Antimicrob Agents Chemother. 2023 Jul 10:e0041423. doi: 10.1128/aac.00414-23. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa remains a challenge in chronic respiratory infections in cystic fibrosis (CF). Ceftolozane-tazobactam has not yet been evaluated against multidrug-resistant hypermutable P. aeruginosa isolates in the hollow-fiber infection model (HFIM). Isolates CW41, CW35, and CW44 (ceftolozane-tazobactam MICs of 4, 4, and 2 mg/L, respectively) from adults with CF were exposed to simulated representative epithelial lining fluid pharmacokinetics of ceftolozane-tazobactam in the HFIM. Regimens were continuous infusion (CI; 4.5 g/day to 9 g/day, all isolates) and 1-h infusions (1.5 g every 8 hours and 3 g every 8 hours, CW41). Whole-genome sequencing and mechanism-based modeling were performed for CW41. CW41 (in four of five biological replicates) and CW44 harbored preexisting resistant subpopulations; CW35 did not. For replicates 1 to 4 of CW41 and CW44, 9 g/day CI decreased bacterial counts to <3 log10 CFU/mL for 24 to 48 h, followed by regrowth and resistance amplification. Replicate 5 of CW41 had no preexisting subpopulations and was suppressed below ~3 log10 CFU/mL for 120 h by 9 g/day CI, followed by resistant regrowth. Both CI regimens reduced CW35 bacterial counts to <1 log10 CFU/mL by 120 h without regrowth. These results corresponded with the presence or absence of preexisting resistant subpopulations and resistance-associated mutations at baseline. Mutations in ampC, algO, and mexY were identified following CW41 exposure to ceftolozane-tazobactam at 167 to 215 h. Mechanism-based modeling well described total and resistant bacterial counts. The findings highlight the impact of heteroresistance and baseline mutations on the effect of ceftolozane-tazobactam and limitations of MIC to predict bacterial outcomes. The resistance amplification in two of three isolates supports current guidelines that ceftolozane-tazobactam should be utilized together with another antibiotic against P. aeruginosa in CF.

PMID:37428034 | DOI:10.1128/aac.00414-23

bioRxiv. 2023 Jun 28:2023.06.26.546583. doi: 10.1101/2023.06.26.546583. Preprint.

ABSTRACT

Cystic fibrosis (CF) is a muco-obstructive lung disease where inflammatory responses due to chronic infection result in the accumulation of neutrophil extracellular traps (NETs) in the airways. NETs are web-like complexes comprised mainly of decondensed chromatin that function to capture and kill bacteria. Prior studies have established excess release of NETs in CF airways increases viscoelasticity of mucus secretions and reduces mucociliary clearance. Despite the pivotal role of NETs in CF disease pathogenesis, current in vitro models of this disease do not account for their contribution. Motivated by this, we developed a new approach to study the pathobiological effects of NETs in CF by combining synthetic NET-like biomaterials, composed of DNA and histones, with an in vitro human airway epithelial cell culture model. To determine the impact of synthetic NETs on airway clearance function, we incorporated synthetic NETs into mucin hydrogels and cell culture derived airway mucus to assess their rheological and transport properties. We found that the addition of synthetic NETs significantly increases mucin hydrogel and native mucus viscoelasticity. As a result, mucociliary transport in vitro was significantly reduced with the addition of mucus containing synthetic NETs. Given the prevalence of bacterial infection in the CF lung, we also evaluated the growth of Pseudomonas aeruginosa in mucus with or without synthetic NETs. We found mucus containing synthetic NETs promoted microcolony growth and prolonged bacterial survival. Together, this work establishes a new biomaterial enabled approach to study innate immunity mediated airway dysfunction in CF.

PMID:37425779 | PMC:PMC10327088 | DOI:10.1101/2023.06.26.546583

Transl Lung Cancer Res. 2023 Jun 30;12(6):1338-1341. doi: 10.21037/tlcr-23-65. Epub 2023 Apr 10.

NO ABSTRACT

PMID:37425400 | PMC:PMC10326774 | DOI:10.21037/tlcr-23-65

Diabetes Res Clin Pract. 2023 Jul 7;202:110822. doi: 10.1016/j.diabres.2023.110822. Online ahead of print.

ABSTRACT

AIMS: To evaluate the frequency and consequences of level 2 (L2H, glucose level < 3.0 mmol/L with autonomous management) and level 3 hypoglycemia (L3H requiring external assistance to treat), in adults living with type 1 diabetes (T1D), while investigating the role of gender.

METHODS: Cross-sectional analysis of self-reported retrospective data from a Canadian registry of 900 adults living with T1D using logistic regression models adjusted for age, T1D management modalities, hypoglycemia history, and validated patient-reported outcomes scales. Changes in diabetes management, seeking healthcare resources, and impacts on daily well-being were explored.

RESULTS: Of the 900 adults (66% women, mean age 43.7 ± 14.8 years, mean T1D duration 25.5 ± 14.6 years), 87% used wearable diabetes technology. L3H in the past year was reported by 15% participants, similar between genders. Women reported more L2H than men (median (Q1, Q3): 4 (2, 10) vs 3 (1,8), p = 0.015), and were more likely to report persistent fatigue after both L2H and L3H (Odds ratio [95% confidence interval]: 1.95 [1.16, 3.28] and 1.86 [1.25, 2.75], respectively) and anxiety (1.70 [1.05, 2.75]) after a L3H.

CONCLUSIONS: The findings suggest taking a gender-based differential approach when addressing hypoglycemia and its various consequences for people living with T1D.

PMID:37423499 | DOI:10.1016/j.diabres.2023.110822

J Cyst Fibros. 2023 Jul 7:S1569-1993(23)00045-0. doi: 10.1016/j.jcf.2023.02.002. Online ahead of print.

ABSTRACT

Meconium ileus (MI) is one presenting manifestation of Cystic Fibrosis (CF), classically associated with class I-III CF transmembrane conductance regulator (CFTR) mutations and pancreatic insufficiency (PI). D1152H is a class IV mutation that corresponds with a milder CF phenotype and pancreatic sufficiency (PS). We present the case of an infant with G542X/D1152H mutations and MI who required surgical intervention with small bowel resection. The sweat testing was normal, and this child presently remains PS, however at age 5 continues to experience short gut syndrome and failure to thrive. Eight cases were identified in the CF Registry and seven cases in the literature describing patients with D1152H and echogenic bowel (EB) or MI. Our case highlights the importance of CFTR gene sequencing in infants with EB or MI and sweat testing not suggestive of CF. It is our practice to perform full CFTR gene sequencing for infants who present with MI, recognizing protocols for newborn screening across the United States vary. Increased awareness of D1152H association with PS may also well inform both prenatal and postnatal genetic counseling.

PMID:37423798 | DOI:10.1016/j.jcf.2023.02.002

Eur J Pharm Sci. 2023 Jul 7:106522. doi: 10.1016/j.ejps.2023.106522. Online ahead of print.

ABSTRACT

Recombinant human deoxyribonuclease I (rhDNase, Pulmozyme®) is the most frequently used mucolytic agent for the symptomatic treatment of cystic fibrosis (CF) lung disease. Conjugation of rhDNase to polyethylene glycol (PEG) has been shown to greatly prolong its residence time in the lungs and improve its therapeutic efficacy in mice. To present an added value over current rhDNase treatment, PEGylated rhDNase needs to be efficiently and less frequently administrated by aerosolization and possibly at higher concentrations than existing rhDNase. In this study, the effects of PEGylation on the thermodynamic stability of rhDNase was investigated, using linear 20 kDa, linear 30 kDa and 2-armed 40 kDa PEGs. The suitability of PEG30-rhDNase to electrohydrodynamic atomization (electrospraying) as well as the feasibility of using two vibrating mesh nebulizers, the optimized eFlow® Technology nebulizer (eFlow) and Innospire Go, at varying protein concentrations were investigated. PEGylation was shown to destabilize rhDNase upon chemical-induced denaturation and ethanol exposure. Yet, PEG30-rhDNase was stable enough to withstand aerosolization stresses using the eFlow and Innospire Go nebulizers even at higher concentrations (5 mg of protein per ml) than conventional rhDNase formulation (1 mg/ml). High aerosol output (up to 1.5 ml per min) and excellent aerosol characteristics (up to 83% fine particle fraction) were achieved while preserving protein integrity and enzymatic activity. This work demonstrates the technical feasibility of PEG-rhDNase nebulization with advanced vibrating membrane nebulizers, encouraging further pharmaceutical and clinical developments of a long-acting PEGylated alternative to rhDNase for treating patients with CF.

PMID:37423579 | DOI:10.1016/j.ejps.2023.106522

Nat Commun. 2023 Jul 8;14(1):4052. doi: 10.1038/s41467-023-39756-z.

ABSTRACT

E217 is a Pseudomonas phage used in an experimental cocktail to eradicate cystic fibrosis-associated Pseudomonas aeruginosa. Here, we describe the structure of the whole E217 virion before and after DNA ejection at 3.1 Å and 4.5 Å resolution, respectively, determined using cryogenic electron microscopy (cryo-EM). We identify and build de novo structures for 19 unique E217 gene products, resolve the tail genome-ejection machine in both extended and contracted states, and decipher the complete architecture of the baseplate formed by 66 polypeptide chains. We also determine that E217 recognizes the host O-antigen as a receptor, and we resolve the N-terminal portion of the O-antigen-binding tail fiber. We propose that E217 design principles presented in this paper are conserved across PB1-like Myoviridae phages of the Pbunavirus genus that encode a ~1.4 MDa baseplate, dramatically smaller than the coliphage T4.

PMID:37422479 | DOI:10.1038/s41467-023-39756-z

J Cyst Fibros. 2023 Jul 6:S1569-1993(23)00819-6. doi: 10.1016/j.jcf.2023.06.005. Online ahead of print.

ABSTRACT

RATIONALE: Limited information is available on the clinical status of people with Cystic Fibrosis (pwCF) carrying 2 nonsense mutations (PTC/PTC). The main objective of this study was to compare disease severity between pwCF PTC/PTC, compound heterozygous for F508del and PTC (F508del/PTC) and homozygous for F508del (F508del+/+).

METHODS: Based on the European CF Society Patient Registry clinical data of pwCF living in high and middle income European and neighboring countries, PTC/PTC (n = 657) were compared with F508del+/+ (n = 21,317) and F508del/PTC(n = 4254).CFTR mRNA and protein activity levels were assessed in primary human nasal epithelial (HNE) cells sampled from 22 PTC/PTC pwCF.

MAIN RESULTS: As compared to F508del+/+ pwCF; both PTC/PTC and F508del/PTC pwCF exhibited a significantly faster rate of decline in Forced Expiratory Volume in 1 s (FEV1) from 7 years (-1.33 for F508del +/+, -1.59 for F508del/PTC; -1.65 for PTC/PTC, p < 0.001) until respectively 30 years (-1.05 for F508del +/+, -1.23 for PTC/PTC, p = 0.048) and 27 years (-1.12 for F508del +/+, -1.26 for F508del/PTC, p = 0.034). This resulted in lower FEV1 values in adulthood. Mortality of pediatric pwCF with one or two PTC alleles was significantly higher than their F508del homozygous pairs. Infection with Pseudomonas aeruginosa was more frequent in PTC/PTC versus F508del+/+ and F508del/PTC pwCF. CFTR activity in PTC/PTC pwCF's HNE cells ranged between 0% to 3% of the wild-type level.

CONCLUSIONS: Nonsense mutations decrease the survival and accelerate the course of respiratory disease in children and adolescents with Cystic Fibrosis.

PMID:37422433 | DOI:10.1016/j.jcf.2023.06.005

J Cyst Fibros. 2023 Jul 6:S1569-1993(23)00824-X. doi: 10.1016/j.jcf.2023.06.010. Online ahead of print.

ABSTRACT

BACKGROUND: Elexacaftor/Tezacaftor/Ivacaftor (ETI) modulator therapy is often associated with increased body mass index (BMI) in people with cystic fibrosis (CF). This is thought to reflect improved clinical stability and increased appetite and nutritional intake. We explored the change in BMI and nutritional intake following ETI modulator therapy in adults with CF.

METHODS: Dietary intake, measured with myfood24®, and BMI were collected from adults with CF at baseline and follow-up as part of an observational study. Changes in BMI and nutritional intake in participants who commenced ETI therapy between time points were assessed. To contextualize findings, we also assessed changes in BMI and nutritional intake between study points in a group on no modulators.

RESULTS: In the pre and post ETI threapy group (n = 40), BMI significantly increased from 23.0 kg/m2 (IQR 21.4, 25.3) at baseline to 24.6 kg/m2 (IQR 23.0, 26.7) at follow-up (p<0.001), with a median of 68 weeks between time points (range 20-94 weeks) and median duration of ETI therapy was 23 weeks (range 7-72 weeks). There was a significant decrease in energy intake from 2551 kcal/day (IQR 2107, 3115) to 2153 kcal/day (IQR 1648, 2606), p<0.001. In the no modulator group (n = 10), BMI and energy intake did not significantly change between time points (p>0.05), a median of 28 weeks apart (range 20-76 weeks).

CONCLUSIONS: These findings tentatively suggest that the increase in BMI with ETI therapy may not simply be attributable to an increase in oral intake. Further exploration into the underlying aetiology of weight gain with ETI therapy is needed.

PMID:37422432 | DOI:10.1016/j.jcf.2023.06.010

J Cyst Fibros. 2023 Jul 6:S1569-1993(23)00822-6. doi: 10.1016/j.jcf.2023.06.007. Online ahead of print.

ABSTRACT

BACKGROUND: Pseudomonas aeruginosa (Pa) infection is detrimental to people with cystic fibrosis (pwCF). Several clinical and genetic factors predispose to early Pa infections. However, the role of earlier infections with other pathogens on the risk of Pa infection in paediatric pwCF remains unknown.

METHODS: Using Kaplan-Meier method, we computed the cumulative incidences of bacterial and fungal initial acquisition (IA) and chronic colonisation (CC) in 1,231 French pwCF under 18 years of age for methicillin-susceptible and resistant Staphylococcus aureus (MSSA and MRSA), Stenotrophomonas maltophilia, Haemophilus influenzae, Achromobacter xylosoxidans, and Aspergillus species. Previous infections were analysed as Pa-IA and Pa-CC risk factors using Cox regression models.

RESULTS: By 2 years of age, 65.5% pwCF had experienced at least one bacterial or fungal IA, and 27.9% had experienced at least one CC. The median age of Pa-IA was 5.1 years, and Pa-CC was present in 25% pwCF by 14.7 years. While 50% acquired MSSA at 2.1 years, 50% progressed to chronic MSSA colonisation at 8.4 years. At 7.9 and 9.7 years, 25% pwCF were infected by S. maltophilia and Aspergillus spp., respectively. The risk of Pa-IA and Pa-CC increased with IAs of all other species, with hazard ratios (HR) up to 2.19 (95% Confidence interval (CI) 1.18-4.07). The risk of Pa-IA increased with the number of previous bacterial/fungal IAs (HR=1.89, 95% CI 1.57-2.28), with a 16% increase per additional pathogen; same trend was noted for Pa-CC.

CONCLUSIONS: This study establishes that the microbial community in CF airways can modulate Pa occurrence. At the dawn of targeted therapies, it paves the way for characterizing future trends and evolution of infections.

PMID:37422431 | DOI:10.1016/j.jcf.2023.06.007

Interdiscip Cardiovasc Thorac Surg. 2023 Jul 8:ivad111. doi: 10.1093/icvts/ivad111. Online ahead of print.

ABSTRACT

A best-evidence topic was written according to a structured protocol. The question addressed was the following: in patient undergoing lung transplantation (LTx), are lungs from donors of age > 60 years old (yo) associated with equivalent outcomes-including primary graft dysfunction (PGD), respiratory function and survival-than lungs from donors ≤60yo? Altogether, more than 200 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journals, dates, country of publication, patients group studied, study type, relevant outcomes, and results of these papers were tabulated. Amongst the 12 papers reviewed, survival results were different depending on whether donor age was analyzed raw or adjusted for recipients' age and initial diagnosis. Indeed, recipients with interstitial lung disease (ILD), pulmonary hypertension or cystic fibrosis (CF) had significantly inferior overall survival when receiving grafts from older donors. When older grafts are allocated to younger donors, a significant decrease in survival has been noticed in the case of single LTx. In addition, three papers showed worse results regarding peak forced expiratory volume in 1 second (FEV1) in patients receiving older organs, and four showed comparable PGD incidence rates. We conclude that when carefully assessed and allocated to the recipient who could benefit most from the transplant (e.g., a patient with a diagnosis of chronic obstructive pulmonary disease (COPD), who would not require a prolonged cardiopulmonary bypass (CPB)), lung grafts from donors of more than 60yo offer comparable results to younger donors.

PMID:37421406 | DOI:10.1093/icvts/ivad111

Mol Pharmacol. 2023 Jul 7:MOLPHARM-AR-2023-000708. doi: 10.1124/molpharm.123.000708. Online ahead of print.

ABSTRACT

The human ether-a-go-go-related gene (hERG) encodes for the pore-forming subunit of the channel that conducts the rapidly activating delayed K+ current (IKr) in the heart. The hERG channel is important for cardiac repolarization, and reduction of its expression in the plasma membrane due to mutations causes long-QT syndrome type 2 (LQT2). As such, promoting hERG membrane expression is a strategy to rescue mutant channel function. In the present study, we applied patch clamp, Western blots, immunocytochemistry, and Quantitative Reverse Transcription PCR (RT-qPCR) techniques to investigate the rescue effects of two drugs, remdesivir and lumacaftor, on trafficking defective mutant hERG channels. As our group has recently reported that the antiviral drug remdesivir increases wild-type (WT) hERG current and surface expression, we studied the effects of remdesivir on trafficking defective LQT2-causing hERG mutants G601S and R582C expressed in HEK293 cells. We also investigated the effects of lumacaftor, a drug used to treat cystic fibrosis that promotes CFTR protein trafficking and has been shown to rescue membrane expression of some hERG mutations. Our results show that neither remdesivir nor lumacaftor rescued the current or cell-surface expression of homomeric mutants G601S and R582C. However, remdesivir decreased while lumacaftor increased the current and cell-surface expression of heteromeric channels formed by WT hERG and mutant G601S or R582C hERG. We concluded that drugs can differentially affect homomeric WT and heteromeric WT+G601S (or WT+R582C) hERG channels. These findings extend our understanding of drug-channel interaction, and may have clinical implications for patients with hERG mutations. Significance Statement Various naturally occurring mutations in a cardiac potassium channel called hERG can impair channel function by decreasing cell-surface channel expression, resulting in cardiac electrical disturbances and even sudden cardiac death. Promotion of cell-surface expression of mutant hERG channels represents a strategy to rescue channel function. This work demonstrates that drugs such as remdesivir and lumacaftor can differently affect homomeric and heteromeric mutant hERG channels, which have biological and clinical implications.

PMID:37419691 | DOI:10.1124/molpharm.123.000708

Eur Respir J. 2023 Jul 7;62(1):2300865. doi: 10.1183/13993003.00865-2023. Print 2023 Jul.

NO ABSTRACT

PMID:37419521 | DOI:10.1183/13993003.00865-2023

J Immunother Cancer. 2023 Jul;11(7):e006785. doi: 10.1136/jitc-2023-006785.

ABSTRACT

BACKGROUND: Most immunotherapies approved for clinical use rely on the use of recombinant proteins and cell-based approaches, rendering their manufacturing expensive and logistics onerous. The identification of novel small molecule immunotherapeutic agents might overcome such limitations.

METHOD: For immunopharmacological screening campaigns, we built an artificial miniature immune system in which dendritic cells (DCs) derived from immature precursors present MHC (major histocompatibility complex) class I-restricted antigen to a T-cell hybridoma that then secretes interleukin-2 (IL-2).

RESULTS: The screening of three drug libraries relevant to known signaling pathways, FDA (Food and Drug Administration)-approved drugs and neuroendocrine factors yielded two major hits, astemizole and ikarugamycin. Mechanistically, ikarugamycin turned out to act on DCs to inhibit hexokinase 2, hence stimulating their antigen presenting potential. In contrast, astemizole acts as a histamine H1 receptor (H1R1) antagonist to activate T cells in a non-specific, DC-independent fashion. Astemizole induced the production of IL-2 and interferon-γ (IFN-γ) by CD4+ and CD8+ T cells both in vitro and in vivo. Both ikarugamycin and astemizole improved the anticancer activity of the immunogenic chemotherapeutic agent oxaliplatin in a T cell-dependent fashion. Of note, astemizole enhanced the CD8+/Foxp3+ ratio in the tumor immune infiltrate as well as IFN-γ production by local CD8+ T lymphocytes. In patients with cancer, high H1R1 expression correlated with low infiltration by TH1 cells, as well as with signs of T-cell exhaustion. The combination of astemizole and oxaliplatin was able to cure the majority of mice bearing orthotopic non-small cell lung cancers (NSCLC), then inducing a state of protective long-term immune memory. The NSCLC-eradicating effect of astemizole plus oxaliplatin was lost on depletion of either CD4+ or CD8+ T cells, as well as on neutralization of IFN-γ.

CONCLUSIONS: These findings underscore the potential utility of this screening system for the identification of immunostimulatory drugs with anticancer effects.

PMID:37419511 | DOI:10.1136/jitc-2023-006785

Chest. 2023 Jun 17:S0012-3692(23)00807-3. doi: 10.1016/j.chest.2023.05.036. Online ahead of print.

ABSTRACT

BACKGROUND: Mycobacterium abscessus is the second most common nontuberculous mycobacterium respiratory pathogen and shows in vitro resistance to nearly all oral antimicrobials. M abscessus treatment success is low in the presence of macrolide resistance.

RESEARCH QUESTION: Does treatment with amikacin liposome inhalation suspension (ALIS) improve culture conversion in treatment-refractory and treatment-naïve patients with M abscessus pulmonary disease?

STUDY DESIGN AND METHODS: In an open-label protocol, patients were given ALIS (590 mg) added to background multidrug therapy for 12 months. The primary outcome was sputum culture conversion defined as three consecutive monthly sputum cultures showing negative results. The secondary end point included development of amikacin resistance.

RESULTS: Of 33 patients (36 isolates) who started ALIS with a mean age of 64 years (range, 14-81 years), 24 patients (73%) were women, 10 patients (30%) had cystic fibrosis, and nine patients (27%) had cavitary disease. Three patients (9%) could not be evaluated for the microbiologic end point because of early withdrawal. All pretreatment isolates were amikacin susceptible and only six isolates (17%) were macrolide susceptible. Eleven patients (33%) were given parenteral antibiotics. Twelve patients (40%) received clofazimine with or without azithromycin as companion therapy. Fifteen patients (50%) with evaluable longitudinal microbiologic data demonstrated culture conversion, and 10 patients (67%) sustained conversion through month 12. Six of the 33 patients (18%) demonstrated mutational amikacin resistance. All were patients using clofazimine, or clofazimine plus azithromycin as companion medication(s). Few serious adverse events occurred for ALIS users; however, reduction of dosing to three times weekly was common (52%).

INTERPRETATION: In a cohort of patients primarily with macrolide-resistant M abscessus, half of the patients using ALIS showed sputum culture conversion to negative findings. The emergence of mutational amikacin resistance was not uncommon and occurred with the use of clofazimine monotherapy.

TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03038178; URL: www.

CLINICALTRIALS: gov.

PMID:37419144 | DOI:10.1016/j.chest.2023.05.036

Alzheimers Dement. 2023 Jul 7. doi: 10.1002/alz.13373. Online ahead of print.

ABSTRACT

INTRODUCTION: Diabetes and dementia are diseases of high health-care burden worldwide. Individuals with diabetes have 1.4 to 2.2 times higher risk of dementia. Our objective was to evaluate evidence of causality between these two common diseases.

METHODS: We conducted a one-sample Mendelian randomization (MR) analysis in the US Department of Veterans Affairs Million Veteran program. The study included 334,672 participants ≥65 years of age with type 2 diabetes and dementia case-control status and genotype data.

RESULTS: For each standard deviation increase in genetically predicted diabetes, we found increased odds of three dementia diagnoses in non-Hispanic White participants (all-cause: odds ratio [OR] = 1.07 [1.05-1.08], P = 3.40E-18; vascular: OR = 1.11 [1.07-1.15], P = 3.63E-09, Alzheimer's disease [AD]: OR = 1.06 [1.02-1.09], P = 6.84E-04) and non-Hispanic Black participants (all-cause: OR = 1.06 [1.02-1.10], P = 3.66E-03, vascular: OR = 1.11 [1.04-1.19], P = 2.20E-03, AD: OR = 1.12 [1.02-1.23], P = 1.60E-02) but not in Hispanic participants (all P > 0.05).

DISCUSSION: We found evidence of causality between diabetes and dementia using a one-sample MR study, with access to individual level data, overcoming limitations of prior studies using two-sample MR techniques.

PMID:37417779 | DOI:10.1002/alz.13373

Lab Med. 2023 Jul 7:lmad058. doi: 10.1093/labmed/lmad058. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF), an autosomal recessive disease, is caused by variants in both alleles of the CF transmembrane conductance regulator (CFTR) gene. A new assay based on allele-specific polymerase chain reaction and high-resolution melting analysis was developed for the detection of 18 CF-causing CFTR variants previously identified in Cuba and Latin America. The assay is also useful for zygosity determination of mutated alleles and includes internal controls. The reaction mixtures were normalized and evaluated using blood samples collected on filter paper. The evaluation of analytical parameters demonstrated the specificity and sensitivity of the method to detect the included CFTR variants. Internal and external validations yielded a 100% agreement between the new assay and the used reference tests. This assay can complement CF newborn screening not only in Cuba but also in Latin America.

PMID:37417450 | DOI:10.1093/labmed/lmad058

J Eur Acad Dermatol Venereol. 2023 Jul 7. doi: 10.1111/jdv.19308. Online ahead of print.

ABSTRACT

BACKGROUND: Aquagenic Wrinkling of the Palms (AWP) is an excessive and early palmar wrinkling occurring after Brief Immersion to Water (BIW), and has been reported as a frequent finding among Cystic Fibrosis (CF) patients.

OBJECTIVES: To investigate any associations of CF patients presenting AWP with other disease characteristics and explore the pathomechanism of AWP phenomenon.

METHODS: We evaluated AWP in CF patients, and assessed the AWP parameters of palmar wrinkling, oedema, papules, pruritus and pain at 3, 7, 11 mins after a BIW test with other disease characteristics. Statistical analyses explored the associations of AWP with genotype, lung function, pancreatic insufficiency, hyperhidrosis, personal and family history of atopy, sweat chloride levels.

RESULTS: One hundred CF patients (mean age 10.4 years) were included in the analysis. The genotypic distribution was ΔF508/ΔF508: 47%, ΔF508/other: 41% and other/other: 12%. Statistically significant associations of Kaplan-Meier curves of the AWP parameters with various disease characteristics and personal/family history were detected. Wrinkling was associated with history of atopy, hyperhidrosis and levels of sweat chloride test. The time to presentation of oedema and the appearance of papules were associated with history of hyperhidrosis and age at diagnosis. Finally, time to appearance of pruritus was related to history of atopy and of hyperhidrosis. Regarding TEWL regression analysis showed significant associations with age at diagnosis (p=0.024), sweat chloride test levels (p=0.005), history of hyperhidrosis (p=0.033), history of atopy (p=0.002) and hepatic-pancreatic involvement (p=0.027).

CONCLUSIONS: The existence of a statistically significant association between AWP and the history of hyperhidrosis, atopy, sweat chloride levels and hepatic-pancreatic function in CF patients was detected. A strong association between AWP and CF was detected. AWP after BIW could be elicited easily and possibly can be used as an initial screening tool to diagnose an individual with symptoms and signs that raise the likelihood of CF.

PMID:37415513 | DOI:10.1111/jdv.19308

Eur Respir J. 2023 Jul 6:2202153. doi: 10.1183/13993003.02153-2022. Online ahead of print.

ABSTRACT

BACKGROUND: Recent studies demonstrated that the triple combination CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) improves lung function and reduces pulmonary exacerbations in CF patients with at least one F508del allele. However, effects of ETI on downstream consequences of CFTR dysfunction, i.e. abnormal viscoelastic properties of airway mucus, chronic airway infection and inflammation have not been studied. The aim of this study was, therefore, to determine the longitudinal effects of ETI on airway mucus rheology, microbiome and inflammation in CF patients with one or two F508del alleles aged 12 years and older throughout the first 12 months of therapy.

METHODS: In this prospective observational study, we assessed sputum rheology, the microbiome, inflammation markers and proteome before and 1, 3 and 12 months after initiation of ETI.

RESULTS: In total, 79 patients with CF and at least one F508del allele and 10 healthy controls were enrolled in this study. ETI improved the elastic modulus and viscous modulus of CF sputum at 3 and 12 months after initiation (all p<0.01). Further, ETI decreased the relative abundance of Pseudomonas aeruginosa in CF sputum at 3 months and increased the microbiome α-diversity at all timepoints. ETI also reduced IL-8 at 3 months (p<0.05) and free NE activity at all timepoints (all p<0.001), and shifted the CF sputum proteome towards healthy.

CONCLUSIONS: Our data demonstrate that restoration of CFTR function by ETI improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least one F508del allele over the first 12 months of therapy, however, without reaching levels close to healthy.

PMID:37414422 | DOI:10.1183/13993003.02153-2022

Mol Immunol. 2023 Jul 4;160:95-102. doi: 10.1016/j.molimm.2023.06.011. Online ahead of print.

ABSTRACT

Despite the wide usage of β2-adrenoceptor agonists in asthma treatment, they do have side effects such as aggravating inflammation. We previously reported that isoprenaline induced Cl- secretion and IL-6 release via cAMP-dependent pathways in human bronchial epithelia, but the mechanisms underlying the inflammation-aggravation effects of β2-adrenoceptor agonists remain pooly understood. In this study, we investigated formoterol, a more specific β2-adrenoceptor agonist, -mediated signaling pathways involved in the production of IL-6 and IL-8 in 16HBE14o- human bronchial epithelia. The effects of formoterol were detected in the presence of PKA, exchange protein directly activated by cAMP (EPAC), cystic fibrosis transmembrane conductance regulator (CFTR), extracellular signal-regulated protein kinase (ERK)1/2 and Src inhibitors. The involvement of β-arrestin2 was determined using siRNA knockdown. Our results indicate that formoterol can induce IL-6 and IL-8 secretion in concentration-dependent manner. The PKA-specific inhibitor, H89, partially inhibited IL-6 release, but not IL-8. Another intracellular cAMP receptor, EPAC, was not involved in either IL-6 or IL-8 release. PD98059 and U0126, two ERK1/2 inhibitors, blocked IL-8 while attenuated IL-6 secretion induced by formoterol. Furthermore, formoterol-induced IL-6 and IL-8 release was attenuated by Src inhibitors, namely dasatinib and PP1, and CFTRinh172, a CFTR inhibitor. In addition, knockdown of β-arrestin2 by siRNA only suppressed IL-8 release when a high concentration of formoterol (1 μM) was used. Taken together, our results suggest that formoterol stimulates IL-6 and IL-8 release which involves PKA/Src/ERK1/2 and/or β-arrestin2 signaling pathways.

PMID:37413911 | DOI:10.1016/j.molimm.2023.06.011