Hum Gene Ther. 2023 Mar 16. doi: 10.1089/hum.2022.188. Online ahead of print.

ABSTRACT

The liver is a prime target for in vivo gene therapies using recombinant adeno-associated viral vectors (rAAV). Multiple clinical trials have been undertaken for this target in the past 15 years, however we are still to see market approval of the first liver-targeted AAV-based gene therapy. Inefficient expression of the therapeutic transgene, vector-induced liver toxicity and capsid, and/or transgene-mediated immune responses reported at high vector doses are the main challenges to date. One of the contributing factors to the insufficient clinical outcomes, despite highly encouraging preclinical data, is the lack of robust, biologically- and clinically-predictive preclinical models. To this end, this study reports findings of a functional evaluation of six AAV vectors in twelve preclinical models of the human liver, with the aim to uncover which combination of models is the most relevant for the identification of AAV capsid variant for safe and efficient transgene delivery to primary human hepatocytes. The results, generated by studies in models ranging from immortalized cells, iPSC-derived and primary hepatocytes, and primary human hepatic organoids to in vivo models, increased our understanding of the strengths and weaknesses of each system. This should allow the development of novel gene therapies targeting the human liver.

PMID:36927149 | DOI:10.1089/hum.2022.188

ACS Pharmacol Transl Sci. 2023 Feb 13;6(3):355-360. doi: 10.1021/acsptsci.2c00233. eCollection 2023 Mar 10.

ABSTRACT

In cystic fibrosis (CF) the ability of the CF transmembrane conductance regulator (CFTR) protein to mediate chloride and water transport is disrupted. While much progress has been made in CF research leading to effective treatments to improve CFTR function, including small molecule modulators, patients present with varying disease manifestations and responses to therapy. For many CF-affected organs, disease onset is known to occur during in utero development before treatments can be administered and progresses over time leading to irreversible damage to these organs. Thus, the role of functional CFTR protein, in particular, during early development needs to be further elucidated. Studies have detected CFTR proteins at very early gestational stages and revealed temporally and spatially variable CFTR expression patterns in fetuses, suggesting a potential role of CFTR in fetal development. However, the actual mechanisms of how defective CFTR in CF results in fetal morphogenetic abnormalities are yet to be established. This review aims to summarize fetal CFTR expression patterns specifically in the lung, pancreas, and gastrointestinal tract (GIT), as compared to adult patterns. Case studies of structural abnormalities in CF fetuses and newborns and the role of CFTR in fetal development will also be discussed.

PMID:36926454 | PMC:PMC10012249 | DOI:10.1021/acsptsci.2c00233

Cell Stress. 2023 Mar 13;7(3):12-19. doi: 10.15698/cst2023.03.277. eCollection 2023 Mar.

ABSTRACT

Recent observations indicate that the pathogenesis and prognosis of hormone-receptor breast cancer is not only dictated by the properties of the malignant cells but also by immune and microbial parameters. Thus, the immunosurveillance system retards the development of hormone-positive breast cancer and contributes to the therapeutic efficacy of estrogen receptor antagonists and aromatase inhibitors. Moreover, the anticancer immune response is profoundly modulated by the local and intestinal microbiota, which influences cancer cell-intrinsic signaling pathways, affects the composition and function of the immune infiltrate present in the tumor microenvironment and modulates the metabolism of estrogens. Indeed, specific bacteria in the gut produce enzymes that affect the enterohepatic cycle of estrogen metabolites, convert estrogens into androgens or generate estrogen-like molecules. The knowledge of these circuitries is in its infancy, calling for further in-depth analyses.

PMID:36926118 | PMC:PMC10012050 | DOI:10.15698/cst2023.03.277

Front Endocrinol (Lausanne). 2023 Feb 27;14:1031066. doi: 10.3389/fendo.2023.1031066. eCollection 2023.

ABSTRACT

INTRODUCTION: Vulvovaginal atrophy (VVA) is a common condition in post-menopausal women. Symptoms of VVA include dyspareunia, vaginal dryness, vaginal and/or vulvar itching, burning and soreness, dysuria and vaginal bleeding accompanying sexual activity. These symptoms are physiological responses to hypoestrogenicity, inducing atrophy of the vagina epithelia and sudden reduction in mucous production. Prevailing therapy for VVA is hormone replacement therapy (HRT), notably estrogen, progesterone or a combination of the two. However, using HRT is associated with an increased incidence of breast and endometrial cancer, venous thromboembolism in the lungs and legs, stroke and cardiovascular complications.

METHODS: This study evaluated Malaysian Gelam honey as a nutraceutical alternative to estrogen HRT (ERT) in alleviating VVA. A total of 24 female 8-weekold Sprague Dawley rats underwent bilateral oophorectomy. A minimum of 14 days elapsed from the time of surgery and administration of the first dose of Gelam honey to allow the female hormones to subside to a stable baseline and complete recovery from surgery. Vaginal tissues were harvested following a 2-week administration of Gelam honey, the harvested vagina tissue underwent immunohistochemistry (IHC) analysis for protein localization and qPCR for mRNA expression analysis.

RESULTS: Results indicated that Gelam honey administration had increased the localization of Aqp1, Aqp5, CFTR and Muc1 proteins in vaginal tissue compared to the menopause group. The effect of Gelam honey on the protein expressions is summarized as Aqp1>CFTR>Aqp5>Muc1.

DISCUSSION: Gene expression analysis reveals Gelam honey had no effect on Aqp1 and CFTR genes. Gelam honey had up-regulated Aqp5 gene expression. However, its expression was lower than in the ERT+Ovx group. Additionally, Gelam honey up-regulated Muc1 in the vagina, with an expression level higher than those observed either in the ERT+Ovx or SC groups. Gelam honey exhibits a weak estrogenic effect on the genes and proteins responsible for regulating water in the vaginal tissue (Aqp1, Aqp5 and CFTR). In contrast, Gelam honey exhibits a strong estrogenic ability in influencing gene and protein expression for the sialic acid Muc1. Muc1 is associated with mucous production at the vaginal epithelial layer. In conclusion, the protein and gene expression changes in the vagina by Gelam honey had reduced the occurrence of vaginal atrophy in surgically-induced menopause models.

PMID:36923220 | PMC:PMC10010262 | DOI:10.3389/fendo.2023.1031066

J Cyst Fibros. 2023 Mar 14:S1569-1993(22)01427-8. doi: 10.1016/j.jcf.2022.12.008. Online ahead of print.

ABSTRACT

BACKGROUND: People living with cystic fibrosis (PwCF) face a lifetime of potentially traumatic illness-related experiences that can lead to posttraumatic stress symptoms. Existing criteria for this type of posttraumatic stress, called medical traumatic stress (MTS), may not fully capture the CF experience. In this study we aimed to explore: 1) illness-related experiences perceived as traumatic in the setting of CF, 2) perceived MTS symptoms in PwCF, and 3) perceived health-related functional impairments from MTS.

METHODS: Informed by our aims, we developed and piloted guides for semi-structured interviews and focus groups with PwCF, family members of PwCF, and CF medical providers. We then conducted a series of interviews and focus groups. The qualitative analytical process followed Deterding and Waters' three stages of flexible coding for in-depth interviews, generating key themes and sub-themes in each domain of study inquiry.

RESULTS: We recruited 51 participants, including 24 PwCF, 7 family members of PwCF, and 20 CF care team members. Illness-related experiences perceived as traumatic were often characterized by themes of loss of agency, threats of bodily harm, and shifts in identity. Prominent MTS symptoms included shame, survivor guilt, burden guilt, germaphobia, and symptom panic. Health-related themes of functional impairments perceived to result from MTS included poor adherence and strained relationships between providers and patients/families.

CONCLUSIONS: This is the first study to explore the specific experiences of MTS in PwCF. It highlights the need for screening that includes these specific exposure types and symptoms, which may be mitigatable with medical trauma-focused interventions.

PMID:36925385 | DOI:10.1016/j.jcf.2022.12.008

Lancet Infect Dis. 2023 Mar 13:S1473-3099(23)00138-X. doi: 10.1016/S1473-3099(23)00138-X. Online ahead of print.

NO ABSTRACT

PMID:36924785 | DOI:10.1016/S1473-3099(23)00138-X

Clin Respir J. 2023 Mar 16. doi: 10.1111/crj.13600. Online ahead of print.

ABSTRACT

INTRODUCTION: Cytomegalovirus (CMV) seropositivity has been recently linked to severity and progression of asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). To date, no longitudinal study has addressed the relation of CMV serology to levels and decline of lung function in the general adult population.

METHODS: We evaluated 403 participants from the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD) who at enrollment were aged 28-55 years and completed lung function tests. During follow-up, the 403 participants completed on average 7.2 lung function tests per subject for a total of 2908 observations over a mean period of 14.7 years. We tested CMV serology in serum samples from enrollment and categorized participants into low, medium, and high CMV serology based on tertiles. The relation of CMV serology at enrollment to lung function levels and decline during follow-up was tested in multivariate random coefficients models.

RESULTS: After full adjustment, participants in the highest CMV serology tertile had faster declines of forced expiratory volume in 1 s (FEV1 ) and FEV1 /forced vital capacity (FVC) compared with subjects in the lowest tertile (by -7.9 ml/year 95% confidence interval [-13.9 ml/year, -1.93 ml/year], and by -0.13%/year [-0.23%/year, -0.026%/year], respectively). These CMV effects were additive with those of cigarette smoking. No associations were found between CMV serology and FVC, indicating specific effects of CMV seropositivity on airflow limitation.

CONCLUSION: High CMV serology in young to mid-adult life may be linked to increased COPD risk through an accelerated decline of lung function.

PMID:36924061 | DOI:10.1111/crj.13600

Front Immunol. 2023 Feb 27;14:1093212. doi: 10.3389/fimmu.2023.1093212. eCollection 2023.

ABSTRACT

Cystic fibrosis (CF) is a rare autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common mutation is F508del-CFTR (ΔF) which leads the encoded ion channel towards misfolding and premature degradation. The disease is characterized by chronic bronchopulmonary obstruction, inflammation and airways colonization by bacteria, which are the major cause of morbidity and mortality. The STING pathway is the main signaling route activated in the presence of both self and pathogen DNA, leading to Type I Interferon (IFN I) production and the innate immune response. In this study, we show for the first time the relationship existing in CF between resistant and recurrent opportunistic infections by Pseudomonas aeruginosa and the innate immunity impairment. We demonstrate through ex vivo and in vivo experiments that the pathway is inadequately activated in ΔF condition and the use of direct STING agonists, as 2',3'-cyclic GMP-AMP (2', 3' cGAMP), is able to restore the immune response against bacterial colonization. Indeed, upon treatment with the STING pathway agonists, we found a reduction of colony forming units (CFUs) consequent to IFN-β enhanced production in Pseudomonas aeruginosa infected bone marrow derived macrophages and lung tissues from mice affected by Cystic Fibrosis. Importantly, we also verified that the impairment detected in the primary PBMCs obtained from ΔF patients can be corrected by 2', 3' cGAMP. Our work indicates that the cGAS/STING pathway integrity is crucial in the Cystic Fibrosis response against pathogens and that the restoration of the pathway by 2', 3' cGAMP could be exploited as a possible new target for the symptomatic treatment of the disease.

PMID:36923406 | PMC:PMC10008931 | DOI:10.3389/fimmu.2023.1093212

JHEP Rep. 2022 Dec 17;5(4):100649. doi: 10.1016/j.jhepr.2022.100649. eCollection 2023 Apr.

ABSTRACT

BACKGROUND & AIMS: Gallbladder enlargement is common in patients with primary sclerosing cholangitis (PSC). The gallbladder may confer hepatoprotection against bile acid overload, through the sequestration and cholecystohepatic shunt of bile acids. The aim of this study was to assess the potential impact of the gallbladder on disease features and bile acid homeostasis in PSC.

METHODS: Patients with PSC from a single tertiary center who underwent liver MRI with three-dimensional cholangiography and concomitant analyses of serum bile acids were included. Gallbladder volume was measured by MRI and a cut-off of 50 ml was used to define gallbladder enlargement. Bile acid profiles and PSC severity, as assessed by blood tests and MRI features, were compared among patients according to gallbladder size (enlarged vs. normal-sized) or presence (removed vs. conserved). The impact of cholecystectomy was also assessed in the Abcb4 knockout mouse model of PSC.

RESULTS: Sixty-one patients with PSC, all treated with ursodeoxycholic acid (UDCA), were included. The gallbladder was enlarged in 30 patients, whereas 11 patients had been previously cholecystectomized. Patients with enlarged gallbladders had significantly lower alkaline phosphatase, a lower tauro-vs. glycoconjugate ratio and a higher UDCA vs. total bile acid ratio compared to those with normal-sized gallbladders. In addition, gallbladder volume negatively correlated with the hydrophobicity index of bile acids. Cholecystectomized patients displayed significantly higher aspartate aminotransferase and more severe bile duct strictures and dilatations compared to those with conserved gallbladder. In the Abcb4 knockout mice, cholecystectomy caused an increase in hepatic bile acid content and in circulating secondary bile acids, and an aggravation in cholangitis, inflammation and liver fibrosis.

CONCLUSION: Altogether, our findings indicate that the gallbladder fulfills protective functions in PSC.

IMPACT AND IMPLICATIONS: In patients with primary sclerosing cholangitis (PSC), gallbladder status impacts on bile acid homeostasis and disease features. We found evidence of lessened bile acid toxicity in patients with PSC and enlarged gallbladders and of increased disease severity in those who were previously cholecystectomized. In the Abcb4 knockout mouse model of PSC, cholecystectomy causes an aggravation of cholangitis and liver fibrosis. Overall, our results suggest that the gallbladder plays a protective role in PSC.

PMID:36923239 | PMC:PMC10009728 | DOI:10.1016/j.jhepr.2022.100649

J Cyst Fibros. 2023 Mar 13:S1569-1993(23)00070-X. doi: 10.1016/j.jcf.2023.03.006. Online ahead of print.

ABSTRACT

At the same level of lung function, some patients with cystic fibrosis have large variations in their FEV1 percent predicted (FEV1pp) values while others have stable values. We hypothesised that lower adherence to nebuliser therapies was associated with higher FEV1pp variability. We conducted a post hoc analysis of the ACtiF trial data. Adherence was calculated using data from data-logging nebulisers, and FEV1pp variability using the coefficient of variation equation. Amongst the 543 patients included in the analysis, those poorly adherent (adherence < 50%) had a higher FEV1pp variability than patients moderately (50 to < 80%) and highly adherent (≥ 80%), with median values (IQR1-3) of 8.1% (4.9-13.7), 6.3% (3.9-9.8), and 6.3% (3.9-9.3) respectively (p < 0.01). This result was confirmed by a multiple linear regression including adherence as a continuous variable (p < 0.01). Further studies are needed to determine the implications of these differences in FEV1pp variability on the prognosis of patients.

PMID:36922289 | DOI:10.1016/j.jcf.2023.03.006

J Cyst Fibros. 2023 Mar 13:S1569-1993(23)00061-9. doi: 10.1016/j.jcf.2023.02.009. Online ahead of print.

ABSTRACT

BACKGROUND: The Cystic Fibrosis Foundation Patient Registry (CFFPR) collects data on individuals with cystic fibrosis (CF) in the United States (US). In 2012, the US CF population was estimated at 33,292 to 34,327 individuals, with 81-84% CFFPR participation.

METHODS: In this study, we update these estimates via simulation to account for uncertainty in CF incidence by race or Hispanic ethnicity, initiation of CF newborn screening (NBS) programs by state, and updated cumulative survival for CF births 1968-2020. We defined registry participation as the proportion of individuals alive as of 2020 with any prior CFFPR participation as well as the proportion with contributing data in 2019 or 2020; we summarize CFFPR participation for those born prior to 1968.

RESULTS: We estimated the 2020 prevalent CF population between 1968-2020 to be 38,804 (95% Uncertainty Interval (UI): 38,532 to 39,065) individuals, with 77% of the prevalent CF population contributing recent data. CFFPR participation differs by age (54% of those born in 1968) and exceeds >90% of the population born in 2009 or later.

CONCLUSIONS: We demonstrate that the CFFPR remains a valid data source generalizable to the CF population. High participation among younger individuals may reflect the success of newborn screening programs and early referral to CF care. If engagement can be sustained, the percentage of individuals participating in the CFFPR will grow over time and there is an opportunity to identify factors associated with loss to follow up among older individuals to optimize the quality of the CFFPR data. (check on to reread..felt like a run on?).

PMID:36922288 | DOI:10.1016/j.jcf.2023.02.009

Int J Med Inform. 2023 Mar 7;173:105039. doi: 10.1016/j.ijmedinf.2023.105039. Online ahead of print.

ABSTRACT

OBJECTIVE: We identify factors related to SARS-CoV-2 infection linked to hospitalization, ICU admission, and mortality and develop clinical prediction rules.

METHODS: Retrospective cohort study of 380,081 patients with SARS-CoV-2 infection from March 1, 2020 to January 9, 2022, including a subsample of 46,402 patients who attended Emergency Departments (EDs) having data on vital signs. For derivation and external validation of the prediction rule, two different periods were considered: before and after emergence of the Omicron variant, respectively. Data collected included sociodemographic data, COVID-19 vaccination status, baseline comorbidities and treatments, other background data and vital signs at triage at EDs. The predictive models for the EDs and the whole samples were developed using multivariate logistic regression models using Lasso penalization.

RESULTS: In the multivariable models, common predictive factors of death among EDs patients were greater age; being male; having no vaccination, dementia; heart failure; liver and kidney disease; hemiplegia or paraplegia; coagulopathy; interstitial pulmonary disease; malignant tumors; use chronic systemic use of steroids, higher temperature, low O2 saturation and altered blood pressure-heart rate. The predictors of an adverse evolution were the same, with the exception of liver disease and the inclusion of cystic fibrosis. Similar predictors were found to be related to hospital admission, including liver disease, arterial hypertension, and basal prescription of immunosuppressants. Similarly, models for the whole sample, without vital signs, are presented.

CONCLUSIONS: We propose risk scales, based on basic information, easily-calculable, high-predictive that also function with the current Omicron variant and may help manage such patients in primary, emergency, and hospital care.

PMID:36921481 | DOI:10.1016/j.ijmedinf.2023.105039

Addict Behav. 2023 Feb 20;142:107669. doi: 10.1016/j.addbeh.2023.107669. Online ahead of print.

ABSTRACT

BACKGROUND: This study assesses use and perceptions of short- and long-term harms associated with cigarettes, e-cigarettes, and smoked marijuana among adolescents and young adults (AYAs) with cystic fibrosis (CF).

METHODS: A total of 205 AYAs with CF completed an online survey querying about use, safety perceptions, and education related to traditional cigarettes, electronic cigarettes (e-cigarettes), and smoked marijuana. In addition, parents of AYAs with CF and CF healthcare providers were asked questions about experiences in avoidance education.

RESULTS: AYA participants with CF reported using tobacco and marijuana at rates lower than that of the general AYA population, with heavy use considerably lower in this population. AYAs with CF perceived lower risk of negative outcomes associated with using e-cigarettes and smoked marijuana compared to combustible cigarettes. Ever-use was correlated with a lower perception of risk across all products. CF providers estimated lower rates of product use in their own patients compared to both the general AYA CF population and the general AYA population, and estimated lower use among the general CF AYA population compared to the general AYA population. Receipt of avoidance education varied greatly when comparing AYAs with CF, parents of individuals with CF, and CF healthcare providers. Reasons for undereducation include but are not limited to lack of familiarity with products, assumption of avoidance, assumption of education, and time constraints.

CONCLUSIONS: Findings concerning safety perceptions and use of combustible tobacco, e-cigarettes, and marijuana in individuals with cystic fibrosis underscore the importance of providing avoidance education to vulnerable patient populations. Insight derived from this study may also inform pediatric to adult clinic transition education, when chronic disease populations are at greatest risk for engaging in risky behaviors.

IMPLICATIONS AND CONTRIBUTION: We report data on use, risk perception, and education of cigarettes, electronic cigarettes, and cannabis in individuals with cystic fibrosis, with a focus on adolescents and young adults. Such Findings will inform prevention education, especially during the critical transition period from pediatric to adult care when these behaviors are prevalent.

PMID:36921439 | DOI:10.1016/j.addbeh.2023.107669

Am J Respir Crit Care Med. 2023 Mar 15. doi: 10.1164/rccm.202209-1653OC. Online ahead of print.

ABSTRACT

RATIONALE: Lung disease is the major cause of morbidity and mortality in persons with cystic fibrosis (pwCF). Variability in CF lung disease has substantial non-CFTR genetic influence. Identification of genetic modifiers has prognostic and therapeutic importance.

OBJECTIVES: Identify genetic modifier loci and genes/pathways associated with pulmonary disease severity.

METHODS: Whole genome sequencing (WGS) data on 4,248 unique pwCF with pancreatic insufficiency (PI) and lung function measures were combined with imputed genotypes from an additional 3,592 PI patients from the US, Canada, and France. This report describes association of ~15.9 million single nucleotide polymorphisms (SNPs), using the quantitative Kulich Normal Residual Mortality Adjusted (KNoRMA) lung disease phenotype in 7,840 pwCF using pre-modulator lung function data.

MEASUREMENTS AND MAIN RESULTS: Testing included common and rare SNPs, transcriptome-wide association, gene level, and pathway analyses. Pathway analyses identified novel associations with genes that have key roles in organ development, and we hypothesize these genes may relate to dysanapsis and/or variability in lung repair. Results confirmed and extended previous GWAS findings. These WGS data provide finely mapped genetic information to support mechanistic studies. No novel primary associations with common single variants or with rare variants were found. Multi-locus effects at chr5p13 (SLC9A3/CEP72) and chr11p13 (EHF/APIP) were identified. Variant effect size estimates at associated loci were consistently ordered across the cohorts, indicating possible age or birth cohort effects.

CONCLUSIONS: This pre-modulator genomic, transcriptomic, and pathway association study of 7,840 pwCF will facilitate mechanistic and post-modulator genetic studies and, development of novel therapeutics for CF lung disease.

PMID:36921087 | DOI:10.1164/rccm.202209-1653OC

Am J Respir Crit Care Med. 2023 Mar 15. doi: 10.1164/rccm.202301-0084OC. Online ahead of print.

ABSTRACT

RATIONALE: Elexacaftor/tezacaftor/ivacaftor has been shown to be safe and effective in people with cystic fibrosis (CF) aged ≥6 years with ≥1 F508del-CFTR allele but has not been studied in younger children.

OBJECTIVES: To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of elexacaftor/tezacaftor/ivacaftor in children with CF aged 2 through 5 years.

METHODS: In this Phase 3, open-label, two-part study (Parts A and B), children weighing <14 kg (on Day 1) received elexacaftor 80 mg once daily, tezacaftor 40 mg once daily, and ivacaftor 60 mg each morning and 59.5 mg each evening; children weighing ≥14 kg received elexacaftor 100 mg once daily, tezacaftor 50 mg once daily, and ivacaftor 75 mg every 12 hours.

MEASUREMENTS AND MAIN RESULTS: The primary endpoints for Part A (15-day treatment period) were pharmacokinetics and safety and tolerability. For Part B (24-week treatment period), the primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics and absolute changes from baseline in sweat chloride concentration and lung clearance index2.5 (LCI2.5) through Week 24. Analysis of pharmacokinetic data from 18 children enrolled in Part A confirmed the appropriateness of the Part B dosing regimen. In Part B, 75 children (F508del/minimal function genotypes, n = 52; F508del/F508del genotype, n = 23) were enrolled and dosed. Seventy-four children (98.7%) had adverse events which were all mild (62.7%) or moderate (36.0%) in severity. The most common adverse events were cough, fever, and rhinorrhea. Decreases in sweat chloride concentration (-57.9 mmol/L [95% confidence interval [CI], -61.3 to -54.6]; n = 69) and LCI2.5 (-0.83 units [95% CI, -1.01 to -0.66]; n = 50) were observed from baseline through Week 24. Mean BMI was within the normal range at baseline and remained stable at Week 24.

CONCLUSIONS: In this open label study in children 2 through 5 years of age, elexacaftor/tezacaftor/ivacaftor treatment was generally safe and well tolerated, with a safety profile consistent with that observed in older age groups, and led to clinically meaningful reductions in sweat chloride concentration and lung clearance index. Clinical trial registration available at www.

CLINICALTRIALS: gov, ID: NCT04537793.

PMID:36921081 | DOI:10.1164/rccm.202301-0084OC

Monaldi Arch Chest Dis. 2023 Mar 13. doi: 10.4081/monaldi.2023.2480. Online ahead of print.

ABSTRACT

Lung disease in cystic fibrosis (CF) is characterized by reduced mucociliary clearance, airway plugging, recurrent infections and chronic pulmonary inflammation. Patients who are affected undergo daily respiratory physiotherapy to improve airway clearance. Intrapulmonary percussive ventilation (IPV) is a technique used in clinical practice, but it is not commonly used in CF patients. Evidence in various respiratory pathologies, particularly in children, is still lacking. We present the case of an eleven-year-old boy with cystic fibrosis who did not respond to traditional respiratory physiotherapy techniques. We proposed and tested the use of IPV during hospitalization. In this case, the use of IPV in physiotherapy treatment reduced the need for intravenous antibiotics, hospitalization, and improved radiologic features. IPV can be used successfully in CF patients who are resistant to traditional physiotherapy techniques.

PMID:36919538 | DOI:10.4081/monaldi.2023.2480

Adv Med Sci. 2023 Mar 12;68(1):111-120. doi: 10.1016/j.advms.2023.02.003. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive disease caused by defects in the CF transmembrane conductance regulator (CFTR) protein. Due to the genetic nature of the disease, interventions in the genome can target any underlying alterations and potentially provide permanent disease resolution. The current development of gene-editing tools, such as designer nuclease technology capable of genome correction, holds great promise for both CF and other genetic diseases. In recent years, Cas9-based technologies have enabled the generation of genetically defined human stem cell and disease models based on induced pluripotent stem cells (iPSC). In this article, we outline the potential and possibilities of using CRISPR/Cas9-based gene-editing technology in CF modeling.

PMID:36917892 | DOI:10.1016/j.advms.2023.02.003

J Cyst Fibros. 2023 Jan;22(1):17-30. doi: 10.1016/j.jcf.2022.10.002. Epub 2022 Oct 28.

ABSTRACT

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF. The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy. We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF. Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy.

PMID:36916675 | DOI:10.1016/j.jcf.2022.10.002

Trop Doct. 2023 Mar 14:494755231160263. doi: 10.1177/00494755231160263. Online ahead of print.

ABSTRACT

Burkholderia, a multidrug-resistant Gram-negative bacteria, is an uncommon cause of infection mostly in immunocompromised patients with a clinical profile very similar to tuberculosis. The most common conditions associated with this organism are cystic fibrosis and chronic granulomatous diseases. Bacteremia with it occurs in patients who are chronically ill and associated with significant morbidity and mortality. We are reporting here a case of perisplenic intra-abdominal abscess caused by Burkholderia cepacia in a patient with sickle cell disease (SCD).

PMID:36916218 | DOI:10.1177/00494755231160263

Allergy Asthma Clin Immunol. 2023 Mar 13;19(1):21. doi: 10.1186/s13223-023-00757-8.

ABSTRACT

PURPOSE: Peanut allergy and its current management, involving peanut avoidance and use of rescue medication during instances of accidental exposure, are burdensome to patients and their caregivers and can be a source of stress, uncertainty, and restriction. Physicians may also be frustrated with a lack of effective and safe treatments other than avoidance in the current management of peanut allergy. Efficacy, determined using double-blind, placebo-controlled food challenges (DBPCFCs), of oral immunotherapy with peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; Palforzia®) was demonstrated versus placebo in children and adolescents aged 4 to 17 years in multiple phase 3 trials; continued benefit of PTAH was shown in a follow-on trial. The DBPCFC is a reproducible, rigorous, and clinically meaningful assessment accepted by regulatory authorities to evaluate the level of tolerance as an endpoint for accidental exposures to peanut in real life. It also provides useful clinical and patient-relevant information, including the amount of peanut protein an individual with peanut allergy can consume without experiencing dose-limiting symptoms, severity of symptoms, and organs affected upon ingestion of peanut protein. We explored symptoms of peanut exposure during DBPCFCs from phase 3 and follow-on trials of PTAH to further characterize treatment efficacy from a perspective relevant to patients, caregivers, and clinicians.

METHODS: Symptom data recorded during screening and/or exit DBPCFCs from participants aged 4 to 17 years receiving PTAH or placebo were examined post hoc across three PTAH trials (PALISADE [ARC003], ARC004 [PALISADE follow-on], and ARTEMIS [ARC010]). The maximum peanut protein administered as a single dose during DBPCFCs was 1000 mg (PALISADE and ARTEMIS) and 2000 mg (ARC004). Symptoms were classified by system organ class (SOC) and maximum severity. Endpoints were changes in symptom severity and freedom from symptoms (ie, asymptomatic) during DBPCFC. Relative risk (RR) was calculated for symptom severity by SOC and freedom from symptoms between groups; descriptive statistics were used to summarize all other data.

RESULTS: The risk of any respiratory (RR 0.42 [0.30-0.60], P < 0.0001), gastrointestinal (RR 0.34 [0.26-0.44], P < 0.0001), cardiovascular/neurological (RR 0.17 [0.08-0.39], P < 0.001), or dermatological (RR 0.33 [0.22-0.50], P < 0.0001) symptoms was significantly lower in participants treated with PTAH versus placebo upon exposure to peanut at the end of the PALISADE trial (ie, exit DBPCFC). Compared with placebo-treated participants (23.4%), the majority (76.3%) of PTAH-treated participants had no symptoms at the exit DBPCFC when tested at the peanut protein dose not tolerated (ie, reactive dose) during the screening DBPCFC. Significantly higher proportions of PTAH-treated participants were asymptomatic at doses ≤ 100 mg in the exit DBPCFC compared with placebo-treated participants (PALISADE: 69.35% vs 12.10%, RR 5.73 [95% confidence interval (CI) 3.55-9.26]; P < 0.0001; ARTEMIS: 67.42% vs 13.95%, RR 4.83 [95% CI 2.28-10.25]; P < 0.0001); findings were similar at peanut protein doses ≤ 1000 mg (PALISADE: RR 15.56 [95% CI 5.05-47.94]; P < 0.0001; ARTEMIS: RR 34.74 [95% CI 2.19-551.03]; P < 0.0001). In ARC004, as the period of PTAH maintenance became longer, greater proportions of participants were asymptomatic at doses of peanut protein ≤ 1000 mg in the exit DBPCFC (from 37.63% after ~ 6 months of maintenance treatment [exit DBPCFC of PALISADE] to 45.54% after ~ 13 months and 58.06% after ~ 20 months of overall PTAH maintenance treatment).

CONCLUSIONS: PTAH significantly reduced symptom severity due to exposure to peanut, which is clinically relevant. When exposed to peanut, participants with peanut allergy treated with PTAH rarely had moderate or severe respiratory or cardiovascular/neurological symptoms. Oral immunotherapy with PTAH appears to reduce frequency and severity of allergic reactions in individuals with peanut allergy after accidental exposure to peanut and may enable them and their families to have an improved quality of life. Trial registration ClinicalTrials.gov, NCT02635776, registered 17 December 2015, https://clinicaltrials.gov/ct2/show/NCT02635776?term=AR101&draw=2&rank=7 ; ClinicalTrials.gov, NCT02993107, registered 08 December 2016, https://clinicaltrials.gov/ct2/show/NCT02993107?term=AR101&draw=2&rank=6 ; ClinicalTrials.gov, NCT03201003, registered 22 June 2017, https://clinicaltrials.gov/ct2/show/NCT03201003 ? term = AR101&draw = 2&rank = 9.

PMID:36915184 | DOI:10.1186/s13223-023-00757-8