Pediatr Pulmonol. 2022 Feb 18. doi: 10.1002/ppul.25865. Online ahead of print.

ABSTRACT

BACKGROUND: The recently described sensor-crosstalk error in the multiple-breath washout (MBW) device Exhalyzer D (Eco Medics AG, Duernten, Switzerland) could highly influence clinimetric properties and the current interpretation of MBW results. This study reanalyzes MBW data from clinical routine in the corrected software version Spiroware® 3.3.1 and evaluates the effect on outcomes.

METHODS: We included nitrogen-MBW data from healthy children and children with cystic fibrosis (CF) from previously published trials and ongoing cohort studies. We specifically compared lung clearance index (LCI) analyzed in Spiroware 3.2.1 and 3.3.1 with regards to i) feasibility, ii) repeatability and iii) validity as outcome parameters in children with CF.

RESULTS: (i) All previously collected measurements could be reanalyzed and resulted in unchanged feasibility in Spiroware 3.3.1. (ii) Short- and midterm repeatability of LCI was similar in both software versions. (iii) Clinical validity of LCI remained similar in Spiroware 3.3.1, however, resulted in lower values. Discrimination between health and disease was comparable between both software versions. The increase in LCI over time was less pronounced with 0.16 LCI units/year (95% CI 0.08; 0.24) vs. 0.30 LCI units/year (95% CI 0.21; 0.38) in 3.2.1. Response to intervention in children receiving CFTR-modulator therapy resulted in a comparable improvement in LCI in both Spiroware versions.

CONCLUSION: Our study confirms that clinimetric properties of LCI remain unaffected after correction for the cross-sensitivity error in Spiroware software. This article is protected by copyright. All rights reserved.

PMID:35182057 | DOI:10.1002/ppul.25865

Acta Paediatr. 2022 Feb 18. doi: 10.1111/apa.16302. Online ahead of print.

ABSTRACT

AIM: Annual chest x-ray is recommended as routine surveillance to track cystic fibrosis (CF) lung disease. The aim of this study was to investigate the clinical utility of chest x-rays to track CF lung disease.

METHODS: Children at Gothenburg's CF centre who underwent chest x-rays, multiple breath washouts and chest computed tomography examinations between 1996-2016 were included in the study. Chest x-rays were interpreted with Northern Score (NS). We compared NS to lung clearance index (LCI) and structural lung damage measured by computed tomography using a logistic regression model.

RESULTS: A total of 75 children were included over a median period of 13 years (range: 3.0-18.0 years). The proportion of children with abnormal NS was significantly lower than the proportion of abnormal LCI up to the age of 4 years (p<0.05). A normal NS and a normal LCI at age 6 years, were associated with a median (10-90th percentile) total airway disease of 1.8% (0.4-4.7%) and bronchiectasis of 0.2% (0.0-1.5%).

CONCLUSION: Chest x-rays were less sensitive than multiple breath washout examinations to detect early CF lung disease. The combined results from both methods can be used as an indicator to perform chest computed tomography less frequently.

PMID:35181935 | DOI:10.1111/apa.16302

J Cyst Fibros. 2022 Feb 15:S1569-1993(22)00038-8. doi: 10.1016/j.jcf.2022.02.006. Online ahead of print.

ABSTRACT

BACKGROUND: People with cystic fibrosis (CF) are living longer, healthier lives. A growing number are considering parenthood. There is a substantial knowledge gap regarding the health impacts of parenthood on people with CF.

METHODS: Using data from the United Kingdom CF registry from 2015 to 2019, we evaluated the impact of having a child on percent predicted forced expiratory volume in 1 second (ppFEV1), body mass index (BMI), and pulmonary exacerbations via multivariable longitudinal data analysis adjusting for age and sex in the year before a person with CF became a parent to the first year following parenthood. We examined whether changes from pre- to post-parenthood differed by sex or CF transmembrane conductance regulator (CFTR) modulator use.

RESULTS: Among 296 people with CF who became parents, we found a significant decrease in ppFEV1, (adjusted mean difference -3.19, CI: -4.31, -2.07; p<0.01) and BMI (adjusted mean difference -0.28, CI: -0.51, -0.05; p<0.02) and a significant increase in pulmonary exacerbations (adjusted rate ratio 1.3, CI: 1.13, 1.49; p<0.01) in the year following the birth of a child compared to the year prior. Further analysis showed that CFTR modulator use mitigated parenthood impacts on ppFEV1, but not on BMI and pulmonary exacerbations. Females experienced significantly worse impacts on BMI from pre- to post-parenthood compared to males.

CONCLUSIONS: Parenthood adversely impacts short-term health outcomes for people with CF and CFTR modulator use mitigates such effects. To better understand the impact of the widespread use of highly effective CFTR modulators, longer-term, prospective parenthood studies are needed.

PMID:35181269 | DOI:10.1016/j.jcf.2022.02.006

J Cell Sci. 2022 Feb 18:jcs.259512. doi: 10.1242/jcs.259512. Online ahead of print.

ABSTRACT

Mutations in SPAG1, a dynein axonemal assembly factor (DNAAF) that facilitates the assembly of dynein arms in the cytoplasm before their transport into the cilium, result in primary ciliary dyskinesia (PCD), a genetically heterogenous disorder characterized by chronic oto-sino-pulmonary disease, infertility, and laterality defects. To further elucidate SPAG1's role in dynein assembly, we examined its expression, interactions, and ciliary defects in control and PCD human airway epithelia. Immunoprecipitations showed that SPAG1 interacts with multiple DNAAFs, dynein chains, and canonical components of the R2TP complex. Dynein heavy chains (DHC) protein levels and their interaction with dynein intermediate chains (DIC) were reduced in SPAG1 mutants. We also identified a previously uncharacterized 60 kDa SPAG1 isoform, through examination of PCD subjects with an atypical ultrastructural defect for SPAG1 variants, that can partially compensate for the absence of full-length SPAG1 to assemble a reduced number of outer dynein arms. In summary, our data show that SPAG1 is necessary for axonemal dynein arm assembly by scaffolding R2TP-like complexes composed of several DNAAFs that facilitate the folding and/or binding of the DHC to the DIC complex.

PMID:35178554 | DOI:10.1242/jcs.259512

Pediatr Res. 2022 Feb 17. doi: 10.1038/s41390-022-01947-7. Online ahead of print.

ABSTRACT

BACKGROUND: Dysnatremias are frequent in acute gastroenteritis. High outdoor temperatures have been associated with hyponatremia in both adults and the elderly, but no data are available among children with gastroenteritis.

METHODS: Children <10 years of age admitted to the emergency department of the Policlinico Hospital, Milan (Italy) between 2009 and 2019 with acute moderate-severe gastroenteritis were enrolled. The association between hyponatremia (sodium < 135 mmol/L) and daily mean levels of temperature or apparent temperature from day of admission up to 14 days before was analyzed by multivariable logistic regression models.

RESULTS: In 202 included children (46% females), we observed an increased risk of hyponatremia per unit increase in outdoor temperature of the sixth, eighth and ninth day before admission [Odds Ratio = 1.24 (95% Confidence Interval: 1.04-1.47), 1.14 (1.01-1.28), and 1.14 (1.01-1.28), respectively]. Analyses considering average temperature levels of the ten days preceding admission returned similar findings as well as those on apparent temperature.

CONCLUSIONS: Our data suggest the existence of an association between outdoor temperature and circulating sodium levels in children with acute gastroenteritis. The role of meteorological conditions on electrolyte imbalance should be further explored in the context of climate change.

IMPACT: The role of meteorological variables in the development of dysnatremias has been demonstrated in children and adolescents with cystic fibrosis. This study shows for the first time that higher outdoor temperatures are associated with a higher risk of hyponatremia in children with gastroenteritis. In the context of climate change, the role of external climate conditions on the risk of electrolyte imbalance in children should be more and more considered and explored in future studies.

PMID:35177815 | DOI:10.1038/s41390-022-01947-7

Elife. 2022 Feb 17;11:e74658. doi: 10.7554/eLife.74658. Online ahead of print.

ABSTRACT

Bacterial survival is fraught with antagonism, including that deriving from viruses and competing bacterial cells. It is now appreciated that bacteria mount complex antiviral responses; however, whether a coordinated defense against bacterial threats is undertaken is not well understood. Previously we showed that Pseudomonas aeruginosa possess a danger sensing pathway that is a critical fitness determinant during competition against other bacteria. Here, we conducted genome-wide screens in P. aeruginosa that reveal three conserved and widespread interbacterial antagonism resistance clusters (arc1-3). We find that although arc1-3 are coordinately activated by the Gac/Rsm danger sensing system, they function independently and provide idiosyncratic defense capabilities, distinguishing them from general stress response pathways. Our findings demonstrate that Arc3 family proteins provide specific protection against phospholipase toxins by preventing the accumulation of lysophospholipids in a manner distinct from previously characterized membrane repair systems. These findings liken the response of P. aeruginosa to bacterial threats to that of eukaryotic innate immunity, wherein threat detection leads to the activation of specialized defense systems.

PMID:35175195 | DOI:10.7554/eLife.74658

Pediatr Pulmonol. 2022 Feb 17. doi: 10.1002/ppul.25860. Online ahead of print.

ABSTRACT

BACKGROUND: Postural and aerobic exercises are essential in rehabilitation in CF. The aim of this study is to examine the effect of telerehabilitation on the quality of life, depression and anxiety levels of children with CF and their caregivers' mood and anxiety levels.

MATERIALS AND METHODS: Patients between the ages of 6-13 with CF were randomized into two groups. Study group received an exercise program three times a week via Zoom for 12 weeks. Cystic Fibrosis Revised Questionnaire (CFQ-R), Anxiety and Depression Scale in Children-Revised (RCADS) were applied to the patients and State-Trait Anxiety Scale (STAI) and Beck Depression Inventory (BDI) were applied to the caregivers in the beginning and at the end of the program. Patients' FEV1 levels and six-minute walk tests were also measured.

RESULTS: Twenty-eight patient-caregiver dyads, fourteen dyads in each group, completed the study. The initial mean RCADS-Major depressive disorder score of the patients in the exercise group was 6.21±3.11, and this value decreased to 3.92±3.79 at the end of the study and was significantly better(p<0.02). A similar significant change was observed when the RCADS-generalized anxiety disorder score decreased from the initial mean level of 6.28±2.81 to 3.42±2.65 (p<0.01). There were significant changes improvement in the body image in telerehabilitation group. Similar significant changes were not observed in the control group. Caregivers' anxiety and depression levels did not change significantly.

CONCLUSION: A short-term telerehabilitation program improved patients' anxiety and depression levels, body image and functional status. However caregiver anxiety and depression levels did not change significantly. This article is protected by copyright. All rights reserved.

PMID:35174670 | DOI:10.1002/ppul.25860

J Paediatr Child Health. 2022 Feb 17. doi: 10.1111/jpc.15909. Online ahead of print.

ABSTRACT

AIM: With progressive impairment of lung function, deposition of inhaled drug in the lungs becomes progressively more central, limiting its effectiveness. This pilot study explored the possibility that long slow inhalations might improve delivery of aerosol to the lung periphery in cystic fibrosis patients with moderate lung disease.

METHODS: Five subjects aged 12-18 years (mean FEV1 72%; range 63-80%) inhaled a radiolabelled aerosol from a jet nebuliser on two occasions. Two inhalation techniques were compared: breathing tidally from a standard continuous output nebuliser and using long slow inhalations from the AKITA® JET system.

RESULTS: Long slow breaths resulted in much lower oropharyngeal deposition with higher lung doses. Importantly, the peripheral lung increased proportionately. The increased lung dose is attributable to more of the larger inhaled droplets passing into the lower airways. This would be expected to increase the central deposition unless significantly more of the smaller droplets were able to penetrate deeper into the lungs. The data support improved delivery of drug to the distal lung when compared with tidal breathing.

CONCLUSION: These pilot data suggest that this approach may prove to be clinically relevant in improving the efficacy of inhaled medication in those with moderate-severe lung disease.

PMID:35174574 | DOI:10.1111/jpc.15909

Immunogenetics. 2022 Feb 16. doi: 10.1007/s00251-022-01256-7. Online ahead of print.

ABSTRACT

S100A7, a member of the S100A family of Ca2+-binding proteins, is considered a key effector in immune response. In particular, S100A7 dysregulation has been associated with several diseases, including autoimmune disorders. At the nuclear level, S100A7 interacts with several protein-binding partners which are involved in transcriptional regulation and DNA repair. By using the BioGRID and GAAD databases, S100A7 nuclear interactors with a putative involvement in autoimmune diseases were retrieved. We selected fatty acid-binding protein 5 (FABP5), autoimmune regulator (AIRE), cystic fibrosis transmembrane conductance regulator (CFTR), chromodomain helicase DNA-binding protein 4 (CHD4), epidermal growth factor receptor (EGFR), estrogen receptor 1 (ESR1), histone deacetylase 2 (HDAC2), v-myc avian myelocytomatosis viral oncogene homolog (MYC), protection of telomeres protein 1 (POT1), telomeric repeat-binding factor (NIMA-interacting) 1 (TERF1), telomeric repeat-binding factor 2 (TERF2), and Zic family member 1 (ZIC1). Linear correlation coefficients between interprotein distances were calculated with MirrorTree. Coevolution clusters were also identified with the use of a recent version of the Blocks in Sequences (BIS2) algorithm implemented in the BIS2Analyzer web server. Analysis of pair positions identified interprotein coevolving clusters between S100A7 and the binding partners CFTR and TERF1. Such findings could guide further analysis to better elucidate the function of S100A7 and its binding partners and to design drugs targeting for these molecules in autoimmune diseases.

PMID:35174412 | DOI:10.1007/s00251-022-01256-7

ERJ Open Res. 2022 Feb 14;8(1):00607-2021. doi: 10.1183/23120541.00607-2021. eCollection 2022 Jan.

ABSTRACT

Disease-specific outcomes in patients with non-cystic fibrosis bronchiectasis following lung transplantation are not well described. We performed a retrospective analysis to describe outcomes in these patients. Patients with non-cystic fibrosis bronchiectasis who have undergone lung transplantation in the USA were identified using the Organ Procurement and Transplant Network database. Survival data were analysed for the post-lung allocation score period with Kaplan-Meier curves, and a log-rank test was conducted to compare survival data among an age-, sex- and activation date-matched non-cystic fibrosis bronchiectasis cohort. 721 patients with non-cystic fibrosis bronchiectasis were listed for lung transplantation between March 1992 and September 2019. 407 patients received lung transplantation with a median age at listing of 47 years. The Kaplan-Meier survival analysis for lung transplantation recipient non-cystic fibrosis bronchiectasis patients during the post-lung allocation score period at 1, 5 and 10 years was 87%, 53% and 16%, respectively. The median survival time post-lung transplantation is 6.0 years (interquartile range: 2.3-11.9 years), which is similar to an age- and sex-matched cohort (p=0.86). This retrospective analysis demonstrates that median survival after lung transplantation in non-cystic fibrosis bronchiectasis was similar to other lung transplantation recipients over the study period. We suggest that the development of specific criteria for lung transplantation in non-cystic fibrosis bronchiectasis may improve patient selection and benefit a larger group of patients with this therapy.

PMID:35174245 | PMC:PMC8841986 | DOI:10.1183/23120541.00607-2021

Front Cell Infect Microbiol. 2022 Jan 31;12:824101. doi: 10.3389/fcimb.2022.824101. eCollection 2022.

ABSTRACT

Chronic Pseudomonas aeruginosa infections play an important role in the progress of lung disease in patients suffering from cystic fibrosis (CF). Recent studies indicate that polymicrobial microbiome profiles in the airway are associated with less inflammation. Thus, the hypothesis was raised that certain commensal bacteria might protect the host from inflammation. We therefore performed a screening study with commensals isolated from CF airway microbiome samples to identify potential beneficial commensals. We isolated more than 80 aerobic or facultative anaerobic commensal strains, including strains from genera Streptococcus, Neisseria, Actinomyces, Corynebacterium, Dermabacter, Micrococcus and Rothia. Through a screening experiment of co-infection in human epithelial cell lines, we identified multiple commensal strains, especially strains belonging to Streptococcus mitis, that reduced P. aeruginosa triggered inflammatory responses. The results were confirmed by co-infection experiments in ex-vivo precision cut lung slices (PCLS) from mice. The underlying mechanisms of the complex host-pathogen-commensal crosstalk were investigated from both the host and the bacterial sides with a focus on S. mitis. Transcriptome changes in the host in response to co-infection and mono-infection were evaluated, and the results indicated that several signalling pathways mediating inflammatory responses were downregulated by co-infection with S. mitis and P. aeruginosa compared to P. aeruginosa mono-infection, such as neutrophil extracellular trap formation. The genomic differences among S. mitis strains with and without protective effects were investigated by whole genome sequencing, revealing genes only present in the S. mitis strains showing protective effects. In summary, through both in vitro and ex vivo studies, we could identify a variety of commensal strains that may reduce host inflammatory responses induced by P. aeruginosa infection. These findings support the hypothesis that CF airway commensals may protect the host from inflammation.

PMID:35174108 | PMC:PMC8842722 | DOI:10.3389/fcimb.2022.824101

Proc Natl Acad Sci U S A. 2022 Feb 22;119(8):e2116836119. doi: 10.1073/pnas.2116836119.

ABSTRACT

The lungs and kidneys are pivotal organs in the regulation of body acid-base homeostasis. In cystic fibrosis (CF), the impaired renal ability to excrete an excess amount of HCO3 - into the urine leads to metabolic alkalosis [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711-1727 (2020); F. Al-Ghimlas, M. E. Faughnan, E. Tullis, Open Respir. Med. J. 6, 59-62 (2012)]. This is caused by defective HCO3 - secretion in the β-intercalated cells of the collecting duct that requires both the cystic fibrosis transmembrane conductance regulator (CFTR) and pendrin for normal function [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711-1727 (2020)]. We studied the ventilatory consequences of acute oral base loading in normal, pendrin knockout (KO), and CFTR KO mice. In wild-type mice, oral base loading induced a dose-dependent metabolic alkalosis, fast urinary removal of base, and a moderate base load did not perturb ventilation. In contrast, CFTR and pendrin KO mice, which are unable to rapidly excrete excess base into the urine, developed a marked and transient depression of ventilation when subjected to the same base load. Therefore, swift renal base elimination in response to an acute oral base load is a necessary physiological function to avoid ventilatory depression. The transient urinary alkalization in the postprandial state is suggested to have evolved for proactive avoidance of hypoventilation. In CF, metabolic alkalosis may contribute to the commonly reduced lung function via a suppression of ventilatory drive.

PMID:35173044 | DOI:10.1073/pnas.2116836119

Immunohorizons. 2022 Feb 16;6(2):144-155. doi: 10.4049/immunohorizons.2200005.

ABSTRACT

Due to the severity of COVID-19 disease, the U.S. Centers for Disease Control and Prevention and World Health Organization recommend that manipulation of active viral cultures of SARS-CoV-2 and respiratory secretions from COVID-19 patients be performed in biosafety level (BSL)3 laboratories. Therefore, it is imperative to develop viral inactivation procedures that permit samples to be transferred to lower containment levels (BSL2), while maintaining the fidelity of complex downstream assays to expedite the development of medical countermeasures. In this study, we demonstrate optimal conditions for complete viral inactivation following fixation of infected cells with commonly used reagents for flow cytometry, UVC inactivation in sera and respiratory secretions for protein and Ab detection, heat inactivation following cDNA amplification for droplet-based single-cell mRNA sequencing, and extraction with an organic solvent for metabolomic studies. Thus, we provide a suite of viral inactivation protocols for downstream contemporary assays that facilitate sample transfer to BSL2, providing a conceptual framework for rapid initiation of high-fidelity research as the COVID-19 pandemic continues.

PMID:35173021 | DOI:10.4049/immunohorizons.2200005

J Leukoc Biol. 2022 Feb 16. doi: 10.1002/JLB.3AB0321-149R. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) airways feature high extracellular levels of the IL-1 family of proinflammatory mediators. These mediators are cleavage products of caspase-1, the final protease in the inflammasome cascade. Due to the proven chronic presence of reprogrammed neutrophils in the CF airway lumen, understanding inflammasome signaling in these cells is of great importance to understand how disease is perpetuated in this milieu. Here, we hypothesized that CF airway neutrophils contribute to chronic inflammation, in part, via the packaging of inflammasome-inducing signals in extracellular vesicles (EVs). We confirmed that CF airway fluid is enriched in IL-1α, IL-1β, and IL-18, and that CF airway neutrophils up-regulate the activating receptor IL-1R1. Meanwhile, down-modulatory signals such as IL-1R2 and IL-1RA are unchanged. Active caspase-1 itself is present in CF airway fluid EVs, with neutrophil-derived EVs being most enriched. Using a transmigration model of CF airway inflammation, we show that CF airway fluid EVs are necessary and sufficient to induce primary granule exocytosis by naïve neutrophils (hallmark of reprogramming) and concomitantly activate caspase-1 and IL-1β production by these cells and that the addition of triple-combination highly effective CFTR modulator therapy does not abrogate these effects. Finally, EVs from activated neutrophils can deliver active caspase-1 to primary tracheal epithelial cells and induce their release of IL-1α. These findings support the existence of a feed-forward inflammatory process by which reprogrammed CF airway neutrophils bypass 2-step control of inflammasome activation in neighboring cells (naïve neutrophils and epithelial cells) via the transfer of bioactive EVs.

PMID:35172381 | DOI:10.1002/JLB.3AB0321-149R

IEEE Trans Biomed Eng. 2022 Feb 16;PP. doi: 10.1109/TBME.2022.3151938. Online ahead of print.

ABSTRACT

OBJECTIVE: Most methods for monitoring sweat gland activity use simple gravimetric methods, which merely measure the average sweat rate of multiple sweat glands over a region of skin. It would be extremely useful to have a method which could quantify individual gland activity in order to improve the treatment of conditions which use sweat tests as a diagnostic tool, such as hyperhidrosis, cystic fibrosis, and peripheral nerve degeneration.

METHODS: An optical method using an infrared camera to monitor the skin surface temperature was developed. A thermodynamics computer model was then implemented to utilize these skin temperature values along with other environmental parameters, such as ambient temperature and relative humidity, to calculate the sweat rates of individual glands using chemically stimulated and unstimulated sweating. The optical method was also used to monitor sweat pulsation patterns of individual sweat glands.

RESULTS: In this preliminary study, the feasibility of the optical approach was demonstrated by measuring sweat rates of individual glands at various bodily locations. Calculated values from this method agree with expected sweat rates given values found in literature. In addition, a lack of pulsatile sweat expulsion was observed during chemically stimulated sweating, and a potential explanation for this phenomenon was proposed.

CONCLUSION: A simple, non-contact optical method to quantify sweat gland activity in-vivo was presented.

SIGNIFICANCE: This method allows researchers and clinicians to investigate several sweat glands simultaneously, which has the potential to provide more accurate diagnoses and treatment as well as increase the potential utility for wearable sweat sensors.

PMID:35171763 | DOI:10.1109/TBME.2022.3151938

Biometals. 2022 Feb 16. doi: 10.1007/s10534-022-00369-6. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a Gram-negative bacterium which can cause serious infections among immune-depressed people including cystic fibrosis patients where it can colonize the lungs causing chronic infections. Iron is essential for P. aeruginosa and can be provided via three sources under aerobic conditions: its own siderophores pyochelin (PCH) and pyoverdine (PVD), xenosiderophores, or heme, respectively. Pyoverdine is the high affinity siderophore and its synthesis and uptake involve more than 30 genes organized in different operons. Its synthesis and uptake are triggered by iron scarcity via the Fur regulator and involves two extra cytoplasmic sigma factors (ECF), PvdS for the biosynthesis of PVD and FpvI for the uptake via the TonB-dependent FpvA outer membrane transporter and other periplasmic and inner membrane proteins. It appeared recently that the regulation of PVD biosynthesis and uptake involves other regulators, including other ECF factors, and LysR regulators. This is the case especially for the genes coding for periplasmic and inner membrane proteins involved in the reduction of Fe3+ to Fe2+ and the transport of ferrous iron to the cytoplasm that appears to represent a crucial step in the uptake process.

PMID:35171432 | DOI:10.1007/s10534-022-00369-6

Rheumatology (Oxford). 2022 Feb 16:keac100. doi: 10.1093/rheumatology/keac100. Online ahead of print.

ABSTRACT

OBJECTIVES: Juvenile dermatomyositis (JDM) is a serious autoimmune and complex genetic disease. Another autoimmune genetic disease, type 1 diabetes (T1D), has been observed for significantly increased prevalence in families with JDM, while increased JDM risk has also been observed in T1D cases. This study aimed to study whether these two autoimmune diseases, JDM and T1D, share common genetic susceptibility.

METHODS: From 169 JDM families, 121 unrelated cases with European ancestry (EA) were identified by genome-wide genotyping, principal component analysis (PCA), and identical-by-descent (IBD) analysis. T1D genetic risk score (GRS) were calculated in these cases, and were compared with 361 EA T1D cases and 1943 non-diabetes EA controls. 113 cases of the 121 unrelated European cases were sequenced by whole exome sequencing (WES).

RESULTS: We observed increased T1D GRS in JDM cases (P=9.42E-05). Using whole exome sequencing (WES), we uncovered the T1D genes, phospholipase B1 (PLB1), cystic fibrosis transmembrane conductance regulator (CFTR), tyrosine hydroxylase (TH), CD6 molecule (CD6), perforin 1 (PRF1), and dynein axonemal heavy chain 2 (DNAH2), potentially associated with JDM by the burden test of rare functional coding variants.

CONCLUSION: Novel mechanisms of JDM related to these T1D genes are suggested by this study, which may imply novel therapeutic targets for JDM and warrant further study.

PMID:35171267 | DOI:10.1093/rheumatology/keac100

Hum Mutat. 2022 Feb 16. doi: 10.1002/humu.24352. Online ahead of print.

ABSTRACT

Current approaches to characterize the mutational profile of the cystic fibrosis transmembrane conductance regulator (CFTR) gene are based on targeted mutation analysis (TMA) or whole gene studies derived from short-read next generation sequencing (NGS). However, these methods lack phasing capability which, in certain scenarios, can provide clinically valuable information. In the present work, we performed near-full length CFTR using Single-Molecule Real-Time Sequencing to produce haplotype-resolved data from both homozygous and heterozygous individuals for mutation c.1521_1523delCTT (p.Phe508del, F508del). This approach utilizes target enrichment of the CFTR gene using biotinylated probes, facilitates multiplexing samples in the same sequencing run, and utilizes fully-automated bioinformatics pipelines for error correction and variant calling. We show a remarkable conservation of F508del haplotype, consistent with the single gene founder effect, as well as diverse mutational profiles in non-F508del alleles. By the same method, 105 single nucleotide polymorphisms (SNPs) exhibiting invariant linkage to F508del CFTR (which better define the founder haplotype) were identified. High level homology between F508del sequences derived from heterozygotes, and those obtained from homozygous individuals, demonstrate accuracy of this method to produce haplotype resolved sequencing. The studies provide a new diagnostic technology for detailed analysis of complex CFTR alleles linked to disease severity. This article is protected by copyright. All rights reserved.

PMID:35170824 | DOI:10.1002/humu.24352

Endocrinol Diabetes Metab Case Rep. 2022 Feb 1;2022:21-0181. doi: 10.1530/EDM-21-0181. Online ahead of print.

ABSTRACT

SUMMARY: Vitamin D intoxication in children is rare but its incidence is increasing as vitamin D is supplemented more often and in higher doses. Children with cystic fibrosis (CF) are at risk for vitamin D intoxication due to incorrect compounded preparations of liposoluble vitamins. Here, we report a severe vitamin D intoxication in a 4-year-old girl with CF, due to an error in the compounded vitamin A, D, E, and K preparation, presenting clinically with weight loss, constipation, polydipsia, polyuria, and nycturia. The administered compounded preparation contained 10 000-fold the prescribed vitamin D dose. The patient was treated with hyperhydration, loop diuretics, and bisphosphonates. Serum calcium levels normalized after 4 days but serum 25-hydroxyvitamin D levels remained elevated even up to 2 months after treatment.

LEARNING POINTS: Vitamin D intoxication should be ruled out when patients with cystic fibrosis (CF) present with acute polyuria, constipation, and weight loss. Prompt treatment is necessary to avert life-threatening complications. Regularly measuring serum calcium and 25-hydroxyvitamin D concentrations in children with CF receiving vitamin A, D, E, and K supplements is important during their follow-up.

PMID:35170432 | DOI:10.1530/EDM-21-0181

Pediatr Pulmonol. 2022 Feb 15. doi: 10.1002/ppul.25859. Online ahead of print.

ABSTRACT

BACKGROUND: While the advent of CFTR modulator use has improved daily life and long term prognosis of CF for many with approved CFTR mutations, approximately 10% of people with CF (pwCF) have only symptomatic treatments available.

METHODS: Between June 10-July 1, 2021, Emily's Entourage distributed a 38-question anonymous survey targeted at pwCF not benefitting from approved modulators via social media and email to pwCF and CF advocacy groups in and outside the U.S. regarding health status, impact of CF, unmet needs and clinical research interest.

RESULTS: There were 431 survey respondents representing pwCF on five continents. The majority of pwCF had moderate lung disease (50.3%). Ineligibility based on CFTR mutation (64.1%) was the most frequently reported reason pwCF were not on modulators. PwCF reported the most impacted aspects of life were mental (66.7%) and physical (40.7%) health. Financial concerns and feelings of isolation were commonly reported. Witnessing improvements for peers with access to modulators was both uplifting and disheartening. The majority of pwCF would be interested in participating in future clinical research (77.6%), although some living outside of the US cited lack of opportunity to participate in clinical trials as a barrier.

CONCLUSIONS: PwCF who are ineligible, intolerant or lack access to modulators have a high burden of disease impacting their physical and mental health. Although most are happy for those who are benefiting from modulators, they are eager for the opportunity to experience similar improvements for themselves, and willing to participate in clinical trials of new therapies. This article is protected by copyright. All rights reserved.

PMID:35170259 | DOI:10.1002/ppul.25859