Lancet Respir Med. 2022 Dec 1:S2213-2600(22)00480-5. doi: 10.1016/S2213-2600(22)00480-5. Online ahead of print.

NO ABSTRACT

PMID:36463912 | DOI:10.1016/S2213-2600(22)00480-5

Respir Res. 2022 Dec 3;23(1):330. doi: 10.1186/s12931-022-02243-y.

NO ABSTRACT

PMID:36463180 | DOI:10.1186/s12931-022-02243-y

Paediatr Respir Rev. 2022 Nov 3:S1526-0542(22)00070-7. doi: 10.1016/j.prrv.2022.10.002. Online ahead of print.

NO ABSTRACT

PMID:36463090 | DOI:10.1016/j.prrv.2022.10.002

EBioMedicine. 2022 Nov 30;86:104384. doi: 10.1016/j.ebiom.2022.104384. Online ahead of print.

NO ABSTRACT

PMID:36462404 | DOI:10.1016/j.ebiom.2022.104384

Arch Dis Child. 2022 Dec 2:archdischild-2022-324874. doi: 10.1136/archdischild-2022-324874. Online ahead of print.

NO ABSTRACT

PMID:36460338 | DOI:10.1136/archdischild-2022-324874

Cochrane Database Syst Rev. 2022 Dec 2;12:CD003733. doi: 10.1002/14651858.CD003733.pub5.

ABSTRACT

BACKGROUND: Bronchodilators are used to treat bronchial hyper-responsiveness in asthma. Bronchial hyper-responsiveness may be a component of acute chest syndrome in people with sickle cell disease. Therefore, bronchodilators may be useful in the treatment of acute chest syndrome. This is an update of a previously published Cochrane Review.

OBJECTIVES: The aim of the review is to determine whether the use of inhaled, short-acting bronchodilators for acute chest syndrome reduces morbidity and mortality in people with sickle cell disease and to assess whether this treatment causes adverse effects.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional searches were carried out on MEDLINE (1966 to 2004) and Embase (1981 to 2004) and ongoing trial registries (28 September 2022). Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 25 July 2022.

SELECTION CRITERIA: Randomised or quasi-randomised controlled trials. Trials using quasi-randomisation methods will be included in future updates of this review if there is sufficient evidence that the treatment and control groups are similar at baseline.

DATA COLLECTION AND ANALYSIS: We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease.

MAIN RESULTS: We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease.

AUTHORS' CONCLUSIONS: If bronchial hyper-responsiveness is an important component of some episodes of acute chest syndrome in people with sickle cell disease, the use of inhaled bronchodilators may be indicated. There is need for a well-designed, adequately-powered randomised controlled trial to assess the benefits and risks of the addition of inhaled bronchodilators to established therapies for acute chest syndrome in people with sickle cell disease.

PMID:36458811 | DOI:10.1002/14651858.CD003733.pub5

J Genet Couns. 2022 Dec 2. doi: 10.1002/jgc4.1658. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF), a genetic disease and chronic illness, affects multiple organ systems and requires exceptional medical care and treatment. Few studies have assessed the diagnosis disclosure process to well children when their sibling(s) have CF, and none have evaluated the association between parental knowledge of CF and the disclosure of CF. The objectives of this study were to assess parental understanding of CF, demonstrate the most commonly shared topics and their frequencies of discussion with well children, and identify associations between parental understanding of CF and aspects of the disclosure process to well children. Parents were recruited from CF support organizations and asked to complete an online, anonymous survey. Individuals were eligible to participate in the study if they had at least one living child with CF and at least one living child without CF. Completed surveys from 48 individuals revealed that most parents began discussing a sibling's diagnosis of CF with the first-born well child at 5.4 years old. Topics related to CF were discussed openly and as needed with their well children (n = 44). The most frequently discussed topic, and the topic ranked most important (1.93 of 5, SD: 1.17) by 40 participants (90.9%), was medical concerns and treatment for CF. Fewer parents (n = 18, 40.9%) reported discussing the financial impact of CF, and many ranked this as least important to share (4.64 of 5, SD: 0.75). The CF knowledge assessment revealed that participants were well-informed about CF, with a mean total score of 8.9/10 (SD: 0.91). There were no associations between CF knowledge assessment scores, education level, income, and the topics discussed with well children. These results can be utilized by genetic counselors and other healthcare specialists in discussion with parents about the disclosure process of a diagnosis of CF to well children.

PMID:36458380 | DOI:10.1002/jgc4.1658

Oman Med J. 2022 Nov 30;37(6):e444. doi: 10.5001/omj.2022.101. eCollection 2022 Nov.

ABSTRACT

OBJECTIVES: To describe the demographic distribution of cystic fibrosis (CF) in Omani children, estimate the national prevalence, and provide updated mutational panels of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

METHODS: We conducted a retrospective cross-sectional study of all CF patients who had been diagnosed and followed-up at Sultan Qaboos University Hospital and Royal Hospital in Oman between 2006 and 2020. Data were collected from electronic hospital records and telephone interviews.

RESULTS: A total of 227 patients with CF were included in the study. Geographical clusters of the disease were identified in the governorates of Al-Batinah, A'Dhahirah, and A'Dakhiliyah. Parental consanguinity and family history of CF were present in 68.3% and 69.6% of the patients, respectively. The most common CFTR mutation was p.Ser549Arg (52.0%), followed by p.Phe508del (12.3%), and c.2988+1G>A (4.4%). Three novel CFTR mutations were identified, viz., Leu88TyrFs*, p.Asp192Val, and c.4242+1G>C.

CONCLUSIONS: The estimated prevalence of CF in Oman is 10.3 per 100 000 individuals. Premarital genetic counseling and preimplantation genetic testing are recommended in CF-prevalent regions.

PMID:36458240 | PMC:PMC9627948 | DOI:10.5001/omj.2022.101

Front Immunol. 2022 Nov 15;13:1072257. doi: 10.3389/fimmu.2022.1072257. eCollection 2022.

ABSTRACT

Mesenchymal stromal cells (MSCs) were identified more than 50 years ago, and research advances have promoted the translation of pre-clinical studies into clinical settings in several diseases. However, we are only starting to uncover the local factors that regulate cell phenotype, cell function, and cell viability across tissues following administration in different diseases. Advances in pre-clinical and translational studies suggest that the host environment, especially inflammatory active environments, plays a significant role in directing the infused MSCs towards different phenotypes with different functions. This can significantly effect their therapeutic efficacy. One way to study this interaction between the host environment and the infused cells is to expose MSCs ex vivo to patient samples such as serum or bronchoalveolar lavage fluid. Using this approach, it has been demonstrated that MSCs are very sensitive to different host factors such as pathogens, inflammatory cytokines, and extra cellular matrix properties. By understanding how different local host factors effect MSC function it will open possibilities to select specific patient sub-groups that are more likely to respond to this type of treatment and will also open possibilities to prime the local host environment to increase viability and to enrich for a specific MSC phenotype. Here, we aim to review the current understanding of the interaction of MSCs with the host microenvironment. To narrow the scope of this mini review, the focus will be on the pulmonary microenvironment, with a specific focus on the diseases acute respiratory distress syndrome (ARDS) and cystic fibrosis (CF).

PMID:36458013 | PMC:PMC9705762 | DOI:10.3389/fimmu.2022.1072257

Am J Respir Crit Care Med. 2022 Dec 1. doi: 10.1164/rccm.202203-0564OC. Online ahead of print.

ABSTRACT

RATIONALE: Shared symptoms and genetic architecture between COVID-19 and lung fibrosis suggests SARS-CoV-2 infection may lead to progressive lung damage.

OBJECTIVES: The UKILD Post-COVID study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 based on risk strata.

METHODS: The Post-HOSPitalisation COVID Study (PHOSP-COVID) was used for capture of routine and research follow-up within 240 days from discharge. Thoracic CTs linked by PHOSP-COVID identifiers were scored for percentage of residual lung abnormalities (ground glass opacities and reticulations). Risk factors in linked CT were estimated with Bayesian binomial regression and risk strata were generated. Numbers within strata were used to estimate post-hospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol driven research follow-up.

MEASUREMENTS AND MAIN RESULTS: The interim cohort comprised 3700 people. Of 209 subjects with linked CTs (median 119 days, interquartile range 83-155), 166 people (79.4%) had >10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (RR 1·21 95%CrI 1·05; 1·40), percent predicted DLco<80% (RR 1·25 95%CrI 1·00; 1·56) and severe admission requiring ventilation support (RR 1·27 95%CrI 1·07; 1·55). In the remaining 3491 people, moderate to very-high risk of residual lung abnormalities was classified in 7·8%, post-hospitalization prevalence was estimated at 8.5% (95%CrI 7.6%; 9.5%) rising to 11.7% (95%CrI 10.3%; 13.1%) in sensitivity analysis.

CONCLUSIONS: Residual lung abnormalities were estimated in up to 11% of people discharged following COVID-19 related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

PMID:36457159 | DOI:10.1164/rccm.202203-0564OC

Nat Commun. 2022 Dec 1;13(1):7402. doi: 10.1038/s41467-022-35030-w.

ABSTRACT

Pseudomonas aeruginosa is a major cause of nosocomial infections and also leads to severe exacerbations in cystic fibrosis or chronic obstructive pulmonary disease. Three intertwined quorum sensing systems control virulence of P. aeruginosa, with the rhl circuit playing the leading role in late and chronic infections. The majority of traits controlled by rhl transcription factor RhlR depend on PqsE, a dispensable thioesterase in Pseudomonas Quinolone Signal (PQS) biosynthesis that interferes with RhlR through an enigmatic mechanism likely involving direct interaction of both proteins. Here we show that PqsE and RhlR form a 2:2 protein complex that, together with RhlR agonist N-butanoyl-L-homoserine lactone (C4-HSL), solubilizes RhlR and thereby renders the otherwise insoluble transcription factor active. We determine crystal structures of the complex and identify residues essential for the interaction. To corroborate the chaperone-like activity of PqsE, we design stability-optimized variants of RhlR that bypass the need for C4-HSL and PqsE in activating PqsE/RhlR-controlled processes of P. aeruginosa. Together, our data provide insight into the unique regulatory role of PqsE and lay groundwork for developing new P. aeruginosa-specific pharmaceuticals.

PMID:36456567 | DOI:10.1038/s41467-022-35030-w

Eur Respir J. 2022 Dec 1:2202096. doi: 10.1183/13993003.02096-2022. Online ahead of print.

NO ABSTRACT

PMID:36455960 | DOI:10.1183/13993003.02096-2022

Eur Respir J. 2022 Dec 1:2200725. doi: 10.1183/13993003.00725-2022. Online ahead of print.

ABSTRACT

QUESTION: Cystic Fibrosis (CF), which is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), is characterized by chronic bacterial lung infection and inflammation. In CF, monocytes and monocyte-derived macrophages have been shown to display defective phagocytosis and antimicrobial activity against relevant lung pathogens, including Pseudomonas aeruginosa. Thus, we addressed the effect of the CFTR triple modulator therapy, Elexacaftor/Tezacaftor/Ivacaftor (ETI), on the activity of CF monocytes against P. aeruginosa.

MATERIALS/PATIENTS AND METHODS: Monocytes from people with CF (PWCF) before and after 1 and 6 months of ETI therapy were isolated from blood and infected with P. aeruginosa to assess phagocytic activity and intracellular bacterial killing. The oxidative burst and IL-6 secretion were also determined. Monocytes from healthy controls were also included.

RESULTS AND ANSWER TO THE QUESTION: Longitudinal analysis of the clinical parameters confirmed an improvement of lung function and lung microbiology by ETI. Both the phagocytic and microbicidal deficiencies of the CF monocytes also improved significantly, although not completely. Furthermore, we measured an exuberant oxidative burst in CF monocytes before therapy, which was reduced considerably by ETI. This led to an improvement of the ROS-dependent bactericidal activity. Inflammatory response to bacterial stimuli was also lowered compared to pre-therapy. PWCF on ETI therapy, in a real-life setting, in addition to clinical recovery, showed significant improvement in monocyte activity against P. aeruginosa, which may have contributed to the overall effect of ETI on pulmonary disease. This also suggests that CF monocyte dysfunctions may be specifically targeted to ameliorate lung function in CF.

PMID:36455959 | DOI:10.1183/13993003.00725-2022

Genet Med. 2022 Dec 1:S1098-3600(22)01002-4. doi: 10.1016/j.gim.2022.10.014. Online ahead of print.

ABSTRACT

PURPOSE: The purpose of this study was to evaluate the clinical performance of carrier screening for cystic fibrosis, hemoglobinopathies, and spinal muscular atrophy with reflex single-gene noninvasive prenatal screening (sgNIPS), which does not require paternal carrier screening.

METHODS: An unselected sample of 9151 pregnant individuals from the general US pregnant population was screened for carrier status, of which 1669 (18.2%) were identified as heterozygous for one or more pathogenic variants and reflexed to sgNIPS. sgNIPS results were compared with newborn outcomes obtained from parent survey responses or provider reports for a cohort of 201 pregnancies.

RESULTS: Overall, 98.7% of pregnant individuals received an informative result (no-call rate = 1.3%), either a negative carrier report or, if identified as heterozygous for a pathogenic variant, a reflex sgNIPS report. In the outcomes cohort, the negative predictive value of sgNIPS was 99.4% (95% CI = 96.0%-99.9%) and average positive predictive value (PPV) of sgNIPS was 48.3% (95% CI = 36.1%-60.1%). Importantly, personalized PPVs accurately reflected the percentage of affected pregnancies in each PPV range, and all pregnancies with a sgNIPS fetal risk of >9 in 10 (90% PPV) were affected.

CONCLUSION: Although traditional carrier screening is most effective when used to assess reproductive risk before pregnancy, more than 95% of the time it is pursued during a pregnancy and is complicated by incomplete uptake of paternal carrier screening (<50%) and misattributed paternity (∼10%). Even in an idealized setting, when both partners have carrier screening, the maximum risk for having an affected pregnancy is 1 in 4 (equivalent of a 25% PPV). Carrier screening with sgNIPS during pregnancy is an alternative that does not require a paternal sample and provides accurate fetal risk in a timely manner that can be used for prenatal counseling and pregnancy management.

PMID:36454238 | DOI:10.1016/j.gim.2022.10.014

Microbiol Spectr. 2022 Dec 1:e0184222. doi: 10.1128/spectrum.01842-22. Online ahead of print.

ABSTRACT

The Pseudomonas aeruginosa bacterium is a common pathogen of cystic fibrosis (CF) patients due to its ability to evolve resistance to antibiotics during treatments. While P. aeruginosa resistance evolution is well-characterized in monocultures, it is less well-understood in polymicrobial CF infections. Here, we investigated how exposure to ciprofloxacin, colistin, or tobramycin antibiotics, administered at sub-minimum inhibitory concentration (MIC) doses, both alone and in combination, shaped the tolerance evolution of P. aeruginosa (PAO1 lab and clinical CF LESB58 strains) in the absence and presence of a commonly co-occurring species, Stenotrophomonas maltophilia. The increases in antibiotic tolerances were primarily driven by the presence of that antibiotic in the treatment. We observed a reciprocal cross-tolerance between ciprofloxacin and tobramycin, and, when combined, the selected antibiotics increased the MICs for all of the antibiotics. Though the presence of S. maltophilia did not affect the tolerance or the MIC evolution, it drove P. aeruginosa into extinction more frequently in the presence of tobramycin due to its relatively greater innate tobramycin tolerance. In contrast, P. aeruginosa dominated and drove S. maltophilia extinct in most other treatments. Together, our findings suggest that besides driving high-level antibiotic tolerance evolution, sub-MIC antibiotic exposure can alter competitive bacterial interactions, leading to target pathogen extinctions in multispecies communities. IMPORTANCE Cystic fibrosis (CF) is a genetic condition that results in thick mucus secretions in the lungs that are susceptible to chronic bacterial infections. The bacterial pathogen Pseudomonas aeruginosa is often associated with morbidity in CF and is difficult to treat due to its high resistance to antibiotics. The resistance evolution of Pseudomonas aeruginosa is poorly understood in polymicrobial infections that are typical of CF. To study this, we exposed P. aeruginosa to sublethal concentrations of ciprofloxacin, colistin, or tobramycin antibiotics in the absence and presence of a commonly co-occurring CF species, Stenotrophomonas maltophilia. We found that low-level antibiotic concentrations selected for high-level antibiotic resistance. While P. aeruginosa dominated in most antibiotic treatments, S. maltophilia drove it into extinction in the presence of tobramycin due to an innately higher tobramycin resistance. Our findings suggest that, besides driving high-level antibiotic tolerance evolution, sublethal antibiotic exposure can magnify competition in bacterial communities, which can lead to target pathogen extinctions in multispecies communities.

PMID:36453898 | DOI:10.1128/spectrum.01842-22

Med J Aust. 2022 Dec 1. doi: 10.5694/mja2.51797. Online ahead of print.

NO ABSTRACT

PMID:36453811 | DOI:10.5694/mja2.51797

Cell Surf. 2022 Nov 17;8:100090. doi: 10.1016/j.tcsw.2022.100090. eCollection 2022 Dec.

ABSTRACT

Mycobacterium abscessus is an increasingly prevalent opportunistic pathogen causing both pulmonary and skin and soft tissue infections. It is of increasing concern for immunocompromised individuals, such as those with cystic fibrosis, due to its highly drug resistant nature and ability to evade the host immune system. Current treatments for M. abscessus pulmonary infections are largely ineffective and treatment outcomes are generally poor, thus we urgently require new treatments to combat these infections. Recently, it has been demonstrated that manuka honey is effective against M. abscessus and can improve the inhibitory effect of amikacin. Here, we explore the potential improvement of both azithromycin and tobramycin with the addition of manuka honey against M. abscessus complex. Improved growth inhibition was observed for azithromycin with manuka honey against all M. abscessus subspecies. Improved bactericidal activity was also observed. Importantly, the macrolide resistant M. abscessus subsp. bolletii showed improved inhibition and bactericidal activity was obtained in response to 0.117 g/mL manuka honey MGO40 with 16 µg/mL azithromycin. No improved activity was observed for tobramycin and manuka honey against any of the M. abscessus isolates tested. This demonstrates the potential for antibiotic enhancement by the addition of manuka honey, furthering the applications of therapeutic manuka honey.

PMID:36452962 | PMC:PMC9703798 | DOI:10.1016/j.tcsw.2022.100090

Front Public Health. 2022 Nov 14;10:978627. doi: 10.3389/fpubh.2022.978627. eCollection 2022.

ABSTRACT

BACKGROUND: Most of the studies on cystic fibrosis (CF) focused on SARS-CoV-2 prevalence and suggested a low incidence of infection in this population. We aimed to assess the impact of the pandemic and related lockdown measures implemented in May 2020 in response to the first wave of SARS-CoV-2 infection on healthcare access, health, and behavior in CF patients.

METHODS: A national questionnaire opened online from May 15th, 2020 to June 11th, 2020 was completed by 751 CF-patients, aged 14 years and over. It comprised questions about access to healthcare, anxiety and depression, smoking, alcohol, drug and psychotropic drug consumption, adherence to CF treatment, and constraints. A semi-structured comprehensive interview was performed no later than 1 month after the end of the lockdown in 16 CF-patients.

RESULTS: The mean age of the population was 28.0 [interquartile range (IQR) 20.0-37.0] years old. More than 75% of in-person consultations scheduled during the lockdown were canceled. Alternatively, 27% were postponed, and telehealth consultations were proposed and accepted in almost 40% of cases. More than 75% of the scheduled physiotherapy sessions were canceled and replaced mainly by self-drainage. Annual follow-up clinic visits were consistently postponed whereas required hospitalizations at CF centers for exacerbation were maintained in most cases. While 43.2% CF-patients had signs of anxiety, 51.0% presented symptoms of depression, both associated with increased use of psychotic medications and inversely correlated to COVID-19 prevalence. Among the lower and lower middle classes, very little medical information was obtained or requested by the patient, participation to sports or other activities was low, while excessive home confinement and isolation were more frequent. In contrast, in the upper middle and upper classes, individuals solicitated help to their CF centre, had more physical activities, and maintained contact with friends or families.

CONCLUSION: The first lockdown in France had only minimal impact on the management care of CF-patients but was associated with increased symptoms of anxiety and depression, together with behavioral changes that varied with social class.

TRIAL REGISTRATION: NCT04463628.

PMID:36452951 | PMC:PMC9703073 | DOI:10.3389/fpubh.2022.978627

Indian J Otolaryngol Head Neck Surg. 2022 Oct;74(Suppl 2):813-820. doi: 10.1007/s12070-020-01861-6. Epub 2020 May 4.

ABSTRACT

Functional endoscopic sinus surgery (FESS) has become one of the most common surgical techniques performed by otolaryngologists with significant data demonstrating its efficacy in managing patients with chronic rhinosinusitis (CRS). However, despite this initial success, patients may continue to present with recurrent symptoms and approximately 10-15% of them will require revision surgery. Failure of FESS may have many different causes which include inappropriate patient selection and preparation, comorbidities like cystic fibrosis and Samter's triad, insufficient surgical skills or anatomical variations that have not been addressed adequately. Two inverse European techniques were introduced in the 1980s. The one promoted by Messer-klinger, who practiced the anterior-to-posterior approach, another one, developed by Wigand who performed posterior-to-anterior dissection, opens the sphenoid ostium or removes the anterior wall of the sphenoid sinus and ends with a total ethmoidectomy. Hereby in RESS we start dissection in posterior-to-anterior fashion by following a structured approach in the identification of the fixed landmarks to allow quick and easy orientation to the skull base and medial orbital wall to avoid the complications.

PMID:36452662 | PMC:PMC9702504 | DOI:10.1007/s12070-020-01861-6

ERJ Open Res. 2022 Nov 28;8(4):00364-2022. doi: 10.1183/23120541.00364-2022. eCollection 2022 Oct.

ABSTRACT

Immune checkpoint inhibitors (ICIs) are drugs growingly employed in the treatment of cancers, but there are still uncertainties about their possible role in the risk of developing nontuberculous mycobacteria (NTM) infections. To understand this, we performed a systematic review of the literature including studies published between 20 June 2012 and 20 June 2022 which described the occurrence of NTM infections among patients treated with ICIs. Overall, we included seven studies describing nine patients with NTM infection occurring during ICIs therapy. NTM infections occurring during ICIs therapy are mainly caused by germs belonging to the Mycobacterium avium complex, involve primarily the lungs, on average 1 year after the start of treatment, and are not associated with immunosuppressive treatments.

PMID:36451841 | PMC:PMC9703143 | DOI:10.1183/23120541.00364-2022