Clin Chim Acta. 2024 Jun 7:119765. doi: 10.1016/j.cca.2024.119765. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations to the CF transmembrane conductance regulator (CFTR). Symptoms and severity of the disease can be quite variable suggesting modifier genes play an important role.

MATERIALS AND METHODS: Exome sequencing was performed on six individuals carrying homozygous deltaF508 for CFTR genotype but present with rapidly progressing CF (RPCF). Data was analyzed using an unbiased genome-wide genetic burden test against 3076 controls. Single cell RNA sequencing data from LungMAP was utilized to evaluate unique and co-expression of candidate genes, and structural modeling to evaluate the deleterious effects of identified candidate variants.

RESULTS: We have identified solute carrier family 26 member 9 (SLC26A9) as a modifier gene to be associated with RPCF Two rare missense SLC26A9 variants were discovered in three of six individuals deemed to have RPCF: c.229G > A; p.G77S (present in two patients), and c.1885C > T; p.P629S. Co-expression of SLC26A9 and CFTR mRNA is limited across different lung cell types, with the highest level of co-expression seen in human (6.3 %) and mouse (9.0 %) alveolar type 2 (AT2) cells. Structural modeling suggests deleterious effects of these mutations as they are in critical protein domains which might affect the anion transport capability of SLC26A9.

CONCLUSION: The enrichment of rare and potentially deleterious SLC26A9 mutations in patients with RPCF suggests SLC26A9 may act as an alternative anion transporter in CF and is a modifier gene associated with this lung phenotype.

PMID:38852790 | DOI:10.1016/j.cca.2024.119765

Respir Med Res. 2024 Mar 15;86:101102. doi: 10.1016/j.resmer.2024.101102. Online ahead of print.

NO ABSTRACT

PMID:38852201 | DOI:10.1016/j.resmer.2024.101102

J Cyst Fibros. 2024 Jun 8:S1569-1993(24)00063-8. doi: 10.1016/j.jcf.2024.04.017. Online ahead of print.

ABSTRACT

BACKGROUND: Progressive, obstructive lung disease resulting from chronic infection and inflammation is the leading cause of morbidity and mortality in persons with cystic fibrosis (PWCF). Metabolomics and next -generation sequencing (NGS) of airway secretions can allow for better understanding of cystic fibrosis (CF) pathophysiology. In this study, global metabolomic profiling on bronchoalveolar lavage fluid (BALF) obtained from pediatric PWCF and disease controls (DCs) was performed and compared to lower airway microbiota, inflammation, and lung function.

METHODS: BALF was collected from children undergoing flexible bronchoscopies for clinical indications. Metabolomic profiling was performed using a platform developed by Metabolon Inc. Total bacterial load (TBL) was measured using quantitative polymerase chain reaction (qPCR), and bacterial communities were characterized using 16S ribosomal RNA (rRNA) sequencing. Random Forest Analysis (RFA), principal component analysis (PCA), and hierarchical clustering analysis (HCA) were performed.

RESULTS: One hundred ninety-five BALF samples were analyzed, 142 (73 %) from PWCF. Most metabolites (425/665) and summed categories (7/9) were significantly increased in PWCF. PCA of the metabolomic data revealed CF BALF exhibited more dispersed clustering compared to DC BALF. Higher metabolite concentrations correlated with increased inflammation, increased abundance of Staphylococcus, and decreased lung function.

CONCLUSIONS: The lower airway metabolome of PWCF was defined by a complex expansion of metabolomic activity. These findings could be attributed to heightened inflammation in PWCF and aspects of the CF airway polymicrobial ecology. CF-specific metabolomic features are associated with the unique underlying biology of the CF airway.

PMID:38853065 | DOI:10.1016/j.jcf.2024.04.017

Pediatr Surg Int. 2024 Jun 9;40(1):154. doi: 10.1007/s00383-024-05725-w.

ABSTRACT

PURPOSE: To characterise the investigations, management and ultimate diagnosis of neonates with distal intestinal obstruction.

METHODS: Retrospective review of term (> 37 weeks) neonates with admission diagnosis of distal intestinal obstruction over 10 years (2012-2022). Patient pathways were identified and associations between presentations, response to treatments and outcome investigated.

RESULTS: A total of 124 neonates were identified and all included. Initial management was colonic irrigation in 108, contrast enema in 4, and laparotomy in 12. Of those responding to irrigations none underwent contrast enema. Ultimately, 22 neonates proceeded to laparotomy. Overall, 106 had a suction rectal biopsy and 41 had genetic testing for cystic fibrosis. Final diagnosis was Hirschsprung disease (HD) in 67, meconium ileus with cystic fibrosis (CF) in 9, meconium plug syndrome in 19 (including 3 with CF), intestinal atresia in 10 and no formal diagnosis in 17. Median length of neonatal unit stay was 11 days (7-19).

CONCLUSIONS: Initial management of neonates with distal bowel obstruction should be colonic irrigation since this is therapeutic in the majority and significantly reduces the need for contrast enema. These infants should all have suction rectal biopsy to investigate for HD unless another diagnosis is evident. If a meconium plug is passed, testing for CF is recommended. Evaluation and therapy are multimodal and time consuming, placing burden on resources and families.

PMID:38852109 | DOI:10.1007/s00383-024-05725-w

J Cyst Fibros. 2024 Jun 7:S1569-1993(24)00081-X. doi: 10.1016/j.jcf.2024.06.002. Online ahead of print.

ABSTRACT

BACKGROUND: Inhibiting ENaC in the airways of people with cystic fibrosis (pwCF) is hypothesized to enhance mucociliary clearance (MCC) and provide clinical benefit. Historically, inhaled ENaC blockers have failed to show benefit in pwCF challenging this hypothesis. It is however unknown whether the clinical doses were sufficient to provide the required long duration of action in the lungs and questions whether a novel candidate could offer advantages where others have failed?

METHODS: Dose-responses with the failed ENaC blockers (VX-371, BI 1265162, AZD5634, QBW276) together with ETD001 (a novel long acting inhaled ENaC blocker) were established in a sheep model of MCC and were used to predict clinically relevant doses that would provide a long-lasting enhancement of MCC in pwCF. In each case, dose predictions were compared with the selected clinical dose.

RESULTS: Each of the failed candidates enhanced MCC in the sheep model. Translating these dose-response data to human equivalent doses, predicted that substantially larger doses of each candidate, than were evaluated in clinical studies, would likely have been required to achieve a prolonged enhancement of MCC in pwCF. In contrast, ETD001 displayed a long duration of action (≥16 h) at a dose level that was well tolerated in Phase 1 clinical studies.

CONCLUSIONS: These data support that the ENaC blocker hypothesis is yet to be appropriately tested in pwCF. ETD001 has a profile that enables dosing at a level sufficient to provide a long duration of action in a Phase 2 clinical study in pwCF scheduled for 2024.

PMID:38851923 | DOI:10.1016/j.jcf.2024.06.002

J Cyst Fibros. 2024 Jun 7:S1569-1993(24)00077-8. doi: 10.1016/j.jcf.2024.05.014. Online ahead of print.

ABSTRACT

INTRODUCTION: People with cystic fibrosis (PwCF) experience frequent symptoms associated with chronic lung disease. A complication of CF is a pulmonary exacerbation (PEx), which is often preceded by an increase in symptoms and a decline in lung function. A symptom cluster is when two or more symptoms co-occur and are related; symptom clusters have contributed meaningful knowledge in other diseases. The purpose of this study is to discover symptom clustering patterns in PwCF during a PEx to illuminate symptom phenotypes and assess differences in recovery from PExs.

METHODS: This study was a secondary, longitudinal analysis (N = 72). Participants at least 10 years of age and being treated with intravenous antibiotics for a CF PEx were enrolled in the United States. Symptoms were collected on treatment days 1-21 using the CF Respiratory Symptom Diary (CFRSD)-Chronic Respiratory Symptom Score (CRISS). K-means clustering was computed on day 1 symptom data to detect clustering patterns. Linear regression and multi-level growth models were performed.

RESULTS: Symptoms significantly clustered based on severity: low symptom (LS)-phenotype (n = 42), high symptom (HS)-phenotype (n = 30). HS-phenotype had worse symptoms and CRISS scores (p< 0.01) than LS-phenotype. HS-phenotype was associated with spending 5 more nights in the hospital annually (p< 0.01) than LS-phenotype. HS-phenotype had worse symptoms over 21 days than LS-phenotype (p< 0.0001).

CONCLUSION: Symptoms significantly cluster on day 1 of a CF-PEx. PwCF with HS-phenotype spend more nights in the hospital and are less likely to experience the same resolution in symptoms by the end of PEx treatment than LS-phenotype.

PMID:38851922 | DOI:10.1016/j.jcf.2024.05.014

J Cyst Fibros. 2024 Jun 7:S1569-1993(24)00003-1. doi: 10.1016/j.jcf.2024.01.003. Online ahead of print.

ABSTRACT

Over the last several decades, substantial treatment advances have improved the quality of life and median predicted survival in people with cystic fibrosis (PwCF). It is critical for CF clinicians to begin to discuss health considerations related to an aging and overall healthier CF population. Such considerations include family planning, reproductive health, and contraception. CF care teams are trusted sources of medical information and therefore often have initial discussions related to contraception for PwCF. The purpose of this article is to review the available pharmacologic contraceptive methods, with a specific focus on the benefits and risks that may be more relevant to PwCF.

PMID:38851921 | DOI:10.1016/j.jcf.2024.01.003

J Cyst Fibros. 2024 Jun 7:S1569-1993(24)00073-0. doi: 10.1016/j.jcf.2024.05.011. Online ahead of print.

ABSTRACT

BACKGROUND: A personalized approach to assessing medication knowledge may identify opportunities for education to support self-management of cystic fibrosis (CF). This project describes the development, scoring, and preliminary validity of the Personalized CF Medication Questionnaire (PCF-MQ), designed to assess knowledge of prescribed CF medication purpose, administration, and dose and frequency.

METHODS: Participants completed the PCF-MQ, the Knowledge of Disease Management (KDM-CF), and the Cystic Fibrosis-Medication Beliefs Questionnaire (CF-MBQ). Prescribed regimens were abstracted from medical records. Eligibility criteria were age 12 years and older, diagnosed with CF, and prescribed a CF medication. Statistical analyses were conducted using R software. Spearman rho was used to test correlations between measures.

RESULTS: Sixty people with CF (pwCF) were enrolled; three people reported a regimen that substantially deviated from the medical record and were excluded from the analyses. The mean (SD) age was 20.2 (7.3) years, 54 % were female, and 74 % had a FEV1pp ≥70 %. The mean (SD) PCF-MQ total score was 77.8 (12.3) and knowledge scores ranged from a low of 58.3 for levalbuterol to 100 for ivacaftor. The PCF-MQ total score correlated with the KDM total score and subscales (Spearman Rho= 0.32-0.59, p < 0.05) and was not correlated with the CF-MBQ subscales (p > 0.05)).

CONCLUSIONS: The PCF-MQ was correlated with another measure of general CF knowledge, but not health beliefs; because of the small sample size, this should be considered preliminary evidence of its validity. Advantages over existing CF knowledge measures include its practicality for use to help assess pwCF's knowledge about their prescribed regimen.

PMID:38851920 | DOI:10.1016/j.jcf.2024.05.011

Microb Pathog. 2024 Jun 6:106730. doi: 10.1016/j.micpath.2024.106730. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen that poses a significant threat to individuals suffering from cystic fibrosis (CF). The pathogen is highly prevalent in CF individuals and is responsible for chronic infection, resulting in severe tissue damage and poor patient outcome. Prolonged antibiotic administration has led to the emergence of multidrug resistance in P. aeruginosa. In this direction, antivirulence strategies achieving targeted inhibition of bacterial virulence pathways, including quorum sensing, efflux pumps, lectins, and iron chelators, have been explored against CF isolates of P. aeruginosa. Hence, this review article presents a bird's eye view on the pulmonary infections involving P. aeruginosa in CF patients by laying emphasis on factors contributing to bacterial colonization, persistence, and disease progression along with the current line of therapeutics against P. aeruginosa in CF. We further collate scientific literature and discusses various antivirulence strategies that have been tested against P. aeruginosa isolates from CF patients.

PMID:38851361 | DOI:10.1016/j.micpath.2024.106730

Lancet Respir Med. 2024 Jun 5:S2213-2600(24)00170-X. doi: 10.1016/S2213-2600(24)00170-X. Online ahead of print.

ABSTRACT

BACKGROUND: Long-term effects of early, recurrent human exposure to general anaesthesia remain unknown. The Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) trial provided an opportunity to examine this issue in children randomly assigned in infancy to either repeated bronchoalveolar-lavage (BAL)-directed therapy with general anaesthesia or standard care with no planned lavages up to 5 years of age when all children received BAL-directed therapy under general anaesthesia.

METHODS: This multicentre, randomised, open-label phase 4 trial (CF-GAIN) used the original ACFBAL trial randomisation at 3·6 months (SD 1·6) to BAL-directed therapy or standard-care groups to assess the impact of general anaesthesia exposures over early childhood. Children who completed the ACFBAL trial, with a mean age of 5·1 (SD 0·18) years, received standardised neurobehavioural and health-related-quality-of-life assessment and brain MRI scans between Oct 8, 2013, and June 30, 2017, at a mean age of 12·8 (SD 1·7) years at three hospitals in Australia and one hospital in New Zealand. The primary outcome was a composite score of performance on a standardised, computer-based assessment of child attention, processing speed, and response inhibition skills (Conners Continuous Performance test, second edition). Secondary outcomes included intellectual function, other neurobehavioural measures, and brain imaging as an exploratory outcome. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12613000057785) and is completed.

FINDINGS: At 2 years, the BAL-directed therapy group (n=52) and standard-care group (n=45) had a median of 2·0 (IQR 1·0-3·0) and 0·0 (0·0-0·0) exposures, respectively. At completion of the ACFBAL trial, the BAL-directed therapy group had a median of 6·0 (4·0-9·5) exposures and the standard-care group 2·0 (1·0-4·0) exposures. At CF-GAIN completion, the BAL-directed therapy group had a median of 10·0 (IQR 6·5-14·5) exposures and the standard-care group 4·0 (3·0-7·0) exposures. Cumulative general anaesthesia exposure time was not prospectively collected but, for those with complete cumulative exposure time data to the end of the ACFBAL trial, the median cumulative exposure time for the BAL-directed therapy group (n=29) was 180 (IQR 140-285) min and for the standard-care group (n=32) was 48 (30-122) min. The mean Conners Continuous Performance test, second edition composite score was 51 (SD 8·1) in BAL-directed therapy group and 53 (8·8) in the standard-care group; difference -1·7 (95% CI -5·2 to 1·7; p=0·32) with similar performance on other neurobehavioural measures, including measures of executive function, intellectual quotient scores, and brain imaging.

INTERPRETATION: Our findings suggest that repeated general anaesthesia exposure in young children with cystic fibrosis is not related to functional impairment in attention, intellectual quotient, executive function, or brain structure compared with a group with fewer and shorter cumulative anaesthesia durations.

FUNDING: National Health and Medical Research Council Australia, Queensland Government Health Service and Clinical Innovation Fellowship, and the Children's Hospital Foundation Queensland.

PMID:38851197 | DOI:10.1016/S2213-2600(24)00170-X

Inflamm Res. 2024 Jun 8. doi: 10.1007/s00011-024-01898-1. Online ahead of print.

ABSTRACT

OBJECTIVE P. AERUGINOSA: (PA), the major pathogen of lung cystic fibrosis (CF), polarizes macrophages into hyperinflammatory tissue damaging phenotype. The main aim of this study was to verify whether training of macrophages with β-glucan might improve their response to P. aeruginosa infections.

METHODS: To perform this task C57BL/6 mice sensitive to infections with P. aeruginosa were used. Peritoneal macrophages were trained with Saccharomyces cerevisiae β-glucan and exposed to PA57, the strong biofilm-forming bacterial strain isolated from the patient with severe lung CF. The release of cytokines and the expression of macrophage phenotypic markers were measured. A quantitative proteomic approach was used for the characterization of proteome-wide changes in macrophages. The effect of in vivo β-glucan-trained macrophages in the air pouch model of PA57 infection was investigated. In all experiments the effect of trained and naïve macrophages was compared.

RESULTS: Trained macrophages acquired a specific phenotype with mixed pro-inflammatory and pro-resolution characteristics, however they retained anti-bacterial properties. Most importantly, transfer of trained macrophages into infected air pouches markedly ameliorated the course of infection. PA57 bacterial growth and formation of biofilm were significantly suppressed. The level of serum amyloid A (SAA), a systemic inflammation biomarker, was reduced.

CONCLUSIONS: Training of murine macrophages with S. cerevisiae β-glucan improved macrophage defense properties along with inhibition of secretion of some detrimental inflammatory agents. We suggest that training of macrophages with such β-glucans might be a new therapeutic strategy in P. aeruginosa biofilm infections, including CF, to promote eradication of pathogens and resolution of inflammation.

PMID:38850343 | DOI:10.1007/s00011-024-01898-1

Genome Med. 2024 Jun 7;16(1):78. doi: 10.1186/s13073-024-01346-z.

ABSTRACT

BACKGROUND: Antimicrobial resistance (AMR) is an intensifying threat that requires urgent mitigation to avoid a post-antibiotic era. Pseudomonas aeruginosa represents one of the greatest AMR concerns due to increasing multi- and pan-drug resistance rates. Shotgun sequencing is gaining traction for in silico AMR profiling due to its unambiguity and transferability; however, accurate and comprehensive AMR prediction from P. aeruginosa genomes remains an unsolved problem.

METHODS: We first curated the most comprehensive database yet of known P. aeruginosa AMR variants. Next, we performed comparative genomics and microbial genome-wide association study analysis across a Global isolate Dataset (n = 1877) with paired antimicrobial phenotype and genomic data to identify novel AMR variants. Finally, the performance of our P. aeruginosa AMR database, implemented in our AMR detection and prediction tool, ARDaP, was compared with three previously published in silico AMR gene detection or phenotype prediction tools-abritAMR, AMRFinderPlus, ResFinder-across both the Global Dataset and an analysis-naïve Validation Dataset (n = 102).

RESULTS: Our AMR database comprises 3639 mobile AMR genes and 728 chromosomal variants, including 75 previously unreported chromosomal AMR variants, 10 variants associated with unusual antimicrobial susceptibility, and 281 chromosomal variants that we show are unlikely to confer AMR. Our pipeline achieved a genotype-phenotype balanced accuracy (bACC) of 85% and 81% across 10 clinically relevant antibiotics when tested against the Global and Validation Datasets, respectively, vs. just 56% and 54% with abritAMR, 58% and 54% with AMRFinderPlus, and 60% and 53% with ResFinder. ARDaP's superior performance was predominantly due to the inclusion of chromosomal AMR variants, which are generally not identified with most AMR identification tools.

CONCLUSIONS: Our ARDaP software and associated AMR variant database provides an accurate tool for predicting AMR phenotypes in P. aeruginosa, far surpassing the performance of current tools. Implementation of ARDaP for routine AMR prediction from P. aeruginosa genomes and metagenomes will improve AMR identification, addressing a critical facet in combatting this treatment-refractory pathogen. However, knowledge gaps remain in our understanding of the P. aeruginosa resistome, particularly the basis of colistin AMR.

PMID:38849863 | DOI:10.1186/s13073-024-01346-z

Sci Rep. 2024 Jun 7;14(1):13178. doi: 10.1038/s41598-024-63904-0.

ABSTRACT

Cardiovascular diseases can be an emerging complication in cystic fibrosis (CF), as the median life expectancy has improved considerably. The objective of this study was to compare vascular, hemodynamic parameters and arterial stiffness in adult CF patients with healthy participants pared by sex and age, and to assess the factors associated with arterial stiffness in the CF group. This is a cross-sectional observational study. The evaluation of cardiovascular parameters was performed non-invasively using Mobil-O-Graph. 36 individuals with CF and 35 controls were evaluated. The mean arterial pressure (96.71 ± 10.98 versus 88.61 ± 7.40 mmHg, p = 0.0005), cardiac output (4.86 ± 0.57 versus 4.48 ± 0.44 L/min, p = 0.002) and systolic volume (64.30 ± 11.91 versus 49.02 ± 9.31 ml, p < 0.0001) were significantly lower in the CF group. The heart rate was higher in the CF when compared to the control (77.18 ± 10.47 versus 93.56 ± 14.57 bpm, p < 0.0001). The augmentation index (AIx@75) was higher in the CF than control (29.94 ± 9.37 versus 16.52 ± 7.179%, p < 0.0001). In the multivariate model controlled by body mass index and Forced Expiratory Volume in the first second, central systolic blood pressure and reflection coefficient directly related to AIx@75. Negatively related to AIx@75 were age and systolic volume. The adjusted determination coefficient was 87.40%. Individuals with CF presented lower arterial blood pressures and changes in cardiac function with lower stroke volume and cardiac output. The AIx@75, an indirect index of arterial stiffness and direct index of left ventricular overload, is increased in this population. The subclinical findings suggest the need for earlier cardiovascular assessment in this population due to increased risks of cardiovascular disease.

PMID:38849403 | DOI:10.1038/s41598-024-63904-0

Nat Commun. 2024 Jun 7;15(1):4889. doi: 10.1038/s41467-024-49150-y.

ABSTRACT

Polymicrobial infection of the airways is a hallmark of obstructive lung diseases such as cystic fibrosis (CF), non-CF bronchiectasis, and chronic obstructive pulmonary disease. Pulmonary exacerbations (PEx) in these conditions are associated with accelerated lung function decline and higher mortality rates. Understanding PEx ecology is challenged by high inter-patient variability in airway microbial community profiles. We analyze bacterial communities in 880 CF sputum samples collected during an observational prospective cohort study and develop microbiome descriptors to model community reorganization prior to and during 18 PEx. We identify two microbial dysbiosis regimes with opposing ecology and dynamics. Pathogen-governed PEx show hierarchical community reorganization and reduced diversity, whereas anaerobic bloom PEx display stochasticity and increased diversity. A simulation of antimicrobial treatment predicts better efficacy for hierarchically organized communities. This link between PEx, microbiome organization, and treatment success advances the development of personalized clinical management in CF and, potentially, other obstructive lung diseases.

PMID:38849369 | DOI:10.1038/s41467-024-49150-y

Liver Int. 2024 Jun 7. doi: 10.1111/liv.15963. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Cystic fibrosis (CF) is considered a multisystemic disorder in which CF-associated liver disease (CFLD) is the third most common cause of mortality. Currently, no effective treatment is available for CFLD because its pathophysiology is still unclear. Interestingly, CFLD exhibits identical vascular characteristics as non-cirrhotic portal hypertension, recently classified as porto-sinusoidal vascular disorders (PSVD).

METHODS: Since endothelial cells (ECs) are an important component in PSVD, we performed single-cell RNA sequencing (scRNA-seq) on four explant livers from CFLD patients to identify differential endothelial characteristics which could contribute to the disease. We comprehensively characterized the endothelial compartment and compared it with publicly available scRNA-seq datasets from cirrhotic and healthy livers. Key gene signatures were validated ex vivo on patient tissues.

RESULTS: We found that ECs from CF liver explants are more closely related to healthy than cirrhotic patients. In CF patients we also discovered a distinct population of liver sinusoidal ECs-coined CF LSECs-upregulating genes involved in the complement cascade and coagulation. Finally, our immunostainings further validated the predominant periportal location of CF LSECs.

CONCLUSIONS: Our work showed novel aspects of human liver ECs at the single-cell level thereby supporting endothelial involvement in CFLD, and reinforcing the hypothesis that ECs could be a driver of PSVD. Therefore, considering the vascular compartment in CF and CFLD may help developing new therapeutic approaches for these diseases.

PMID:38847551 | DOI:10.1111/liv.15963

Skin Health Dis. 2024 Mar 12;4(3):e361. doi: 10.1002/ski2.361. eCollection 2024 Jun.

ABSTRACT

Aquagenic keratoderma, also known as aquagenic wrinkling of the palms, transient reactive papulotranslucent acrokeratoderma, or transient aquagenic hyper-wrinkling, is an uncommon disorder that affects the palms and occasionally the soles. It presents with translucent whitish to yellowish papules and increased wrinkling upon water exposure. The frequency of this condition is yet to be determined among the general population. However, it is frequently observed in patients among patients with cystic fibrosis or carriers of the cystic fibrosis gene, with frequency estimated to be up to 41%. In this paper, we report the utility and novelty of Wood's light as a bedside adjunct tool to aid in diagnosing aquagenic keratoderma. To our knowledge, this is the first case reporting the use of Wood's light in diagnosing aquagenic keratoderma.

PMID:38846695 | PMC:PMC11150738 | DOI:10.1002/ski2.361

Acta Med Philipp. 2024 Apr 15;58(6):69-73. doi: 10.47895/amp.vi0.7570. eCollection 2024.

ABSTRACT

Cystic Fibrosis (CF) is a rare condition among Asians and has not been reported in the Philippines as of this time. The inclusion of this disease in the Philippines' Expanded Newborn Screening Program (ENBS) has provided this Filipino family the opportunity of early detection and appropriate management of this condition that could ensure the survival of the proband and his other surviving siblings. Here we present a case of a 24-month-old male who had a positive Expanded Newborn Screening (ENBS) test for cystic fibrosis and eventually underwent further tests to confirm a homozygous deletion of exons 1 - 2 of the CFTR gene. He subsequently had recurrent pneumonia but is being managed by a team consisting of a pulmonologist, gastroenterologist, and a metabolic dietitian. The proband had an older sibling whose Newborn Screening (NBS) test was normal and who eventually expired from recurrent bouts of pneumonia. This sibling was never managed as a case of cystic fibrosis. Implications on the diagnosis and management of CF in the local setting is also discussed. The importance of an appropriate CF panel customized to the local population should be reiterated and carrier testing should be encouraged to help with proper family counseling for future pregnancies for the family involved.

PMID:38846171 | PMC:PMC11151128 | DOI:10.47895/amp.vi0.7570

J Cyst Fibros. 2024 Jun 5:S1569-1993(24)00079-1. doi: 10.1016/j.jcf.2024.06.001. Online ahead of print.

ABSTRACT

BACKGROUND: The management of cystic fibrosis (CF) requires knowledge of the patient's microbiological status. The serology of anti-Pseudomonas aeruginosa antibodies against exoenzymes or water-soluble antigens has gained diagnostic value, particularly to detect the onset of colonization with P. aeruginosa. However, the diversity and variable expression of these antigens, which was unknown when the ELISAs became common diagnostic procedures at CF clinics, prohibits the quantitative evaluation of bacterial antigen load during intermittent and chronic infection.

METHODS: An ELISA was developed to measure the serum IgG antibody levels against P. aeruginosa porin OprF, a species-specific, conserved, immunogenic and constitutively expressed protein present in the outer membrane and extracellular vesicles.

RESULTS: Serial serum samples were collected from 310 people with CF (pwCF) over a period of up to 15 years. Compared to a reference of P. aeruginosa - negative CF sera set to 1, OprF antibody titers ranged from 0.3 to 13.2 (median: 1.7) in 56 intermittently colonized patients and from 0.5 to 51.2 (median: 11.8) in 176 chronically colonized pwCF showing higher anti-OprF antibody levels during chronic than during intermittent colonization with P. aeruginosa (P = 0, Z = - 21.7, effect size 0.62). Inhalation with twice daily 80 mg tobramycin decreased OprF antibody titers (P = 5 × 10-5), particularly during the third and fourth year of chronic colonization.

CONCLUSION: The OprF ELISA should be an appropriate tool to monitor Pseudomonas serology at all stages of infection and disease severity and to study the impact of short- and long-term therapeutic interventions.

PMID:38845269 | DOI:10.1016/j.jcf.2024.06.001

Am J Case Rep. 2024 Jun 7;25:e943397. doi: 10.12659/AJCR.943397.

ABSTRACT

BACKGROUND Calcium gluconate is used to treat neonatal hypocalcemia, severe hyperkalemia, and neonatal convulsions. Calcium gluconate can extravasate into the skin's soft tissues, resulting in redness, skin nodules, and calcification of soft tissue, which can cause tissue necrosis. This report presents 2 cases of neonatal calcinosis cutis following the treatment of hypocalcemia with calcium gluconate. CASE REPORT Case 1. The patient was a 12-day-old male neonate who presented with a mass in the right foot. He was recently discharged from the hospital after evacuation of subdual hematoma triggering his seizures. The swelling was associated with erythema but no discharge. His radiograph showed soft tissue calcification. He had received 2 peripheral intravenous calcium gluconate infusions to manage hypocalcemia during the last hospitalization. Symptomatic treatments were provided, and full resolution of the swelling was reported after 3 weeks. Case 2. The patient was a 1-month-old female infant newly diagnosed with cystic fibrosis who presented with a mass in her left foot. She underwent exploratory laparotomy in another hospital to manage meconium ileus. The mass was not mobile but there was no skin ulceration. Her radiograph showed soft tissue calcification. During her last admission, she had received 3 doses of intravenous calcium gluconate to manage hypocalcemia. The patient was observed and managed symptomatically. After 4 weeks, there was almost complete clinical and radiographic disappearance of the swelling without any skin necrosis. CONCLUSIONS This report has highlighted the importance of monitoring neonates treated with calcium gluconate who may develop skin rashes or nodules due to calcinosis cutis.

PMID:38845168 | DOI:10.12659/AJCR.943397

J Biol Chem. 2024 Jun 4:107440. doi: 10.1016/j.jbc.2024.107440. Online ahead of print.

ABSTRACT

ABC transporters are found in all organisms and almost every cellular compartment. They mediate the transport of various solutes across membranes, energized by ATP binding and hydrolysis. Dysfunctions can result in severe diseases, such as cystic fibrosis or antibiotic resistance. In type IV ABC transporters, each of the two nucleotide-binding domains is connected to a transmembrane domain by two coupling helices, which are part of cytosolic loops. Although there are many structural snapshots of different conformations, the interdomain communication is still enigmatic. Therefore, we analyzed the function of three conserved, charged residues in the intra-cytosolic loop 1 of the human homodimeric, lysosomal peptide transporter TAPL. Substitution of D278 in coupling helix 1 by alanine interrupted peptide transport by impeding ATP hydrolysis. Alanine substitution of R288 and D292, both localized next to the coupling helix 1 extending to transmembrane helix 3, reduced peptide transport but increased basal ATPase activity. Surprisingly, the ATPase activity of the R288A variant dropped in a peptide-dependent manner while ATPase activity of wildtype and D292A was unaffected. Interestingly, R288A and D292A mutants did not differentiate between ATP and GTP in respect of hydrolysis. However, in contrast to wildtype TAPL, only ATP energized peptide transport. In sum, D278 seems to be involved in bidirectional interdomain communication mediated by network of polar interactions while the two residues in the cytosolic extension of TMH3 are involved in regulation of ATP hydrolysis, most likely by stabilization of the outward facing conformation.

PMID:38844133 | DOI:10.1016/j.jbc.2024.107440