Front Endocrinol (Lausanne). 2022 Sep 27;13:953879. doi: 10.3389/fendo.2022.953879. eCollection 2022.

ABSTRACT

OBJECTIVE: Studies investigating strategies to limit the risk of nocturnal hypoglycemia associated with physical activity (PA) are scarce and have been conducted in standardized, controlled conditions in people with type 1 diabetes (T1D). This study sought to investigate the effect of daily PA level on nocturnal glucose management in free-living conditions while taking into consideration reported mitigation strategies to limit the risk of nocturnal hyoglycemia in people with T1D.

METHODS: Data from 25 adults (10 males, 15 females, HbA1c: 7.6 ± 0.8%), 20-60 years old, living with T1D, were collected. One week of continuous glucose monitoring and PA (assessed using an accelerometer) were collected in free-living conditions. Nocturnal glucose values (midnight-6:00 am) following an active day "ACT" and a less active day "L-ACT" were analyzed to assess the time spent within the different glycemic target zones (<3.9 mmol/L; 3.9 - 10.0 mmol/L and >10.0 mmol/L) between conditions. Self-reported data about mitigation strategies applied to reduce the risk of nocturnal hypoglycemia was also analyzed.

RESULTS: Only 44% of participants reported applying a carbohydrate- or insulin-based strategy to limit the risk of nocturnal hypoglycemia on ACT day. Nocturnal hypoglycemia occurrences were comparable on ACT night versus on L-ACT night. Additional post-meal carbohydrate intake was higher on evenings following ACT (27.7 ± 15.6 g, ACT vs. 19.5 ± 11.0 g, L-ACT; P=0.045), but was frequently associated with an insulin bolus (70% of participants). Nocturnal hypoglycemia the night following ACT occurred mostly in people who administrated an additional insulin bolus before midnight (3 out of 5 participants with nocturnal hypoglycemia).

CONCLUSIONS: Although people with T1D seem to be aware of the increased risk of nocturnal hypoglycemia associated with PA, the risk associated with additional insulin boluses may not be as clear. Most participants did not report using compensation strategies to reduce the risk of PA related late-onset hypoglycemia which may be because they did not consider habitual PA as something requiring treatment adjustments.

PMID:36237197 | PMC:PMC9551602 | DOI:10.3389/fendo.2022.953879

Pediatr Pulmonol. 2022 Oct 13. doi: 10.1002/ppul.26209. Online ahead of print.

ABSTRACT

BACKGROUND: Newborn screening (NBS) algorithms for cystic fibrosis (CF) vary in the USA and include different CFTR variants. CFTR variant distribution varies among racial and ethnic groups.

OBJECTIVE: Our objectives were to identify differences in detection rate by race and ethnicity for CFTR variant panels, identify each U.S. state detection rate for CFTR variant panels, and describe the rate of false-negative NBS and delayed diagnoses by race and ethnicity.

METHODS: This is a cross-sectional analysis of the detection rate of at least 1 CFTR variant for 7 panels by race and ethnicity in genotyped people with CF (PwCF) or CRMS/CFTR-related disorders in CF Foundation Patient Registry (CFFPR) in 2020. We estimated the case detection rate of CFTR variant panels by applying the detection rate to Census data. Using data from CFFPR, we compared the rate of delayed diagnosis or false-negative NBS by race and ethnicity.

RESULTS: For all panels, detection of at least 1 CFTR variant was highest in non-Hispanic White PwCF (87.5-97.0%), and lowest in Black, Asian, and Hispanic PwCF (41.9-93.1%). Detection of at least 1 CFTR variant was lowest in Black and Asian people with CRMS/CFTR-related disorders (48.4-64.8%). States with increased racial and ethnic diversity have lower detection rates for all panels. Overall, 3.8% PwCF had a false-negative NBS and 11.8% had a delayed diagnosis; Black, Hispanic, and mixed-race PwCF were over-represented.

CONCLUSION: CFTR variant panels have lower detection rates in minoritized racial and ethnic groups leading to false-negative NBS, delayed diagnosis, and likely health disparities. This article is protected by copyright. All rights reserved.

PMID:36237137 | DOI:10.1002/ppul.26209

Int J Mol Sci. 2022 Sep 29;23(19):11528. doi: 10.3390/ijms231911528.

ABSTRACT

A small library of new angelicin derivatives was designed and synthesized with the aim of bypassing the side effects of trimethylangelicin (TMA), a promising agent for the treatment of cystic fibrosis. To prevent photoreactions with DNA, hindered substituents were inserted at the 4 and/or 6 positions. Unlike the parent TMA, none of the new derivatives exhibited significant cytotoxicity or mutagenic effects. Among the synthesized compounds, the 4-phenylderivative 12 and the 6-phenylderivative 25 exerted a promising F508del CFTR rescue ability. On these compounds, preliminary in vivo pharmacokinetic (PK) studies were carried out, evidencing a favorable PK profile per se or after incorporation into lipid formulations. Therefore, the selected compounds are good candidates for future extensive investigation to evaluate and develop novel CFTR correctors based on the angelicin structure.

PMID:36232826 | DOI:10.3390/ijms231911528

Int J Mol Sci. 2022 Sep 28;23(19):11443. doi: 10.3390/ijms231911443.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic, and ultimately fatal diffuse parenchymal lung disease. The molecular mechanisms of fibrosis in IPF patients are not fully understood and there is a lack of effective treatments. For decades, different types of drugs such as immunosuppressants and antioxidants have been tested, usually with unsuccessful results. Although two antifibrotic drugs (Nintedanib and Pirfenidone) are approved and used for the treatment of IPF, side effects are common, and they only slow down disease progression without improving patients' survival. Macrophages are central to lung homeostasis, wound healing, and injury. Depending on the stimulus in the microenvironment, macrophages may contribute to fibrosis, but also, they may play a role in the amelioration of fibrosis. In this review, we explore the role of macrophages in IPF in relation to the fibrotic processes, epithelial-mesenchymal transition (EMT), and their crosstalk with resident and recruited cells and we emphasized the importance of macrophages in finding new treatments.

PMID:36232756 | DOI:10.3390/ijms231911443

Int J Mol Sci. 2022 Sep 27;23(19):11396. doi: 10.3390/ijms231911396.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a plasma membrane protein expressed on the apical surface of secretory epithelia of the airways. In the airways, defective or absent function of the CFTR protein determines abnormalities of chloride and bicarbonate secretion and, in general, of the transepithelial homeostasis that lead to alterations of airway surface liquid (ASL) composition and properties. The reduction of ASL volume impairs ciliary beating with the consequent accumulation of a sticky mucus. This situation prevents normal mucociliary clearance, favoring the survival and proliferation of bacteria and contributing to the genesis of the CF pulmonary disease. We explored the potential of some CFTR modulators, namely ivacaftor, tezacaftor, elexacaftor and their combination KaftrioTM, capable of partially recovering the basic defects of the CFTR protein, to ameliorate the transepithelial fluid transport and the viscoelastic properties of the mucus when used singly or in combination. Primary human bronchial epithelial cells obtained from CF and non-CF patients were differentiated into a mucociliated epithelia in order to assess the effects of correctors tezacaftor, elexacaftor and their combination with potentiator ivacaftor on the key properties of ASL, such as fluid reabsorption, viscosity, protein content and pH. The treatment of airway epithelia bearing the deletion of a phenylalanine at position 508 (F508del) in the CFTR gene with tezacaftor and elexacaftor significantly improved the pericilial fluid composition, reducing the fluid reabsorption, correcting the ASL pH and reducing the viscosity of the mucus. KaftrioTM was more effective than single modulators in improving all the evaluated parameters, demonstrating once more that this combination recently approved for patients 6 years and older with cystic fibrosis who have at least one F508del mutation in the CFTR gene represents a valuable tool to defeat CF.

PMID:36232697 | DOI:10.3390/ijms231911396

Eur Respir J. 2022 Oct 13:2200611. doi: 10.1183/13993003.00611-2022. Online ahead of print.

ABSTRACT

INTRODUCTION: Identifying risk factors for poor outcomes can help with risk stratification and targeting of treatment. Risk factors for mortality and exacerbations have been identified in bronchiectasis but have been almost exclusively studied in European and North American populations. This study investigated the risk factors for poor outcome in a large population of bronchiectasis patients enrolled in India.

METHODS: The EMBARC-India registry is a prospective observational study of adults with CT confirmed bronchiectasis enrolled at 31 sites across India. Baseline characteristics of patients were used to investigate associations with key clinical outcomes: Mortality, severe exacerbations requiring hospital admission, overall exacerbation frequency and FEV1 decline.

RESULTS: 1018 patients with at least 12 months follow-up data were enrolled in the follow-up study. Frequent exacerbations (3 or more per year) at baseline were associated with an increased risk of mortality (hazard ratio(HR) 3.23 95%CI 1.39-7.50), severe exacerbations (HR 2.71 95%CI 1.92-3.83), future exacerbations (rate ratio(RR) 3.08 95%CI 2.36-4.01) and lung function decline. Co-existing COPD, dyspnoea and current cigarette smoking were similarly associated with a worse outcome across all endpoints studied. Additional predictors of mortality and severe exacerbations were increasing age and cardiovascular co-morbidity. Infection with Gram-negative pathogens (predominantly Klebsiella pneumoniae) was independently associated with increased mortality (HR 3.13 95%CI 1.62-6.06), while Pseudomonas aeruginosa infection was associated with severe exacerbations (HR 1.41 95%CI 1.01-1.97) and overall exacerbation rate (RR 1.47 95%CI 1.13-1.91).

CONCLUSION: This study identifies risk factors for morbidity and mortality among bronchiectasis patients in India. Identification of these risk factors may support treatment approaches optimised to an Asian setting.

FUNDING: EU/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative inhaled Antibiotics in Bronchiectasis and Cystic Fibrosis Consortium, European Respiratory Society, and Asthma and Lung UK.

PMID:36229049 | DOI:10.1183/13993003.00611-2022

Eur Respir J. 2022 Oct 13:2200606. doi: 10.1183/13993003.00606-2022. Online ahead of print.

ABSTRACT

BACKGROUND: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) working group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies.

METHODS: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult, and paediatric clinicians, pharmaceutical representatives and health regulators from across Europe. Evidence included a systematic review of development, validity, and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria.

RESULTS: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire, and Asthma Control Test (ACT) or Childhood-ACT while the adult COM includes the Severe Asthma Questionnaire and the Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately).

CONCLUSIONS: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.

PMID:36229046 | DOI:10.1183/13993003.00606-2022

Adv Drug Deliv Rev. 2022 Oct 10:114540. doi: 10.1016/j.addr.2022.114540. Online ahead of print.

ABSTRACT

Mucin glycoproteins are the major component of mucus and coat epithelial cell surfaces forming the glycocalyx. The glycocalyx and mucus are involved in the transport of nutrients, drugs, gases, and pathogens toward the cell surface. Mucins are also involved in diverse diseases such as cystic fibrosis and cancer. Due to inherent heterogeneity in native mucin structure, many synthetic materials have been designed to probe mucin chemistry, biology, and physics. Such materials include various glycopolymers, low molecular weight glycopeptides, glycopolypeptides, polysaccharides, and polysaccharide-protein conjugates. This review highlights advances in the area of design and synthesis of mucin mimic materials, and their biomedical applications in glycan binding, epithelial models of infection, therapeutic delivery, vaccine formulation, and beyond.

PMID:36228896 | DOI:10.1016/j.addr.2022.114540

JMIR Res Protoc. 2022 Jun 16. doi: 10.2196/39080. Online ahead of print.

ABSTRACT

BACKGROUND: The COVID-19 pandemic is negatively impacting the mental health of both COVID-19 patients and the general population. As current guidelines are limiting in-person contacts to reduce the spread of the virus, the development of a digital approach to implement in psychiatric and psychological consultation is needed. In this paper we present the DigiCOVID protocol, a digital approach to offer remote, personalized psychological and psychiatric support to former or current COVID-19 patients and/or their relatives.

OBJECTIVE: The main goal of this project is to evaluate the feasibility, acceptability and usability of the DigiCOVID protocol. Furthermore, we also aim to assess the impact of the abovementioned protocol by means of pre-post changes in psychological clinical variables.

METHODS: Participants undergo an initial telephonic screening to ensure inclusion criteria are met. Secondly, participants complete a video-assisted neuropsychological IQ test, and complete online self-reports of health and general wellbeing. Participants are then assigned to a psychotherapist who offers 8 tele-therapy sessions. At the end of the therapy cycle, the online questionnaires are administered for a post-treatment evaluation.

RESULTS: As of April 2022, we enrolled a total of 122 subjects, of which 94 have completed neuropsychological tests and online questionnaires.

CONCLUSIONS: Our study aims at testing the feasibility and preliminary efficacy of DigiCOVID, a remote tele-medicine protocol for the improvement of psychological and psychiatric health in COVID-19 patients and their relatives. To date, the approach used seems to be feasible and highly customizable to patients' needs, and thus the DigiCOVID protocol might pave the way for future tele-psychiatry-based interventions.

CLINICALTRIAL: This study was approved by our local Ethics Committee (IRCCS Ca' Granda Ospedale Maggiore Policlinico) on 28.10.2020. The trial is registered on clinicaltrials.gov with the following ID: NCT05231018.

INTERNATIONAL REGISTERED REPORT: DERR1-10.2196/39080.

PMID:36228130 | DOI:10.2196/39080

J Antimicrob Chemother. 2022 Oct 13:dkac320. doi: 10.1093/jac/dkac320. Online ahead of print.

ABSTRACT

BACKGROUND: Pseudomonas aeruginosa infection is the leading cause of death among patients with cystic fibrosis (CF) and a common cause of difficult-to-treat hospital-acquired infections. P. aeruginosa uses several mechanisms to resist different antibiotic classes and an individual CF patient can harbour multiple resistance phenotypes.

OBJECTIVES: To determine the rates and distribution of polyclonal heteroresistance (PHR) in P. aeruginosa by random, prospective evaluation of respiratory cultures from CF patients at a large referral centre over a 1 year period.

METHODS: We obtained 28 unique sputum samples from 19 CF patients and took multiple isolates from each, even when morphologically similar, yielding 280 unique isolates. We performed antimicrobial susceptibility testing (AST) on all isolates and calculated PHR on the basis of variability in AST in a given sample. We then performed whole-genome sequencing on 134 isolates and used a machine-learning association model to interrogate phenotypic PHR from genomic data.

RESULTS: PHR was identified in most sampled patients (n = 15/19; 79%). Importantly, resistant phenotypes were not detected by routine AST in 26% of patients (n = 5/19). The machine-learning model, using the extended sampling, identified at least one genetic variant associated with phenotypic resistance in 94.3% of isolates (n = 1392/1476).

CONCLUSION: PHR is common among P. aeruginosa in the CF lung. While traditional microbiological methods often fail to detect resistant subpopulations, extended sampling of isolates and conventional AST identified PHR in most patients. A machine-learning tool successfully identified at least one resistance variant in almost all resistant isolates by leveraging this extended sampling and conventional AST.

PMID:36227655 | DOI:10.1093/jac/dkac320

Lab Med. 2022 Oct 11:lmac101. doi: 10.1093/labmed/lmac101. Online ahead of print.

ABSTRACT

A burdensome, atypical phenotype of Staphylococcus aureus (SA) called S aureus small colony variant (SA-SCV) has been identified, which is induced as a result of a combination of environmental stressors, including polymicrobial interactions. The SA-SCVs exhibit altered phenotypes as a result of metabolic dormancy caused by electron transport deficiency, leading to increased biofilm production and alterations to antimicrobial susceptibility. The SA-SCVs typically exhibit altered colony morphology and biochemical reactions compared with wild-type SA, making them difficult to detect via routine diagnostics. The SA-SCVs have been found to contribute to chronic or recurrent infections, including skin and soft-tissue infections, foreign-body associated infection, cystic fibrosis, and sepsis. There is evidence that SA-SCVs contribute to patient morbidity and mortality as a result of diagnostic difficulties and limited treatment options. New detection methods may need to be developed that can be incorporated into routine diagnostics, which would allow for better assessment of specimens and introduce new considerations for treatment.

PMID:36226897 | DOI:10.1093/labmed/lmac101

Clin Chem. 2022 Oct 13:hvac150. doi: 10.1093/clinchem/hvac150. Online ahead of print.

NO ABSTRACT

PMID:36226752 | DOI:10.1093/clinchem/hvac150

Cardiol Young. 2022 Oct 13:1-6. doi: 10.1017/S1047951122003249. Online ahead of print.

ABSTRACT

BACKGROUND: This study aimed to assess the ventricular anatomy, function of the right ventricle, and the haemodynamic findings of pulmonary artery in children with cystic fibrosis using cardiac MRI.

PATIENTS: This prospective study consisted of 32 children with mild cystic fibrosis and 30 age-matched healthy control participants.

METHODS: Cardiac MRI was used to assess right ventricular volumes, anatomy, and function and to assessment of haemodynamic findings of pulmonary artery in the control and study groups. Haemodynamic findings of pulmonary arteries were determined using pulmonary arteries peak velocity (cm/s), and pulmonary arteries time-to-peak velocity (ms) and pulmonary artery systolic pressure. All data of children with mild cystic fibrosis were compared with those of 30 age-matched healthy control group participants.

RESULTS: Our patients and their age-matched controls were aged from 6 to 17 years and from 7 to 15 years, respectively. We found that ejection fraction (%), cardiac output (L/ml), cardiac output (L/ml/m2), and systolic volume (ml/m2) were significantly lower in children with cystic fibrosis (p < 0.01). Right ventricular anterior wall thickness (mm) was significantly higher in children with cystic fibrosis (p = 0.01). No significant difference was observed between the haemodynamic parameters of pulmonary artery in the patient group.

CONCLUSION: In our study, cardiac MRI was used to investigate whether the right ventricle was affected functionally and anatomically in children with mild cystic fibrosis. We detected a significant decrease in right ventricular systolic functions and notable alterations in the right ventricular geometry of children with mild cystic fibrosis. These alterations usually manifest themselves as hypertrophy of the right ventricle. Our study's results demonstrate no relationship between the development of pulmonary hypertension in mild cystic fibrosis children.

PMID:36226672 | DOI:10.1017/S1047951122003249

Bosn J Basic Med Sci. 2022 Oct 12. doi: 10.17305/bjbms.2022.8034. Online ahead of print.

ABSTRACT

Cigarette smoke (CS) is the leading cause of chronic obstructive pulmonary disease (COPD), which is characterized by chronic bronchial inflammation and emphysema. Growing evidence supports the hypothesis that dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is critically involved in the pathogenesis of CS-mediated COPD. However, the underlying mechanism remains unclear. Here, we report that supressed CFTR expression is strongly associated with abnormal phospholipid metabolism and increased pulmonary inflammation. In a CS-exposed mouse model with COPD-like symptoms, we found that pulmonary expression of sphingosine kinase 2 (SphK2) and sphingosine-1-phosphate (S1P) secretion were significantly upregulated. Therefore, we constructed a SphK2 gene knockout (SphK2-/-) mouse. After CS exposure for six months, histological lung section staining showed disorganized alveolar structure, increased pulmonary fibrosis, and emphysema-like symptoms in wild-type (WT) mice, which were less pronounced in SphK2-/- mice. Further, SphK2 deficiency also decreased CS-induced pulmonary inflammation, which was reflected by a remarkable reduction in pulmonary infiltration of CD45+CD11b+ neutrophils subpopulation and low levels of IL-6 and IL-33 in bronchial alveolar lavage fluid. However, treatment with S1P receptor agonist suppressed CFTR expression and increased Nf-κB-p65 expression and its nuclear translocation in CS-exposed SphK2-/-mice, which also aggravated small airways fibrosis and pulmonary inflammation. In contrast, inhibition of S1P signaling with the S1P receptor analogue FTY720 rescued CFTR expression, suppressed Nf-κB-p65 expression and nuclear translocation, and alleviated pulmonary fibrosis and inflammation after CS exposure. Our results demonstrate that SphK2-mediated S1P production plays a crucial role in the pathogenesis of CS-induced COPD-like disease by impairing CFTR activity and promoting pulmonary inflammation and fibrosis.

PMID:36226596 | DOI:10.17305/bjbms.2022.8034

Indian Dermatol Online J. 2022 May 5;13(3):380-383. doi: 10.4103/idoj.idoj_657_21. eCollection 2022 May-Jun.

ABSTRACT

Aquagenic wrinkling of the palms (AWoP) is a rare dermatosis of significant psychosocial embarrassment and missed employment opportunities. It is characterized by development of translucent papules and wrinkling of the palms and rarely of soles shortly after immersion in water. Associated burning pain or pruritus of variable intensity is often distressing. The symptoms subside spontaneously 10-60 minutes after drying of hands only to recur following contact with water resulting in mild palmar hyperkeratosis over time. Although, cystic fibrosis remains the most described association, its cause is unknown in majority. The treatment is usually unsatisfactory and remains challenging. Response to antihistamines, iontophoresis, topical aluminum chloride 15-20% solution, and aluminum chloride hexahydrate 20% in anhydrous ethyl alcohol remains inconsistent. Keratolytic creams, petroleum jelly and/or use of gloves are not found useful at all. This paper describes a case of AWoP treated successfully with topical tacrolimus 0.1% ointment. We feel that topical tarolimus provides an effective and safe therapeutic option in AWoP.

PMID:36226015 | PMC:PMC9549565 | DOI:10.4103/idoj.idoj_657_21

Front Psychol. 2022 Sep 26;13:991771. doi: 10.3389/fpsyg.2022.991771. eCollection 2022.

ABSTRACT

This study explored the evidence of validity of internal structure of the 12-item Functional Assessment of Chronic Illness Therapy-Spiritual Wellbeing Scale (FACIT-Sp-12) in Brazilian adolescents with chronic health conditions. The study involved 301 Brazilian adolescents with cancer, type 1 diabetes mellitus, or cystic fibrosis. Exploratory Factor Analysis (EFA), Confirmatory Factor Analysis (CFA), and Item Response Theory (IRT) were used to test the internal structure. Reliability was determined with Cronbach's Alpha and McDonald's Omega. The EFA suggested a one-dimensional scale structure in contrast to the original 2-factor model or the 3-factor model which were not reproduced in the current CFA. All quality indicators for the EFA one-factor exceeded the required criteria (FDI = 0.97, EAP = 0.97, SR = 3.96 and EPTD = 0.96, latent GH = 0.90. and the observed GH = 0.85). The FACIT-Sp-12 for adolescents yielded strong evidence for a 1-factor model and with good reliability.

PMID:36225684 | PMC:PMC9549338 | DOI:10.3389/fpsyg.2022.991771

Neurooncol Adv. 2022 Aug 18;4(1):vdac131. doi: 10.1093/noajnl/vdac131. eCollection 2022 Jan-Dec.

ABSTRACT

BACKGROUND: Chromosomal translocation has been detected in many human cancers including gliomas and is considered a driving force in tumorigenesis. Co-deletion of chromosome arms 1p and 19q is a hallmark for oligodendrogliomas. On the molecular level, 1p/19q co-deletion results from t(1;19)(q10;p10), which leads to the concomitant formation of a hybrid chromosome containing the 1q and 19p arms. A method to generate 1p/19q co-deletion is lacking, which hinders the investigation of how 1p/19q co-deletion contributes to gliomagenesis.

METHODS: We hypothesized that chromosomal translocation, such as t(1;19)(q10;p10) resulting in the 1p/19q co-deletion, may be induced by simultaneously introducing DNA double-strand breaks (DSBs) into chromosomes 1p and 19q using CRISPR/Cas9. We developed a CRISPR/Cas9-based strategy to induce t(1;19)(q10;p10) and droplet digital PCR (ddPCR) assays to detect the hybrid 1q/19p and 1p/19q chromosomes.

RESULTS: After translocation induction, we detected both 1p/19q and 1q/19p hybrid chromosomes by PCR amplification of the junction regions in HEK 293T, and U-251 and LN-229 glioblastoma cells. Sequencing analyses of the PCR products confirmed DNA sequences matching both chromosomes 1 and 19. Furthermore, the 1p/19q hybrid chromosome was rapidly lost in all tested cell lines. The 1q/19p hybrid chromosome also become undetectable over time likely due to cell survival disadvantage.

CONCLUSION: We demonstrated that t(1;19)(q10;p10) may be induced by CRISPR/Cas9-mediated genomic editing. This method represents an important step toward engineering the 1p/19q co-deletion to model oligodendrogliomas. This method may also be generalizable to engineering other cancer-relevant translocations, which may facilitate the understanding of translocation roles in cancer progression.

PMID:36225650 | PMC:PMC9547542 | DOI:10.1093/noajnl/vdac131

Front Pharmacol. 2022 Sep 26;13:1012723. doi: 10.3389/fphar.2022.1012723. eCollection 2022.

ABSTRACT

Vegetable glycerin (VG) and propylene glycol (PG) serve as delivery vehicles for nicotine and flavorings in most e-cigarette (e-cig) liquids. Here, we investigated whether VG e-cig aerosols, in the absence of nicotine and flavors, impact parameters of mucociliary function in human volunteers, a large animal model (sheep), and air-liquid interface (ALI) cultures of primary human bronchial epithelial cells (HBECs). We found that VG-containing (VG or PG/VG), but not sole PG-containing, e-cig aerosols reduced the activity of nasal cystic fibrosis transmembrane conductance regulator (CFTR) in human volunteers who vaped for seven days. Markers of inflammation, including interleukin-6 (IL6), interleukin-8 (IL8) and matrix metalloproteinase-9 (MMP9) mRNAs, as well as MMP-9 activity and mucin 5AC (MUC5AC) expression levels, were also elevated in nasal samples from volunteers who vaped VG-containing e-liquids. In sheep, exposures to VG e-cig aerosols for five days increased mucus concentrations and MMP-9 activity in tracheal secretions and plasma levels of transforming growth factor-beta 1 (TGF-β1). In vitro exposure of HBECs to VG e-cig aerosols for five days decreased ciliary beating and increased mucus concentrations. VG e-cig aerosols also reduced CFTR function in HBECs, mechanistically by reducing membrane fluidity. Although VG e-cig aerosols did not increase MMP9 mRNA expression, expression levels of IL6, IL8, TGFB1, and MUC5AC mRNAs were significantly increased in HBECs after seven days of exposure. Thus, VG e-cig aerosols can potentially cause harm in the airway by inducing inflammation and ion channel dysfunction with consequent mucus hyperconcentration.

PMID:36225570 | PMC:PMC9549247 | DOI:10.3389/fphar.2022.1012723

J Cardiothorac Surg. 2022 Oct 11;17(1):266. doi: 10.1186/s13019-022-01882-y.

ABSTRACT

INTRODUCTION: The efficacy of azithromycin to prevent exacerbation for non-cystic fibrosis bronchiectasis remains controversial. We conduct this meta-analysis to explore the influence of azithromycin versus placebo for the treatment of non-cystic fibrosis bronchiectasis.

METHODS: We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through July 2019 for randomized controlled trials (RCTs) assessing the efficacy of azithromycin versus placebo for non-cystic fibrosis bronchiectasis. This meta-analysis was performed using the random-effect model.

RESULTS: Four RCTs were included in the meta-analysis. Overall, compared with control group for non-cystic-fibrosis bronchiectasis, azithromycin treatment was associated with improved free of exacerbation (odd ratios [OR] = 3.66; 95% confidence interval [CI] = 1.69-7.93; P = 0.001), reduced pulmonary exacerbations (OR = 0.27; 95% CI 0.13-0.59; P = 0.001) and number of pulmonary exacerbations (standard mean difference [SMD] = - 0.87; 95% CI - 1.21 to - 0.54; P < 0.00001), but demonstrate no obvious impact on forced expiratory volume in 1 s (FEV1), score on St George's respiratory questionnaire, nausea or vomiting, adverse events.

CONCLUSIONS: Azithromycin is effective to prevent exacerbation of non-cystic fibrosis bronchiectasis.

PMID:36221151 | DOI:10.1186/s13019-022-01882-y

J Cyst Fibros. 2022 Oct 8:S1569-1993(22)00691-9. doi: 10.1016/j.jcf.2022.09.011. Online ahead of print.

ABSTRACT

This paper is the first in a series providing updated guidance on the definition, evaluation and management of people with a Cystic Fibrosis Transmembrane conductance Regulator (CFTR)-Related Disorder (CFTR-RD). The need for this update relates to more precise characterisation of CFTR gene variants and improved assessment of CFTR protein dysfunction. The exercise is co-ordinated by the European CF Society Standards of Care Committee and Diagnostic Network Working Group and involves stakeholder engagement. This first paper was produced by a core group using an extensive literature review and papers graded for their quality. Subsequent wider stakeholder agreement was achieved. The definition of a CFTR-RD remains "a clinical condition with evidence of CFTR protein dysfunction that does not fulfil the diagnostic criteria for CF". Clearer guidance on CFTR dysfunction and relevant CFTR variants will be provided. Thresholds for clinical presentations are presented and the paradigm that pathobiological processes may be evident in more than one organ is agreed. In this paper we reflect on the early patient journey, highlighting that CF specialists as well as other relevant specialists should be involved in the care of people with a CFTR-RD.

PMID:36220763 | DOI:10.1016/j.jcf.2022.09.011