Proc Natl Acad Sci U S A. 2022 Jan 25;119(4):e2119759119. doi: 10.1073/pnas.2119759119.

ABSTRACT

Submucosal glands (SMGs) protect lungs but can also contribute to disease. For example, in cystic fibrosis (CF), SMGs produce abnormal mucus that disrupts mucociliary transport. CF is an ion transport disease, yet knowledge of the ion transporters expressed by SMG acini, which produce mucus, and SMG ducts that carry it to the airway lumen is limited. Therefore, we isolated SMGs from newborn pigs and used single-cell messenger RNA sequencing, immunohistochemistry, and in situ hybridization to identify cell types, gene expression, and spatial distribution. Cell types and transcript levels were the same in non-CF and CF SMGs, suggesting that loss of epithelial anion secretion rather than an intrinsic cell defect causes CF mucus abnormalities. Gene signatures of acinar mucous and acinar serous cells revealed specialized functions in producing mucins and antimicrobials, respectively. However, surprisingly, these two cell types expressed the same ion transporters and neurohumoral receptors, suggesting the importance of balancing mucin and liquid secretion to produce optimal mucus properties. SMG duct cell transcripts suggest that they secrete HCO3 - and Cl-, and thus have some similarity to pancreatic ducts that are also defective in CF. These and additional findings suggest the functions of the SMG acinus and duct and provide a baseline for understanding how environmental and genetic challenges impact their contribution to lung disease.

PMID:35046051 | DOI:10.1073/pnas.2119759119

J Pediatr Gastroenterol Nutr. 2022 Jan 18. doi: 10.1097/MPG.0000000000003381. Online ahead of print.

NO ABSTRACT

PMID:35045562 | DOI:10.1097/MPG.0000000000003381

Ann Am Thorac Soc. 2022 Jan 19. doi: 10.1513/AnnalsATS.202108-969OC. Online ahead of print.

ABSTRACT

RATIONALE: Many lung transplant recipients with cystic fibrosis (CF) have low pre-operative body mass index (BMI); however, post-transplant BMI recovery is not well understood.

OBJECTIVE: To evaluate BMI recovery (≥18.5 kg/m2) among CF lung transplant recipients with low pre-operative BMI and investigate the association of survival with BMI recovery.

METHODS: United Network for Organ Sharing and CF Foundation Patient registries (June 2005-December 2016) were used to identify CF lung transplant recipients. Among recipients surviving ≥1 year, Cox modeling compared post-transplant 1-year conditional survival between recipients with low (<17 and 17-18.49 kg/m2) versus normal pre-operative BMI, stratified by BMI recovery.

RESULTS: Of 1,977 CF lung transplant recipients, 272 (14%) and 449 (23%) had pre-operative BMI of <17 and 17-18.49 kg/m2, respectively. For BMI subgroups <17 and 17-18.49 kg/m2, 29% vs 49% of those alive at 1 year recovered their BMI, respectively. Among recipients with low pre-operative BMI, adjusted post-transplant 1-year conditional survival was worse compared to those with pre-operative BMI ≥18.5 kg/m2; however, BMI recovery mitigated this. Pre-operative BMI <17 kg/m2 had an adjusted HR of 1.29 (95% CI 0.92, 1.81) with BMI recovery vs 1.57 (95% CI 1.09, 2.25) without recovery, and pre-operative BMI 17-18.49 kg/m2 had an adjusted HR of 1.28 (95% CI 1.02, 1.61) with BMI recovery vs 1.72 (95% CI 1.14, 2.59) without recovery.

CONCLUSIONS: Patients with lower pre-operative BMI were less likely to achieve BMI recovery within 1 year. However, for those who did, BMI recovery within 1-year post-transplant was associated with longer survival.

PMID:35044894 | DOI:10.1513/AnnalsATS.202108-969OC

Am J Physiol Cell Physiol. 2022 Jan 19. doi: 10.1152/ajpcell.00409.2021. Online ahead of print.

ABSTRACT

The small conductance calcium-activated potassium channel (KCa2.3) has long been recognized for its role in mediating vasorelaxation through the endothelium-derived hyperpolarization (EDH) response. Histone deacetylases (HDACs) have been implicated as potential modulators of blood pressure and histone deacetylase inhibitors (HDACi) are being explored as therapeutics for hypertension. Herein, we show that HDACi increase KCa2.3 expression when heterologously expressed in HEK cells and endogenously expressed in primary cultures of human umbilical vein endothelial cells (HUVECs) and human intestinal microvascular endothelial cells (HIMECs). When primary endothelial cells were exposed to HDACi, KCa2.3 transcripts, subunits, and functional current are reproducibly increased. Quantitative RT-PCR (qPCR) demonstrated increased KCa2.3 mRNA following HDACi, confirming transcriptional regulation of KCa2.3 by HDACs. By using pharmacological agents selective for different classes of HDACs, we discriminated between cytoplasmic and epigenetic modulation of KCa2.3. Biochemical analysis revealed an association between the cytoplasmic HDAC6 and KCa2.3 in immunoprecipitation studies. Specifically inhibiting HDAC6 increases expression of KCa2.3. In addition to increasing the expression of KCa2.3, we show that non-specific inhibition of HDACs cause an increase in the expression of the molecular chaperone Hsp70 in endothelial cells. When Hsp70 is inhibited in the presence of HDACi, the magnitude of the increase in KCa2.3 expression is diminished. Finally, we show a slower rate of endocytosis of KCa2.3 as a result of exposure of primary endothelial cells to HDACi. These data provide the first demonstrated approach to increase KCa2.3 channel number in endothelial cells and may partially account for the mechanism by which HDACi induces vasorelaxation.

PMID:35044858 | DOI:10.1152/ajpcell.00409.2021

mSphere. 2022 Jan 19:e0084721. doi: 10.1128/msphere.00847-21. Online ahead of print.

ABSTRACT

Smoke exposure is a risk factor for community-acquired pneumonia, which is typically caused by host-adapted airway opportunists like nontypeable Haemophilus influenzae (NTHi). Genomic analyses of NTHi revealed homologs of enzymes with predicted roles in reduction of protein thiols, which can have key roles in oxidant resistance. Using a clinical NTHi isolate (NTHi 7P49H1), we generated isogenic mutants in which homologs of glutathione reductase (open reading frame NTHI 0251), thioredoxin-dependent thiol peroxidase (NTHI 0361), thiol peroxidase (NTHI 0907), thioredoxin reductase (NTHI 1327), and glutaredoxin/peroxiredoxin (NTHI 0705) were insertionally inactivated. Bacterial protein analyses revealed that protein oxidation after hydrogen peroxide treatment was elevated in all the mutant strains. Similarly, each of these mutants was less resistant to oxidative killing than the parental strain; these phenotypes were reversed by genetic complementation. Analysis of biofilm communities formed by the parental and mutant strains showed reduction in overall biofilm thickness and density and significant sensitization of bacteria within the biofilm structure to oxidative killing. Experimental respiratory infection of smoke-exposed mice with NTHi 7P49H1 showed significantly increased bacterial counts compared to control mice. Immunofluorescent staining of lung tissues showed NTHi communities on lung mucosae, interspersed with neutrophil extracellular traps; these bacteria had transcript profiles consistent with NTHi biofilms. In contrast, infection with the panel of NTHi mutants showed a significant decrease in bacterial load. Comparable results were observed in bactericidal assays with neutrophil extracellular traps in vitro. Thus, we conclude that thiol-mediated redox homeostasis is a determinant of persistence of NTHi within biofilm communities. IMPORTANCE Chronic bacterial respiratory infections are a significant problem for smoke-exposed individuals, especially those with chronic obstructive pulmonary disease (COPD). These infections often persist despite antibiotic use. Thus, the bacteria remain and contribute to the development of inflammation and other respiratory problems. Respiratory bacteria often form biofilms within the lungs; during growth in a biofilm, their antibiotic and oxidative stress resistance is incredibly heightened. It is well documented that redox homeostasis genes are upregulated during this phase of growth. Many common respiratory pathogens, such as NTHi and Streptococcus pneumoniae, are reliant on scavenging from the host the necessary components they need to maintain these redox systems. This work begins to lay the foundation for exploiting this requirement and thiol redox homeostasis pathways of these bacteria as a therapeutic target for managing chronic respiratory bacterial infections, which are resistant to traditional antibiotic treatments alone.

PMID:35044805 | DOI:10.1128/msphere.00847-21

Microbiol Spectr. 2022 Jan 19:e0133421. doi: 10.1128/spectrum.01334-21. Online ahead of print.

ABSTRACT

Staphylococcus aureus is a prominent nosocomial pathogen that causes several life-threatening diseases, such as pneumonia and bacteremia. S. aureus modulates the expression of its arsenal of virulence factors through sensing and integrating responses to environmental signals. The agr (accessory gene regulator) quorum sensing (QS) system is a major regulator of virulence phenotypes in S. aureus. There are four agr specificity groups each with a different autoinducer peptide sequence encoded by the agrD gene. Although agr is critical for the expression of many toxins, paradoxically, S. aureus strains often have nonfunctional agr activity due to loss-of-function mutations in the four-gene agr operon. To understand patterns in agr variability across S. aureus, we undertook a species-wide genomic investigation. We developed a software tool (AgrVATE; https://github.com/VishnuRaghuram94/AgrVATE) for typing and detecting frameshift mutations in the agr operon. In an analysis of over 40,000 S. aureus genomes, we showed a close association between agr type and S. aureus clonal complex. We also found a strong linkage between agrBDC alleles (encoding the peptidase, autoinducing peptide itself, and peptide sensor, respectively) but not agrA (encoding the response regulator). More than 5% of the genomes were found to have frameshift mutations in the agr operon. While 52% of these frameshifts occurred only once in the entire species, we observed cases where the recurring mutations evolved convergently across different clonal lineages with no evidence of long-term phylogenetic transmission, suggesting that strains with agr frameshifts were evolutionarily short-lived. Overall, genomic analysis of agr operon suggests evolution through multiple processes with functional consequences that are not fully understood. IMPORTANCE Staphylococcus aureus is a globally pervasive pathogen that produces a plethora of toxic molecules that can harm host immune cells. Production of these toxins is mainly controlled by an active agr quorum-sensing system, which senses and responds to bacterial cell density. However, there are many reports of S. aureus strains with genetic changes leading to impaired agr activity that are often found during chronic bloodstream infections and may be associated with increased disease severity. We developed an open-source software called AgrVATE to type agr systems and identify mutations. We used AgrVATE for a species-wide genomic survey of S. aureus, finding that more than 5% of strains in the public database had nonfunctional agr systems. We also provided new insights into the evolution of these genetic mutations in the agr system. Overall, this study contributes to our understanding of a common but relatively understudied means of virulence regulation in S. aureus.

PMID:35044202 | DOI:10.1128/spectrum.01334-21

Pediatr Pulmonol. 2022 Jan 18. doi: 10.1002/ppul.25836. Online ahead of print.

ABSTRACT

Primary ciliary dyskinesis (PCD) is an autosomal recessive disorder associated with impaired mucociliary clearance caused by defects in ciliary structure and function. The major clinical feature of PCD is recurring or persistent respiratory tract infection. Respiratory tract colonization with drug-resistant organisms impacts the frequency of infections and lung function decline. Protective gear has been employed by caregivers in an attempt to control respiratory tract bacterial spread between patients with cystic fibrosis, but use in PCD is not known. We conducted a web-based survey to investigate infection control and prevention practices of PCD centers in North America, and how practices have been influenced by the COVID-19 pandemic. The response rate was 87.0%. Prior to the COVID-19 pandemic, glove, gown and mask use was variable, and only 3.7% of centers used masks during encounters with PCD outpatients. After COVID-19 mandates are lifted, 48.1% of centers plan to continue to use masks during outpatient care, while the practice regarding use of gloves and gowns was not influenced by the current pandemic. There is no uniform practice for infection control in PCD care indicating the need for practice guidelines. Mitigation of respiratory virus transmission learned during the COVID-19 pandemic may impact future infection control approaches used for patients with PCD and other lung diseases. This article is protected by copyright. All rights reserved.

PMID:35043594 | DOI:10.1002/ppul.25836

J Med Case Rep. 2022 Jan 19;16(1):27. doi: 10.1186/s13256-021-03234-1.

ABSTRACT

BACKGROUND: Previous reports have shown an increased number of colorectal cancers in patients with cystic fibrosis. We assessed the database of our cystic fibrosis center to identify patients with all kinds of cancer retrospectively. All patients visiting the Cystic Fibrosis Centre Innsbruck between 1995 and 2019 were included.

CASE PRESENTATION: Among 229 patients with cystic fibrosis treated at the Cystic Fibrosis Centre in Innsbruck between 1995 and 2019, 11 subjects were diagnosed with a malignant disease. The median age at diagnosis was 25.2 years (mean 24.3 years). There were four gynecological malignancies (cervical intraepithelial neoplasia and cervical cancer), two hematological malignancies (acute lymphocytic leukemia), one gastrointestinal malignancy (peritoneal mesothelioma), and four malignancies from other origins (malignant melanoma, neuroblastoma, adrenocortical carcinoma, and thyroid cancer). One malignancy occurred after lung transplantation. There was a strong preponderance of females, with 10 of the 11 cases occurring in women. Six deaths were attributed to cancer.

CONCLUSIONS: Most diagnoses were made below 30 years of age, and half of the subjects died from the malignant disease. Awareness of a possible malignancy is needed in patients with atypical symptoms. Regular screenings for cancer should also be considered, not only for gastrointestinal tumors.

PMID:35042562 | DOI:10.1186/s13256-021-03234-1

Physiother Theory Pract. 2022 Jan 18:1-7. doi: 10.1080/09593985.2021.2023932. Online ahead of print.

ABSTRACT

BACKGROUND: Physiotherapy is an essential component in the management of cystic fibrosis (CF).

OBJECTIVE: To explore how parents of infants with CF experience physiotherapy clinic consultations.

METHODS: A qualitative study, informed by hermeneutic phenomenology, utilizing in-depth semi-structured interviews and daily diaries was conducted with 13 parents of infants (aged 0-2 yrs.) receiving physiotherapy care for CF in Australia.

RESULTS: Three themes arose from the text. The first was that parents' physiotherapy clinic experience is influenced by the manner in which health professionals communicate to parents about physiotherapy in CF, as well as their own prior experience and knowledge. Secondly, parents receive conflicting messages from the physiotherapy consultation, but perceive the key message to be to prioritize adherence to physiotherapy. The final theme was that parents' expectations of the physiotherapy interaction were often not met, in particular a lack of practical physiotherapy education and training was reported.

CONCLUSION: Parents of infants with CF seek an optimistic, practical and hands on approach during physiotherapy consultations. Exploring options for providing physiotherapy input outside of traditional clinic environments may help accommodate individual needs. Investigation into the manner in which physiotherapy education is communicated to parents is warranted in light of the influence on parents' expectations of physiotherapy.

PMID:35042441 | DOI:10.1080/09593985.2021.2023932

Antimicrob Agents Chemother. 2022 Jan 18:aac0220321. doi: 10.1128/aac.02203-21. Online ahead of print.

ABSTRACT

Acute exacerbations of chronic respiratory infections in patients with cystic fibrosis are highly challenging due to hypermutable Pseudomonas aeruginosa, biofilm formation and resistance emergence. We aimed to systematically evaluate the effects of intravenous versus inhaled tobramycin with and without intravenous ceftazidime. Two hypermutable P. aeruginosa isolates, CW30 (MICCAZ 0.5mg/L, MICTOB 2mg/L) and CW8 (MICCAZ 2mg/L, MICTOB 8mg/L), were investigated for 120h in dynamic in vitro biofilm studies. Treatments were: intravenous ceftazidime 9g/day (33% lung fluid penetration); intravenous tobramycin 10mg/kg 24-hourly (50% lung fluid penetration); inhaled tobramycin 300mg 12-hourly, and both ceftazidime-tobramycin combinations. Total and less-susceptible planktonic and biofilm bacteria were quantified over 120h. Mechanism-based modeling was performed. All monotherapies were ineffective for both isolates, with regrowth of planktonic (≥4.7log10 CFU/mL) and biofilm (>3.8log10 CFU/cm2) bacteria, and resistance amplification by 120h. Both combination treatments demonstrated synergistic or enhanced bacterial killing of planktonic and biofilm bacteria. With the combination simulating tobramycin inhalation, planktonic bacterial counts of the two isolates at 120h were 0.47% and 36% of those for the combination with intravenous tobramycin; for biofilm bacteria the corresponding values were 8.2% and 13%. Combination regimens achieved substantial suppression of resistance of planktonic and biofilm bacteria compared to each antibiotic in monotherapy for both isolates. Mechanism-based modeling well described all planktonic and biofilm counts, and indicated synergy of the combination regimens despite reduced activity of tobramycin in biofilm. Combination regimens of inhaled tobramycin with ceftazidime hold promise to treat acute exacerbations caused by hypermutable P. aeruginosa strains and warrant further investigation.

PMID:35041509 | DOI:10.1128/aac.02203-21

Radiologe. 2022 Jan 18. doi: 10.1007/s00117-021-00954-9. Online ahead of print.

ABSTRACT

CLINICAL ISSUE: Chest X‑ray is the most commonly performed X‑ray examination in children and adolescents. The aim of this review is to present the benefit of this radiologic modality, but also its limitations.

METHODS: Compared with older children, most X‑ray examinations of the chest were performed in newborns. After the neonatal period, this review focusses on the diagnosis of inflammatory pulmonary changes, foreign body aspiration, detection of pulmonary nodules, and cystic fibrosis.

METHODOLOGICAL INNOVATIONS: The radiation exposure of X‑ray examinations is continuously decreasing due to technical innovations. However, other imaging modalities were also continuously being optimized; therefore, alternatives without radiation exposure, i.e., magnetic resonance imaging [MRI] and ultrasound, should be considered in case of specific clinical indications.

PRACTICAL RECOMMENDATION: Even if the diagnostic performance of chest X‑ray examinations is often minor compared to computed tomography or MRI, chest X‑ray still has a high value in children and adolescents, due to its ubiquitous availability and the relatively simple acquisition.

PMID:35041027 | DOI:10.1007/s00117-021-00954-9

Pediatr Pulmonol. 2022 Jan 18. doi: 10.1002/ppul.25834. Online ahead of print.

ABSTRACT

BACKGROUND: This study examined the drug-specific and overall adherence of teenagers and adults with Cystic Fibrosis (CF) to inhaled therapies, to assess the degree of adherence, stability over a period of four years, and its association to health outcomes.

METHODS: 55 participants (30 women and 25 men) aged 14 years or older from two CF centers were enrolled in a retrospective review of inhaled medication adherence over 4 years. Adherence was assessed by the number of doses which were obtained by each participant based on the "e-prescription.gr" platform and the calculation of the medication possession ratio (MPR).

RESULTS: The mean composite MPR (cMPR) for the entire research period was 0.75±0.19. 43.4% of participants showed a variance of adherence less than 25%. Participants with stable adherence had a significantly higher mean cMPR compared to those with variable adherence (0.86±0.16 vs 0.66±0.17, p<0.001). A statistically significant difference between groups of patients with different degree of mean cMPR and mean weight was observed (p=0.011). Patients with a mean cMPR ≥0.80 weighed significantly more than those with moderate and low adherence. In addition, mean weight correlated significantly with the mean cMPR (Β (95% CI) = 14.845 (0.191-29.498), r=0.269, p=0.047).

CONCLUSIONS: In our setting, the cMPR was easy to assess and showed that adherence was probably better than expected. cMPR association to weight should be further investigated. Stable adherence seemed to be related to high adherence. This observation could enhance our understanding of people with CF and their approach to treatment. This article is protected by copyright. All rights reserved.

PMID:35040288 | DOI:10.1002/ppul.25834

J Physiol. 2022 Jan 17. doi: 10.1113/JP282586. Online ahead of print.

NO ABSTRACT

PMID:35038767 | DOI:10.1113/JP282586

J Liposome Res. 2022 Jan 17:1-15. doi: 10.1080/08982104.2021.2019762. Online ahead of print.

ABSTRACT

Liposomes are nano-structured vesicles, made up of phospholipids that provide active ingredients at the site of action at a predetermined rate and add the advantage of the sustained-release formulation. Liposomes have stability issues that tend to agglomerate and fuse upon storage, which reflects their drawback. Hence to overcome the aggregation, fusion, hydrolysis, and/or oxidation problems associated with liposomes a new technology named Proliposomes has been introduced. Proliposomes are defined as carbohydrate carriers coated with phospholipids, which upon addition of water generate liposomes. The objective of the review is to cover the concept of proliposomes for pulmonary or alveolar delivery of drugs and compare it with that of liposomes; highlight the methods used for preparations along with the characterization parameters. This is the first systematic review that covers the categorization of liposomes, characteristic methods, and recent examples of drugs from 2015 to 2021, supplied in form of proliposomes to the macrophages as well as others and offers an advantage over the free drug by offering a prolonged drug release and sufficient bioavailability in addition to overcome the stability issues related to liposomes. Since this is a very new technology and many scientists are continuously working in this field to make the drug available for clinical trials and ultimately in the market for the targeted delivery of drugs with better storage life.HIGHLIGHTSProliposomes as an alternative to overwhelm the stability and storage-related issues of liposomes.Anhydrous carbohydrate carriers are utilized for proliposomal preparation.Inhaled delivery of drugs as solid lipid nanoparticles offers a significant impact on pulmonary tract infections, particularly in cystic fibrosis.Size of liposomes attained after proliposome hydrolysis is critical for drug delivery via respiration.

PMID:35037565 | DOI:10.1080/08982104.2021.2019762

ACS Infect Dis. 2022 Jan 17. doi: 10.1021/acsinfecdis.1c00432. Online ahead of print.

ABSTRACT

Mycobacterium abscessus (Mab) has emerged as a challenging threat to individuals with cystic fibrosis. Infections caused by this pathogen are often impossible to treat due to the intrinsic antibiotic resistance leading to lung malfunction and eventually death. Therefore, there is an urgent need to develop new drugs against novel targets in Mab to overcome drug resistance and subsequent treatment failure. In this study, SAICAR synthetase (PurC) from Mab was identified as a promising target for novel antibiotics. An in-house fragment library screen and a high-throughput X-ray crystallographic screen of diverse fragment libraries were explored to provide crucial starting points for fragment elaboration. A series of compounds developed from fragment growing and merging strategies, guided by crystallographic information and careful hit-to-lead optimization, have achieved potent nanomolar binding affinity against the enzyme. Some compounds also show a promising inhibitory effect against Mab and Mtb. This work utilizes a fragment-based design and demonstrates for the first time the potential to develop inhibitors against PurC from Mab.

PMID:35037462 | DOI:10.1021/acsinfecdis.1c00432

Breathe (Sheff). 2021 Dec;17(4):210112. doi: 10.1183/20734735.0112-2021.

ABSTRACT

The genetic multisystem condition cystic fibrosis (CF) has seen a paradigm shift in therapeutic approaches within the past decade. Since the first clinical descriptions in the 1930s, treatment advances had focused on the downstream consequences of a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion channel. The discovery of the gene that codes for CFTR and an understanding of the way in which different genetic mutations lead to disruption of normal CFTR function have led to the creation and subsequent licensing of drugs that target this process. This marks an important move towards precision medicine in CF and results from clinical trials and real-world clinical practice have been impressive. In this review we outline how CFTR modulator drugs restore function to the CFTR protein and the progress that is being made in this field. We also describe the real-world impact of CFTR modulators on both pulmonary and multisystem complications of CF and what this will mean for the future of CF care.

PMID:35035569 | PMC:PMC8753614 | DOI:10.1183/20734735.0112-2021

Breathe (Sheff). 2021 Sep;17(3):210088. doi: 10.1183/20734735.0088-2021.

ABSTRACT

Newborn bloodspot screening (NBS) for cystic fibrosis (CF) is an effective strategy for the early recognition of infants with a CF diagnosis. Some infants with a positive NBS result for CF have an inconclusive diagnosis and evidence suggests the number of these infants is increasing, as more extensive gene analysis is integrated into screening protocols. There is an internationally agreed, but complex, designation for infants with an unclear diagnosis after a positive screening result: cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID). Infants with a CRMS/CFSPID designation have no clinical evidence of disease and do not meet the criteria for a CF diagnosis, but the NBS result indicates some risk of developing CF or a CFTR-related disorder. In this review, we describe the accurate designation of these and reflect on emerging management pathways, with particular attention given to clear and consistent communication.

EDUCATIONAL AIMS: To clarify the definition of the global harmonised designation: cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS)/cystic fibrosis screen positive, inconclusive diagnosis (CFSPID).To understand what impact a CRMS/CFSPID result has for the patient and their family.

PMID:35035555 | PMC:PMC8753618 | DOI:10.1183/20734735.0088-2021

Breathe (Sheff). 2021 Sep;17(3):210053. doi: 10.1183/20734735.0053-2021.

ABSTRACT

Airway diseases were initially described by nonspecific patterns of symptoms, for example "dry and wheezy" and "wet and crackly". The model airway disease is cystic fibrosis, which has progressed from nonspecific reactive treatments such as antibiotics for airway infection to molecular sub-endotype, proactive therapies with an unequivocal evidence base, early diagnosis, and biomarkers of treatment efficacy. Unfortunately, other airway diseases lag behind, not least because nonspecific umbrella labels such as "asthma" are considered to be diagnoses not mere descriptions. Pending the delineation of molecular sub-endotypes in other airway disease the concept of treatable traits, and consideration of airway disease in a wider context is preferable. A treatable trait is a characteristic amenable to therapy, with measurable benefits of treatment. This approach determines what pathology is actually present and treatable, rather than using umbrella labels. We determine if airway inflammation is present, and whether there is airway eosinophilia which will likely respond to inhaled corticosteroids; whether there is variable airflow obstruction due to bronchoconstriction which will respond to β2-agonists; and whether there is unsuspected underlying airway infection which should be treated with antibiotics unless there is an underlying endotype which can be addressed, as for example an immunodeficiency. The context of airway disease should also be extrapulmonary comorbidities, social and environmental factors, and a developmental perspective, particularly this last aspect if preventive strategies are being contemplated. This approach allows targeted treatment for maximal patient benefit, as well as preventing the discarding of therapies which are useful for appropriate subgroups of patients. Failure to appreciate this almost led to the discarding of valuable treatments such as prednisolone.

EDUCATIONAL AIMS: To use cystic fibrosis as a paradigm to show the benefits of the journey from nonspecific umbrella terms to specific endotypes and sub-endotypes, as a road map for other airway diseases to follow.Demonstrate that nonspecific labels to describe airway disease can and should be abandoned in favour of treatable traits to ensure diagnostic and therapeutic precision.Begin to learn to see airway disease in the context of extrapulmonary comorbidities, and social and environmental factors, as well as with a developmental perspective.

PMID:35035544 | PMC:PMC8753662 | DOI:10.1183/20734735.0053-2021

Cell Mol Life Sci. 2022 Jan 15;79(1):73. doi: 10.1007/s00018-021-04112-1.

ABSTRACT

Transmembrane (TM) proteins are major drug targets, but their structure determination, a prerequisite for rational drug design, remains challenging. Recently, the DeepMind's AlphaFold2 machine learning method greatly expanded the structural coverage of sequences with high accuracy. Since the employed algorithm did not take specific properties of TM proteins into account, the reliability of the generated TM structures should be assessed. Therefore, we quantitatively investigated the quality of structures at genome scales, at the level of ABC protein superfamily folds and for specific membrane proteins (e.g. dimer modeling and stability in molecular dynamics simulations). We tested template-free structure prediction with a challenging TM CASP14 target and several TM protein structures published after AlphaFold2 training. Our results suggest that AlphaFold2 performs well in the case of TM proteins and its neural network is not overfitted. We conclude that cautious applications of AlphaFold2 structural models will advance TM protein-associated studies at an unexpected level.

PMID:35034173 | DOI:10.1007/s00018-021-04112-1

Respir Med. 2021 Dec 7;192:106713. doi: 10.1016/j.rmed.2021.106713. Online ahead of print.

ABSTRACT

BACKGROUND: Exercise ventilatory limitation conventionally defined by reduced breathing reserve (BR) may underestimate the effect of lung disease on exercise capacity in patients with mild to moderate obstructive lung diseases.

OBJECTIVE: To investigate whether ventilatory limitation may be present despite a normal BR in Cystic Fibrosis (CF).

METHODS: Twenty adult CF patients (age 16-58y) with a wide range of pulmonary obstruction severity completed a symptom-limited incremental exercise test on a cycle ergometer. Operating lung volumes were derived from inspiratory capacity (IC) measurement during exercise and exercise tidal flow volume loop analysis.

RESULTS: six patients had a severe airway obstruction (FEV1<45% predicted) and conventional evidence of ventilatory limitation (low BR). Fourteen patients had mild to moderate-severe airway obstructive (FEV1 46-103% predicted), and a normal BR [12-62 L/min, BR% (17-40)]. However, dynamic respiratory mechanics demonstrated that even CF patients with mild to moderate-severe lung disease had clear evidence of ventilatory limitation during exercise. IC was decreased by (median) 580 ml (range 90-1180 ml) during exercise, indicating dynamic hyperinflation. Inspiratory reserve volume at peak exercise was 445 ml (241-1350 ml) indicating mechanical constraint on the respiratory system. The exercise tidal flow met or exceeded the expiratory boundary of the maximal flow volume loop over 72% of the expiratory volume (range 40-90%), indicating expiratory flow limitation.

CONCLUSION: Reduced BR as a sole criterion underestimates ventilatory limitation during exercise in mild to moderate-severe CF patients. Assessment of dynamic respiratory mechanics during exercise revealed ventilatory limitation, present even in patients with mild obstruction.

PMID:35033964 | DOI:10.1016/j.rmed.2021.106713