Pediatr Pulmonol. 2022 Oct 3. doi: 10.1002/ppul.26179. Online ahead of print.

ABSTRACT

BACKGROUND: Investigating inconclusive cystic fibrosis (CF) diagnosis in children is difficult without advanced cystic fibrosis transmembrane conductance regulator (CFTR) function tests. This study investigated the utility of beta (β)-adrenergic sweat test to exclude CF in participants with inconclusive diagnosis (CF suspects) in South Africa.

METHODS: β-adrenergic sweat test and sweat chloride tests (SCT) were performed simultaneously in CF suspects and adult controls (healthy, CFTR heterozygotes and CF). Cholinergic and β-adrenergic induced sweat rate was measured by evaporimetry (transepithelial water loss, TEWL: gm H2 O/m2 /hr) following intradermal injections. Next generation sequencing of CFTR was performed in CF suspects. CF diagnosis was defined by genotype.

RESULTS: Thirty-seven controls (10 healthy, 14 CF, 13 CFTR heterozygotes) and 32 CF suspects (26 children; 6 adults) were enrolled. Six were excluded from formal analyses due to β-adrenergic sweat test failure. In adults, evaporimetry was superior to SCT for diagnosis of CF with β-adrenergic:cholinergic ratio TEWL ≤ 0.05 achieving100% sensitivity and specificity. Twenty-two CF suspect children (age range 3.4 -15.6 years) completed β-adrenergic sweat testing of which none had CF confirmed by genotyping: β-adrenergic:cholinergic ratio >0.05 successfully excluded CF in all but one child who was CFTR heterozygous. Median peak β-adrenergic TEWL and β-adrenergic:cholinergic ratio in CFTR negative and CFTR heterozygous children was significantly lower than adult controls.

CONCLUSION: β-adrenergic sweat test is more accurate than SCT for excluding CF in children with inconclusive diagnosis. Established reference ranges for β-adrenergic sweat test may not be suitable for children due to lower β-adrenergic sweat secretion compared to adults. This article is protected by copyright. All rights reserved.

PMID:36193559 | DOI:10.1002/ppul.26179

Pediatr Pulmonol. 2022 Oct 3. doi: 10.1002/ppul.26182. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a multisystemic autosomal recessive disease caused by a defect in the expression of CFTR protein. This article is protected by copyright. All rights reserved.

PMID:36193028 | DOI:10.1002/ppul.26182

Phys Ther. 2022 Oct 4:pzac136. doi: 10.1093/ptj/pzac136. Online ahead of print.

ABSTRACT

In looking back on 2020 and 2021, this Perspective reflects on the monumental impacts of the rollout of cystic fibrosis (CF) transmembrane conductance regulator highly effective modulator therapies and the COVID-19 pandemic on the management of CF. Advancements in the clinical management of people with CF have been both enormous and rapid, and physical therapists specializing in the care of people with CF have been at the forefront of driving this evolution in care. This year sees the thirtieth anniversary of the UK Association of Chartered Physiotherapists in Cystic Fibrosis and, as is inevitable in reaching such milestones, thoughts have turned to origins, role, impacts, and the future. With the changing demographics of the population of people with CF after the introduction of highly effective modulator therapies, potentially with fewer secondary complications, the future role of the physical therapist who specializes in CF is in question. This Perspective reflects upon and highlights the role of physical therapy within CF and provides insights into how physical therapists and respiratory therapists can evolve their roles to ensure relevance for the future.

PMID:36193006 | DOI:10.1093/ptj/pzac136

Commun Biol. 2022 Oct 3;5(1):1054. doi: 10.1038/s42003-022-03991-9.

ABSTRACT

Projected potential of 2.5-4.0 Å cryo-EM structures for structure-based drug design is not well realized yet. Here we show that a 3.1 Å structure of PRMT5 is suitable for selecting computed poses of a chemical inhibitor and its analogs for enhanced potency. PRMT5, an oncogenic target for various cancer types, has many inhibitors manifesting little cooperativity with MTA, a co-factor analog accumulated in MTAP-/- cells. To achieve MTA-synergic inhibition, a pharmacophore from virtual screen leads to a specific inhibitor (11-2 F). Cryo-EM structures of 11-2 F / MTA-bound human PRMT5/MEP50 complex and its apo form resolved at 3.1 and 3.2 Å respectively show that 11-2 F in the catalytic pocket shifts the cofactor-binding pocket away by ~2.0 Å, contributing to positive cooperativity. Computational analysis predicts subtype specificity of 11-2 F among PRMTs. Structural analysis of ligands in the binding pockets is performed to compare poses of 11-2 F and its redesigned analogs and identifies three new analogs predicted to have significantly better potency. One of them, after synthesis, is ~4 fold more efficient in inhibiting PRMT5 catalysis than 11-2 F, with strong MTA-synergy. These data suggest the feasibility of employing near-atomic resolution cryo-EM structures and computational analysis of ligand poses for small molecule therapeutics.

PMID:36192627 | DOI:10.1038/s42003-022-03991-9

Aust J Prim Health. 2022 Oct 4. doi: 10.1071/PY21247. Online ahead of print.

ABSTRACT

BACKGROUND: The Royal Australian and New Zealand College of Obstetricians and Gynaecologists and The Royal Australian College of General Practice recommend that information on carrier screening for at least the most common inherited genetic conditions in our population, that is, thalassaemia, cystic fibrosis (CF), spinal muscular atrophy (SMA), and fragile X syndrome (FXS), should be offered to all women planning pregnancy or in early pregnancy regardless of family history or ethnicity. The aim of this study was to investigate patterns of participation by healthcare providers (HCP) and the community in screening.

METHODS: Participation in a Victorian program screening for CF, SMA and FXS between September 2013 and October 2018 was analysed. Requesting HCP and patient data were extracted from screening request forms. Data were analysed with respect to profession of requesting HCP, and characteristics of women screened (age, pregnancy status, socioeconomic status, geographic location, and family history of CF, SMA or FXS). In total, 21 172 women and 1288 HCPs participated in the program over this period.

RESULTS: There was a steep socioeconomic gradient in screening uptake, with nearly half the women screened (10 349) being in the highest socioeconomic quintile. The screening rate was much higher in metropolitan areas than in regional areas. Obstetricians made most of the requests for screening, whereas 20% of requests were by GPs. Most participating GPs only made a single screening request (78%) and very few GPs made >100 screening requests compared with obstetricians (0.2% vs 17%). GPs were more likely to screen women before pregnancy compared with obstetricians (47% vs 11%). Approximately 1.5% of Victorian women of child-bearing age and 3% of pregnant Victorian women were screened by this program over the period of this study.

CONCLUSION: This study highlights the translation gap between recommendations and practice, with marked inequity of access to reproductive genetic carrier screening in relation to socioeconomic status and geography. Increased participation by GPs could improve community access to reproductive genetic carrier screening, particularly access to preconception screening. Addressing the causes of inequity of access will allow more women and couples the opportunity to make informed choices about participation in screening.

PMID:36192111 | DOI:10.1071/PY21247

Microbiol Spectr. 2022 Oct 3:e0169722. doi: 10.1128/spectrum.01697-22. Online ahead of print.

ABSTRACT

Multidrug-resistant (MDR) Pseudomonas aeruginosa increasingly causes health care-associated infections. In this study, we determined the activity of ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol against 223 MDR P. aeruginosa clinical isolates recovered from 2013 to 2017 at the University Hospital Frankfurt by using MIC test strips. Furthermore, we evaluated the presence of genes encoding major β-lactamases, such as VIM, IMP, NDM, GIM, SPM, and KPC; the extended spectrum β-lactamase (ESBL)-carbapenemase GES; and the virulence-associated traits ExoS and ExoU, as in particular ExoU is thought to be associated with poor clinical outcome. For MDR P. aeruginosa isolates, the MIC50/MIC90 values of ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol were 8/>256 mg/L, 16/>256 mg/L, and 0.25/1 mg/L, respectively. Cefiderocol showed the highest susceptibility rate (97.3%) followed by ceftazidime-avibactam (48.4%) and ceftolozane-tazobactam (46.6%). In 81 (36.3%) isolates, carbapenemase gene blaVIM was detected, and in 5 (2.2%) isolates, blaGES was detected (with a positive association of exoU and blaVIM). More than half of the isolates belong to the so-called international P. aeruginosa "high-risk" clones, with sequence type 235 (ST235) (24.7%) being the most prevalent. This study underlines that ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol are important options for the treatment of infections due to MDR P. aeruginosa, with cefiderocol currently being the most active available antipseudomonal β-lactam agent. According to our clinical experience, the outcome of cefiderocol therapy (8 patients) was favorable especially in cases of MDR P. aeruginosa-associated complicated urinary tract infections. IMPORTANCE After testing ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol against a collection of 233 multidrug-resistant (MDR) Pseudomonas aeruginosa, we showed that cefiderocol is the most active antipseudomonal β-lactam agent (susceptibility rates were 46.6%, 48.4%, and 97.4%, respectively). The most prevalent one was sequence type 235 (ST235) (24.7%), followed by ST244, ST175, and ST233, with all belonging to the top 10 P. aeruginosa high-risk clones with worldwide distribution. Our data indicate that during surveillance studies special attention should be paid to the MDR and highly virulent VIM- and ExoU-producing variant of ST235. Furthermore, in the case of infections caused by carbapenemase-producing MDR P. aeruginosa, cefiderocol is the preferred treatment option, while outcomes of complicated urinary tract infections and hospital-acquired pneumonia with cefiderocol were favorable.

PMID:36190424 | DOI:10.1128/spectrum.01697-22

mSystems. 2022 Oct 3:e0035422. doi: 10.1128/msystems.00354-22. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa populations evolving in cystic fibrosis lungs, animal hosts, natural environments and in vitro undergo extensive genetic adaption and diversification. A common mutational target is the quorum sensing (QS) system, a three-unit regulatory system that controls the expression of virulence factors and secreted public goods. Three evolutionary scenarios have been advocated to explain selection for QS mutants: (i) disuse of the regulon, (ii) cheating through the exploitation of public goods, or (ii) modulation of the QS regulon. Here, we examine these scenarios by studying a set of 61 QS mutants from an experimental evolution study. We observed nonsynonymous mutations in all three QS systems: Las, Rhl, and Pseudomonas Quinolone Signal (PQS). The majority of the Las mutants had large deletions of the Las regulon, resulting in loss of QS function and the inability to produce QS-regulated traits, thus supporting the first or second scenarios. Conversely, phenotypic and gene expression analyses of Rhl mutants support network modulation (third scenario), as these mutants overexpressed the Las and Rhl receptors and showed an altered QS-regulated trait production profile. PQS mutants also showed patterns of regulon modulation leading to strain diversification and phenotypic tradeoffs, where the upregulation of certain QS traits is associated with the downregulation of others. Overall, our results indicate that mutations in the different QS systems lead to diverging effects on the QS trait profile in P. aeruginosa populations. These mutations might not only affect the plasticity and diversity of evolved populations but could also impact bacterial fitness and virulence in infections. IMPORTANCE Pseudomonas aeruginosa uses quorum sensing (QS), a three-unit multilayered network, to coordinate expression of traits required for growth and virulence in the context of infections. Despite its importance for bacterial fitness, the QS regulon appears to be a common mutational target during long-term adaptation of P. aeruginosa in the host, natural environments, and experimental evolutions. This raises questions of why such an important regulatory system is under selection and how mutations change the profile of QS-regulated traits. Here, we examine a set of 61 experimentally evolved QS mutants to address these questions. We found that mutations involving the master regulator, LasR, resulted in an almost complete breakdown of QS, while mutations in RhlR and PqsR resulted in modulations of the regulon, where both the regulon structure and the QS-regulated trait profile changed. Our work reveals that natural selection drives diversification in QS activity patterns in evolving populations.

PMID:36190124 | DOI:10.1128/msystems.00354-22

Arch Comput Methods Eng. 2022 Sep 28:1-34. doi: 10.1007/s11831-022-09818-4. Online ahead of print.

ABSTRACT

Airway disease is a major healthcare issue that causes at least 3 million fatalities every year. It is also considered one of the foremost causes of death all around the globe by 2030. Numerous studies have been undertaken to demonstrate the latest advances in artificial intelligence algorithms to assist in identifying and classifying these diseases. This comprehensive review aims to summarise the state-of-the-art machine and deep learning-based systems for detecting airway disorders, envisage the trends of the recent work in this domain, and analyze the difficulties and potential future paths. This systematic literature review includes the study of one hundred fifty-five articles on airway diseases such as cystic fibrosis, emphysema, lung cancer, Mesothelioma, covid-19, pneumoconiosis, asthma, pulmonary edema, tuberculosis, pulmonary embolism as well as highlights the automated learning techniques to predict them. The study concludes with a discussion and challenges about expanding the efficiency and machine and deep learning-assisted airway disease detection applications.

PMID:36189431 | PMC:PMC9516534 | DOI:10.1007/s11831-022-09818-4

Front Microbiol. 2022 Sep 15;13:979610. doi: 10.3389/fmicb.2022.979610. eCollection 2022.

ABSTRACT

Multi drug resistant (MDR) bacteria are insensitive to the most common antibiotics currently in use. The spread of antibiotic-resistant bacteria, if not contained, will represent the main cause of death for humanity in 2050. The situation is even more worrying when considering patients with chronic bacterial infections, such as those with Cystic Fibrosis (CF). The development of alternative approaches is essential and novel therapies that combine exogenous and host-mediated antimicrobial action are promising. In this work, we demonstrate that asymmetric phosphatidylserine/phosphatidic acid (PS/PA) liposomes administrated both in prophylactic and therapeutic treatments, induced a reduction in the bacterial burden both in wild-type and cftr-loss-of-function (cftr-LOF) zebrafish embryos infected with Pseudomonas aeruginosa (Pa) PAO1 strain (PAO1). These effects are elicited through the enhancement of phagocytic activity of macrophages. Moreover, the combined use of liposomes and a phage-cocktail (CKΦ), already validated as a PAO1 "eater", improves the antimicrobial effects of single treatments, and it is effective also against CKΦ-resistant bacteria. We also address the translational potential of the research, by evaluating the safety of CKΦ and PS/PA liposomes administrations in in vitro model of human bronchial epithelial cells, carrying the homozygous F508del-CFTR mutation, and in THP-1 cells differentiated into a macrophage-like phenotype with pharmacologically inhibited CFTR. Our results open the way to the development of novel pharmacological formulations composed of both phages and liposomes to counteract more efficiently the infections caused by Pa or other bacteria, especially in patients with chronic infections such those with CF.

PMID:36188006 | PMC:PMC9520727 | DOI:10.3389/fmicb.2022.979610

Front Med (Lausanne). 2022 Sep 14;9:959584. doi: 10.3389/fmed.2022.959584. eCollection 2022.

ABSTRACT

Along with the significant elongation in the average life expectancy of patients with cystic fibrosis (CF), there are still significant discrepancies in the height, weight, and body mass index (BMI) of patients compared to controls without CF. The correlation between hormones that regulate appetite and body fat mass may be an additional factor in weight loss or poor weight gain in CF patients. Our objective was to estimate serum concentrations of leptin and neuropeptide Y in patients with CF as well as to assess correlations between studied hormones and the clinical parameters of CF. Leptin and neuropeptide Y serum concentrations after an overnight fast were measured using an enzyme-linked immunosorbent assay. All study participants had anthropometric tests and spirometry. In addition, fasting serum lipid profile was also analyzed. Fasting leptin levels in CF were significantly higher in patients with CF patients (13.9 ± 6.9 vs. 6.5 ± 2.6 ng/mL, p < 0.001) compared to controls. There were no differences in leptin concentration between female and male CF participants (15.7 ± 7.8 vs. 12.2 ± 5.6 ng/mL, p = 0.13). Leptin was correlated with age (R = 0.64, p < 0.001), BMI (R = 0.65, p < 0.001), spirometry results (R = -0.49, p < 0.01), and body fat (R = 0.5, p < 0.05). There were no differences in neuropeptide Y concentration between participants with CF and controls as well as neuropeptide Y was not correlated with any studied parameters. The results of our study suggest that weight loss may be associated with a decreased level of leptin, while reduced pulmonary function in CF may be related to an elevated level of leptin.

PMID:36186778 | PMC:PMC9515389 | DOI:10.3389/fmed.2022.959584

Front Pediatr. 2022 Sep 15;10:953429. doi: 10.3389/fped.2022.953429. eCollection 2022.

ABSTRACT

BACKGROUND: In the absence of randomized controlled trials (RCTs) on the benefits of therapeutic exercise programs involving children with bronchiectasis, we undertook a pilot RCT to evaluate the effects of a play-based therapeutic exercise program on fundamental movement skill (FMS) proficiency. The effects of the program on cardiorespiratory fitness, perceived competence, and health-related quality of life (HR-QoL) were examined as secondary outcomes.

METHODS: Children [median (IQR) age: 6.8 (5.3-8.8) years] with bronchiectasis unrelated to cystic fibrosis were randomized to a 7-week therapeutic exercise program (n = 11) or wait-list control (n = 10). The exercise program comprised 7 × 60-min weekly sessions and was supplemented by a home-based program 2-days/week. Participants were assessed on: FMS (locomotor and object control skills) using the Test of Gross Motor Development 2nd Edition (TGMD-2); cardiovascular fitness by calculating the percent change in heart rate (%ΔHR) from rest to completion of the first stage of a submaximal treadmill test; perceived competence using Harter's athletic competence subscale; and QoL with the PedsQL.

RESULTS: Significant group by time interactions were observed for locomotor and object control skills. Children completing the therapeutic exercise program exhibited significant improvements in both locomotor (pre 29.0 ± 2.0, post 35.2 ± 2.2, p = 0.01) and object control (pre 27.0 ± 2.0, post 35.5 ± 2.2, p = 0.01) skills, with no significant change in controls (pre 31.6 ± 2.1, post 31.8 ± 2.3 and pre 31.0 ± 2.1, post 32.3 ± 2.3, respectively). Among children completing the program, %ΔHR declined by 6% points, while %ΔHR declined only marginally among controls (0.9% points), but the group by time interaction was not statistically significant. The program had a small positive impact on competence perceptions (Cohen's d = 0.2) and HR-QoL (Cohen's d = 0.3).

CONCLUSION: This pilot RCT provides preliminary evidence for the efficacy of a play-based therapeutic exercise program to improve proficiency in FMS and fitness in children with bronchiectasis. The results are sufficiently positive to warrant conducting a larger RCT testing the efficacy of the exercise program in children with bronchiectasis and/or other chronic respiratory conditions.

PMID:36186646 | PMC:PMC9520333 | DOI:10.3389/fped.2022.953429

Front Pediatr. 2022 Sep 16;10:1010016. doi: 10.3389/fped.2022.1010016. eCollection 2022.

ABSTRACT

Bronchiectasis (not related to cystic fibrosis) is a chronic lung disease caused by a range of etiologies but characterized by abnormal airway dilatation, recurrent respiratory symptoms, impaired quality of life and reduced life expectancy. Patients typically experience episodes of chronic wet cough and recurrent pulmonary exacerbations requiring hospitalization. Early diagnosis and management of childhood bronchiectasis are essential to prevent respiratory decline, optimize quality of life, minimize pulmonary exacerbations, and potentially reverse bronchial disease. Disease monitoring potentially allows for (1) the early detection of acute exacerbations, facilitating timely intervention, (2) tracking the rate of disease progression for prognostic purposes, and (3) quantifying the response to therapies. This narrative review article will discuss methods for monitoring disease progression in children with bronchiectasis, including lung imaging, respiratory function, patient-reported outcomes, respiratory exacerbations, sputum biomarkers, and nutritional outcomes.

PMID:36186641 | PMC:PMC9523123 | DOI:10.3389/fped.2022.1010016

J Pediatr Pharmacol Ther. 2022;27(7):655-662. doi: 10.5863/1551-6776-27.7.655. Epub 2022 Sep 26.

ABSTRACT

OBJECTIVE: Aminoglycosides are frequently used for empiric and definitive treatment of cystic fibrosis (CF) pulmonary exacerbations. Various methods have been described for aminoglycoside therapeutic drug monitoring. The objective of this study is to evaluate the effect of patient-specific pharmacokinetic calculations for aminoglycosides used to treat CF pulmonary exacerbations.

METHODS: Ambidirectional cohort study of patients admitted to a children's hospital from June 1, 2018, through February 28, 2019, and June 1, 2019, through February 8, 2021. The primary outcome was the occurrence of dosing changes after analysis of initial serum concentrations in either group. Secondary outcomes included occurrence of nephrotoxicity, duration of antibiotics, and length of stay.

RESULTS: Twenty-four patients (75%) in the intervention group versus zero in the control group required dosing adjustments after initial analysis of serum concentrations were completed (p < 0.001). There was not a statistically significant between-group difference for duration of antibiotics in days (median, 14 vs 13.5; Z, 1.07; p = 0.29) or length of stay (median, 11 vs 11; Z, -0.31; p = 0.76). There was also not a statistically significant between-group difference in forced expiratory volume in one second (FEV1) change from admission to discharge (11.4% vs 13.9%; t, 0.61; Degrees of Freedom, 39; p = 0.55). Two patients (6.25%) in the intervention group experienced nephrotoxicity compared with zero patients in the control group (risk difference, 6.25%; 95% CI, -2.14 to 14.64; number needed to harm, 16).

CONCLUSIONS: Patient-specific pharmacokinetic monitoring led to significantly more dosing changes and was associated with similar patient outcomes as trough-only monitoring. Further studies are needed to identify methods to optimize aminoglycoside dosing and monitoring for these patients with the goal of reducing toxicities while maximizing efficacy.

PMID:36186239 | PMC:PMC9514759 | DOI:10.5863/1551-6776-27.7.655

Oncoimmunology. 2022 Sep 23;11(1):2127273. doi: 10.1080/2162402X.2022.2127273. eCollection 2022.

NO ABSTRACT

PMID:36185805 | PMC:PMC9518991 | DOI:10.1080/2162402X.2022.2127273

Clin Nutr ESPEN. 2022 Oct;51:367-376. doi: 10.1016/j.clnesp.2022.07.018. Epub 2022 Aug 8.

ABSTRACT

BACKGROUND & AIMS: Children with cystic fibrosis (CF) are susceptible to fat-soluble vitamin deficiencies unless supplemented, but even large doses of vitamin D may not prevent low 25-hydroxyvitamin D (25OHD) concentrations. The explanation for these vitamin D non-responders has been elusive. We utilized data from whole genome sequencing (WGS) to test the hypothesis that genetic variations predict responsiveness to vitamin D supplementation in a prospective cohort study of children with CF in the first 3 years of life.

METHODS: One hundred and one infants born during 2012-2017 and diagnosed with CF through newborn screening were studied. Serum 25OHD concentrations and vitamin D supplement doses were assessed during early infancy and annually thereafter. WGS was performed, the resultant variant calling files processed, and the summary statistics from a recent genome-wide association study were utilized to construct a polygenic risk score (PRS) for each subject.

RESULTS: Overall, the prevalence of vitamin D insufficiency (<30 ng/mL) was 21% in the first 3 years of life. Among the 70 subjects who always adhered to vitamin D supplement doses recommended by the US CF Foundation guidelines, 89% were responders (achieved vitamin D sufficiency) by 3 years of age, while 11% were transient or non-responders. Multiple regression analysis revealed that PRS was a significant predictor of 25OHD concentrations (p < 0.001) and the likelihood of being an earlier responder in the first 3 years of life (p < 0.01). A limited SNP analysis revealed variants in four important genes (GC, LIPC, CYP24A1, and PDE3B) that were shown to be associated with 25OHD concentrations and vitamin D responder status. Other determinants included vitamin D supplement dose, season at 25OHD measurement, and pancreatic functional status.

CONCLUSIONS: Applying WGS in conjunction with utilizing a PRS approach revealed genetic variations that partially explain the unresponsiveness of some children with CF to vitamin D supplementation. Our findings suggest that a nutrigenomics strategy could help promote personalized treatment in CF.

PMID:36184229 | DOI:10.1016/j.clnesp.2022.07.018

Chest. 2022 Sep 29:S0012-3692(22)03896-X. doi: 10.1016/j.chest.2022.08.2240. Online ahead of print.

ABSTRACT

There is now ample evidence that differences in sex and gender contribute to the incidence, susceptibility, presentation, diagnosis, and clinical course of many lung diseases. Some conditions are more prevalent in females, such as pulmonary arterial hypertension (PAH) and sarcoidosis. Some life stages -such as pregnancy- are unique to females and can affect the onset and course of lung disease. Clinical presentation may differ as well, such as higher number of exacerbations experienced by women with cystic fibrosis (CF), more fatigue in women with sarcoidosis, and more difficulty in achieving smoking cessation. Outcomes such as mortality may be different as well, as noted by higher mortality in females with CF. In addition, response to therapy and medication safety may also differ by sex, and yet, pharmacogenomic factors are often not adequately addressed in clinical trials. Various aspects of lung/sleep biology and pathobiology are impacted by female sex and female reproductive transitions. Differential gene expression or organ development can be impacted by these biologic differences. Understanding these differences is the first step in moving towards precision medicine for all patients.. This article is the second part of a state-of-the-art review of specific effects of sex and gender focused on epidemiology, disease presentation, risk factors and management of selected lung diseases. We review the recent literature and focus on recent guidelines incorporating sex and gender differences in pulmonary hypertension, cystic fibrosis (CF) and non-CF bronchiectasis, sarcoidosis, restless legs syndrome (RLS) and insomnia, and critical illness. We also provide a brief summary on effects of pregnancy on lung diseases and discuss impact of sex and gender on tobacco use and treatment of nicotine use disorder.

PMID:36183784 | DOI:10.1016/j.chest.2022.08.2240

FASEB J. 2022 Nov;36(11):e22534. doi: 10.1096/fj.202200313RR.

ABSTRACT

The solute carrier 26 family member A9 (SLC26A9) is an epithelial anion transporter that is assumed to contribute to airway chloride secretion and surface hydration. Whether SLC26A9 or CFTR is responsible for airway Cl- transport under basal conditions is still unclear, due to the lack of a specific inhibitor for SLC26A9. In the present study, we report a novel potent and specific inhibitor for SLC26A9, identified by screening of a drug-like molecule library and subsequent chemical modifications. The most potent compound S9-A13 inhibited SLC26A9 with an IC50 of 90.9 ± 13.4 nM. S9-A13 did not inhibit other members of the SLC26 family and had no effects on Cl- channels such as CFTR, TMEM16A, or VRAC. S9-A13 inhibited SLC26A9 Cl- currents in cells that lack expression of CFTR. It also inhibited proton secretion by HGT-1 human gastric cells. In contrast, S9-A13 had minimal effects on ion transport in human airway epithelia and mouse trachea, despite clear expression of SLC26A9 in the apical membrane of ciliated cells. In both tissues, basal and stimulated Cl- secretion was due to CFTR, while acidification of airway surface liquid by S9-A13 suggests a role of SLC26A9 for airway bicarbonate secretion.

PMID:36183361 | DOI:10.1096/fj.202200313RR

BMC Med Inform Decis Mak. 2022 Oct 1;22(1):257. doi: 10.1186/s12911-022-01989-1.

ABSTRACT

BACKGROUND: Chronic respiratory conditions are a prominent public health issue and thus, building a patient registry might facilitate both policy decision making and improvement of clinical management processes. Hellenic Registry of patients with Home Mechanical Ventilation (HR-HMV) was initiated in 2017 and a web-based platform is used to support patient data collection. Eighteen hospital departments (including sleep labs) across Greece participate in this initiative, focusing on recording data for both children and adult patients supported by mechanical ventilation at home, including patients with Sleep Apnea-Hypopnea Syndrome (SAHS) under Positive Airway Pressure (PAP) therapy.

METHODS: The HR-HMV initiative ultimately aims to provide a database for evidence-based care and policy making in this specific domain. To this end, a web information system was developed and data were manually collected by clinics and hospital departments. Legal and privacy issues (such as General Data Protection Rule compliance and technical information security measures) have been considered while designing the web application. Based on the collected data, an exploratory statistical report of SAHS patients in Greece is presented.

RESULTS: Eleven out of the eighteen participating clinics and hospital departments have contributed with data by the time of the current study. More than 5000 adult and children patient records have been collected so far, the vast majority of which (i.e., 4900 patients) diagnosed with SAHS.

CONCLUSION: The development and maintenance of patient registries is a valuable tool for policy decision making, observational/epidemiological research and beyond (e.g., health technology assessment procedures). However, as all data collection and processing approaches, registries are also related with potential biases. Along these lines, strengths and limitations must be considered when interpreting the collected data, and continuous validation of the collected clinical data per se should be emphasized. Especially for Greece, where the lack of national registries is eminent, we argue that HR-HMV could be a useful tool for the development and the update of related policies regarding the healthcare services for patients with home mechanical ventilation support and SAHS patients, which could be useful for related initiatives at a European level as well.

PMID:36182922 | DOI:10.1186/s12911-022-01989-1

Value Health. 2022 Sep 28:S1098-3015(22)02142-8. doi: 10.1016/j.jval.2022.08.002. Online ahead of print.

ABSTRACT

OBJECTIVES: The Munich Breathlessness Service (MBS) significantly improved control of breathlessness measured by the Chronic Respiratory Questionnaire (CRQ) Mastery in a randomized controlled fast track trial with waitlist group design spanning 8 weeks in Germany. This study aimed to assess the within-trial cost-effectiveness of MBS from a societal perspective.

METHODS: Data included generic (5-level version of EQ-5D) health-related quality of life and disease-specific CRQ Mastery. Quality-adjusted life years (QALYs) were calculated based on 5-level version of EQ-5D utilities valued with German time trade-off. Direct medical costs and productivity loss were calculated based on standardized unit costs. Incremental cost-effectiveness ratios (ICER) and cost-effectiveness-acceptance curves were calculated using adjusted mean differences (AMD) in costs (gamma-distributed model) and both effect parameters (Gaussian-distributed model) and performing 1000 simultaneous bootstrap replications. Potential gender differences were investigated in stratified analyses.

RESULTS: Between March 2014 and April 2019, 183 eligible patients were enrolled. MBS intervention demonstrated significantly better effects regarding generic (AMD of QALY gains of 0.004, 95% confidence interval [CI] 0.0003 to 0.008) and disease-specific health-related quality of life at nonsignificantly higher costs (AMD of €605 [95% CI -1109 to 2550]). At the end of the intervention, the ICER was €152 433/QALY (95% CI -453 545 to 1 625 903) and €1548/CRQ Mastery point (95% CI -3093 to 10 168). Intervention costs were on average €357 (SD = 132). Gender-specific analyses displayed dominance for MBS in males and higher effects coupled with significantly higher costs in females.

CONCLUSIONS: Our results show a high ICER for MBS. Considering dominance for MBS in males, implementing MBS on approval within the German health care system should be considered.

PMID:36182632 | DOI:10.1016/j.jval.2022.08.002

Transplant Proc. 2022 Sep 27:S0041-1345(22)00566-8. doi: 10.1016/j.transproceed.2022.08.022. Online ahead of print.

ABSTRACT

BACKGROUND: Lung transplantation (LuTx) is a challenge when right heart function fails. Mechanical circulatory support (MCS) is then necessary.

METHODS: We aimed to investigate whether preoperative transthoracic echocardiography (TTE) can predict MCS use and help to exclude the sickest patients. Between 2011 and 2018, 52 patients at our institution received LuTx and qualified for this study: 35 bilateral, 16 single, 1 lobar [1] and 1 retransplantation procedure. Of these, 22 were operated using MCS and 30 without MCS. The patients were aged between 18 and 65 years, and 23 were women. The indications were lung fibrosis for 18 patients, chronic obstructive lung disease for 16, cystic fibrosis for 15, primary pulmonary hypertension for 2 and bronchiectasis for 1. TTE was performed up to 30 days before treatment and 1 to 7 days after.

RESULTS: Patients undergoing MCS versus patients not undergoing MCS: preoperative right ventricular systolic pressure 56.5 (30) vs 37.8 (11.5) mm Hg (P = .03); tricuspid regurgitation pressure gradient 48.7 (27) vs 30.2 (10.8) mm Hg (P = .015); tricuspid annular plane systolic excursion 17.8 (4.3) vs 19.9 (2.8) mm Hg (P = .04); pulmonary artery diameter 27.5 (5.2) vs 23.9 (4.1) mm (P = .004); age 41.9 (14.1) vs 54.3 (11.8) years (P = .001). Patients who were Dead versus patients who were alive pulmonary valve acceleration time of 82.8 (24.1) vs 104.9 (27.2) ms (hazard ratio [HR] = 0.959, 95% confidence interval [CI] = 0.923-0.996 per ms, P = .02) and pulmonary artery diameter of 28.9 (5.8) vs 24.4 (4.1) mm HR = 1.225, 95% CI = 1.028-1.460 per 1 mm, P = .016 were predictors of death.

CONCLUSIONS: Preoperative TTE parameters: right ventricular systolic pressure, tricuspid regurgitation pressure gradient, tricuspid annular plane systolic excursion, and pulmonary artery diameter predicted MCS use during LuTx. Certain values of valve acceleration time and pulmonary artery diameter could help discern LuTx qualification.

PMID:36180254 | DOI:10.1016/j.transproceed.2022.08.022