Pharmgenomics Pers Med. 2022 Feb 5;15:91-104. doi: 10.2147/PGPM.S245603. eCollection 2022.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive genetic condition that is caused by variants in the cystic fibrosis transmembrane conductance regulator gene. This causes multisystem disease due to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel at the apical surface of epithelia. Until recently, treatment was directed at managing the downstream effects in affected organs, principally improving airway clearance and treating infection in the lungs and improving malabsorption in the gastrointestinal tract. Care delivered by multidisciplinary teams has yielded incremental improvements in outcomes. However, the development of small-molecule CFTR modulator drugs over the last decade has heralded a new era of CF therapeutics. Modulators target the underlying defect and improve CFTR function. Either monotherapy or a combination of modulators is used depending on the specific genotype and class of CFTR disease-causing variants that an individual has. Both ivacaftor and the ivacaftor/tezacaftor/elexacaftor combination have been demonstrated to be associated with clinically very significant benefits in randomised trials and have rapidly been made available as part of standard care in many countries. CFTR modulators represent one of the best examples of precision medicine to date. They are expensive, however, and equity of access to them worldwide remains an issue. Studies and approvals are also ongoing for children under the age of 6 years for ivacaftor/tezacaftor/elexacaftor. Furthermore, no modulators are available for around 10% of the people with CF. In this review, we firstly summarise the genetics, pathophysiology and clinical problems associated with CF. We then discuss the development of CFTR modulators and key clinical trials to support their use along with other potential future therapeutic approaches.

PMID:35153502 | PMC:PMC8828078 | DOI:10.2147/PGPM.S245603

J Cyst Fibros. 2022 Jan;21(1):13-14. doi: 10.1016/j.jcf.2021.12.017.

NO ABSTRACT

PMID:35151416 | DOI:10.1016/j.jcf.2021.12.017

Eur J Pharmacol. 2022 Feb 10:174821. doi: 10.1016/j.ejphar.2022.174821. Online ahead of print.

ABSTRACT

Chronic respiratory diseases have collectively become a major public health concern and have now taken form as one of the leading causes of mortality worldwide. Most chronic respiratory diseases primarily occur due to prolonged airway inflammation. In addition, critical environmental factors such as cigarette smoke, industrial pollutants, farm dust, and pollens may also exacerbate such diseases. Moreover, alterations in the genetic sequence of an individual, abnormalities in the chromosomes or immunosuppression resulting from bacterial, fungal, and viral infections may also play a key role in the pathogenesis of respiratory diseases. Over the years, multiple in vitro models have been employed as the basis of existing as well as emerging advancements in chronic respiratory disease research. These include cell lines, gene expression techniques, single cell RNA sequencing, cytometry, culture techniques, as well as serum/sputum biomarkers that can be used to elucidate the molecular mechanisms underlying these diseases, and to identify novel diagnostic and management options for these diseases. This review summarizes the current understanding of the pathogenesis of various chronic respiratory diseases derived through in vitro experimental models, where the knowledge obtained from these studies can greatly benefit researchers in the discovery and development of novel screening techniques and advanced therapeutic strategies that could be translated into clinical use in the future.

PMID:35151643 | DOI:10.1016/j.ejphar.2022.174821

J Inorg Biochem. 2022 Feb 5;230:111751. doi: 10.1016/j.jinorgbio.2022.111751. Online ahead of print.

ABSTRACT

The use of inhalable nanoparticles (NPs) for cystic fibrosis (CF) has been advocated as a promising tool to improve the efficacy of antimicrobials taking advantage of their ability to penetrate airway mucus and pathogen biofilm and to release the drug in or in proximity to the enclosed bacteria. Here, inhalable calcium phosphate (CaP) NPs were functionalized with colistin (Col) which is one of the most active antimicrobials against Gram-negative bacteria. The adsorption kinetic and isotherm of Col on CaP-NPs were investigated and fitted according to different mathematical models and revealed an electrostatic interaction between positively charged amine groups of Col and negatively charged surface of CaP-NPs. The maximum Col payload was of about 50 mg g-1 of CaP-NPs. After functionalization, despite an increase of size (213 vs 95 nm), in citrate solution, CaP-NPs maintained a dimension and surface charge considered suitable for crossing mucus barrier. CaP-NPs do not interact with mucin and are able to permeate a layer of artificial mucus. In vitro tests on pulmonary cells demonstrated that CaP-NPs are not cytotoxic up to a concentration of 125 μg mL-1. The antimicrobial and antibiofilm activity of Col loaded CaP-NPs tested on Pseudomonas aeruginosa RP73, a clinical strain isolated from a CF patient, was similar to that of free Col demonstrating that the therapeutic effect of Col adsorbed on CaP-NPs was retained. This work represents the first attempt to use CaP-NPs as delivery system for the CF treatment. The encouraging results open the way to further studies.

PMID:35151101 | DOI:10.1016/j.jinorgbio.2022.111751

Infect Dis Ther. 2022 Feb 12. doi: 10.1007/s40121-022-00591-2. Online ahead of print.

ABSTRACT

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates are frequent causes of serious nosocomial infections that may compromise the selection of antimicrobial therapy. The goal of this review is to summarize recent epidemiologic, microbiologic, and clinical data pertinent to the therapeutic management of patients with infections caused by MDR/XDR-P. aeruginosa. Historically, conventional antipseudomonal β-lactam antibiotics have been used for the empiric treatment of MDR/XDR-P. aeruginosa. Owing to the remarkable capacity of P. aeruginosa to confer resistance via multiple mechanisms, these traditional therapies are often rendered ineffective. To increase the likelihood of administering empiric antipseudomonal therapy with in vitro activity, a second agent from a different antibiotic class is often administered concomitantly with a traditional antipseudomonal β-lactam. However, combination therapy may pose an increased risk of antibiotic toxicity and secondary infection, notably, Clostridioides difficile. Multiple novel agents that demonstrate in vitro activity against MDR-P. aeruginosa (e.g., β-lactam/β-lactamase inhibitor combinations and cefiderocol) have been recently granted US Food and Drug Administration (FDA) approval and are promising additions to the antipseudomonal armamentarium. Even so, comparative clinical data pertaining to these novel agents is sparse, and concerns surrounding the scarcity of antibiotics active against refractory MDR/XDR-P. aeruginosa necessitates continued assessment of alternative therapies. This is particularly important in patients with cystic fibrosis (CF) who may be chronically colonized and suffer from recurrent infections and disease exacerbations due in part to limited efficacious antipseudomonal agents. Bacteriophages represent a promising candidate for combatting recurrent and refractory infections with their ability to target specific host bacteria and circumvent traditional mechanisms of antibiotic resistance seen in MDR/XDR-P. aeruginosa. Future goals for the management of these infections include increased comparator clinical data of novel agents to determine in what scenario certain agents may be preferred over others. Until then, appropriate treatment of these infections requires a thorough evaluation of patient- and infection-specific factors to guide empiric and definitive therapeutic decisions.

PMID:35150435 | DOI:10.1007/s40121-022-00591-2

Pulm Ther. 2022 Feb 11. doi: 10.1007/s41030-022-00184-x. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is due to a mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR), which leads to unusual water and chloride secretion across epithelial surfaces. The lungs are responsible for most morbidity, though other organs are frequently affected. Sleep abnormalities have long been recognized in CF. Abnormal ventilation and oxygenation, sinus disease, deconditioning due to muscle weakness and recurrent infections, and inflammation have been thought to play a role in sleep disorders in CF. However, there is evidence that CFTR gene dysregulation can affect circadian rhythms in CF. Early recognition and treatment of circadian rhythms may improve outcomes in CF.

PMID:35149967 | DOI:10.1007/s41030-022-00184-x

Thorax. 2022 Feb 11:thoraxjnl-2021-217941. doi: 10.1136/thoraxjnl-2021-217941. Online ahead of print.

ABSTRACT

INTRODUCTION: Acute exacerbations (AEs) increase morbidity and mortality of patients with chronic pulmonary diseases. Little is known about the characteristics and impact of AEs on children's interstitial lung disease (chILD).

METHODS: The Kids Lung Register collected data on AEs, the clinical course and quality of life (patient-reported outcomes - PRO) of rare paediatric lung diseases. Characteristics of AEs were obtained.

RESULTS: Data of 2822 AEs and 2887 register visits of 719 patients with chILD were recorded. AEs were characterised by increased levels of dyspnoea (74.1%), increased respiratory rate (58.6%) and increased oxygen demand (57.4%). Mostly, infections (94.4%) were suspected causing an AE. AEs between two register visits revealed a decline in predicted FEV1 (median -1.6%, IQR -8.0 to 3.9; p=0.001), predicted FVC (median -1.8%, IQR -7.5 to 3.9; p=0.004), chILD-specific questionnaire (median -1.3%, IQR -3.6 to 4.5; p=0.034) and the physical health summary score (median -3.1%, IQR -15.6 to 4.3; p=0.005) compared with no AEs in between visits. During the median observational period of 2.5 years (IQR 1.2-4.6), 81 patients died. For 49 of these patients (60.5%), mortality was associated with an AE.

CONCLUSION: This is the first comprehensive study analysing the characteristics and impact on the clinical course of AEs in chILD. AEs have a significant and deleterious effect on the clinical course and health-related quality of life in chILD.

PMID:35149584 | DOI:10.1136/thoraxjnl-2021-217941

BMC Pulm Med. 2022 Feb 11;22(1):59. doi: 10.1186/s12890-022-01855-w.

ABSTRACT

BACKGROUND: In this study we tested the hypothesis that in patients with cystic fibrosis (pwCF) respiratory rate (RR) is associated with antibiotic treatment, exacerbation status, forced expiratory volume in one second (FEV1) and C-reactive protein (CRP).

METHODS: Between June 2018 and May 2019, we consecutively enrolled pwCF who were referred to our hospital. We determined RR and heart rate (HR) by using the minimal-impact system VitaLog during the hospital stay. Furthermore, we performed spirometry and evaluated CRP.

RESULTS: We included 47 patients: 20 with pulmonary exacerbation and 27 without. RR decreased in patients with exacerbation (27.5/min (6.0/min) vs. 24.4/min (6.0/min), p = 0.004) and in patients with non-exacerbation (22.5/min (5.0/min) vs. 20.9/min (3.5/min), p = 0.024). Patients with exacerbation showed higher RR than patients with non-exacerbation both at the beginning (p = 0.004) and at the end of their hospital stay (p = 0.023). During the hospital stay, HR did not change in the total cohort (66.8/min (11.0/min) vs. 66.6/min (12.0/min), p = 0.440). Furthermore, we did not find significant differences between patients with exacerbation and patients with non-exacerbation (67.0/min (12.5/min) vs. 66.5/min (10.8/min), p = 0.658). We observed a correlation of ρ = -0.36 between RR and FEV1. Moreover, we found a correlation of ρ = 0.52 between RR and CRP.

CONCLUSION: In pwCF requiring intravenous therapy, respiratory rate is higher at their hospital admittance and decreased by the time of discharge; it is also associated with C-reactive protein. Monitoring RR could provide important information about the overall clinical conditions of pwCF.

PMID:35148739 | DOI:10.1186/s12890-022-01855-w

J Med Chem. 2022 Feb 11. doi: 10.1021/acs.jmedchem.1c02067. Online ahead of print.

ABSTRACT

Compelling new support has been provided for histone deacetylase isoform 6 (HDAC6) as a common thread in the generation of the dysregulated proinflammatory and fibrotic phenotype in cystic fibrosis (CF). HDAC6 also plays a crucial role in bacterial clearance or killing as a direct consequence of its effects on CF immune responses. Inhibiting HDAC6 functions thus eventually represents an innovative and effective strategy to tackle multiple aspects of CF-associated lung disease. In this Perspective, we not only showcase the latest evidence linking HDAC(6) activity and expression with CF phenotype but also track the new dawn of HDAC(6) modulators in CF and explore potentialities and future perspectives in the field.

PMID:35148101 | DOI:10.1021/acs.jmedchem.1c02067

J Clin Psychol Med Settings. 2022 Feb 11. doi: 10.1007/s10880-022-09859-8. Online ahead of print.

ABSTRACT

To investigate the current psychosocial challenges faced by adults with Cystic Fibrosis (CF), while exploring attitudes and experiences of mindfulness and self-compassion. Mindfulness and self-compassion are important resources for supporting psychological and physical well-being, yet there is limited research exploring these positive psychology concepts in CF literature. Twenty UK domiciled adults with a diagnosis of CF, took part in a semi-structured interview. Using a thematic analysis approach, four themes were developed: (a) "I didn't expect to be here": Surpassing the CF life expectancy, (b) "Am I psychologically bringing this upon myself?": Psychological complexities of CF, (c) "I've had to really learn to be kind to myself": The importance of compassion and being self-compassionate, (d) "I think it's a great tool": The benefits of practising mindfulness. This research demonstrates a robust need for increased integration of accessible psychological practices into routine CF-care and self-care for adults with CF. Particularly, practises and interventions that draw on the concepts of mindfulness and self-compassion, which may benefit patient's health and wellbeing profoundly.

PMID:35147829 | DOI:10.1007/s10880-022-09859-8

Pediatr Transplant. 2022 Feb 10:e14247. doi: 10.1111/petr.14247. Online ahead of print.

ABSTRACT

BACKGROUND: Long-term survival after lung transplantation (LTx) is limited by chronic lung allograft dysfunction (CLAD).

METHODS: We report an analysis of cytokine profiles in bronchoalveolar lavage samples collected during a prospective multicenter non-interventional trial primarily designed to determine the impact of community-acquired respiratory viral infections (CARV) in outcomes after pediatric LTx. In this analysis, we identify potential biomarkers of auto-inflammation and auto-immunity associated with survival and risk of bronchiolitis obliterans (BOS) after LTx with cytokine analysis of bronchoalveolar lavage fluid (BALF) from 61 pediatric recipients.

RESULTS: Higher IL-23 (p = .048) and IL-31 (p = .035) levels were associated with the risk of BOS, and lower levels of epithelial growth factor (EGF) (p = .041) and eotaxin (EOX) (p = .017) were associated with BOS. Analysis using conditional inference trees to evaluate cytokines at each visit associated with survival identified soluble CD30 (p < .001), pro-inflammatory cytokine IL-23 (p = .02), and sTNFRI (p = .01) below cutoff levels as associated with BOS-free survival.

CONCLUSIONS: Our results indicate that post-LTx survival in children may be linked to activation of alternate pathways of the immune system that affect airway remodeling in addition to activation of "classical" pathways that have been described in adult LTx recipients. These may indicate pathways to target for intervention.

PMID:35146849 | DOI:10.1111/petr.14247

Ann Am Thorac Soc. 2022 Feb 10. doi: 10.1513/AnnalsATS.202105-532OC. Online ahead of print.

ABSTRACT

RATIONALE: Cystic Fibrosis (CF) Centers transitioned to telemedicine during the Spring 2020 peak of the COVID-19 pandemic.

OBJECTIVES: We hypothesized that people with CF (pwCF) with more severe disease would be more likely to be seen in-person.

METHODS: We used paired t-tests to compare within-subject changes in BMI and percent predicted forced expiratory volume in one second (FEV1), and calculated relative risk (RR) to compare pulmonary exacerbations (PEx) between pwCF enrolled in the CF Foundation Patient Registry with at least one in-person clinic visit after March 15 in both 2019 and 2020.

RESULTS: Overall, the proportion of clinical encounters that were in-person clinic visits decreased from 91% in 2019 to a low of 9% in April, 2020. Among pwCF seen after March 15 in both 2019 and 2020, the mean (95% CI) FEV1 % predicted was 1.3 (0.1, 2.4)% predicted higher in 2020 for children 6-<12 years of age, and 7.5 (7.1, 7.9)% predicted higher in 2020 among pwCF ≥12 years of age eligible for the highly effective CFTR modulator, elexacaftor-tezacaftor-ivacaftor (ETI). There was no difference in FEV1 % predicted for pwCF ≥12 years of age who were not eligible for ETI. Similarly, the mean (95% CI) BMI percentile was 2.4 (2.0, 2.8) higher in 2020 for children 6-<12 years of age, and 5.2 (4.8, 5.7) higher in 2020 among children 12-<18 years of age eligible for ETI. Mean (95% CI) BMI (kg/m2) was 1.2 (1.2, 1.3) higher for pwCF ≥18 years of age eligible for ETI, and 0.2 (0.1, 0.3) higher for pwCF ≥18 years of age not eligible for ETI. The proportion of in-person clinic visits where any PEx was present was lower in 2020 compared with 2019, 25% as compared to 38%, RR 0.82 (0.79, 0.86).

CONCLUSION: The care of pwCF was substantially changed during the Spring 2020 peak of the COVID-19 pandemic. Among pwCF seen in-person in both 2019 and 2020 after the Spring peak of the COVID-19 pandemic, lung function and BMI were higher in 2020 for children 6-<12 years of age and pwCF eligible for ETI.

PMID:35143374 | DOI:10.1513/AnnalsATS.202105-532OC

FP Essent. 2022 Feb;513:32-38.

ABSTRACT

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that results from impaired lung development or lung injury from ventilatory support. It primarily is seen in infants born prematurely. Approximately 95% of infants with BPD had a low birth weight (ie, less than 1,500 g). This condition affects pulmonary function throughout the life span. Many children with BPD develop asthmalike symptoms with recurrent wheezing beginning in the preschool-aged years. Complications include pulmonary hypertension, tracheomalacia, glottic damage, sleep apnea, and more frequent and/or severe respiratory infections. Measures should be taken to prevent respiratory infections in these patients. Cystic fibrosis (CF) is caused by an autosomal recessive sequence variation in the CF transmembrane conductance regulator (CFTR) gene that results in mucus accumulation on cell surfaces. Mucus accumulation in the airways causes chronic cough, wheezing, recurrent infections, and progressive loss of lung function. Treatment includes clearance of mucus from the lungs and infection management. Complications and associated conditions include sinusitis, nutritional and gastrointestinal issues, dehydration, pancreatic insufficiency, and CF-related diabetes. All of these should be addressed. Most cases of CF are diagnosed via newborn screening and follow-up sweat tests. New CFTR modulators that improve CFTR protein function offer hope of improved longevity and quality of life for patients with specific CFTR sequence variants.

PMID:35143153

Clin Infect Dis. 2022 Feb 10:ciac117. doi: 10.1093/cid/ciac117. Online ahead of print.

ABSTRACT

BACKGROUND: People with cystic fibrosis (CF) routinely suffer from recurrent sino-pulmonary infections. Such infections require frequent courses of antimicrobials and often involve multidrug-resistant organisms. The goal of this study was to identify real-world evidence for the effectiveness of Elexacaftor-Tezacaftor-Ivacaftor (ELX/TEZ/IVA) at decreasing infection-related visits and antimicrobial use in people with CF.

METHODS: Using IBM MarketScan data, we identified 389 enrollees with CF who began taking ELX/TEZ/IVA prior to 12/1/2019 and were enrolled from 7/1/2019-3/14/2020. We also identified a comparison population who did not begin ELX/TEZ/IVA during the study period. We compared the following outcomes in the 15 weeks before and after medication initiation: total healthcare visits, inpatient visits, infection-related visits, and antimicrobial prescriptions. We analyzed outcomes using both a case-crossover analysis and a difference-in-differences analysis, to control for underlying trends.

RESULTS: For the case-crossover analysis, ELX/TEZ/IVA initiation was associated with 2.20 (95% CI: -3.26, -1.14) fewer overall healthcare visit-days, 0.16 (95% CI: -0.22, -0.11) fewer inpatient admissions, 0.33 (95% CI: -0.59, -0.07) fewer infection-related visit-days, and 0.78 (95% CI: -1.03, -0.54) fewer antibiotic prescriptions over a 15 week period. Results from the difference-in-differences approach were similar.

CONCLUSIONS: We show a rapid reduction of infection-related visits and antimicrobial use among people with CF after starting a therapy that was not explicitly designed to treat infections. Currently, there are over 30,000 people living with CF in the United States alone. Given that this therapy is effective for approximately 90% of people with CF, the impact on respiratory infections and antimicrobial use may be substantial.

PMID:35142340 | DOI:10.1093/cid/ciac117

Front Cell Infect Microbiol. 2022 Jan 24;11:773496. doi: 10.3389/fcimb.2021.773496. eCollection 2021.

ABSTRACT

INTRODUCTION: Non-cystic fibrosis bronchiectasis is a respiratory health condition with many possible aetiologies, some of which are potentially reversible in childhood with early diagnosis and appropriate treatment. It is important to understand factors which contribute to progression or potential resolution of bronchiectasis. It is evident that respiratory exacerbations are a key feature of bronchiectasis disease progression. In this pilot study we document how the microbiota of the upper and lower airways presents during the course of an exacerbation and treatment.

METHODS: We recruited children (aged 1-15) undergoing antibiotic treatment for bronchiectasis exacerbations at Starship Children's Hospital and outpatient clinics. Sputum and nasal swabs were taken before and after antibiotic treatment. Sample DNA was extracted, then bacterial 16S rRNA genes amplified and sequenced via Illumina MiSeq.

RESULTS: Thirty patients were recruited into this study with 81 samples contributing to the final dataset, including 8 patients with complete sets of upper and lower airway samples at both (before and after antibiotics) timepoints. Changes in alpha-diversity over the course of an exacerbation and treatment were non-significant. However, sample composition did alter over the course of an exacerbation, with most notably a reduction in the relative abundance of amplicon sequence variants assigned to Haemophilus.

DISCUSSION: Haemophilus has been associated with more severe symptoms in respiratory infections and a reduction in its relative abundance may represent a positive shift in a patient's microbiota. Current treatments for bronchiectasis may preserve bacterial diversity while altering microbiota composition.

PMID:35141165 | PMC:PMC8818954 | DOI:10.3389/fcimb.2021.773496

Front Physiol. 2022 Jan 24;12:830285. doi: 10.3389/fphys.2021.830285. eCollection 2021.

NO ABSTRACT

PMID:35140634 | PMC:PMC8819176 | DOI:10.3389/fphys.2021.830285

Dtsch Arztebl Int. 2022 Apr 29;(Forthcoming):arztebl.m2022.0075. doi: 10.3238/arztebl.m2022.0075. Online ahead of print.

ABSTRACT

BACKGROUND: Neonatal screening in Germany currently comprises 19 congenital diseases, 13 of which are metabolic diseases. Approximately one in 1300 newborns suffers from one of these target diseases. Early diagnosis and treatment enable the affected children to undergo better development and even, in many cases, to have a normal life.

METHODS: This review is based on pertinent publications retrieved by a selective search in the PubMed and Embase databases.

RESULTS: Positive screening findings are confirmed in approximately one out of five newborns. The prompt evaluation of suspected diagnoses is essential, as treatment for some of these diseases must be initiated immediately after birth to prevent long-term sequelae. The most commonly identified diseases are primary hypothyroidism (1:3338), phenylketonuria/hyperphenylalaninemia (1 : 5262), cystic fibrosis (1 : 5400), and mediumchain acyl-CoA dehydrogenase deficiency (1 : 10 086). Patient numbers are rising as new variants of the target diseases are being identified, and treatments must be adapted to their heterogeneous manifestations. Precise diagnosis and the planning of treatment, which is generally lifelong, are best carried out in a specialized center.

CONCLUSION: Improved diagnosis and treatment now prolong the lives of many patients with congenital diseases. The provision of appropriate long-term treatment extending into adulthood will be a central structural task for screening medicine in the future.

PMID:35140012 | DOI:10.3238/arztebl.m2022.0075

Am J Respir Crit Care Med. 2022 Feb 9. doi: 10.1164/rccm.202201-0008ED. Online ahead of print.

NO ABSTRACT

PMID:35139320 | DOI:10.1164/rccm.202201-0008ED

Ned Tijdschr Geneeskd. 2022 Jan 12;166:D6011.

ABSTRACT

With the development of organoids as three-dimensional model organs it is now possible to mimic the growth of human organs in a culture dish. As these model organs can be generated from patients' (diseased) tissue and capture the (genetic) properties thereof, they are more representative disease models than cell lines and animal models. The use of organoids in pathophysiological research has already increased our understanding of many human diseases. Furthermore, organoids are used for patient-specific drug tests for cystic fibrosis, and this will soon be possible for other genetic diseases. Also, transplantation of (own genetically corrected) organoids could become a new treatment option. To fully employ the potential of organoids in medicine, cultures need to be standardized and further optimized for better organ/disease representation. With this, organoids hold the promise to quickly revolutionize personalized and regenerative medicine.

PMID:35138705

J Bras Pneumol. 2022 Feb 2;48(1):e20220023. doi: 10.36416/1806-3756/e20220023.

NO ABSTRACT

PMID:35137878 | DOI:10.36416/1806-3756/e20220023