 0.001, respectively). Compared to the year before the transfer, total number of exacerbations (p = 0.001), outpatient clinic visits (p < 0.001), total antibiotic days (p < 0.001), and intravenous antibiotic days (p = 0.001) significantly increased.

CONCLUSIONS: The findings of this study show that the pulmonary functions of CF patients decline and clinical conditions deteriorated after the transfer to the adult clinic. Simple transfer, rather than transition, may be one of the reasons for adverse outcomes in this patient population.

PMID:39679729 | DOI:10.1002/ppul.27442

Contemp Clin Trials Commun. 2024 Oct 5;42:101378. doi: 10.1016/j.conctc.2024.101378. eCollection 2024 Dec.

ABSTRACT

BACKGROUND: It has been commonly reported that therapeutic treatments in cystic fibrosis (CF) have ceiling effects, such that their efficacy is diminished for persons with high pre-treatment health (Montgomery et al., 2012 and Newsome et al., 2019). Floor effects have also been reported where decline is of lower magnitude in those with below-average pre-treatment health (Harun et al., 2016; Konstan et al., 2012 and Szczesniak et al., 2017). When measurement error is present, the statistical literature has warned of exaggerated or spurious associations between pre-treatment measures and subsequent change (Chambless and Davis, 2003 and Yanez et al., 1998). Measurement error, equivalently described as day-to-day variation, has been described to occur in CF outcome measurements such as forced expiratory volume in 1 s taken by spirometry (FEV 1 pp) (Magaret et al., 2024; Stanojevic et al., 2020 and Thornton et al., 2023).

METHODS: We conducted a simulation study to assess the potential for spurious floor or ceiling effects in studies of CF therapeutics. We considered uncontrolled or single-arm studies, and evaluated estimated association between pre-treatment FEV 1 pp and treatment-induced change: post-versus pre-treatment.

RESULTS: When day-to-day variation was present in FEV 1 pp, at levels equivalent to those reported in large studies measuring spirometry both at home and in clinic, naive analytic approaches found spurious associations of change with baseline (Paynter et al., 2022 and Saiman et al., 2003). Type I error ranged from 31.9% to 98.3% for day-to-day variation as high as 3% to 15% relative to biological variation. Incorporating known day-to-day variation, the regression calibration approach corrected bias and controlled type I error (Chambless and Davis, 2003).

CONCLUSION: Exaggerated ceiling effects are possible. Further studies could provide meaningful confirmation of ceiling effects in CF, perhaps reducing day-to-day variation by incorporating multiple pre- and post-treatment measurements.

PMID:39678155 | PMC:PMC11639362 | DOI:10.1016/j.conctc.2024.101378

medRxiv [Preprint]. 2024 Dec 5:2024.12.02.24318364. doi: 10.1101/2024.12.02.24318364.

ABSTRACT

Genetic mutations that yield defective cystic fibrosis transmembrane regulator ( CFTR ) protein cause cystic fibrosis, a life-limiting autosomal recessive Mendelian disorder. A protective role of CFTR loss-of-function mutations in inflammatory bowel disease (IBD) has been suggested, but its evidence has been inconclusive and contradictory. Here, leveraging the largest IBD exome sequencing dataset to date, comprising 38,558 cases and 66,945 controls in the discovery stage, and 35,797 cases and 179,942 controls in the replication stage, we established a protective role of CF-risk variants against IBD based on evidence from the association test of CFTR delF508 (p-value=8.96E-11) and the gene-based burden test of CF-risk variants (p-value=3.9E-07). Furthermore, we assessed variant prioritization methods, including AlphaMissense, using clinically annotated CF-risk variants as the gold standard. Our findings highlight the critical and unmet need for effective variant prioritization in gene-based burden tests.

PMID:39677473 | PMC:PMC11643156 | DOI:10.1101/2024.12.02.24318364

Cureus. 2024 Nov 12;16(11):e73562. doi: 10.7759/cureus.73562. eCollection 2024 Nov.

ABSTRACT

Introduction Children with cystic fibrosis (CF) have lipid maldigestion due to pancreatic insufficiency, which causes malabsorption of fat-soluble vitamins. The primary objective of this study was to assess the prevalence of vitamin E deficiency among children with CF. The secondary objective was to examine the correlation between vitamin E levels with demographic data, laboratory findings, and the number of pulmonary exacerbations. Furthermore, the study aimed to identify potential predictors of vitamin E deficiency in this population. Methods A prospective cohort study was conducted from July 1, 2017, to April 30, 2019. Medical records of children diagnosed with CF at the Department of Pediatrics, Salmaniya Medical Complex, Bahrain were reviewed. Patients who didn't receive fat-soluble vitamin supplementation for at least three days were recruited for the study. Light-protected blood samples were tested for vitamin E and D levels and fasting serum cholesterol levels. Patients with vitamin E deficiency were compared with those without regarding demography, laboratory results, and number of pulmonary exacerbations. Results Of 109 patients with CF, 35 (32.1%) fulfilled the inclusion criteria. Eighteen (51.4%) were males. The mean age was 6.8 ± 4.7 years. Eleven (31.4%) patients were symptomatic. Vitamin E and D were deficient in nine (25.7%) and 28/34 (82.4%) patients, respectively. Cholesterol was low in 29 (82.9%). The mean vitamin E level in the deficient group was significantly lower (3.2 ± 1.7 mg/L) than that (10.3 ± 3.1 mg/L) of the vitamin E-sufficient group (P < 0.0001). A significant negative correlation was noted between vitamin E levels and white blood cell (WBC) count (r = -0.408; P = 0.015). However, no correlation was found between vitamin E levels and cholesterol, vitamin D levels, or the number of pulmonary exacerbations. Vitamin E-deficient patients had lower weight at presentation (P = 0.045), hemoglobin level (P = 0.001), and salbutamol use (P = 0.022), but higher reticulocyte percentage (P = 0.034) and WBC count (P = 0.001) compared to the vitamin E-sufficient group. Conclusion Vitamin E deficiency is common among patients with CF in Bahrain and may increase the risk of hemolytic anemia. This deficiency did not seem to affect the frequency of pulmonary exacerbations. Management of vitamin E deficiency in patients with CF should be hastened to avoid irreversible complications.

PMID:39677137 | PMC:PMC11645181 | DOI:10.7759/cureus.73562

Curr Med Sci. 2024 Dec 16. doi: 10.1007/s11596-024-2936-5. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a hereditary disorder characterized by mutations in the CFTR gene, leading to impaired chloride ion transport and subsequent thickening of mucus in various organs, particularly the lungs. Despite significant progress in CF management, current treatments focus mainly on symptom relief and do not address the underlying genetic defects. Stem cell and gene therapies present promising avenues for tackling CF at its root cause. Stem cells, including embryonic, induced pluripotent, mesenchymal, hematopoietic, and lung progenitor cells, offer regenerative potential by differentiating into specialized cells and modulating immune responses. Similarly, gene therapy aims to correct CFTR gene mutations by delivering functional copies of the gene into affected cells. Various approaches, such as viral and nonviral vectors, gene editing with CRISPR-Cas9, small interfering RNA (siRNA) therapy, and mRNA therapy, are being explored to achieve gene correction. Despite their potential, challenges such as safety concerns, ethical considerations, delivery system optimization, and long-term efficacy remain. This review provides a comprehensive overview of the current understanding of CF pathophysiology, the rationale for exploring stem cell and gene therapies, the types of therapies available, their mechanisms of action, and the challenges and future directions in the field. By addressing these challenges, stem cell and gene therapies hold promise for transforming CF management and improving the quality of life of affected individuals.

PMID:39676146 | DOI:10.1007/s11596-024-2936-5

Gastroenterol Hepatol. 2024 Dec 13:502321. doi: 10.1016/j.gastrohep.2024.502321. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive, chronic, potentially lethal genetic disease. CF manifestations are due to mutations in the CF transmembrane receptor transporter (CFTR) gene which codes for a protein (CFTR) that acts as an anion transporter, mainly chlorine, at epithelial cells where it is expressed. Cystic fibrosis related liver disease (CFRLD) includes a spectrum of hepatobiliary manifestations whose diagnosis and follow-up remains a challenge.

METHODS: Cross-sectional, descriptive study from 10 Spanish Cystic fibrosis Units. Clinical and biochemical data obtained. Patients categorized into 3 groups according to liver involvement based on ESPGHAN 2017 criteria. Liver stiffness assessed by transient elastography (TE) and findings from abdominal ultrasound recorded. Statistics performed using SPSS v25.0.

RESULTS: We obtained hepatic TE data from 155 pediatric CF patients. Forty-four classified as CFRLD, 38 (86%) had CFRLD without cirrhosis and 6 (14%) had cirrhosis. Fourteen patients without CFRLD (12%) had ultrasound abnormalities. Mean liver elastography value (kPa) was 4.7 (3.5-5.3) in non-CFRLD and 6.09 (4.4-6.7) in CFRLD (p=0.01;Tstudent [T]).

CONCLUSIONS: CFRLD is common in children with CF. Transient elastography is a useful method for diagnosis and follow-up, as higher values of TE are found in patients with CFRLD.

PMID:39675556 | DOI:10.1016/j.gastrohep.2024.502321

Biosens Bioelectron. 2024 Dec 5;271:117041. doi: 10.1016/j.bios.2024.117041. Online ahead of print.

ABSTRACT

Noninvasive diagnostics play a crucial role in health monitoring and disease detection. Sweat is a representative sample type containing various clinical biomarkers that provide information on certain disease risks. We developed a hydrogel-based colorimetric sensor for sweat analysis using a low-power battery. The hydrogel-based sensor comprised highly flexible bacterial cellulose (BC), highly water-absorbent carboxymethyl cellulose (CMC), and antibacterial chitosan (Ch), which functioned independently or in conjunction with a reusable three-dimensional printed polydimethylsiloxane-based microfluidic device. The highest tensile strength of 4.16 N for the hydrogel material of BC-CMC under the 0.6% Ch reaction indicated that this material had the best properties for absorbing sweat and measuring Cl- and glucose concentrations while attached to the surface of human skin. Our sensor was able to detect chloride ions (Cl-) and glucose concentrations in sweat. The sensor exhibited a linear relationship between the Cl- concentration and b∗ value with a detection limit of 0.56 mM and a detection range of 20-100 mM, encompassing the critical diagnostic window of cystic fibrosis. For glucose detection, color changes were observed visually, and there was a linear relationship between the glucose concentration and the -b∗ value. The detection limit of 0.1 μM and wide detection range of 6.25-500 μM were suitable for the diagnosis of diabetes. The as-prepared sensor maintained stability for one month under specific storage conditions, suggesting the potential of this analytical method for excellent water absorption and selectivity. The sensor can be used for real-time diagnostics to detect cystic fibrosis and its potential complications, such as diabetes, in clinical medicine.

PMID:39675232 | DOI:10.1016/j.bios.2024.117041

J Allergy Clin Immunol Pract. 2024 Dec 12:S2213-2198(24)01244-3. doi: 10.1016/j.jaip.2024.12.003. Online ahead of print.

ABSTRACT

BACKGROUND: Piperacillin-tazobactam is used in patients with cystic fibrosis to treat recurrent respiratory infections. Exposure is associated with a high frequency of non-immediate hypersensitivity.

OBJECTIVE: To assess the applicability of the lymphocyte transformation test (LTT) for the diagnosis of piperacillin hypersensitivity and the influence of desensitization on piperacillin-specific T-cell responses.

METHODS: Study-arm one was an analysis of LTT responses from 58 naïve/baseline tolerant patients with samples collected over a three-year interventional phase. In study-arm two, seventeen hypersensitive patients were recruited and LTTs were conducted before and post-desensitization. Clinical hypersensitivity reactions in both arms were monitored over an eight-year observational period.

RESULTS: Fifty-eight patients in study arm one received 611 (range, 2-40; mean±SD, 10.5±8.1) piperacillin-tazobactam courses during the interventional phase, of which 11 developed hypersensitivity. The patients that remained tolerant received 236 piperacillin-tazobactam courses in the observational period, of which 9 developed hypersensitivity. Ten/eleven interventional phase hypersensitive patients had a positive LTT, while one remained negative. 136 negative LTTs were recorded with 39 tolerant patients, while eight patients recorded a positive LTT, with 4 developing hypersensitivity during the observational period. Ten LTT positive patients in study arm two underwent piperacillin-tazobactam desensitization, with seven tolerating the drug. The strength of the LTT decreased during desensitization and negative results were recorded for a minimum of 14-days. During follow-up, eight patients tolerated 62 piperacillin-tazobactam courses through desensitization.

CONCLUSIONS: LTT is a sensitive marker of drug sensitisation that could be used to inform future patient management. Desensitization is associated with attenuation of the piperacillin-specific T-cell response.

PMID:39674278 | DOI:10.1016/j.jaip.2024.12.003

Nucleic Acids Res. 2024 Nov 30:gkae1112. doi: 10.1093/nar/gkae1112. Online ahead of print.

ABSTRACT

Nonsense suppressor transfer RNAs (tRNAs) or AntiCodon-Edited tRNAs (ACE-tRNAs) have long been envisioned as a therapeutic approach to overcome genetic diseases resulting from the introduction of premature termination codons (PTCs). The ACE-tRNA approach for the rescue of PTCs has been hampered by ineffective delivery through available modalities for gene therapy. Here we have screened a series of ACE-tRNA expression cassette sequence libraries containing >1800 members in an effort to optimize ACE-tRNA function and provide a roadmap for optimization in the future. By optimizing PTC suppression efficiency of ACE-tRNAs, we have decreased the amount of ACE-tRNA required by ∼16-fold for the most common cystic fibrosis-causing PTCs.

PMID:39673265 | DOI:10.1093/nar/gkae1112

Eur J Pediatr. 2024 Dec 14;184(1):82. doi: 10.1007/s00431-024-05905-9.

ABSTRACT

Bacterial infections of the lower airways are the main cause of mortality and morbidity in cystic fibrosis. The most frequently isolated pathogens are S. aureus and P. aeruginosa; bacterial co-infections are frequently observed. The aim of this review is to provide, in the current context, the indications regarding the best antibiotic strategy to adopt in subjects affected by CF infected with the most common pathogens. We selected relevant publications (guidelines, systematic reviews and clinical studies published so far on these topics) and we analysed the sampling methods used and antibiotic strategies adopted. Oropharyngeal sampling methods are considered less sensitive for pathogen detection than sputum. In non-expectorating people, induced sputum is considered equivalent to two-lobe bronchoalveolar lavage, which is considered invasive. Antibiotic treatment against the main pathogens can consist in eradication treatment in the early stages of infection, chronic suppressive therapy and treatment of the pulmonary exacerbations. This scheme is valid for P. aeruginosa but remains to be demonstrated for the other pathogens. For S. aureus, no evidence-based therapeutic strategies on how to treat the different stages of bacterial infection have been established with certainty. With regard to the treatment of the other classic pathogens (B. cepacia complex, A. xylosoxidans and S. maltophilia), no evidence-based indications exist and decision is left to the clinician. The recent introduction of highly effective modulators on the CFTR protein, in addition to the favourable effects described in regulatory trials, has led to a reduction in bacterial isolations; the real effect of which in clinical practice has still to be assessed on the basis of scientific data. CONCLUSIONS: The reliability of culture examination depends on sampling methods, and expectorated sputum continues to be the best method as it is simple and non-invasive. P. aeruginosa is the pathogen for which antibiotic strategies for the various stages of infection appear best established, and the efficacy of early eradication treatment and chronic suppressive therapy have been underlined in clinical trials and systematic reviews. The recent introduction of modulators into clinical practice, despite their widely described efficacy, has not yet led to suggestions for changes in antibiotic strategies against the pathogens most frequently isolated.

PMID:39672981 | DOI:10.1007/s00431-024-05905-9

Dig Dis Sci. 2024 Dec 13. doi: 10.1007/s10620-024-08784-0. Online ahead of print.

ABSTRACT

BACKGROUND: The reported prevalence of cystic fibrosis (CF)-related liver disease (CFLD) reaches up to 40% in some cohorts. CFLD is the 3rd leading cause of mortality among patients with CF. The aims of this study were to evaluate the prevalence of CFLD in a cohort followed at a tertiary university center, to define the types of liver involvement, and to determine how non-invasive screening methods can be optimally integrated into clinical practice.

METHODS: The files of patients followed at the CF clinic of the Centre hospitalier de l'Université de Montréal (CHUM) between 2020 and 2022 were retrospectively reviewed. The NIH criteria were used to define CFLD through the presence of one major criterion (abnormal imaging) or two minor criteria (persistently abnormal laboratory values, hepatosplenomegaly, or transient elastography (TE) ≥ 7 kPa).

RESULTS: A total of 357 patients were included in this study. CFLD was observed in 46 patients (13%). Among these, major criteria led to diagnosis in 43 patients (with or without minor criteria). TE performed best in non-invasive assessment of CLFD (area under the curve (AUROC) 0.80 (0.68-0.92, p = 0.0007)). A nodular liver was detected in 27 patients (7%), and was associated with higher non-invasive markers of fibrosis. In addition, presence of a nodular liver was associated with significant short-term mortality (14.8% vs. 1.5%, p = 0.003).

CONCLUSION: Early recognition of CFLD in clinical care can potentially prevent complications of cirrhosis and portal hypertension. The use of abdominal imaging and TE seems promising for detecting CFLD.

PMID:39671064 | DOI:10.1007/s10620-024-08784-0

Clin Transplant. 2024 Dec;38(12):e70054. doi: 10.1111/ctr.70054.

ABSTRACT

Suppurative lung diseases leading to end-stage respiratory failure are typical indications for bilateral lung transplantation (LuTx). Some cases may present severe chest asymmetry because of recurrent infections or previous surgical procedures, and the most used surgical options are single LuTx and contralateral pneumonectomy or bilateral transplantation with graft downsizing. Our purpose is to evaluate our treatment protocols for these patients and review surgical strategies reported by others. We prospectively collected clinical data of patients with significant pleural cavity asymmetry who underwent bilateral LuTx at our center from 2017 to 2022. Clinical reports of all patients who underwent LuTx for end-stage suppurative disease in the same period were reviewed as the control group. During the study period, 74 patients underwent bilateral LuTx for suppurative disease; seven of them presented with severe thoracic asymmetry, and all of them were extubated by the second postoperative day. The mean intensive care unit stay was 4 days. The postoperative radiological evaluation did not show clustering or atelectasis of the graft implanted in the smaller hemithorax. No perioperative major complications were recorded, and the average length of stay was 23 days. The perioperative course appeared remarkably good, and both the short- and long-term follow-up were similar to that of the control group.

PMID:39670964 | DOI:10.1111/ctr.70054

J Bacteriol. 2024 Dec 13:e0034424. doi: 10.1128/jb.00344-24. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa uses quorum sensing (QS) to regulate the expression of dozens of genes, many of which encode shared products, called "public goods." P. aeruginosa possesses two complete acyl-homoserine lactone (AHL) QS circuits: the LasR-I and RhlR-I systems. Canonically, these systems are hierarchically organized: RhlR-I activity depends on LasR-I activation. However, in contrast to laboratory strains, isolates from people with cystic fibrosis can engage in AHL QS using only the transcription factor RhlR. In these isolates, RhlR regulates AHL QS and the production of secreted public goods, such as the exoprotease elastase, which are accessible to both producing and non-producing cells. When P. aeruginosa strains that use LasR to regulate elastase production are grown on casein as the sole carbon and energy source, LasR-null mutant "cheaters" commonly arise in populations due to a selective growth advantage. We asked if these social dynamics might differ in "RhlR cooperators": populations that use RhlR, not LasR, to regulate public goods. We passaged RhlR cooperators from several genetic backgrounds in casein broth. We found that cheaters emerged among most RhlR cooperators. However, in one isolate background, E90, RhlR-null mutants were dramatically outcompeted by RhlR cooperators. In this background, the mechanism by which RhlR mutants are outcompeted by RhlR cooperators is AHL-dependent and occurs in stationary phase but is not the same as previously described "policing" mechanisms. Our data suggest that cheating, or the lack thereof, does not explain the lack of RhlR mutants observed in most infection environments.IMPORTANCEQuorum sensing (QS) mutants arise in a variety of populations of bacteria, but mutants of the gene encoding the transcription factor RhlR in Pseudomonas aeruginosa appear to be infrequent. Our work provides insight on the mechanisms through which RhlR-mediated cooperation is maintained in a LasR-null population of P. aeruginosa. Characterizing the selective pressure(s) that disfavor mutations from occurring in RhlR may enhance our understanding of P. aeruginosa evolution in chronic infections and potentially guide the development of therapeutics targeting the RhlR-I QS circuit.

PMID:39670758 | DOI:10.1128/jb.00344-24

Appl Environ Microbiol. 2024 Dec 13:e0185324. doi: 10.1128/aem.01853-24. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is considered one of the most challenging, drug-resistant, opportunistic pathogens partly due to its ability to synthesize robust biofilms. Biofilm is a mixture of extracellular polymeric substances (EPS) that encapsulates microbial cells, leading to immune evasion, antibiotic resistance, and thus higher risk of infection. In the cystic fibrosis lung environment, P. aeruginosa undergoes a mucoid transition, defined by overproduction of the exopolysaccharide alginate. Alginate encapsulation results in bacterial resistance to antibiotics and the host immune system. Given its role in airway inflammation and chronic infection, alginate is an obvious target to improve treatment for P. aeruginosa infection. Previously, we demonstrated polysaccharide lyase Smlt1473 from Stenotrophomonas maltophilia strain k279a can catalyze the degradation of multiple polyuronides in vitro, including D-mannuronic acid (poly-ManA). Poly-ManA is a major constituent of P. aeruginosa alginate, suggesting that Smlt1473 could have potential application against multidrug-resistant P. aeruginosa and perhaps other microbes with related biofilm composition. In this study, we demonstrate that Smlt1473 can inhibit and degrade alginate from P. aeruginosa. Additionally, we show that tested P. aeruginosa strains are dominant in acetylated alginate and that all but one have similar M-to-G ratios. These results indicate that variation in enzyme efficacy among the isolates is not primarily due to differences in total EPS or alginate chemical composition. Overall, these results demonstrate Smlt1473 can inhibit and degrade P. aeruginosa alginate and suggest that other factors including rate of EPS production, alginate sequence/chain length, or non-EPS components may explain differences in enzyme efficacy.

IMPORTANCE: Pseudomonas aeruginosa is a major opportunistic human pathogen in part due to its ability to synthesize biofilms that confer antibiotic resistance. Biofilm is a mixture of polysaccharides, DNA, and proteins that encapsulate cells, protecting them from antibiotics, disinfectants, and other cleaning agents. Due to its ability to increase antibiotic and immune resistance, the exopolysaccharide alginate plays a large role in airway inflammation and chronic P. aeruginosa infection. As a result, colonization with P. aeruginosa is the leading cause of morbidity and mortality in CF patients. Thus, it is an obvious target to improve the treatment regimen for P. aeruginosa infection. In this study, we demonstrate that polysaccharide lyase, Smlt1473, inhibits alginate secretion and degrades established alginate from a variety of mucoid P. aeruginosa clinical isolates. Additionally, Smlt1473 differs from other alginate lyases in that it is active against acetylated alginate, which is secreted during chronic lung infection. These results suggest that Smlt1473 may be useful in treating infections associated with alginate-producing P. aeruginosa, as well as have the potential to reduce P. aeruginosa EPS in non-clinical settings.

PMID:39670718 | DOI:10.1128/aem.01853-24