Methods Mol Biol. 2023;2590:31-48. doi: 10.1007/978-1-0716-2819-5_2.

ABSTRACT

Targeted locus amplification (TLA) allows for the detection of all genetic variation (including structural variation) in a genomic region of interest. As TLA is based on proximity ligation, variants can be linked to each other, thereby enabling allelic phasing and the generation of haplotypes. This allows for the study of genetic variants in an allele-specific manner. Here, we provide a step-by-step protocol for TLA sample preparation and a complete bioinformatics pipeline for the allelic phasing of TLA data. Additionally, to illustrate the protocol, we show the ability of TLA to re-sequence and haplotype the complete cystic fibrosis transmembrane (CFTR) gene (> 200 kb in size) from patient-derived intestinal organoids.

PMID:36335490 | DOI:10.1007/978-1-0716-2819-5_2

J Heart Lung Transplant. 2022 Oct 12:S1053-2498(22)02170-2. doi: 10.1016/j.healun.2022.10.004. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with structural lung disease and immunocompromised status are at increased risk of pulmonary non-tuberculous mycobacteria (NTM) infection. However, literature on NTM in lung transplant recipients (LTR) is limited. We sought to systematically review the literature and perform a meta-analysis to examine associations with NTM disease and isolation in LTRs and their influence on mortality and chronic lung allograft dysfunction (CLAD).

METHODS: A literature search of MEDLINE and Embase was performed on February 23, 2022. NTM disease was defined according to international guidelines. Isolation was defined as any growth of NTM in culture. Odds ratios (OR) were pooled for risk factors of NTM disease or isolation, and hazard ratios (HR) were pooled for mortality or CLAD.

RESULTS: Eleven studies totaling 3,371 patients were eligible for inclusion, 10 of which underwent meta-analysis. Cystic fibrosis (OR 1.84, 95% confidence interval [CI] 1.03-3.30; I2 = 0%) and pre-transplant NTM isolation (OR 2.40, 95% CI 1.20-4.83; I2 = 0%) were associated with NTM disease. Only male sex was associated with NTM isolation (OR 1.45, 95% CI 1.01-2.10; I2 = 0%). NTM disease was associated with increased mortality (HR 2.69, 95% CI 1.70-4.26; I2 = 0%) and CLAD (HR 2.11, 95% CI 1.03-4.35; I2 = 44%). NTM isolation was not associated with mortality in pooled analysis or CLAD in 1 included study.

CONCLUSIONS: NTM disease, but not isolation, is associated with worse outcomes. Several factors were associated with development of NTM disease, including cystic fibrosis and pretransplant NTM isolation. Strategies to optimize prevention and treatment of NTM disease in lung transplant recipients are needed.

PMID:36334962 | DOI:10.1016/j.healun.2022.10.004

J Infect. 2022 Nov 2:S0163-4453(22)00635-1. doi: 10.1016/j.jinf.2022.10.037. Online ahead of print.

ABSTRACT

Toxoplasma gondii is a widespread parasitic protozoan causing pulmonary toxoplasmosis. As the first line of host defense, airway epithelial cells play critical roles in orchestrating pulmonary innate immunity. However, the mechanism underlying the airway inflammation induced by the T. gondii infection remains largely unclear. This study demonstrated that after infection with T. gondii, the major anion channel located in the apical membranes of airway epithelial cells, cystic fibrosis transmembrane conductance regulator (CFTR), was degraded by the parasite-secreted cysteine proteases. The intracellular Cl- concentration ([Cl-]i) was consequently elevated, leading to activation of nuclear factor-κB (NF-κB) signaling via serum/glucocorticoid regulated kinase 1. Furthermore, the heightened [Cl-]i and activated NF-κB signaling could be sustained in a positive feedback regulatory manner resulting from decreased intracellular cAMP level through NF-κB-mediated up-regulation of phosphodiesterase 4. Conversely, the sulfur-containing compound allicin conferred anti-inflammatory effects on pulmonary toxoplasmosis by decreasing [Cl-]i via activation of CFTR. These results suggest that the intracellular Cl- dynamically modulated by T. gondii mediates sustained airway inflammation, which provides a potential therapeutic target against pulmonary toxoplasmosis.

PMID:36334726 | DOI:10.1016/j.jinf.2022.10.037

Ann Endocrinol (Paris). 2022 Nov 1:S0003-4266(22)00858-7. doi: 10.1016/j.ando.2022.09.025. Online ahead of print.

ABSTRACT

OBJECTIVES: Cystic fibrosis-related diabetes (CFRD) may be diagnosed by fasting blood glucose ≥ 7.0 mmol/L and/or glucose ≥11.1 mmol/L following oral glucose tolerance test (OGTT). We compared the role of fasting and stimulated glucose for diagnosis of CFRD.

METHODS: We performed a cross-sectional review of the prevalence of fasting glycemic abnormalities and Kaplan-Meier survival analysis of risk of progression to CFRD according to baseline fasting glucose in the prospective Montreal Cystic Fibrosis Cohort.

RESULTS: Isolated fasting hyperglycemia was detected in only 8% of participants at study onset. Eighty percent of subjects had isolated post-challenge hyperglycemia on their first OGTT meeting criteria for CFRD. Kaplan Meier survival analysis demonstrated that impaired fasting glucose (IFG) alone is not a risk factor for CFRD. Subjects with combined IFG and impaired glucose tolerance at baseline (IGT) had the highest risk of progression to CFRD.

CONCLUSION: Post-prandial elevations in blood glucose are more common at diagnosis of CFRD. While IGT is a significant risk factor for CFRD, IFG alone is uncommon and does not increase the risk of CFRD. Patients with both IGT and IFG have the highest risk of CFRD.

PMID:36332698 | DOI:10.1016/j.ando.2022.09.025

Neurotoxicology. 2022 Oct 28;93:301-310. doi: 10.1016/j.neuro.2022.10.013. Online ahead of print.

ABSTRACT

It is known that ototoxicity is the main cause of toxicity induced by aminoglycoside antibiotics. Effects on cochlea and vestibule in vertebrates are variable, depending on the typology of the aminoglycoside and the animal model examined. Despite this, they are routinely used to prevent postoperative and urinary tract infections and in the treatment of tuberculosis and cystic fibrosis. Gentamicin causes hearing loss by damaging stereocilia and by causing degeneration of hair cells due to free radical formation and eventual activation of caspase-dependent pathways. Its toxicity increases with the frequency of administration, dose concentration, and duration of treatment. Turnover of new hair cells may occur spontaneously, throughout life, or may be triggered by an acoustic or ototoxic insult to replace dead cells. Turnover and repair of damage are common in fish and amphibians and in birds' vestibule. In contrast, in the papilla basilaris of birds, and in the vestibule of mammals, hair cell regeneration is activated only after damage. Sensory epithelium repair and hair cell regeneration also occur in the reptiles' vestibule, but no data is available on regeneration or repair in the basilar papilla, involved in sound perception. The purpose of this work is therefore to assess the damage induced by gentamicin on the papilla basilaris of a reptile model organism, the Lacertidae Podarcis siculus. Recovery was also evaluated 3, 8 and 18 days after the end of exposure, in absence of gentamicin and in presence of the otoprotective salicylate. Scanning electron microscopy (SEM) was carried out to check for morphological damage while the occurrence of cell proliferation events was evaluated by fluorescence microscopy, after administration of 5-Bromo-2'-deoxyuridine (BrdU). Results show that salicylate administration facilitates recovery and reduces damage to hair cells after gentamicin treatment. Following the incorporation of bromodeoxyuridine, we demonstrated that sensory epithelium repair and hair cell regeneration have occurred, and that the recovery is due to either proliferation of the supporting cells and/or self-repair of hair cell bundles in the weakly damaged sensory cells.

PMID:36330896 | DOI:10.1016/j.neuro.2022.10.013

Infect Control Hosp Epidemiol. 2022 Nov 4:1-7. doi: 10.1017/ice.2022.262. Online ahead of print.

ABSTRACT

OBJECTIVE: To describe the natural course of procalcitonin (PCT) in patients with coronavirus disease 2019 (COVID-19) and the correlation between PCT and antimicrobial prescribing to provide insight into best practices for PCT data utilization in antimicrobial stewardship in this population.

DESIGN: Single-center, retrospective, observational study.

SETTING: Michigan Medicine.

PATIENTS: Inpatients aged ≥18 years hospitalized March 1, 2020, through October 31, 2021, who were positive for severe acute respiratory coronavirus virus 2 (SARS-CoV-2), with ≥1 PCT measurement. Exclusion criteria included antibiotics for nonpulmonary bacterial infection on admission, treatment with azithromycin only for chronic obstructive pulmonary disease (COPD) exacerbation, and pre-existing diagnosis of cystic fibrosis with positive respiratory cultures.

METHODS: A structured query was used to extract data. For patients started on antibiotics, bacterial pneumonia (bPNA) was determined through chart review. Multivariable models were used to assess associations of PCT level and bPNA with antimicrobial use.

RESULTS: Of 793 patients, 224 (28.2%) were initiated on antibiotics: 33 (14.7%) had proven or probable bPNA, 125 (55.8%) had possible bPNA, and 66 (29.5%) had no bPNA. Patients had a mean of 4.1 (SD, ±5.2) PCT measurements if receiving antibiotics versus a mean of 2.0 (SD, ±2.6) if not. Initial PCT level was highest for those with proven/probable bPNA and was associated with antibiotic initiation (odds ratio 95% confidence interval [CI], 1.17-1.30). Initial PCT (rate ratio [RR] 95% CI, 1.01-1.08), change in PCT over time (RR 95% CI, 1.01-1.05), and bPNA group (RR 95% CI, 1.23-1.84) were associated with antibiotic duration.

CONCLUSIONS: PCT trends are associated with the decision to initiate antibiotics and duration of treatment, independent of bPNA status and comorbidities. Prospective studies are needed to determine whether PCT level can be used to safely make decisions regarding antibiotic treatment for COVID-19.

PMID:36330692 | DOI:10.1017/ice.2022.262

J Gastroenterol Hepatol. 2022 Nov 3. doi: 10.1111/jgh.16049. Online ahead of print.

ABSTRACT

BACKGROUNDS: NAFLD is linked to obesity and metabolic syndrome conditions. However, a subset of NAFLD patients express a normal or low body mass index (Lean NAFLD, L-NAFLD). Our aim is to compare the prevalence of L-NAFLD to the obesity-associated NAFLD in the United States by assessing prevalence, potential risk factors, liver-related complications and coronary artery disease outcomes.

METHODOLOGY: A multi-center database (Explorys Inc.) of >70 million patients across the US was screened. A cohort of patients with "Non-Alcoholic Fatty Liver" between 1999-2021 was identified. two sub-cohorts of NAFLD patients were identified; those with a Body Mass Index (BMI) <25 kg/m2 (Lean NAFLD) and those with a BMI >30 kg/m2 (Obesity-associated NAFLD). We excluded patients with age<18, and those who have viral hepatitis, hemochromatosis, Wilson's disease, biliary cirrhosis, alcoholic liver disease, cystic fibrosis, alpha-1-antitrypsin deficiency, and autoimmune hepatitis. Multivariate analysis was performed to adjust for confounders.

RESULTS: 68,892,260 individuals were screened. NAFLD prevalence was 4 per 100,000 and L-NAFLD prevalence was 0.6 per 100,000. Comparing to those without, patients with L-NAFLD tended to be older (OR 2.16), females (OR 1.28), smokers (OR 4.67) and of Asian race (OR 2.12). L-NAFLD patients were more likely to have Acute Coronary Syndromes (ACS) (OR 30.00) and metabolic syndrome (OR 2.31) despite the normal/low BMI. Esophageal varices (EV) and hepatocellular carcinoma risks were high in both cirrhosis patients.

CONCLUSION: This is the largest study to assess L-NAFLD prevalence in the US. L-NAFLD are at a significantly higher risk for ACS, EV and HCC.

PMID:36328950 | DOI:10.1111/jgh.16049

Biofilm. 2022 Oct 22;4:100089. doi: 10.1016/j.bioflm.2022.100089. eCollection 2022 Dec.

ABSTRACT

Pseudomonas aeruginosa (PA) is a highly, if not the most, versatile microorganism capable of colonizing diverse environments. One of the niches in which PA is able to thrive is the lung of cystic fibrosis (CF) patients. Due to a genetic aberration, the lungs of CF-affected patients exhibit impaired functions, rendering them highly susceptible to bacterial colonization. Once PA attaches to the epithelial surface and transitions to a mucoid phenotype, the infection becomes chronic, and antibiotic treatments become inefficient. Due to the high number of affected people and the severity of this infection, CF-chronic infection is a well-documented disease. Still, numerous aspects of PA CF infection remain unclear. The scientific reports published over the last decades have stressed how PA can adapt to CF microenvironmental conditions and how its surrounding matrix of extracellular polymeric substances (EPS) plays a key role in its pathogenicity. In this context, it is of paramount interest to present the nature of the EPS together with the local CF-biofilm microenvironment. We review how the PA biofilm microenvironment interacts with drugs to contribute to the pathogenicity of CF-lung infection. Understanding why so many drugs are inefficient in treating CF chronic infection while effectively treating planktonic PA is essential to devising better therapeutic targets and drug formulations.

PMID:36324525 | PMC:PMC9618985 | DOI:10.1016/j.bioflm.2022.100089

Gut. 2022 Nov 2:gutjnl-2022-328829. doi: 10.1136/gutjnl-2022-328829. Online ahead of print.

NO ABSTRACT

PMID:36323505 | DOI:10.1136/gutjnl-2022-328829

J Allergy Clin Immunol Pract. 2022 Oct 30:S2213-2198(22)01129-1. doi: 10.1016/j.jaip.2022.10.027. Online ahead of print.

ABSTRACT

Bronchiectasis is a complex and heterogeneous disease caused by a myriad of pulmonary and extrapulmonary aetiologies. Bronchiectasis has a predominantly neutrophilic inflammatory profile, however, eosinophilic inflammation has also been documented in both the airways and systemic circulation. Various diseases (e.g. asthma, allergic bronchopulmonary aspergillosis, chronic rhinosinusitis with nasal polyps) characterized by heightened type 2 airway inflammatory responses, including blood or sputum eosinophilia, may co-exist with bronchiectasis. Apart from those eosinophilic etiologies or comorbidities related to bronchiectasis, around 20% of patients with bronchiectasis have peripheral eosinophilia (at least 3% or 300 eosinophils/μL) without any identified concomitant disease (also termed "eosinophilic bronchiectasis") whose roles have not been fully understood. The two key points surrounding these observations are that eosinophils confer both bactericidal and antiviral properties against the common pathogenic microorganisms which are usually detected in bronchiectasis, and that eosinophilic bronchiectasis has been associated with better therapeutic responses to inhaled corticosteroids and other anti-Th2 profile treatments. In this review, we summarize the most significant evidence on the role of eosinophils in patients with bronchiectasis, including the association of bronchiectasis with eosinophilic diseases (as etiologies or comorbidities), and the existing data on eosinophilic bronchiectasis not related to eosinophilic disorders.

PMID:36323380 | DOI:10.1016/j.jaip.2022.10.027

Games Health J. 2022 Nov 2. doi: 10.1089/g4h.2022.0137. Online ahead of print.

ABSTRACT

Motivation and adherence are the main factors that limit participation in physiotherapy exercise sessions and airway clearance in cystic fibrosis (CF) population. One of the newly developed techniques is to use virtual reality (VR) games to increase motivation and adherence during exercise sessions for this population. However, this area is still poorly investigated. This review aims to evaluate, summarize, and review published literature regarding the effects of VR exercise on cardiopulmonary function and the use of VR games as a tool for airway clearance technique in CF population. A systematic search was conducted using PEDro, MEDLINE, AMED, CINAHL Plus, and relevant associated keywords. Seventy-three citations were identified from the search, of which 10 were included in this review. Overall, the use of VR was found to have positive effects on cardiac function and improved adherence and motivation during the exercise sessions in people with CF. Incorporating VR into exercise and airway clearance interventions may be beneficial for people with CF. However, further studies with larger sample size and wider range of disease severity are required to be conducted in future.

PMID:36322890 | DOI:10.1089/g4h.2022.0137

Inflamm Res. 2022 Nov 2. doi: 10.1007/s00011-022-01657-0. Online ahead of print.

ABSTRACT

BACKGROUND: Respiratory inflammation is the body's response to lung infection, trauma or hypersensitivity and is often accompanied by comorbidities, including gastrointestinal (GI) symptoms. Why respiratory inflammation is accompanied by GI dysfunction remains unclear. Here, we investigate the effect of lipopolysaccharide (LPS)-induced lung inflammation on intestinal barrier integrity, tight-junctions, enteric neurons and inflammatory marker expression.

METHODS: Female C57bl/6 mice (6-8 weeks) were intratracheally administered LPS (5 µg) or sterile saline, and assessed after either 24 or 72 h. Total and differential cell counts in bronchoalveolar lavage fluid (BALF) were used to evaluate lung inflammation. Intestinal barrier integrity was assessed via cross sectional immunohistochemistry of tight junction markers claudin-1, claudin-4 and EpCAM. Changes in the enteric nervous system (ENS) and inflammation in the intestine were quantified immunohistochemically using neuronal markers Hu + and nNOS, glial markers GFAP and S100β and pan leukocyte marker CD45.

RESULTS: Intratracheal LPS significantly increased the number of neutrophils in BALF at 24 and 72 h. These changes were associated with an increase in CD45 + cells in the ileal mucosa at 24 and 72 h, increased goblet cell expression at 24 h, and increased expression of EpCAM at 72 h. LPS had no effect on the expression of GFAP, S100β, nor the number of Hu + neurons or proportion of nNOS neurons in the myenteric plexus.

CONCLUSIONS: Intratracheal LPS administration induces inflammation in the ileum that is associated with enhanced expression of EpCAM, decreased claudin-4 expression and increased goblet cell density, these changes may contribute to systemic inflammation that is known to accompany many inflammatory diseases of the lung.

PMID:36322182 | DOI:10.1007/s00011-022-01657-0

Microbiol Spectr. 2022 Nov 2:e0231222. doi: 10.1128/spectrum.02312-22. Online ahead of print.

ABSTRACT

Previously, it was reported that natural phenazines are able to support the anaerobic survival of Pseudomonas aeruginosa PA14 cells via electron shuttling, with electrodes poised as the terminal oxidants (Y. Wang, S. E. Kern, and D. K. Newman, J Bacteriol 192:365-369, 2010, https://doi.org/10.1128/JB.01188-09). The present study shows that both pyocyanin (PYO) and 1-hydroxyphenazine (1-OHPHZ) promoted the anaerobic killing of PA14 Δphz cells presumably via a single-electron transfer reaction with ferrous iron. However, phenazine-1-carboxylic acid (PCA) did not affect anaerobic survival in the presence of ferrous iron. Anaerobic cell death was alleviated by the addition of antioxidant compounds, which inhibit electron transfer via DNA damage. Neither superoxide dismutase (SOD) nor catalase was able to alleviate P. aeruginosa cell death, ruling out the possibility of reactive oxygen species (ROS)-induced killing. Further, the phenazine degradation profile and the redox state-associated color changes suggested that phenazine radical intermediates are likely generated by single-electron transfer. In this study, we showed that the phenazines 1-OHPHZ and PYO anaerobically killed the cell via single-electron transfer with ferrous iron and that the killing might have resulted from phenazine radicals. IMPORTANCE Pseudomonas aeruginosa is an opportunistic human pathogen which infects patients with burns, immunocompromised individuals, and in particular, the mucus that accumulates on the surface of the lung in cystic fibrosis (CF) patients. Phenazines as redox-active small molecules have been reported as important compounds for the control of cellular functions and virulence as well as anaerobic survival via electron shuttles. We show that both pyocyanin (PYO) and 1-hydroxyphenazine (1-OHPHZ) generate phenazine radical intermediates via presumably single-electron transfer reaction with ferrous iron, leading to the anaerobic killing of Pseudomonas cells. The recA mutant defect in the DNA repair system was more sensitive to anaerobic conditions. Our results collectively suggest that both phenazines anaerobically kill cells via DNA damage during electron transfer with iron.

PMID:36321913 | DOI:10.1128/spectrum.02312-22

Pediatr Int. 2022 May 24;64(1):e15249. doi: 10.1111/ped.15249. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic Pseudomonas aeruginosa colonization (Pa-CC) affects cystic fibrosis (CF) progression, including pulmonary exacerbations and pulmonary function tests. There are few studies of the effects of eradication protocols on colonization time. Here, we aimed to evaluate the effect of eradication regimens on chronic colonization and assess the impact of Pa-CC on body mass index, lung functions, and pulmonary exacerbations.

METHODS: A retrospective review was conducted of medical records, over a period of 11 years, of children aged under 18 years with CF who had Pa-CC in our tertiary care pediatric hospital.

RESULTS: Pseudomonas aeruginosa was detected in 215 of our patients with CF during the study period. Forty-four patients with Pa-CC were recruited for the study. The eradication treatment for the initial acquisition of P. aeruginosa was inhaled antibiotics in 27 (61.4%) patients; the remainder were given intravenous antibiotics. It was observed that eradication treatment with either IV or inhaled antibiotics did not affect the time between the P. aeruginosa and the time of Pa-CC(P = 0.791). There was a non-significant decrease in the body mass index z-score from the Pa-IA to the last visit(P = 0.27), a significant decline in forced expiratory volume in 1 s (FEV1%) (P = 0.01) over time, and the annual number of exacerbations after colonization was significantly higher than before colonization (P = 0.03).

CONCLUSIONS: There was no difference between eradication regimens in delaying the age at Pa-CC. Pseudomonas aeruginosa colonization in patients with CF was also associated with poorer lung functions, lower body mass index, and more pulmonary exacerbation regardless of mucoid type. Consequently, to slow the progression of lung disease, we must prevent Pa-CC, which we can achieve with early eradication. Despite conventional eradication protocols, future studies need to evaluate those who fail to clear P. aeruginosa.

PMID:36321341 | DOI:10.1111/ped.15249

Health Sci Rep. 2022 Oct 28;5(6):e910. doi: 10.1002/hsr2.910. eCollection 2022 Nov.

ABSTRACT

BACKGROUND: A major focus in cystic fibrosis (CF) care aims to increase weight gain. Rates of overweight and obese people with CF have gradually increased over the past decade. Obesity could be a risk for restriction of lung volumes and airway obstruction as well as increase rates of pulmonary exacerbations in people with CF.

AIM: To assess the relationship between weight categories and pulmonary outcomes in children and adults with CF.

METHODS: Patients 6 years of age and older were categorized into weight categories based on the Centers for Disease Control and Prevention (CDC) definitions. A retrospective chart review was conducted to obtain lung function testing and other outcomes.

RESULTS: One hundred five patients with a median age of 20.6 years were included in this analysis. 8.4%, 64%, 18%, and 10% of patients were underweight, normal/healthy weight, overweight, and obese, respectively. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) (% predicted) did not differ between patients with weights in the normal range versus patients in the overweight/obese categories. Linear regression analysis showed a direct correlation between body mass index (BMI) and FEV1 that continued as BMI entered overweight and obese categories in both pediatric and adult patients. Overweight/obese patients did not have increased rates of pulmonary exacerbations compared to those in the normal/healthy weight category.

CONCLUSION: As CF therapies continue to improve, an increasing number of people with CF are exceeding the CDC's normal-weight range. Gaining weight past the normal range does not appear to negatively impact pulmonary health of people with CF. If this trend of increased weight gain continues, it remains to be seen if it will eventually negatively affect lung health.

PMID:36320654 | PMC:PMC9616171 | DOI:10.1002/hsr2.910

Hepat Med. 2022 Oct 26;14:173-183. doi: 10.2147/HMER.S348888. eCollection 2022.

ABSTRACT

Sarcopenia, a pathologic deficiency of muscle mass and function, has emerged as an important secondary feature of many chronic disease states. For adults with end stage liver disease, there are multiple mechanisms which contribute to sarcopenia and its presence has proven to be an important predictor of morbidity and mortality. In children, there are only a limited number of reports which investigate the role of sarcopenia in liver disease. These studies, which are discussed and summarized in this review, report small, single-center analyses with dissimilar study cohorts and varying clinical definitions. Still, children meeting the study entry criteria have sarcopenia with a reported prevalence of 24-70%. When assessed, sarcopenia appears to be associated with more severe disease but is independent of the Pediatric End-Stage Liver Disease (PELD) score and does not correlate with age, gender, or traditional anthropometric measures such as weight, height, weight-for-height, or body mass index (BMI). While individual studies may identify sarcopenia as a statistically significant risk factor for certain post-transplant outcomes such as longer ICU stay, longer duration of intubation, repeat operation, development of serious infection, longer hospital stay, death, or long-term growth failure, such associations are not consistently replicated across studies. Finally, although various methods of muscle mass quantification are utilized, the most reported is the total psoas muscle surface area (tPMSA) on computed tomography. This method, along with others such as skeletal muscle area and skeletal muscle index, have had normative values recently defined and these collective efforts should enable researchers a common basis of comparison when delineating sarcopenia, and its impact, across various study populations in future investigations - including in children with liver disease.

PMID:36320211 | PMC:PMC9618237 | DOI:10.2147/HMER.S348888

Pulm Ther. 2022 Nov 1. doi: 10.1007/s41030-022-00202-y. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Approximately 5% of people with CF have residual function (RF) CFTR mutations that result in partially retained CFTR activity. Published literature on disease trajectory among those with RF mutations is limited. In this retrospective study, we characterized lung function decline across different age groups in CFTR modulator-untreated people with CF heterozygous for F508del and an RF mutation (F/RF).

METHODS: Rate of decline in percent predicted forced expiratory volume in 1 s (ppFEV1) was analyzed using data from the US CF Foundation Patient Registry (2006-2014) in F/RF (all), F/RF (excluding R117H), and F508del homozygous (F/F) cohorts. Annual rates of ppFEV1 decline were estimated over 2-year periods based on calendar year. Subgroup analyses by age [6-12 (children), 13-17 (adolescents), 18-24 (young adults), and ≥ 25 years (adults)] were performed.

RESULTS: The estimated annualized rate of ppFEV1 decline was - 0.70 percentage points per year (95% CI -1.09, -0.30) in the F/RF (all) cohort (N = 1242) versus -1.91 percentage points per year (95% CI -2.01, -1.80) in the F/F cohort (N = 11,916) [difference, 1.29 percentage points per year (95% CI 0.88, 1.70); P < 0.001]. In the F/RF (all) cohort, all age groups demonstrated lung function decline ranging from -0.30 to -1.38. In the F/RF (excluding R117H) cohort, the rate of decline was -1.05 percentage points per year (95% CI -1.51, -0.60) [difference versus F/F cohort, 0.95 percentage points per year (95% CI 0.48, 1.41; P < 0.001); not statistically significant in children and young adults].

CONCLUSION: Progressive lung function decline was observed in people with F/RF genotypes across all assessed age groups, reinforcing the importance of early intervention and clinical monitoring to preserve lung function in all people with CF.

PMID:36319933 | DOI:10.1007/s41030-022-00202-y

J Cyst Fibros. 2022 Oct 30:S1569-1993(22)01389-3. doi: 10.1016/j.jcf.2022.10.007. Online ahead of print.

ABSTRACT

Despite the major advances and successes in finding and establishing new treatments that tackle the basic defect in Cystic Fibrosis (CF), there is still an unmet need to bring these potentially curative therapies to all individuals with CF. Here, we review aspects of what is still missing to treat all individuals with CF by such approaches. On the one hand, we discuss novel holistic (high-throughput) approaches to elucidate mechanistic defects caused by distinct classes of mutations to identify novel drug targets. On the other hand, we examine therapeutic approaches to correct the gene in its own environment, i.e., in the genome.

PMID:36319570 | DOI:10.1016/j.jcf.2022.10.007

J Cyst Fibros. 2022 Oct 29:S1569-1993(22)01388-1. doi: 10.1016/j.jcf.2022.10.006. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: People with cystic fibrosis (PwCF) suffer from gastrointestinal (GI) symptoms affecting their quality of life (QOL). Despite the relevance of GI symptoms to the overall health of PwCF, a paucity of studies only have comprehensively assessed the prevalence, severity and QOL of GI symptoms in both children and adults with Cystic Fibrosis (CF).

METHODS: Eligible participants ≥2 years of age across 26 US CF centers were followed for 4 weeks. Three validated GI electronic patient-reported outcome measures (ePROMs) with a recall period of 2 weeks and a stool-specific questionnaire were administered weekly over four weeks. Total and domain scores of ePROMs were evaluated overall and in subgroups using linear mixed-effect models.

RESULTS: Of 402 enrolled, 58% were ≥ 18 years of age (52% male). The mean (SD) of the total score for PAC-SYM was 0.52 (0.55), for PAGI-SYM was 0.63 (0.67), and for PAC-QOL was 0.67 (0.55). For specific ePROM questions, prevalence of moderate to very severe symptoms were as follows: straining (20.3%), fullness (18.3%), incomplete bowel movements (17.1%), bloating (16.4%), distension (16.4%), abdominal pain (upper-5.1%, lower-7.5%). Comparing participants ≥18 versus <18, a higher prevalence of bloating (63.7% versus 27.3%), lower abdominal pain (39.8% vs 26.2%), stomach fullness (75.6% versus 56.2%), and abdominal distension (60.2% versus 34.9%) was found. Both age groups reported high treatment dissatisfaction as measured with PAC-QOL, mean 1.39 (95% CI: 1.30, 1.47).

CONCLUSION: GI symptoms were reported in all age ranges irrespective of gender, with higher prevalence observed amongst older and female subgroups. Dissatisfaction with GI targeted treatments were reported in a large proportion of participants despite therapy, highlighting an unmet need for clinical interventions.

CLINICALTRIALS: GOV: NCT03801993.

PMID:36319569 | DOI:10.1016/j.jcf.2022.10.006

Transplant Proc. 2022 Oct 29:S0041-1345(22)00656-X. doi: 10.1016/j.transproceed.2022.10.003. Online ahead of print.

ABSTRACT

BACKGROUND: The outcomes of heart-lung transplant (HLT) are worse than those of heart transplant (HT) and lung transplant alone; this and the availability of mechanical assistance have meant that the indications for HLT have been changing. This study aims to analyze the evolution of indications for HLT in a country of 47 million inhabitants.

METHODS: We performed a retrospective observational study of all HLTs performed in Spain (performed in 2 centers) from 1990 to 2020. The total number of patients included was 1751 (HT 1673 and HLT 78). After clinical adjustment, overall survival was compared between the 2 groups. Seven etiological subgroups were considered within the HLT group: (1) cardiomyopathy with pulmonary hypertension (CM + PH);, (2) Eisenmenger syndrome, (3) congenital heart disease without Eisenmenger syndrome, (4) idiopathic pulmonary arterial hypertension (IPAH), (5) cystic fibrosis, (6) chronic obstructive pulmonary disease (COPD) and/or emphysema), and (7) diffuse interstitial lung disease.

RESULTS: There were a large number of differences between patients with HLT vs HT. HLT had a 2.69-fold increased probability of death in the first year compared with HT. The indications for HLT have changed over the years. In the recent period the indications are mainly congenital heart disease and Eisenmenger syndrome, with some cases of CM + PH. Other indications for HLT have virtually disappeared, mainly lung diseases (IPAH, COPD, cystic fibrosis). Median survival was low in CM + PH (18 days), diffuse interstitial lung disease (29 days), and ischemic heart disease (114 days); intermediate in Eisenmenger syndrome (600 days); and longer in IPAH, COPD and/or emphysema, and cystic fibrosis.

CONCLUSIONS: HLT is a procedure with high mortality. This and mechanical assists mean that the indications have changed over the years. Etiological analysis is of utmost interest to take advantage of organs and improve survival.

PMID:36319494 | DOI:10.1016/j.transproceed.2022.10.003