Cell Mol Life Sci. 2021 May 23. doi: 10.1007/s00018-021-03859-x. Online ahead of print.

ABSTRACT

Positively charged amino acid side-chains play important roles in anion binding and permeation through the CFTR chloride channel. One pore-lining lysine residue in particular (K95) has been shown to be indispensable for anion binding, conductance, and selectivity. Here, we use functional investigation of CFTR to show that a nearby arginine (R134) plays a functionally analogous role. Removal of this positive charge (in the R134Q mutant) drastically reduces single-channel conductance, weakens binding of both permeant and blocking anions, and abolishes the normal anion conductance selectivity pattern. Each of these functional effects was reversed by a second-site mutation (S1141K) that introduces an ectopic positive charge to a nearby pore-lining residue. Substituted cysteine accessibility experiments confirm that R134-but not nearby residues in the same transmembrane helix-is accessible within the pore lumen. These results suggest that K95 and R134, which are very close together within the inner vestibule of the pore, play analogous, important roles, and that both are required for the normal anion binding and anion conductance properties of the pore. Nevertheless, that fact that both positive charges can be "transplanted" to other sites in the inner vestibule with little effect on channel permeation properties indicates that it is the overall number of charges-rather than their exact locations-that controls pore function.

PMID:34023918 | DOI:10.1007/s00018-021-03859-x

J Glob Antimicrob Resist. 2021 May 20:S2213-7165(21)00121-1. doi: 10.1016/j.jgar.2021.04.021. Online ahead of print.

ABSTRACT

OBJECTIVES: Hypermutable Pseudomonas aeruginosa strains are a major challenge in cystic fibrosis. We investigated bacterial killing and resistance emergence for approved ceftazidime and tobramycin regimens alone and in combination.

METHODS: P. aeruginosa PAOΔmutS and six hypermutable clinical isolates were examined using 48-h static concentration time-kill studies (SCTK; inoculum ∼107.5 CFU/mL); four of the strains were studied in a dynamic in vitro model (IVM; inoculum ∼108 CFU/mL). The IVM simulated concentration-time profiles in epithelial lining fluid (ELF) following intravenous administration of ceftazidime (3 g/day and 9 g/day continuous infusion), tobramycin (5 mg/kg and 10 mg/kg via 30-min infusion 24-hourly; half-life 3.5 h), and their combinations. Time-courses of total and less-susceptible populations were determined.

RESULTS: Ceftazidime plus tobramycin demonstrated synergistic killing in SCTK for all strains, although to a lesser extent in those resistant to ceftazidime. In the IVM, ceftazidime and tobramycin monotherapies provided ≤5.4 and ≤3.4 log10 initial killing, respectively; however, regrowth with resistance occurred by 72 h. Against strains susceptible to one or both antibiotics, high-dose combination regimens provided >6 log10 initial killing which was generally synergistic from 8-24 h, and marked suppression of regrowth and resistance at 72 h. The time-course of bacterial density in the IVM was well described by mechanism-based models, enabling Monte Carlo simulations (MCS) to predict likely effectiveness of the combination in patients.

CONCLUSIONS: Results of the IVM studies and MCS suggested antibacterial effect depends on both the susceptibility and hypermutability of the strain. Further investigation of the combination against hypermutable P. aeruginosa strains is warranted.

PMID:34023531 | DOI:10.1016/j.jgar.2021.04.021

J Clin Endocrinol Metab. 2021 May 22:dgab365. doi: 10.1210/clinem/dgab365. Online ahead of print.

ABSTRACT

PURPOSE: Impaired incretin secretion may contribute to the defective insulin secretion and abnormal glucose tolerance (AGT) that associate with worse clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). The study objective was to test the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitor-induced increases in intact incretin hormone (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) concentrations augment insulin secretion and glucagon suppression and lower post-prandial glycemia in PI-CF with AGT.

METHODS: Twenty-six adults from Children's Hospital of Philadelphia and University of Pennsylvania CF Center with PI-CF and AGT (defined by oral glucose tolerance test glucose [mg/dL]: early glucose intolerance [1-hour ≥155 & 2-hour <140], impaired glucose tolerance [2-hour ≥140 and <200 mg/dl], or diabetes [2-hour ≥200]) were randomized to a 6-month double-blind trial of DPP-4 inhibitor sitagliptin 100 mg daily or matched-placebo; 24 completed the trial (n=12 sitagliptin; n=12 placebo). Main outcome measures were mixed-meal tolerance test (MMTT) responses for intact GLP-1 and GIP, insulin secretory rates (ISR), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of β- and α-cell function.

RESULTS: Following 6-months of sitagliptin vs. placebo, MMTT intact GLP-1 and GIP responses increased (P <0.001), ISR dynamics improved (P <0.05), and glucagon suppression was modestly enhanced (P <0.05) while GPA test responses for glucagon were lower. No improvements in glucose tolerance or β-cell sensitivity to glucose, including for second-phase insulin response were found.

CONCLUSIONS: In glucose intolerant PI-CF, sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression without affecting post-prandial glycemia.

PMID:34022051 | DOI:10.1210/clinem/dgab365

Chest. 2021 Apr;159(4):e185-e187. doi: 10.1016/j.chest.2020.11.045. Epub 2021 Apr 6.

ABSTRACT

Inhaled antibiotics have long been used for chronic lung infections, especially in patients with cystic fibrosis and increasingly for non-cystic fibrosis bronchiectasis. Amikacin liposome inhalation suspension (ALIS) has emerged as a promising treatment for Mycobacterium avium complex infection refractory to oral antibiotics. However, despite its efficacy, nearly one-half of patients in phase II and III trials experienced dysphonia as a treatment-associated adverse effect. Here, we describe a patient who experienced severe, acute-onset laryngitis while receiving ALIS for refractory M avium complex infection, prompting discontinuation of ALIS therapy. This is the first report directly describing vocal fold injury due to such therapy. Given the high frequency of dysphonia reported with ALIS, this case highlights the potential severity of laryngeal toxicity, the importance of coordination of care for patients receiving inhaled antibiotics for chronic pulmonary disease, and the need for better insight into mechanisms of toxicity.

PMID:34022015 | DOI:10.1016/j.chest.2020.11.045

Chest. 2021 Apr;159(4):1677-1678. doi: 10.1016/j.chest.2020.11.029. Epub 2021 Apr 6.

NO ABSTRACT

PMID:34021997 | DOI:10.1016/j.chest.2020.11.029

J Mol Med (Berl). 2021 May 21. doi: 10.1007/s00109-021-02086-y. Online ahead of print.

ABSTRACT

Gene therapy of genetically determined diseases, including some pathologies of the respiratory system, requires an efficient method for transgene delivery. Recombinant adeno-associated viral (rAAV) vectors are well studied and employed in gene therapy, as they are relatively simple and low immunogenic and able to efficiently transduce eukaryotic cells. To date, many natural and artificial (with modified capsids) AAV serotypes have been isolated, demonstrating preferential tropism toward different tissues and cells in accordance with the prevalent receptors on the cell surface. However, rAAV-mediated delivery is not strictly specific due to wide tropism of some viral serotypes. Thus, the development of the methods allowing modulating specificity of these vectors could be beneficial in some cases. This review describes various approaches for retargeting rAAV to respiratory cells, for example, using different types of capsid modifications and regulation of a transgene expression by tissue-specific promoters. Part of the review is devoted to the issues of transduction of stem and progenitor lung cells using AAV, which is a complicated task today.

PMID:34021360 | DOI:10.1007/s00109-021-02086-y

Hum Reprod. 2021 May 22:deab087. doi: 10.1093/humrep/deab087. Online ahead of print.

ABSTRACT

STUDY QUESTION: What is the clinical validity and utility of preconception Expanded Carrier Screening (ECS) application on the management of prospective parents?

SUMMARY ANSWER: The high detection rate of at-risk couples (ARCs) and the high proportion opting for IVF/preimplantation genetic testing (PGT) treatment demonstrate the clinical utility of ECS in the preconception space in IVF and general population.

WHAT IS KNOWN ALREADY: About 2-4% of couples are at risk of conceiving a child with an autosomal recessive or X-linked genetic disorder. In recent years, the increasing cost-effectiveness of genetic diagnostic techniques has allowed the creation of ECS panels for the simultaneous detection of multiple recessive disorders. Comprehensive preconception genetic screening holds the potential to significantly improve couple's genetic risk assessment and reproductive planning to avoid detectable inheritable genetic offspring.

STUDY DESIGN, SIZE, DURATION: A total of 3877 individuals without a family history of genetic conditions were analyzed between January 2017 and January 2020. Of the enrolled individuals, 1212 were gamete donors and 2665 were patients planning on conceiving from both the IVF and the natural conception group. From the non-donor cohort, 1133 were analyzed as individual patients, while the remaining ones were analyzed as couples, for a total of 766 couples.

PARTICIPANTS/MATERIALS, SETTING, METHODS: A focused ECS panel was developed following American College of Obstetrics and Gynecology ACOG-recommended criteria (prevalence, carrier rate, severity), including highly penetrant severe childhood conditions. Couples were defined at-risk when both partners carried an autosomal recessive pathogenic/likely pathogenic variant (PLP) on the same gene or when the woman was a carrier of an X-linked PLP variant. ARC detection rate defined the clinical validity of the ECS approach. Clinical utility was evaluated by monitoring ARCs reproductive decision making.

MAIN RESULTS AND THE ROLE OF CHANCE: A total of 402 individuals (10.4%) showed PLP for at least one of the genes tested. Among the 766 couples tested, 173 showed one carrier partner (22.6%), whereas 20 couples (2.6%) were found to be at increased risk. Interestingly, one ARC was identified as a result of cascade testing in the extended family of an individual carrying a pathogenic variant on the Survival Of Motor Neuron 1SMN1 gene. Of the identified ARCs, 5 (0.7%) were at risk for cystic fibrosis, 5 (0.7%) for fragile X syndrome, 4 (0.5%) for spinal muscular atrophy, 4 (0.5%) for Beta-Thalassemia/Sickle Cell Anemia, 1 (0.1%) for Smith-Lemli-Opitz Syndrome and 1 (0.1%) for Duchenne/Becker Dystrophy. Fifteen ARCs were successfully followed up from both the IVF and the natural conception groups. All of these (15/15) modified their reproductive planning by undergoing ART with Preimplantation Genetic Testing for Monogenic disease and Aneuploidies (PGT-M and PGT-A). To date, 6/15 (40%) couples completed their PGT cycle with euploid/unaffected embryos achieving a pregnancy after embryo transfer and three of them have already had an unaffected baby.

LIMITATIONS, REASONS FOR CAUTION: The use of a limited panel of core gene-disease pairs represents a limitation on the research perspective as it can underestimate the rate of detectable carriers and ARCs in this cohort of prospective parents. Expanding the scope of ECS to a larger panel of conditions is becoming increasingly feasible, thanks to a persistent technological evolution and progressive cataloging of gene-disease associations.

WIDER IMPLICATIONS OF THE FINDINGS: These results highlight the potential clinical validity and utility of ECS in reducing the risk of a pregnancy affected by a detectable inheritable genetic condition. The steady reduction in the costs of genetic analyses enables the expansion of monogenic testing/screening applications at the preimplantation stage, thus, providing valid decisional support and reproductive autonomy to patients, particularly in the context of IVF.

STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. A.C., M.F., S.C., M.P., L.G., and C.P. are employees of Igenomix Italy. C.S. is the head of the scientific board of Igenomix.

TRIAL REGISTRATION NUMBER: N/A.

PMID:34021342 | DOI:10.1093/humrep/deab087

J Investig Med. 2021 May 21:jim-2021-001824. doi: 10.1136/jim-2021-001824. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a chronic lung disease characterized by acute pulmonary exacerbations (PExs) that are frequently treated with antibiotics. The impact of antibiotics on airway microbial diversity remains a critical knowledge gap. We sought to define the association between beta-lactam pharmacokinetic (PK) and pharmacodynamic target attainment on richness and alpha diversity. Twenty-seven children <18 years of age with CF participated in the prospective study. Airway samples were collected at hospital admission for PEx, end of antibiotic treatment (Tr), and >1 month in follow-up (FU). Metagenomic sequencing was performed to determine richness, alpha diversity, and the presence of antibiotic resistance genes. Free plasma beta-lactam levels were measured, and PK modeling was performed to determine time above the minimum inhibitory concentration (fT>MIC). 52% of study subjects had sufficient fT>MIC for optimal bacterial killing. There were no significant differences in demographics or PEx characteristics, except for F508del homozygosity. No significant differences were noted in richness or alpha diversity at individual time points, and both groups experienced a decrease in richness and alpha diversity at Tr compared with PEx. However, alpha diversity remained decreased at FU compared with PEx in those with sufficient fT>MIC but increased in those with insufficient fT>MIC (Shannon -0.222 vs +0.452, p=0.031, and inverse Simpson -1.376 vs +1.388, p=0.032). Fluoroquinolone resistance was also more frequently detected in those with insufficient fT>MIC (log2 fold change (log2FC) 2.29, p=0.025). These findings suggest sufficient beta-lactam fT>MIC is associated with suppressed recovery of alpha diversity following the antibiotic exposure period.

PMID:34021052 | DOI:10.1136/jim-2021-001824

J Cyst Fibros. 2021 May 18:S1569-1993(21)00123-5. doi: 10.1016/j.jcf.2021.04.013. Online ahead of print.

ABSTRACT

BACKGROUND: The clinical response to cystic fibrosis transmembrane conductance regulator (CFTR) modulators varies between people with cystic fibrosis (CF) of the same genotype, in part through the action of solute carriers encoded by modifier genes. Here, we investigate whether phosphate transport by SLC34A2 modulates the function of F508del-CFTR after its rescue by CFTR correctors.

METHODS: With Fischer rat thyroid (FRT) cells heterologously expressing wild-type and F508del-CFTR and fully-differentiated CF and non-CF human airway epithelial cells, we studied SLC34A2 expression and the effects of phosphate on CFTR-mediated transepithelial ion transport. F508del-CFTR was trafficked to the plasma membrane by incubation with different CFTR correctors (alone or in combination) or by low temperature.

RESULTS: Quantitative RT-PCR demonstrated that both FRT and primary airway epithelial cells express SLC34A2 mRNA and no differences were found between cells expressing wild-type and F508del-CFTR. For both heterologously expressed and native F508del-CFTR rescued by either VX-809 or C18, the magnitude of CFTR-mediated Cl- currents was dependent on the presence of extracellular phosphate. However, this effect of phosphate was not detected with wild-type and low temperature-rescued F508del-CFTR Cl- currents. Importantly, the modulatory effect of phosphate was observed in native CF airway cells exposed to VX-445, VX-661 and VX-770 (Trikafta) and was dependent on the presence of both sodium and phosphate.

CONCLUSIONS: Extracellular phosphate modulates the magnitude of CFTR-mediated Cl- currents after F508del-CFTR rescue by clinically-approved CFTR correctors. This effect likely involves electrogenic phosphate transport by SLC34A2. It might contribute to inter-individual variability in the clinical response to CFTR correctors.

PMID:34020896 | DOI:10.1016/j.jcf.2021.04.013

Clin Mol Allergy. 2021 May 21;19(1):5. doi: 10.1186/s12948-021-00146-9.

ABSTRACT

BACKGROUND: Asthma is a chronic disease characterized by airway hyperresponsiveness, inflammation and mucus production. In Type 2 asthma, two phenotypic components are often co-expressed (eosinophilic and allergic). Elevated biomarker levels, such as eosinophils (EOS), fraction of exhaled nitric oxide (FeNO) and immunoglobulin E (IgE), are key clinical indicators of Type 2 inflammation. Dupilumab has been recently approved for the treatment of uncontrolled severe Type 2 asthma. Type 2 asthma includes allergic and/or eosinophilic phenotypes. The aim of this analysis was to estimate the dupilumab-eligible population in Italy and characterize it by expected biomarker status.

METHODS: A 4-step approach was carried out to calculate dupilumab-eligible population. The approach consisted in: (1) estimating the total number of asthma patients in Italy (using 2016-2017 Italian-adapted Global Initiative for Asthma -GINA- guidelines); (2) estimating the number of severe asthma patients with poorly controlled or uncontrolled disease (using the findings of two recent administrative claim analyses conducted in Italy); (3) stratifying the severe uncontrolled population by biomarker levels (EOS, FeNO and IgE) according to the outcomes of the QUEST trial (a clinical study assessing the efficacy of dupilumab in patients with uncontrolled moderate-to-severe asthma; NCT02414854); (4) identifying the sub-populations of severe uncontrolled asthma patients characterised by raised blood EOS and/or FeNO level (thus indicated to receive dupilumab).

RESULTS: According to these estimates, about 3.3 million asthmatic patients live in Italy (6.10% of the population). Of them, almost 20 thousand (N = 19,960) have uncontrolled severe asthma. Dupilumab-eligible patients would be N = 15,988, corresponding to 80.1% of the total uncontrolled severe population. Most of these patients (89.3%; N = 14,271) have at least an increase of EOS level, while slightly more than half (51.9%; N = 8,303) have raised levels of both biomarkers. Increased FeNO levels without increased EOS are observed less frequently (N = 1,717; 10.7% of the eligible population).

CONCLUSIONS: There is a strong rationale for testing all asthma biomarkers during diagnosis and disease follow-up. Given the large availability and the limited costs, these tests are cost-effective tools to detect severe Type 2 asthma, stratify patients by phenotype, and drive appropriate treatment decisions.

PMID:34020658 | DOI:10.1186/s12948-021-00146-9

Respir Res. 2021 May 21;22(1):156. doi: 10.1186/s12931-021-01752-6.

ABSTRACT

BACKGROUND: Although cardiac autonomic modulation has been studied in several respiratory diseases, the evidence is limited on lung transplantation, particularly on its acute and chronic effects. Thus, we aimed to evaluate cardiac autonomic modulation before and after bilateral lung transplantation (BLT) through a prospective study on patients enrolled while awaiting transplant.

METHODS: Twenty-two patients on the waiting list for lung transplantation (11 women, age 33 [24-51] years) were enrolled in a prospective study at Ospedale Maggiore Policlinico Hospital in Milan, Italy. To evaluate cardiac autonomic modulation, ten minutes ECG and respiration were recorded at different time points before (T0) and 15 days (T1) and 6 months (T2) after bilateral lung transplantation. As to the analysis of cardiac autonomic modulation, heart rate variability (HRV) was assessed using spectral and symbolic analysis. Entropy-derived measures were used to evaluate complexity of cardiac autonomic modulation. Comparisons of autonomic indices at different time points were performed.

RESULTS: BLT reduced HRV total power, HRV complexity and vagal modulation, while it increased sympathetic modulation in the acute phase (T1) compared to baseline (T0). The HRV alterations remained stable after 6 months (T2).

CONCLUSION: BLT reduced global variability and complexity of cardiac autonomic modulation in acute phases, and these alterations remain stable after 6 months from surgery. After BLT, a sympathetic predominance and a vagal withdrawal could be a characteristic autonomic pattern in this population.

PMID:34020646 | DOI:10.1186/s12931-021-01752-6

Adv Exp Med Biol. 2021;1304:227-258. doi: 10.1007/978-3-030-68748-9_14.

ABSTRACT

Sex differences in the anatomy and physiology of the respiratory system have been widely reported. These intrinsic sex differences have also been shown to modulate the pathophysiology, incidence, morbidity, and mortality of several lung diseases across the life span. In this chapter, we describe the epidemiology of sex differences in respiratory diseases including neonatal lung disease (respiratory distress syndrome, bronchopulmonary dysplasia) and pediatric and adult disease (including asthma, cystic fibrosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, lung cancer, lymphangioleiomyomatosis, obstructive sleep apnea, pulmonary arterial hypertension, and respiratory viral infections such as respiratory syncytial virus, influenza, and SARS-CoV-2). We also discuss the current state of research on the mechanisms underlying the observed sex differences in lung disease susceptibility and severity and the importance of considering both sex and gender variables in research studies' design and analysis.

PMID:34019273 | DOI:10.1007/978-3-030-68748-9_14

Indian J Pediatr. 2021 May 20. doi: 10.1007/s12098-021-03784-8. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the correlation between severity of lung disease determined by chest computed tomography (CT) and 6-min walk test (6MWT) with health-related quality of life (HRQoL) score in cystic fibrosis (CF) patients.

METHODS: This cross-sectional study evaluated 76 CF patients referred to CF Clinic, aged 7-14 y. Subjects were asked to complete Pediatric quality of life (PedsQL4.0) forms, during their outpatient visits to determine their HRQoL score. Patients' lung disease severity was quantified by Bhalla score determined by the child's chest CT and their 6MWT. These three variables were then analyzed to determine whether there is correlation between HRQoL with severity of lung disease.

RESULTS: The mean distance of patients 6MWT score was 447.4 ± 81.4 m. There was a positive correlation between distance and HRQoL score in total, social, school and emotional function (p < 0.05). However, in physical function the correlation lacked significance (p = 0.07). Patients with a Bhalla score of less than 15 were older than patients with a Bhalla score of more than 15 (p < 0.001). Physical, emotional, social, school, and total function scores were significantly lower in patients with Bhalla score less than 15, compared to those with Bhalla score greater than 15 (p < 0.05).

CONCLUSIONS: The correlation among Bhalla score on CT scan, 6-min walk test, and HRQoL indicates that pulmonary disease has a clear impact on the quality of life of CF patients. HRQoL can be used in the care program of children with CF.

PMID:34018133 | DOI:10.1007/s12098-021-03784-8

Front Pediatr. 2021 May 4;9:649904. doi: 10.3389/fped.2021.649904. eCollection 2021.

ABSTRACT

Cystic fibrosis (CF) is the most common fatal genetic disease of the Caucasian population. Sweat testing is the principal diagnostic test for CF, and it is used for the evaluation of infants with positive CF newborn screening (NBS) and in patients with clinical findings suggesting CF. This article describes the classical sweat test method in detail and also provides an overwiew of recent advances.

PMID:34017807 | PMC:PMC8129525 | DOI:10.3389/fped.2021.649904

Front Endocrinol (Lausanne). 2021 Apr 29;12:673539. doi: 10.3389/fendo.2021.673539. eCollection 2021.

ABSTRACT

Cystic fibrosis related diabetes (CFRD) is a comorbidity of cystic fibrosis (CF) that negatively impacts on its clinical course. Prediabetes is an important predictor of either CFRD development and unfavorable prognosis of CF in both pediatric and adult patients. International guidelines recommend insulin only in case of CFRD diagnosis. Whether early detection and treatment of prediabetes may contribute to improve the clinical course of CF is still debated. A subgroup of pediatric diabetologists of the Italian Society for Pediatric Endocrinology and Diabetology (ISPED) performed a systematic review of the literature based on predefined outcomes: impact of pre-diabetes on clinical outcomes and on the risk of developing CFRD; diagnosis of diabetes and pre-diabetes under 10 years of age; effectiveness of therapy on glycemic control, impact of therapy on pulmonary function and nutritional status. Thirty-one papers were selected for the analysis data presented in these papers were reported in tables sorted by outcomes, including comprehensive evidence grading according to the GRADE approach. Following the grading of the quality of the evidence, the entire ISPED diabetes study group achieved consensus for the Italian recommendations based on both evidence and clinical experience. We concluded that in patients with CF, prediabetes should be carefully considered as it can evolve into CFRD. In patients with CF and prediabetic conditions, after complete evaluation of the OGTT trend, glucometrics, glycemic values measured during pulmonary exacerbations and/or steroid therapy, early initiation of insulin therapy could have beneficial effects on clinical outcomes of patients with CF and prediabetes.

PMID:34017312 | PMC:PMC8130616 | DOI:10.3389/fendo.2021.673539

Pancreas. 2021 May 19. doi: 10.1097/MPA.0000000000001815. Online ahead of print.

ABSTRACT

OBJECTIVES: We hypothesized that hospitalizations in cystic fibrosis (CF) would reflect the development of age-related comorbidities.

METHODS: A retrospective analysis was performed using the Nationwide Inpatient Sample (2002-2017). Hospitalizations for which the principal diagnosis was CF were analyzed regarding age at discharge and presence of comorbidities. Trends were assessed for significance using the Cochran-Armitage test.

RESULTS: The mean age of patients hospitalized for CF increased from 19.7 years in 2002 to 23.0 years in 2017 (P = 0.017). Several comorbidities are more than 10 times more prevalent among adults as compared with children, including congestive heart failure, substance abuse, and chronic kidney disease (P < 0.001). In addition, diabetes with chronic complications was more prevalent in adults than children (10.0% vs 3.9%; P < 0.001), as was hypertension (7.2% vs 1.3%; P < 0.001) and osteoporosis (10.2% vs 1.9%; P < 0.001). More than 65% of CF hospitalizations in 2017 were in individuals older than 18 years.

CONCLUSIONS: Hospitalizations for adults with CF are increasing, and individuals with CF are developing age-related comorbidities. Providers equipped to manage the health care needs of adults need to be ready and able to care for this unique and growing patient population.

PMID:34016889 | DOI:10.1097/MPA.0000000000001815

J Pediatr Gastroenterol Nutr. 2021 May 11. doi: 10.1097/MPG.0000000000003168. Online ahead of print.

ABSTRACT

Transient elastography is an imaging technique utilizing shear wave technology to measure liver stiffness. Recent studies have shown success in utilizing this technique in children. Transient elastography is useful in estimating degree of fibrosis in various pediatric liver diseases, including biliary atresia, alpha-1-antitrypsin deficiency, Alagille syndrome, cystic fibrosis related liver disease, and NASH among others. However, confounding factors may affect elastography measurements such as obesity, severe inflammation, non-fasting state and hepatic congestion and should be considered when interpreting these measurements. Future studies will correlate liver stiffness on transient elastography and severity of disease.

PMID:34016882 | DOI:10.1097/MPG.0000000000003168

J Pediatr Gastroenterol Nutr. 2021 May 18. doi: 10.1097/MPG.0000000000003173. Online ahead of print.

ABSTRACT

OBJECTIVES: To identify factors that increase risk of gastrointestinal-related (GI-related) hospitalization of infants with cystic fibrosis (CF) during the first year of life.

METHODS: The Baby Observational and Nutrition Study was a longitudinal, observational cohort of 231 infants diagnosed with CF by newborn screening. We performed a post-hoc assessment of the frequency and indications for GI-related admissions during the first year of life.

RESULTS: Sixty-five participants had at least one admission in the first 12 months of life. High pancreatic enzyme replacement therapy (PERT) dosing (>2000 LU/kg/meal) (hazard ratio, HR = 14.75, p = 0.0005) and use of acid suppressive medications (HR = 4.94, p = 0.01) during the study period were positively associated with subsequent GI-related admissions. High levels of fecal calprotectin (fCP) (>200 μg/g) and higher relative abundance of fecal Klebsiella pneumoniae were also positively associated with subsequent GI-related admissions (HR = 2.64, p = 0.033 and HR = 4.49, p = 0.002, respectively). During the first 12 months of life, participants with any admission had lower weight-for-length z-scores (WLZ) (p = 0.01). The impact of admission on WLZ was particularly evident in participants with a GI-related admission (p < 0.0001).

CONCLUSIONS: Factors associated with higher risk for GI-related admission during the first 12 months include high PERT dosing, exposure to acid suppressive medications, higher fCP levels, and/or relative abundance of fecal Klebsiella pneumoniae early in life. Infants with CF requiring GI-related hospitalization had lower WLZ at 12 months of age than those not admitted as well as those admitted for non GI-related indications.

PMID:34016873 | DOI:10.1097/MPG.0000000000003173

Microbiol Resour Announc. 2021 May 20;10(20):e00402-21. doi: 10.1128/MRA.00402-21.

ABSTRACT

Burkholderia gladioli is known to cause respiratory tract infections in cystic fibrosis patients. Here, we describe the annotation of the 38,038-bp genome sequence of Mana, a P2-like phage of B. gladioli Understanding the genomic characteristics of phages infecting pathogens like B. gladioli can lead to advancements in phage therapy.

PMID:34016684 | DOI:10.1128/MRA.00402-21

BMJ Case Rep. 2021 May 20;14(5):e240448. doi: 10.1136/bcr-2020-240448.

ABSTRACT

We present to you a case of life-threatening haemoptysis secondary to non-cystic fibrosis bronchiectasis complicated by bronchial artery pseudoaneurysms. We discuss this patient's emergency medical management using intravenous tranexamic acid, which resulted in successful resuscitation and eventual survival, and evaluate the need for urgent anaesthetic and interventional radiology input in such a case.

PMID:34016628 | DOI:10.1136/bcr-2020-240448