J Cyst Fibros. 2021 Oct 4:S1569-1993(21)01417-X. doi: 10.1016/j.jcf.2021.09.012. Online ahead of print.

ABSTRACT

BACKGROUND: The sweat test has been the "gold standard" diagnostic test for cystic fibrosis for more than 40 years. We hypothesized that there would be a change in the pattern of sweat testing in Ireland since the introduction of cystic fibrosis newborn screening in 2011, when practices were last reviewed. This is a follow up survey looking at sweat testing numbers and practices.

METHODS: A national survey compiled data on sweat collection, conductivity and sweat chloride testing in all hospitals previously identified as performing sweat tests.

RESULTS: All 13 centres in Ireland performing sweat testing in 2018 responded to the survey (100% return rate). Our results indicate that 1007 sweat tests were performed in 2018 compared to 2555 in 2011, equating to a 61% reduction. Seven out of 13 centres are performing less than 50 sweat tests per year. Nine out of 13 centres (69%) had a sweat test failure rate greater than the recommended allowable rate of ≤ 10%. We detected a trend of sweat testing in patients with an existing diagnosis of CF who had commenced cystic fibrosis transmembrane conductance regulator (CFTR) modulators.

CONCLUSIONS: There has been a significant reduction in the number of sweat tests performed in Ireland since the introduction of newborn screening for CF. There remains a lack of standardisation in many aspects of the service ranging from sample collection to reporting of results. We have identified a new trend of sweat testing in the cystic fibrosis transmembrane conductance regulator modulator era.

PMID:34620573 | DOI:10.1016/j.jcf.2021.09.012

Clin Nutr ESPEN. 2021 Oct;45:229-235. doi: 10.1016/j.clnesp.2021.08.020. Epub 2021 Sep 3.

ABSTRACT

BACKGROUND & AIMS: Low bone mineral density (BMD) for age in people with Cystic Fibrosis (CF) is associated with worse nutritional status. The aim of this study is to assess body composition by anthropometry as a predictor of BMD in people with CF.

METHODS: Multicenter cross-sectional study with 39 people aged 5 and 20 years with CF. BMD was assessed by dual energy x-ray emission (DXA) in the incidence of the total body less head (TBLH) and the TBLH Z-score (Z-TBLH) was calculated, adjusted by sex, age, height and ethnicity. Anthropometry was assessed by weight, height, mid-upper arm circumference (MUAC) and triceps skinfold (TSF). Arm muscle area (AMA) and Body Mass Index (BMI) were calculated. Lean mass (LM), fat mass (FM) and free-fat mass (FFM) were identified by DXA. The molecular analysis method by sequencing was used to identify and classify the participants regarding the presence of the F508del pathogenic variant of the CFTR gene. Statistical models of simple and multiple linear regression were created to establish the predictive power of Z-TBLH in the variables.

RESULTS: Average age of the participants was 13.31 ± 3.86 years, 59% of whom were male. They showed more LM (30.97 Kg ± 11.29) than females (23 Kg ± 6.73). 20 of 30 participants (66.7%) had at least copy of F508del. Among the multiple models, adjusted by height, age and sex, it found BMI (R2 = 0.367), Weight (R2 = 0.220), AMA (R2 = 0.338) as significant predictors of Z-TBLH. The final model composed of AMA, TSF and Age (p = 0.001; R2 = 0.381) had AMA and Age as significant predictors. AMA was associated with an increase in the BMD Z-score in the participants studied. 66.7% of genetically tested participants had the F508del pathogenic variant. The presence of the F508del variant was associated with worse nutritional status.

CONCLUSION: A statistical model composed of the values of AMA, TSF and Age can predict Z-TBLH, as well as anthropometric variables Weight, or BMI, or AMA associated with height, age and sex, in children and adolescents aged 5-20 years old, of both sexes. Anthropometric markers, as they are easy and relatively inexpensive to obtain, it is a promising alternative to the use of DXA in predicting BMD in these people with CF.

PMID:34620322 | DOI:10.1016/j.clnesp.2021.08.020

Ann Am Thorac Soc. 2021 Oct 7. doi: 10.1513/AnnalsATS.202103-250OC. Online ahead of print.

ABSTRACT

RATIONALE: Extracorporeal membrane oxygenation (ECMO) is increasingly used to bridge waitlisted children failing conventional respiratory support to lung transplantation.

OBJECTIVES: To compare in-hospital mortality and a composite outcome of 1-year mortality or re-transplantation in children bridged with ECMO with those on mechanical ventilation (MV), and neither support.

METHODS: The United Network for Organ Sharing (UNOS) was used to analyze lung transplant recipients, aged ≤ 20 y, from January 2004 to August 2019. Recipients were categorized according to level of respiratory support at time of transplant, including ECMO, MV, or neither. Multivariable analysis was used to evaluate support type and in-hospital mortality.

RESULTS: Of 1,014 children undergoing lung transplant, 68 (6.7%) required ECMO as a bridge-to-transplant, 144 (14.2%) MV, and 802 (79.1%) neither. Primary diagnosis in the ECMO cohort included cystic fibrosis (43%), pneumonia/ARDS (10.3%), interstitial pulmonary fibrosis (7.4%) and pulmonary hypertension (5.9%). Number of patients bridged with ECMO increased throughout the study period from none in 2004 to 16.7% in 2018. Multivariable analysis showed bridging with both ECMO (aOR = 3.57; 95% CI: 1.42, 8.97) and MV (aOR = 2.67; 95% CI: 1.26, 5.57) increased in-hospital mortality after lung transplantation. However, there was no difference in composite outcome of mortality and re-transplantation at 1-year between the three groups.

CONCLUSIONS: ECMO to bridge children to lung transplantation has increased. Despite this, ECMO is a high-risk bridge strategy for children awaiting lung transplantation. Future research should target interventions that can be focused on improving survival in these patients.

PMID:34619069 | DOI:10.1513/AnnalsATS.202103-250OC

Telemed J E Health. 2021 Oct 7. doi: 10.1089/tmj.2021.0228. Online ahead of print.

ABSTRACT

Objectives: This study aimed to monitor the health and nutritional status of pediatric cystic fibrosis (CF) patients via telehealth services during the novel coronavirus disease 2019 (COVID-19). Additional aims were to determine the level of anxiety in the patients and their caregivers and to determine the COVID-19 transmission status among CF patients. Materials and Methods: The CF team supported the patients via remote contact. During telehealth services interviews, in addition to obtaining information about the patients' anthropometric measurements, health status, and CF-related complaints, the State-Trait Anxiety Inventory (STAI) was administered to the patients and controls. The Hospital Anxiety and Depression Scale (HAD) was administered to their caregivers. Results: The study included 144 pediatric CF patients (74 males and 70 females). Mean age of the patients was 8.9 years. In all, 42 (29.2%) of the patients were tested for COVID-19, of which 4 were positive. The mean STAI score was significantly lower in the patient group than in the control group (p < 0.001). The mean HAD anxiety score was significantly higher in the caregivers of the CF patients, compared to the caregivers of the controls (p = 0.005). In addition, the mean HAD depression score was significantly higher in the caregivers of the CF patients (p < 0.001). Conclusions: Telehealth is an innovative method for providing health care services while maintaining social distance and avoiding the risk of exposure and spread of COVID-19. Telehealth services reduce patient and parental anxiety and increase the level of confidence in managing CF-related complications.

PMID:34619057 | DOI:10.1089/tmj.2021.0228

Cochrane Database Syst Rev. 2021 Oct 7;10:CD004447. doi: 10.1002/14651858.CD004447.pub3.

ABSTRACT

BACKGROUND: Conventional treatment of X-linked hypophosphatemia with oral phosphate and calcitriol can heal rickets, but it does not always raise serum phosphate concentrations significantly, nor does it always normalize linear growth. Some clinical trials suggest that combining recombinant human growth hormone therapy with conventional treatment improves growth velocity, phosphate retention, and bone mineral density, but some clinical trials suggest that it appears to aggravate the pre-existent disproportionate stature of such children. This is an updated version of a previously published review.

OBJECTIVES: To determine whether recombinant human growth hormone therapy for children with X-linked hypophosphatemia is associated with changes in longitudinal growth, mineral metabolism, endocrine function, renal function, bone mineral density, body proportions, and also with any adverse effects.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. In addition, we searched the Cochrane Central Register of Controlled Trials, Ovid MEDLINE and the reference lists of identified trials and other reviews. We also undertook some additional handsearching of relevant journals and conference proceedings. Date of the most recent search: 12 January 2021 SELECTION CRITERIA: All randomized controlled studies or quasi-randomized controlled studies comparing growth hormone (alone or combined with conventional treatment) with either placebo or conventional treatment alone in children with X-linked hypophosphatemia.

DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for risk of bias and extracted data from eligible studies. GRADE criteria were used to assess the certainty of the evidence for each outcome.

MAIN RESULTS: We included two studies (20 participants) in the review. In one cross-over study, results showed that recombinant human growth hormone therapy may improve the height standard deviation (SDS) score (z score), but we are unsure whether the intervention was the reason behind a transient increase in serum phosphate and tubular maximum for phosphate reabsorption. In the second, parallel study, treatment may also have improved the height SDS from baseline in the rhGH group compared to the control group, although no significant difference was seen between groups after three years, MD 0.50 SDS (95 % CI -0.54 to 1.54) (low-certainty evidence). The treatment was possibly well-tolerated during both studies with only transient adverse effects seen in three participants (low-certainty evidence). We are uncertain whether growth hormone improves serum phosphate levels or change in TmP/GFR (very low-certainty evidence). The treatment may make little or no difference to alkaline phosphatase levels (low-certainty evidence).

AUTHORS' CONCLUSIONS: We do not have enough high-certainty evidence to recommend the use of recombinant human growth hormone therapy in children with X-linked hypophosphatemia.

PMID:34618915 | DOI:10.1002/14651858.CD004447.pub3

European J Pediatr Surg Rep. 2021 Oct 1;9(1):e65-e67. doi: 10.1055/s-0041-1731274. eCollection 2021 Jan.

ABSTRACT

We report on an 11-year-old girl with cystic fibrosis who presented with thoracic pain and an extensive subcutaneous emphysema and subsequently developed progressive respiratory distress. The chest computed tomography revealed a huge pneumomediastinum. Due to the development of severe respiratory failure, urgent needle thoracocentesis was necessary that resulted in only temporary improvement. Therefore, under general anesthesia two mediastinal drains were introduced. Using active suction, the size of the pneumomediastinum decreased gradually and the drains were removed after 3 weeks. Here, we describe an extremely rare situation, when acute surgical intervention was necessary in a child with spontaneous pneumomediastinum.

PMID:34616649 | PMC:PMC8486495 | DOI:10.1055/s-0041-1731274

World J Gastrointest Oncol. 2021 Sep 15;13(9):1121-1131. doi: 10.4251/wjgo.v13.i9.1121.

ABSTRACT

Based on systematic review and meta-analysis, the risk for developing cancers in patients with cystic fibrosis (CF) is known to be significantly greater than in the general population, including site-specific cancers of the esophagus, small bowel, colon, liver, biliary tract, and pancreas. An even higher risk has been found in patients who have severe CF transmembrane conductance regulator (CFTR) genotypes or who have undergone organ transplantation and are immunosuppressed. The risk continues to rise as life expectancies steadily climb due to advancements in medical care and treatment for CF. The colorectal cancer risk is at such a high level that CF has now been declared a hereditary colon cancer syndrome by the Cystic Fibrosis Foundation. The CFTR gene has been strongly-associated with the development of gastrointestinal (GI) cancers and mortality in the CF population. Even CF carriers have shown an increased rate of GI cancers compared to the general population. Several limitations exist with the reported guidelines for screening of GI and hepatopancreatobiliary cancers in the CF population, which are largely universal and are still emerging. There is a need for more precise screening based on specific risk factors, including CFTR mutation, medical co-morbidities (such as gastroesophageal reflux disease, distal intestinal obstruction syndrome, and diabetes mellitus), familial risks for each cancer, gender, age, and other factors. In this review, we propose changes to the guidelines for GI screening of patients with CF. With the development of CFTR modulators, additional studies are necessary to elucidate if there is an effect on cancer risk.

PMID:34616517 | PMC:PMC8465437 | DOI:10.4251/wjgo.v13.i9.1121

Sci Rep. 2021 Oct 6;11(1):19810. doi: 10.1038/s41598-021-99184-1.

ABSTRACT

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which lead to early death due to progressive lung disease. The development of small-molecule modulators that directly interact with CFTR to aid in protein folding ("correctors") and/or increase channel function ("potentiators") have proven to be highly effective in the therapeutic treatment of CF. Notably, incorporation of the next-generation CFTR corrector, elexacaftor, into a triple combination therapeutic (marketed as Trikafta) has shown tremendous clinical promise in treating CF caused by F508del-CFTR. Here, we report on a newly-described role of elexacaftor as a CFTR potentiator. We explore the acute and chronic actions, pharmacology, and efficacy of elexacaftor as a CFTR potentiator in restoring function to multiple classes of CFTR mutations. We demonstrate that the potentiating action of elexacaftor exhibits multiplicative synergy with the established CFTR potentiator ivacaftor in rescuing multiple CFTR class defects, indicating that a new combination therapeutic of ivacaftor and elexacaftor could have broad impact on CF therapies.

PMID:34615919 | DOI:10.1038/s41598-021-99184-1

PLoS One. 2021 Oct 6;16(10):e0257838. doi: 10.1371/journal.pone.0257838. eCollection 2021.

ABSTRACT

RATIONALE: Chronic airway infection and inflammation resulting in progressive, obstructive lung disease is the leading cause of morbidity and mortality in cystic fibrosis. Understanding the lower airway microbiota across the ages can provide valuable insight and potential therapeutic targets.

OBJECTIVES: To characterize and compare the lower airway microbiota in cystic fibrosis and disease control subjects across the pediatric age spectrum.

METHODS: Bronchoalveolar lavage fluid samples from 191 subjects (63 with cystic fibrosis) aged 0 to 21 years were collected along with relevant clinical data. We measured total bacterial load using quantitative polymerase chain reaction and performed 16S rRNA gene sequencing to characterize bacterial communities with species-level sensitivity for select genera. Clinical comparisons were investigated.

MEASUREMENTS AND MAIN RESULTS: Cystic fibrosis samples had higher total bacterial load and lower microbial diversity, with a divergence from disease controls around 2-5 years of age, as well as higher neutrophilic inflammation relative to bacterial burden. Cystic fibrosis samples had increased abundance of traditional cystic fibrosis pathogens and decreased abundance of the Streptococcus mitis species group in older subjects. Interestingly, increased diversity in the heterogeneous disease controls was independent of diagnosis and indication. Sequencing was more sensitive than culture, and antibiotic exposure was more common in disease controls, which showed a negative relationship with load and neutrophilic inflammation.

CONCLUSIONS: Analysis of lower airway samples from people with cystic fibrosis and disease controls across the ages revealed key differences in airway microbiota and inflammation. The divergence in subjects during early childhood may represent a window of opportunity for intervention and additional study.

PMID:34613995 | DOI:10.1371/journal.pone.0257838

Am J Physiol Cell Physiol. 2021 Oct 6. doi: 10.1152/ajpcell.00234.2021. Online ahead of print.

ABSTRACT

Airway secretions contain many signalling molecules and peptides/proteins that are not found in airway surface liquid (ASL) generated by normal human bronchial epithelial cells (NHBE) in vitro. These play a key role in innate defence and mediate communication between the epithelium, immune cells and the external environment. We investigated how culture of NHBE with apically applied secretions from healthy or disease (Cystic Fibrosis, CF) lungs affected epithelial function with a view to providing better in vitro models of the in vivo environment. NHBE from 6-8 different donors were cultured at air-liquid interface (ALI), with apically applied sputum from normal healthy donors (NLS) or CF donors (CFS) for 2-4 hours, 48 hours or with sputum reapplied over 48 hours. Proteomic analysis was carried out on the sputa and on NHBE ASL before and after culture with sputa. Transepithelial electrical resistance (TEER), short circuit current (Isc) and changes to ASL height were measured. There were 71 proteins common to both sputa but not ASL. The protease:protease inhibitor balance was increased in CFS compared to NLS and ASL. Culture of NHBE with sputa for 48 hours identified additional factors not present in NLS, CFS or ASL alone. Culture with either NLS or CFS for 48 hours increased CFTR activity, calcium activated chloride channel (CaCC) activity and changed ASL height. These data indicate that culture with healthy or disease sputum changes the proteomic profile of ASL and ion transport properties of NHBE and this may increase physiological relevance when using in vitro airway models.

PMID:34613844 | DOI:10.1152/ajpcell.00234.2021

Respir Care. 2021 Oct 5:respcare.09197. doi: 10.4187/respcare.09197. Online ahead of print.

ABSTRACT

BACKGROUND: Although guidelines for inhaled therapies for individuals with cystic fibrosis (CF) are available, recommendations for compressors/nebulizers to optimize care are lacking. The CF Foundation (CFF) convened a multidisciplinary task force to assess the use, durability, accessibility, and cost burden of compressors/nebulizers.

METHODS: Online surveys were developed and distributed to 287 CFF programs and adults with CF and parents of children with CF (adults with CF/parents).

RESULTS: Health care providers from 38 states completed the survey (59% response rate). Respiratory therapists were mostly responsible to coordinate ordering nebulizers and compressors. Durable medical equipment companies were the most common source of acquisition of compressors (71.8%) and nebulizers (45.9%). A majority of health care providers did not feel the compressors were durable (51.1%) or that they could get enough nebulizers to their patients (69.2%). Barriers to procure compressors were reported. The survey was completed by 734 adults with CF/parents from 48 states. Most adults with CF/parents rated their compressor as durable (65.8%); however, 85.5% of respondents reported some user-experience problem(s). "Hoses popping off" and "increased nebulization time" were most commonly reported. Almost 20% of respondents did not have access to a compressor at some point in the previous year. Most adults with CF/parents did not change compressor filters per manufacturer's recommendation (40% never). Adults with CF/parents reported performing a median of 4 inhaled treatments per day. Median use of nebulizers was 6 months. Most adults with CF/parents thought they had enough nebulizers (53.7%). Individuals with CF doing more inhaled treatments reported more compressor malfunctions. The median out-of-pocket expense was $75-99 and $50-74 for compressors and nebulizers, respectively.

CONCLUSIONS: Although the perceptions of health care providers and adults with CF/parents differed to a certain extent, the surveys uncovered several significant issues that may compromise quality of care. Improvement in access to devices and education are needed.

PMID:34610985 | DOI:10.4187/respcare.09197

Hosp Pediatr. 2021 Oct 5:hpeds.2020-004788. doi: 10.1542/hpeds.2020-004788. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Extensive literature supports using dexamethasone (DEX) in children presenting to the emergency department (ED) with mild-to-moderate asthma exacerbations; however, only limited studies have assessed this in hospitalized children. In this study, we evaluate the outcomes of DEX versus prednisone/prednisolone (PRED) use in children hospitalized for mild-to-moderate asthma exacerbations.

METHODS: This multisite retrospective cohort study included children between 3 and 21 years of age hospitalized to a tertiary care children's hospital system between January 1, 2013, and December 31, 2017, with a primary discharge diagnosis of acute asthma exacerbation or status asthmaticus. Primary study outcome was mean hospital length of stay (LOS). Secondary outcomes included PICU transfers during initial hospitalization and ED revisits and hospital readmissions within 10 days after discharge. Generalized linear models were used to model logged LOS as a function of steroid and demographic and clinical covariates. The analysis was stratified by initial steroid timing.

RESULTS: Of the 1410 children included, 981 received only DEX and 429 received only PRED. For children who started oral steroids after hospital arrival, DEX cohort had a significantly shorter adjusted mean hospital LOS (DEX 24.43 hours versus PRED 29.38 hours; P = .03). For children who started oral steroids before hospital arrival, LOS did not significantly differ (DEX 26.72 hours versus PRED 25.20 hours; P = .45). Rates of PICU transfers, ED revisits, and hospital readmissions were uncommon events.

CONCLUSION: Children hospitalized with mild-to-moderate asthma exacerbations have significantly shorter hospital LOS when starting DEX rather than PRED on admission.

PMID:34610967 | DOI:10.1542/hpeds.2020-004788

J Cyst Fibros. 2021 Oct 2:S1569-1993(21)01418-1. doi: 10.1016/j.jcf.2021.09.013. Online ahead of print.

ABSTRACT

INTRODUCTION: Pseudo-Bartter syndrome (PBS) is a rare manifestation of Cystic fibrosis (CF) and can often be the initial presentation in these patients, however, due to significantly overlapping symptoms it is often misdiagnosed as simple dehydration or Bartter syndrome. The objective of our study was to highlight the key features of PBS and electrolyte imbalance in CF patients helping in early and prompt diagnosis.

METHOD: We performed a retrospective study from January 2015 to December 2019 at the Aga Khan University Hospital (AKUH), Pakistan. CF patients aged from 1-18 years, admitted at AKUH were enrolled and their laboratory data and individual charts were reviewed. Patients were categorized into three groups based on their serum electrolyte profile and their clinical findings were compared.

RESULT: We enrolled 72 CF patients, out of which 42 (58%) were categorized into the Normal Electrolyte (NE) group, 19 (26%) into the Electrolyte Imbalance (EI) group and 11 (15%) in the PBS group. Out of 11 cases, 6 (54.54%) patients in PBS group presented with features consistent with PBS leading to CF diagnosis labeled as "early presenters". Mean age of patients in the PBS group was 3.81± 0.86 years and their age at diagnosis were significantly lower as compared to other groups. Gastrointestinal disturbances including diarrhea, vomiting and constipation were more common in the EI and PBS groups. Polyuria was most common in the PBS (72%) group. Length of hospital stay showed no significant difference.

CONCLUSION: Pseudo-Bartter syndrome can be a presenting feature of cystic fibrosis. Electrolyte imbalance should be anticipated in hospitalized CF children and adolescent.

PMID:34610890 | DOI:10.1016/j.jcf.2021.09.013

Cell Rep. 2021 Oct 5;37(1):109795. doi: 10.1016/j.celrep.2021.109795.

ABSTRACT

A controversial hypothesis pertaining to cystic fibrosis (CF) lung disease is that the CF transmembrane conductance regulator (CFTR) channel fails to inhibit the epithelial Na+ channel (ENaC), yielding increased Na+ reabsorption and airway dehydration. We use a non-invasive self-referencing Na+-selective microelectrode technique to measure Na+ transport across individual folds of distal airway surface epithelium preparations from CFTR-/- (CF) and wild-type (WT) swine. We show that, under unstimulated control conditions, WT and CF epithelia exhibit similar, low rates of Na+ transport that are unaffected by the ENaC blocker amiloride. However, in the presence of the cyclic AMP (cAMP)-elevating agents forskolin+IBMX (isobutylmethylxanthine), folds of WT tissues secrete large amounts of Na+, while CFTR-/- tissues absorb small, but potentially important, amounts of Na+. In cAMP-stimulated conditions, amiloride inhibits Na+ absorption in CFTR-/- tissues but does not affect secretion in WT tissues. Our results are consistent with the hypothesis that ENaC-mediated Na+ absorption may contribute to dehydration of CF distal airways.

PMID:34610318 | DOI:10.1016/j.celrep.2021.109795

Elife. 2021 Oct 5;10:e71310. doi: 10.7554/eLife.71310. Online ahead of print.

ABSTRACT

Expansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic mouse knockouts of b-catenin, one with b-catenin loss is hepatocytes and BECs (KO1), and another with loss in only hepatocytes (KO2), we demonstrate disparate long-term repair after an initial injury by 2-week choline-deficient ethionine-supplemented diet. KO2 show gradual liver repopulation with BEC-derived b-catenin-positive hepatocytes, and resolution of injury. KO1 showed persistent loss of b-catenin, NF-kB activation in BECs, progressive DR and fibrosis, reminiscent of CF histology. We identify interactions of b-catenin, NFkB and CF transmembranous conductance regulator (CFTR) in BECs. Loss of CFTR or b-catenin led to NF-kB activation, DR and inflammation. Thus, we report a novel b-catenin-NFkB-CFTR interactome in BECs, and its disruption may contribute to hepatic pathology of CF.

PMID:34609282 | DOI:10.7554/eLife.71310

Biochem J. 2021 Oct 4:BCJ20210252. doi: 10.1042/BCJ20210252. Online ahead of print.

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) gene lies within a TAD in which multiple cis-regulatory elements (CREs) and transcription factors (TFs) regulate its cell-specific expression. The CREs are recruited to the gene promoter by a looping mechanism that depends upon both architectural proteins and specific TFs. An siRNA screen to identify TFs coordinating CFTR expression in airway epithelial cells suggested an activating role for BTB Domain and CNC Homolog 1 (BACH1). BACH1 is a ubiquitous master regulator of the cellular response to oxidative stress. Here we show that BACH1 may have a dual effect on CFTR expression by direct occupancy of CREs at physiological oxygen (~8%), while indirectly modulating expression under conditions of oxidative stress. Hence BACH1, can activate or repress the same gene, to fine tune expression in response to environmental cues such as cell stress. Furthermore, our 4C-seq data suggest that BACH1 can also directly regulate CFTR gene expression by modulating locus architecture through occupancy at known enhancers and structural elements, and depletion of BACH1 alters the higher order chromatin structure.

PMID:34605540 | DOI:10.1042/BCJ20210252

Int J Clin Pharmacol Ther. 2021 Oct 4. doi: 10.5414/CP204073. Online ahead of print.

ABSTRACT

Tigecycline is a tetracycline-class antibacterial indicated for the treatment of complicated skin and skin-structure infections, complicated intra-abdominal infections, and community-acquired bacterial pneumonia. It has a broad-spectrum antibacterial activity. It has identified gastrointestinal side-effects, particularly nausea and vomiting. With the increasing clinical use of tigecycline, its associated acute pancreatitis has been frequently reported in adults. However, cases of tigecycline-induced acute pancreatitis have rarely been described in children. In this study, we report a case of acute pancreatitis caused by the use of tigecycline in a child with pulmonary cystic fibrosis. In this case, abdominal pain, nausea, and vomiting occurred on the 5th day after the use of tigecycline. Elevated pancreatic enzymes occurred, and abdominal computed tomography findings were compatible with pancreatitis. After 2 weeks of discontinuation of tigecycline, the pancreatic enzyme level decreased to normal, and the symptoms of abdominal pain, nausea, and vomiting disappeared completely. In conclusion, we hope to improve the clinical awareness of children with tigecycline-associated pancreatitis, so as to reduce the probability of adverse reactions through the analysis of this case.

PMID:34605395 | DOI:10.5414/CP204073

J Biomater Sci Polym Ed. 2021 Oct 3:1-23. doi: 10.1080/09205063.2021.1982159. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is the most common pathogen that causes chronic lung infections and recurrence of the disease in cystic fibrosis patients by hiding inside cells and biofilm matrix. Herein, we developed gentamicin and curcumin-loaded lipid-polymer hybrid nanoparticle- (termed CG-HNPs) to evaluate in vitro activities against biofilm-embedded P. aeruginosa and compared with lipid nanoparticles containing the same drugs (CG-Lip). The nanoparticles were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic light scattering (DLS), fluorescence spectroscopy, and ultraviolet-visible (UV-vis) spectroscopy, which demonstrated that HNPs with a diameter of approximately 340 nm were uniform. The optimal CG-HNPs formulation illustrated high encapsulation (∼70%) and controlled release characteristics (gradually released in 72 h). The antibacterial activities of generated nanoparticles are maintained against planktonic and biofilm bacteria and it is effective in damage established biofilms. Besides, HNPs were biocompatible and nontoxic to J774 and HFF cell lines and uptake by the macrophages (J774), which facilitated the killing of intracellular bacteria in macrophages. These results introduced CG-HNPs as a promising antibacterial agent for the treatment of chronic infections and intracellular bacteria due to excellent antibacterial activity.

PMID:34605363 | DOI:10.1080/09205063.2021.1982159

JAMIA Open. 2021 Sep 29;4(3):ooab084. doi: 10.1093/jamiaopen/ooab084. eCollection 2021 Jul.

ABSTRACT

OBJECTIVES: Patient-generated health data (PGHD) are important for tracking and monitoring out of clinic health events and supporting shared clinical decisions. Unstructured text as PGHD (eg, medical diary notes and transcriptions) may encapsulate rich information through narratives which can be critical to better understand a patient's condition. We propose a natural language processing (NLP) supported data synthesis pipeline for unstructured PGHD, focusing on children with special healthcare needs (CSHCN), and demonstrate it with a case study on cystic fibrosis (CF).

MATERIALS AND METHODS: The proposed unstructured data synthesis and information extraction pipeline extract a broad range of health information by combining rule-based approaches with pretrained deep-learning models. Particularly, we build upon the scispaCy biomedical model suite, leveraging its named entity recognition capabilities to identify and link clinically relevant entities to established ontologies such as Systematized Nomenclature of Medicine (SNOMED) and RXNORM. We then use scispaCy's syntax (grammar) parsing tools to retrieve phrases associated with the entities in medication, dose, therapies, symptoms, bowel movements, and nutrition ontological categories. The pipeline is illustrated and tested with simulated CF patient notes.

RESULTS: The proposed hybrid deep-learning rule-based approach can operate over a variety of natural language note types and allow customization for a given patient or cohort. Viable information was successfully extracted from simulated CF notes. This hybrid pipeline is robust to misspellings and varied word representations and can be tailored to accommodate the needs of a specific patient, cohort, or clinician.

DISCUSSION: The NLP pipeline can extract predefined or ontology-based entities from free-text PGHD, aiming to facilitate remote care and improve chronic disease management. Our implementation makes use of open source models, allowing for this solution to be easily replicated and integrated in different health systems. Outside of the clinic, the use of the NLP pipeline may increase the amount of clinical data recorded by families of CSHCN and ease the process to identify health events from the notes. Similarly, care coordinators, nurses and clinicians would be able to track adherence with medications, identify symptoms, and effectively intervene to improve clinical care. Furthermore, visualization tools can be applied to digest the structured data produced by the pipeline in support of the decision-making process for a patient, caregiver, or provider.

CONCLUSION: Our study demonstrated that an NLP pipeline can be used to create an automated analysis and reporting mechanism for unstructured PGHD. Further studies are suggested with real-world data to assess pipeline performance and further implications.

PMID:34604710 | PMC:PMC8480545 | DOI:10.1093/jamiaopen/ooab084

Front Mol Biosci. 2021 Sep 15;8:698358. doi: 10.3389/fmolb.2021.698358. eCollection 2021.

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have transformed the treatment of cystic fibrosis (CF) by targeting the basis of the disease. In particular, treatment regimen consisting of multiple compounds with complementary mechanisms of action have been shown to result in optimal efficacy. Here, we assessed the efficacy of combinations of the CFTR modulators ABBV/GLPG-2222, GLPG/ABBV-2737 and ABBV/GLPG-2451, and compared it to VX-770/VX-809 in 28 organoid lines heterozygous for F508del allele and a class I mutation and seven homozygous F508del organoid lines. The combination ABBV/GLPG-2222/ABBV-2737/ABBV/GLPG-2451 showed increased efficacy over VX-770/VX-809 for most organoids, despite considerable variation in efficacy between the different organoid cultures. These differences in CFTR restoration between organoids with comparable genotypes underline the relevance of continuing to optimize the ABBV/GLPG-Triple therapy, as well as the in vitro characterization of efficacy in clinically relevant models.

PMID:34604301 | PMC:PMC8479794 | DOI:10.3389/fmolb.2021.698358