Tomography. 2022 Oct 13;8(5):2574-2587. doi: 10.3390/tomography8050215.

ABSTRACT

3D Single-breath Chemical Shift Imaging (3D-SBCSI) is a hybrid MR-spectroscopic imaging modality that uses hyperpolarized xenon-129 gas (Xe-129) to differentiate lung diseases by probing functional characteristics. This study tests the efficacy of 3D-SBCSI in differentiating physiology among pulmonary diseases. A total of 45 subjects-16 healthy, 11 idiopathic pulmonary fibrosis (IPF), 13 cystic fibrosis (CF), and 5 chronic obstructive pulmonary disease (COPD)-were given 1/3 forced vital capacity (FVC) of hyperpolarized Xe-129, inhaled for a ~7 s MRI acquisition. Proton, Xe-129 ventilation, and 3D-SBCSI images were acquired with separate breath-holds using a radiofrequency chest coil tuned to Xe-129. The Xe-129 spectrum was analyzed in each lung voxel for ratios of spectroscopic peaks, chemical shifts, and T2* relaxation. CF and COPD subjects had significantly more ventilation defects than IPF and healthy subjects, which correlated with FEV1 predicted (R = -0.74). FEV1 predicted correlated well with RBC/Gas ratio (R = 0.67). COPD and IPF had significantly higher Tissue/RBC ratios than other subjects, longer RBC T2* relaxation times, and greater RBC chemical shifts. CF subjects had more ventilation defects than healthy subjects, elevated Tissue/RBC ratio, shorter Tissue T2* relaxation, and greater RBC chemical shift. 3D-SBCSI may be helpful in the detection and characterization of pulmonary disease, following treatment efficacy, and predicting disease outcomes.

PMID:36287814 | DOI:10.3390/tomography8050215

Antimicrob Agents Chemother. 2022 Oct 26:e0110422. doi: 10.1128/aac.01104-22. Online ahead of print.

ABSTRACT

Nontuberculous mycobacteria (NTM) are the pathogens of concern in people with cystic fibrosis (pwCF) due to their association with deterioration of lung function. Treatment requires the use of a multidrug combination regimen, creating the potential for drug-drug interactions (DDIs) with cystic fibrosis transmembrane conductance regulator (CFTR)-modulating therapies, including elexacaftor, tezacaftor, and ivacaftor (ETI), which are eliminated mainly through cytochrome P450 (CYP) 3A-mediated metabolism. An assessment of the DDI risk for ETI coadministered with NTM treatments, including rifabutin, clofazimine, and clarithromycin, is needed to provide appropriate guidance on dosing. The CYP3A-mediated DDIs between ETI and the NTM therapies rifabutin, clarithromycin, and clofazimine were evaluated using physiologically based pharmacokinetic (PBPK) modeling by incorporating demographic and physiological "system" data with drug physicochemical and in vitro parameters. Models were verified and then applied to predict untested scenarios to guide continuation of ETI during antibiotic treatment, using ivacaftor as the most sensitive CYP3A4 substrate. The predicted area under the concentration-time curve (AUC) ratios of ivacaftor when coadministered with rifabutin, clofazimine, or clarithromycin were 0.31, 2.98, and 9.64, respectively, suggesting moderate and strong interactions. The simulation predicted adjusted dosing regimens of ETI administered concomitantly with NTM treatments, which required delayed resumption of the standard dose of ETI once the NTM treatments were completed. The dosing transitions were determined based on the characteristics of the perpetrator drugs, including the mechanism of CYP3A modulation and their elimination half-lives. This study suggests increased doses of elexacaftor/tezacaftor/ivacaftor 200/100/450 mg in the morning and 100/50/375 mg in the evening when ETI is coadministered with rifabutin and reduced doses of elexacaftor/tezacaftor 200/100 mg every 48 h (q48h) and ivacaftor 150 mg daily or a dose of elexacaftor/tezacaftor/ivacaftor 200/100/150 mg q72h when coadministered with clofazimine or clarithromycin, respectively. Importantly, the PBPK simulations provide evidence in support of the use of treatments for NTM in pwCF receiving concomitant dose-adjusted ETI therapy.

PMID:36286508 | DOI:10.1128/aac.01104-22

Infect Immun. 2022 Oct 26:e0041322. doi: 10.1128/iai.00413-22. Online ahead of print.

ABSTRACT

Staphylococcus aureus is the most prevalent cystic fibrosis (CF) pathogen. During chronic airway infections, S. aureus adaptation to antibiotics includes evolving small colony variants (SCVs). Observational studies correlate SCVs with deteriorating lung function in CF, but it is unclear whether SCVs cause disease progression or if they are markers of intensified treatment. G. E. Bollar, J. D. Keith, A. M. Oden, M. R. Kiedrowski, and S. E. Birket (Infect Immun 90:e00237-22, 2022, https://doi.org/10.1128/iai.00237-22) provide intriguing new experimental evidence that an SCV elicits greater inflammation than its normal colony progenitor strain in CF rats.

PMID:36286497 | DOI:10.1128/iai.00413-22

Curr Issues Mol Biol. 2022 Oct 21;44(10):5126-5138. doi: 10.3390/cimb44100349.

ABSTRACT

The presence of complex alleles in the CFTR gene can lead to difficulties in diagnosing cystic fibrosis and cause resistance to therapy with CFTR modulators. Tezacaftor/ivacaftor therapy for 8 months in a patient with the initially established F508del/F508del genotype did not lead to an improvement in her condition-there was no change in spirometry and an increase in the patient's weight, while there was only a slight decrease in NaCl values, measured by a sweat test. The intestinal current measurements of the patient's rectal biopsy showed no positive dynamics in the rescue of CFTR function while taking tezacaftor/ivacaftor. The assumption that the patient had an additional mutation in the cis position was confirmed by sequencing the CFTR gene, and the complex allele [L467F;F508del] was identified. Based on the rescue of CFTR function by elexacaftor/tezacaftor/ivacaftor obtained using forskolin-induced swelling on intestinal organoids, the patient was prescribed therapy with this targeted drug. The use of elexacaftor/tezacaftor/ivacaftor for 7 months resulted in a significant improvement in the patient's clinical condition.

PMID:36286063 | DOI:10.3390/cimb44100349

EMBO Mol Med. 2022 Oct 26:e16283. doi: 10.15252/emmm.202216283. Online ahead of print.

ABSTRACT

Our current understanding of the spectrum of TB and COVID-19 lesions in the human lung is limited by a reliance on low-resolution imaging platforms that cannot provide accurate 3D representations of lesion types within the context of the whole lung. To characterize TB and COVID-19 lesions in 3D, we applied micro/nanocomputed tomography to surgically resected, postmortem, and paraffin-embedded human lung tissue. We define a spectrum of TB pathologies, including cavitary lesions, calcium deposits outside and inside necrotic granulomas and mycetomas, and vascular rearrangement. We identified an unusual spatial arrangement of vasculature within an entire COVID-19 lobe, and 3D segmentation of blood vessels revealed microangiopathy associated with hemorrhage. Notably, segmentation of pathological anomalies reveals hidden pathological structures that might otherwise be disregarded, demonstrating a powerful method to visualize pathologies in 3D in TB lung tissue and whole COVID-19 lobes. These findings provide unexpected new insight into the spatial organization of the spectrum of TB and COVID-19 lesions within the framework of the entire lung.

PMID:36285507 | DOI:10.15252/emmm.202216283

Arch Razi Inst. 2022 Apr 30;77(2):717-725. doi: 10.22092/ARI.2022.357464.2041. eCollection 2022 Apr.

ABSTRACT

Burkholderia cepacia is found as part of the B. cepacia complex (Bcc), a collection of highly pathogenic organisms. The Bcc is present almost everywhere in nature; however, it is most prevalent in damp settings, plant roots, and soils. Moreover, Bcc is a major source of morbidity and death in patients due to its high intrinsic antibiotic resistance. The present study aims to isolate and identify gram-negative aerobic bacteria from clinical samples derived from a variety of pathological diseases and investigate the bacterium's virulence factors and genes. The current study included 250 specimens collected from patients suffering from diabetic foot ulcers, urine, burn, wound, sputum, and discharge from the eyes. The samples were collected from both sexes with the age range of 1-75 years. The recorded data showed that males had a higher frequency of infection (79.2%) than females (52%). The results revealed that 7.6% of infected females were between 1-15 years old, while 22% of infected males were aged between 31-45 years. In addition, 26.8% of infected patients (both males and females) were aged between 31-45 years.

PMID:36284953 | PMC:PMC9548255 | DOI:10.22092/ARI.2022.357464.2041

Cureus. 2022 Sep 20;14(9):e29359. doi: 10.7759/cureus.29359. eCollection 2022 Sep.

ABSTRACT

A cystic fibrosis (CF) transmembrane conductor regulator (CFTR) gene modulating triple therapy combining elexacaftor-tezacaftor-ivacaftor (Trikafta) has been recently discovered. Its approval by the Food and Drug Administration (FDA) in 2019 has expanded the target therapy group to individuals aged twelve and up with at least one Phe508del (phenylalanine 508 deletion) mutation in the CFTR gene. This systematic review aims to assess this combination therapy's safety and efficacy. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, an in-depth search was performed. The search was done by utilizing databases such as PubMed Central (PMC), Google Scholar, and Science Direct for articles related to this topic. Studies published in the last five years in the English language were chosen preliminarily. Further eligibility criteria and quality assessment tools were employed to assess the risk of bias and finalize ten articles to be used in this review. The chosen articles constituted four randomized control trials (RCTs), four systematic reviews, and two narrative reviews. The last date for data collection was April 24, 2022. Based on the findings of this review, we concluded that by combining three CFTR modulators, this therapy had outperformed all the currently available medications in terms of improving pulmonary function, reducing exacerbations, and enhancing the quality of life of CF patients. In clinical trials, headache and rash were the most common side effects, and laboratory testing to assess liver function is suggested. Long-term safety and effectiveness must be confirmed by the continued review of real-life patient data. Studies done on triple therapy thus far have been promising. Unfortunately, a small proportion of the CF population remains ineligible for any form of CFTR modulator therapy owing to their type of genetic mutation, and this provides ground for further research in this field.

PMID:36284811 | PMC:PMC9583755 | DOI:10.7759/cureus.29359

Int Rev Cell Mol Biol. 2022;373:125-158. doi: 10.1016/bs.ircmb.2022.08.003. Epub 2022 Sep 26.

ABSTRACT

Numerous pro-autophagic dietary interventions are being investigated for their potential cancer-preventive or therapeutic effects. This applies to different fasting regimens, methionine restriction and ketogenic diets. In addition, the supplementation of specific micronutrients such as nicotinamide (vitamin B3) or spermidine induces autophagy. In humans, leanness, plant-based diets (that may lead to partial methionine restriction) and high dietary uptake of spermidine are associated with a low incidence of cancers. Moreover, clinical trials have demonstrated the capacity of nicotinamide to prevent non-melanoma skin carcinogenesis. Multiple interventional trials are evaluating the capacity of autophagy-inducing regimens to improve the outcome of chemotherapy and immunotherapy. Here, we discuss the mechanistic underpinnings of autophagy induction by nutritional interventions, as well as the mechanisms through which autophagy induction in malignant or immune cells improves anticancer immunosurveillance.

PMID:36283765 | DOI:10.1016/bs.ircmb.2022.08.003

Syst Biol Reprod Med. 2022 Oct-Dec;68(5-6):315-330. doi: 10.1080/19396368.2022.2122761.

ABSTRACT

Sperm hyperactivation is described as a fast whip movement of the flagellum, an irregular trajectory, and an asymmetrically flagellum bend. This motility pattern is achieved during the passage of the sperm along the female genital tract. It helps the spermatozoa to cross through different viscous ambient fluids to finally reach the oocyte. Important signaling proteins are located in the sperm head and flagellum, and they all play an important role in the cascade that controls the sperm hyperactivation. The presence of HCO3- modulates the activity of the soluble adenylyl cyclase (sAC), leading to the production of cAMP. In turn, cAMP modulates the sperm-specific Na+/H+ exchanger (sNHE) and the t-complex protein 11 (TCP11) which play an essential role on the signaling pathway (cAMP/PKA and tyrosine phosphorylation) and sperm hypermotility. sNHE, cystic fibrosis transmembrane conductance regulator (CFTR), and voltage-gated proton channel (Hv) mainly contribute to the regulation of the intracellular pH (pHi) during capacitation. HCO3- entrance and the removal of H+ from the cytoplasm induces the alkalization of pHi, and this change will contribute to the activation of the cation channel of sperm (CatSper). Recently, it was described the participation on sperm motility and the regulation of calcium channels of an autophagy-related protein, the microtubule-associated protein light chain 3 (LC3). This review gathers important literature about the essential roles of sAC, sNHE, CFTR, Hv, and CatSper in the acquisition of sperm hyperactivation, and provides an integrated overview of recently described roles of TCP11 and LC3 on the sperm signaling pathway. Additionally, we provide insight into the infertility induced by the dysfunction of these critical proteins.

PMID:36282206 | DOI:10.1080/19396368.2022.2122761

J Pak Med Assoc. 2022 Aug;72(8):1525-1528. doi: 10.47391/JPMA.3729.

ABSTRACT

OBJECTIVE: To determine the role of systemic steroids in cystic fibrosis patients and its effects on pulmonary exacerbation in children and adolescents.

METHODS: The retrospective cohort study was conducted at the Aga Khan University Hospital, Karachi, and comprised data from January 2015 to December 2019 of cystic fibrosis patients aged 3-18 years hospitalised with pulmonary exacerbations. The patients were divided into systemic steroid group A and non-systemic steroid group B. Patients in group A received parenteral steroids during acute exacerbation of cystic fibrosis in the first two weeks of admission, while those in group B did not receive systemic steroids. Length of hospital stay and number of days on oxygen support were compared between the groups. Data was analysed using SPSS 22.

RESULTS: Of the 124 patient charts evaluated, 84(67.7%) were included; 40(47.6%) in group A and 44(52.4%) in group B. There were no significant differences between the groups related to age, age at diagnosis, weight, height, and pulmonary exacerbations (p>0.05). Group A had significantly fewer days on oxygen support compared to group B (p<0.001), but there was inter-group difference in mean length of hospital stay (p=0.53).

CONCLUSIONS: Systemic steroid usage during hospitalisation for acute exacerbation of cystic fibrosis was associated with decreased duration of oxygen requirement with standard treatment.

PMID:36280913 | DOI:10.47391/JPMA.3729

Front Immunol. 2022 Oct 6;13:983570. doi: 10.3389/fimmu.2022.983570. eCollection 2022.

ABSTRACT

OBJECTIVE: Lung adenocarcinoma (LUAD) is the most prevalent lung cancer subtype, but its immune infiltration features are not comprehensively understood. To address the issue, the present study was initiated to describe the immune infiltrations across LUAD from cellular compositional, functional, and mechanism perspectives.

METHODS: We adopted five LUAD datasets (GSE32863, GSE43458, GSE75037, TCGA-LUAD, and GSE72094). Differentially expressed genes between LUAD and controls were selected for co-expression network analysis. Risky immune cell types were determined for classifying LUAD patients as diverse subtypes, followed by a comparison of antitumor immunity and therapeutic response between subtypes. Then, LUAD- and subtype-related key module genes affected by DNA methylation were determined for quantifying a scoring scheme. EXO1 was chosen for functional analysis via in vitro assays.

RESULTS: Two immune cell infiltration-based subtypes (C1 and C2) were established across LUAD, with poorer prognostic outcomes and lower infiltration of immune cell types in C1. Additionally, C1 presented higher responses to immune checkpoint blockade and targeted agents (JNK inhibitor VIII, BI-D1870, RO-3306, etc.). The scoring system (comprising GAPDH, EXO1, FYN, CFTR, and KLF4) possessed higher accuracy in estimating patients' prognostic outcomes. EXO1 upregulation contributed to the growth, migration, and invasion of LUAD cells. In addition, EXO1 facilitated PD-L1 and sPD-L1 expression in LUAD cells.

CONCLUSION: Altogether, our findings offer a comprehensive understanding of the immune infiltration landscape on prognosis and therapeutic response of LUAD as well as unveil potential epigenetic and transcriptomic mechanisms, which might assist personalized treatment.

PMID:36275753 | PMC:PMC9582346 | DOI:10.3389/fimmu.2022.983570

J Cyst Fibros. 2022 Oct 21:S1569-1993(22)01384-4. doi: 10.1016/j.jcf.2022.10.003. Online ahead of print.

ABSTRACT

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) improves pulmonary disease in people with cystic fibrosis (PwCF), but its effect on gastrointestinal symptoms, which also affect quality of life, is not clear.

METHODS: PROMISE is a 56-center prospective, observational study of ETI in PwCF >12 years and at least one F508del allele. Gastrointestinal symptoms, evaluated by validated questionnaires: Patient Assessment of Upper Gastrointestinal Disorders-Symptom (PAGI-SYM), Patient Assessment of Constipation-Symptom (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL)), fecal calprotectin, steatocrit and elastase-1 were measured before and 6 months after ETI initiation. Mean difference and 95% confidence intervals were obtained from linear regression with adjustment for age and sex.

RESULTS: 438 participants fully completed at least 1 questionnaire. Mean (SD) for baseline PAGI-SYM, PAC-SYM, and PAC-QOL total scores were 0.56 (0.59), 0.47 (0.45), and 0.69 (0.53) out of maximum 5, 4, and 5, respectively (higher score indicates greater severity). Corresponding age- and sex-adjusted 6 months mean changes (95% CI) in total scores were -0.15 (-0.21, -0.09) for PAGI-SYM, -0.14 (-0.19, -0.09) for PAC-SYM, and -0.15 (-0.21, -0.10) for PAC-QOL. While statistically significant, changes were small and unlikely to be of clinical importance. Fecal calprotectin showed a change (95% CI) from baseline of -66.2 µg/g (-86.1, -46.2) at 6 months, while fecal elastase and steatocrit did not meaningfully change.

CONCLUSIONS: After 6 months of ETI, fecal markers of inflammation decreased. Gastrointestinal symptoms improved, but the effect size was small. Pancreatic insufficiency did not improve.

PMID:36280527 | DOI:10.1016/j.jcf.2022.10.003

Am J Physiol Cell Physiol. 2022 Oct 24. doi: 10.1152/ajpcell.00370.2022. Online ahead of print.

ABSTRACT

All cell types must maintain homeostasis under periods of stress. To prevent the catastrophic effects of stress, all cell types also respond to stress by inducing protective pathways. Within the cell, the endoplasmic reticulum (ER) is exquisitely stress-sensitive, primarily because this organelle folds, post-translationally processes, and sorts one-third of the proteome. In the 1990s, a specialized ER stress response pathway was discovered, the unfolded protein response (UPR), which specifically protects the ER from damaged proteins and toxic chemicals. Not surprisingly, UPR-dependent responses are essential to maintain the function and viability of cells continuously exposed to stress, such as those in the kidney, which have high metabolic demands, produce myriad protein assemblies, continuously filter toxins, and synthesize ammonia. In this mini-review, we highlight recent papers that link ER stress and the UPR with acute kidney injury (AKI), a disease that arises in ~10% of all hospitalized individuals and nearly half of all people admitted to intensive care units. We conclude with a discussion of prospects for treating AKI with emerging drugs that improve ER function.

PMID:36280391 | DOI:10.1152/ajpcell.00370.2022

Med Clin North Am. 2022 Nov;106(6):1001-1012. doi: 10.1016/j.mcna.2022.07.005. Epub 2022 Oct 3.

ABSTRACT

People with Cystic Fibrosis (CF) are living longer and healthier lives due in part to new therapies, called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators. However, disparities in outcomes still exist, with females demonstrating a shorter life expectancy than males; this is opposed to the typical female versus male life expectancy in the general United States population. In addition, minority populations such as those of Hispanic ethnicity and African Americans are less frequently eligible for these new CFTR modulators. The mechanisms driving this difference and the relative contribution of CFTR to the etiology are not yet elucidated.

PMID:36280328 | DOI:10.1016/j.mcna.2022.07.005

Biochim Biophys Acta Biomembr. 2022 Oct 21:184078. doi: 10.1016/j.bbamem.2022.184078. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is caused by mutations in the gene that codes for the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR). Recent advances in CF treatment have included use of small-molecule drugs known as modulators, such as Lumacaftor (VX-809), but their detailed mechanism of action and interplay with the surrounding lipid membranes, including cholesterol, remain largely unknown. To examine these phenomena and guide future modulator development, we prepared a set of wild type (WT) and mutant helical hairpin constructs consisting of CFTR transmembrane (TM) segments 3 and 4 and the intervening extracellular loop (termed TM3/4 hairpins) that represent minimal membrane protein tertiary folding units. These hairpin variants, including CF-phenotypic loop mutants E217G and Q220R, and membrane-buried mutant V232D, were reconstituted into large unilamellar phosphatidylcholine (POPC) vesicles, and into corresponding vesicles containing 70 mol% POPC +30 mol% cholesterol, and studied by single-molecule FRET and circular dichroism experiments. We found that the presence of 30 mol% cholesterol induced an increase in helicity of all TM3/4 hairpins, suggesting an increase in bilayer cross-section and hence an increase in the depth of membrane insertion compared to pure POPC vesicles. Importantly, when we added the corrector VX-809, regardless of the presence or absence of cholesterol, all mutants displayed folding and helicity largely indistinguishable from the WT hairpin. Fluorescence spectroscopy measurements suggest that the corrector alters lipid packing and water accessibility. We propose a model whereby VX-809 shields the protein from the lipid environment in a mutant-independent manner such that the WT scaffold prevails. Such 'normalization' to WT conformation is consistent with the action of VX-809 as a protein-folding chaperone.

PMID:36279907 | DOI:10.1016/j.bbamem.2022.184078

Radiologie (Heidelb). 2022 Oct 24. doi: 10.1007/s00117-022-01076-6. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Approximately 90% of the morbidity and mortality are caused by pulmonary involvement. The mean life expectancy of patients with CF in 2020 was more than 52 years in Germany. The introduction of neonatal screening for CF and the development of a causally acting CFTR modulator treatment have clearly improved the prognosis of these patients. As an introduction, this article describes important aspects of CF in this context in order to go into details of the CF neonatal screening which was introduced in Germany in 2016.

PMID:36278998 | DOI:10.1007/s00117-022-01076-6

Int J Neonatal Screen. 2022 Sep 27;8(4):54. doi: 10.3390/ijns8040054.

ABSTRACT

Our objective was to develop and test a new approach to obtaining parental policy guidance about disclosure of incidental findings of newborn screening for cystic fibrosis (CF), including heterozygote carrier status and the conditions known as CFTR-related metabolic syndrome (CRMS) and/or cystic fibrosis screen positive inconclusive diagnosis, CFSPID. The participants were parents of infants up to 6 months old recruited from maternity hospitals/clinics, parent education classes and stores selling baby products. Data were collected using an anonymous, one-time Internet-based survey. The survey introduced two scenarios using novel, animated videos. Parents were asked to rank three potential disclosure policies-Fully Informed, Parents Decide, and Withholding Information. Regarding disclosure of information about Mild X (analogous to CRMS/CFSPID), 57% of respondents ranked Parents Decide as their top choice, while another 41% ranked the Fully Informed policy first. Similarly, when considering disclosure of information about Disease X (CF) carrier status, 50% and 43% gave top rankings to the Fully Informed and Parents Decide policies, respectively. Less than 8% ranked the Withholding Information policy first in either scenario. Data from value comparisons suggested that parents believed knowing everything was very important even if they became distressed. Likewise, parents preferred autonomy even if they became distressed. However, when there might not be enough time to learn everything, parents showed a slight preference for deferring decision-making. Because most parents strongly preferred the policies of full disclosure or making the decision, rather than the withholding option for NBS results, these results can inform disclosure policies in NBS programs, especially as next-generation sequencing increases incidental findings.

PMID:36278624 | DOI:10.3390/ijns8040054

Front Pharmacol. 2022 Oct 6;13:1038369. doi: 10.3389/fphar.2022.1038369. eCollection 2022.

NO ABSTRACT

PMID:36278180 | PMC:PMC9583128 | DOI:10.3389/fphar.2022.1038369

Front Cardiovasc Med. 2022 Oct 5;9:994068. doi: 10.3389/fcvm.2022.994068. eCollection 2022.

ABSTRACT

INTRODUCTION: It is increasingly common to simultaneously determine a large number of metabolites in order to assess the metabolic state of, or clarify biochemical pathways in, an organism ("metabolomics"). This approach is increasingly used in the investigation of the development of heart failure. Recently, the first reports with respect to a metabolomic approach for the assessment of patients with complex congenital heart disease have been published. Classical statistical analysis of such data is challenging.

OBJECTIVE: This study aims to present an alternative to classical statistics with respect to identifying relevant metabolites in a classification task and numerically estimating their relative impact.

METHODS: Data from two metabolomic studies on 20 patients with complex congenital heart disease and Fontan circulation and 20 controls were reanalysed using random forest (RF) methodology. Results were compared to those of classical statistics.

RESULTS: RF analysis required no elaborate data pre-processing. The ranking of the variables with respect to classification impact (subject diseased, or not) was remarkably similar irrespective of the evaluation method used, leading to identical clinical interpretation.

CONCLUSION: In metabolomic classification in adult patients with complex congenital heart disease, RF analysis as a one-step method delivers the most adequate results with minimum effort. RF may serve as an adjunct to traditional statistics also in this small but crucial-to-monitor patient group.

PMID:36277761 | PMC:PMC9581308 | DOI:10.3389/fcvm.2022.994068

Cureus. 2022 Sep 17;14(9):e29276. doi: 10.7759/cureus.29276. eCollection 2022 Sep.

ABSTRACT

The combination of medication containing elexacaftor, ivacaftor, and tezacaftor (EIT) has dramatically impacted the treatment and prognosis for patients with cystic fibrosis (CF). Lung function, weight, and self-reported quality of life have improved for many of these patients, but little is known about whether this treatment will have a beneficial effect in preventing morbidity and/or mortality from respiratory infections such as COVID-19. EIT received Food and Drug Administration (FDA) approval shortly before the first cases of COVID-19 appeared in the United States. We performed an analysis using the TriNetX (Cambridge, MA, USA) research database to determine if patients being treated with EIT who became infected with COVID-19 experienced significantly different outcomes compared to patients who were not receiving it.

PMID:36277555 | PMC:PMC9578654 | DOI:10.7759/cureus.29276