Thorax. 2022 Sep 30:thoraxjnl-2022-218702. doi: 10.1136/thorax-2022-218702. Online ahead of print.

ABSTRACT

BACKGROUND: Physical activity levels are known to decline following hospitalisation for people with cystic fibrosis (pwCF). However, optimal physical activity promotion strategies are unclear. This study investigated the effect of a web-based application (ActivOnline) in promoting physical activity in young pwCF.

METHODS: Multicentre randomised controlled trial with assessor blinding and qualitative evaluation. People with CF (12-35 years) admitted to hospital for a respiratory cause were eligible and randomised to the 12-week ActivOnline intervention (AO) or usual care (UC). The primary outcome was change in device-based time spent in moderate-to-vigorous physical activity (MVPA) from baseline to post-intervention. Follow-up was at 6 months from hospital discharge when qualitative evaluation was undertaken.

RESULTS: 107 participants were randomised to AO (n=52) or UC (n=55). Sixty-three participants (59%) contributed to the intention-to-treat analysis. Mean (SD) age was 21 (6) years (n=46, <18 years). At baseline, physical activity levels were high in both groups (AO 102 (52) vs UC 127 (73) min/day). There was no statistically significant difference in MVPA between groups at either timepoint (post-intervention mean difference (95% CI) -14 mins (-45 to 16)). Uptake of the intervention was low with only 40% (n=21) of participants accessing the web application.

CONCLUSION: A web-based application, including individualised goal setting, real-time feedback and motivation for behavioural change, was no better than usual care at promoting physical activity in young pwCF following hospital discharge. High levels of baseline physical activity levels in both groups, and limited engagement with the intervention, suggest alternative strategies may be necessary to identify and support young pwCF who would benefit from enhanced physical activity.

TRIAL REGISTRATION NUMBER: ACTRN12617001009303, 13 July 13 2017.

PMID:36180067 | DOI:10.1136/thorax-2022-218702

Thorax. 2022 Sep 30:thorax-2022-219429. doi: 10.1136/thorax-2022-219429. Online ahead of print.

NO ABSTRACT

PMID:36180065 | DOI:10.1136/thorax-2022-219429

Org Lett. 2022 Sep 30. doi: 10.1021/acs.orglett.2c02729. Online ahead of print.

ABSTRACT

ABBV-3748 is a C2 corrector for the treatment of cystic fibrosis profiled among AbbVie's CFTR portfolio. A decagram-scale enabling asymmetric synthesis is described which addresses numerous shortcomings of the original route. Highlights include an InBr3-catalyzed intramolecular hydroarylation reaction that rapidly assembles the chromane core, an exceptionally efficient asymmetric hydrogenation of a primary enamide, and identification of tBuMgCl as a uniquely effective base in a challenging acyl sulfonamide formation.

PMID:36178872 | DOI:10.1021/acs.orglett.2c02729

Cancer Causes Control. 2022 Sep 30. doi: 10.1007/s10552-022-01635-1. Online ahead of print.

ABSTRACT

BACKGROUND: Adults with cystic fibrosis (CF) have an increased risk of a variety of cancers, notably gastrointestinal cancers. In CF higher body mass index (BMI) is associated with improved long-term outcomes, yet in the general population high BMI is associated with increased cancer risk. We aimed to delineate associations between BMI and other factors with cancer risk in adults with CF.

METHODS: This was a retrospective cohort study using CF Foundation Patient Registry data from 1992 to 2015. Data were collected on age, sex, CFTR mutation class, pancreatic insufficiency, and annualized data on BMI and FEV1. The primary analysis was the association between BMI and cancer, with secondary analyses focused on BMI trajectory. Multivariable logistic regression was performed, with analyses stratified by history of transplant.

RESULTS: Of 26,199 adults with CF, 446 (1.7%) had cancer diagnosed by histology at a mean age of 40.0 years (SD 12.2), with a higher proportion of transplanted patients developing cancer (137 (3.8%) v 309(1.4%), p < 0.001). Among non-transplanted patients, there was no association between BMI and cancer (p for trend = 0.43). Pancreatic insufficiency (p < 0.01) and higher FEV1 (p < 0.01) were associated with increased cancer risk. In transplanted patients, higher BMI was associated with reduced risk of cancer (p for trend = 0.04). Older age was associated with increased risk in both groups (p < 0.001). BMI trajectories were not associated with cancer risk in either group.

CONCLUSION: Higher BMI is associated with a reduced risk of cancer in transplanted adults with CF. Pancreatic insufficiency is a risk factor for cancer in non-transplanted CF patients.

PMID:36178608 | DOI:10.1007/s10552-022-01635-1

Cranio. 2022 Sep 30:1-10. doi: 10.1080/08869634.2022.2128587. Online ahead of print.

ABSTRACT

OBJECTIVE: To compare masticatory muscle activity between people with cystic fibrosis (pwCF) and healthy controls and to verify whether craniocervical dysfunction is associated with the presence of CF.

METHODS: Fifty-six participants were assessed and divided into pwCF and healthy control (HC) groups, each one composed of 13 children and adolescents at 9 (SD 3) years old and 15 adults at 25 (SD 6) years old. Craniocervical Dysfunction Index assessed symptoms of dysfunction and cervical spine mobility. Electromyography was used to evaluate the jaw and neck muscle activity during chewing.

RESULTS: Muscle activity during chewing was not statistically different between groups. Prevalence of craniocervical dysfunction was 75% for pwCF vs 64% for healthy controls. Individuals with CF are 1.53 [1.260, 1.870] times more likely to have reduced cervical mobility compared to healthy controls (p = 0.000).

CONCLUSION: These results reinforce the need for musculoskeletal disorders treatment in the management of pwCF.

PMID:36178327 | DOI:10.1080/08869634.2022.2128587

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2022 Aug;34(8):831-836. doi: 10.3760/cma.j.cn121430-20220310-00234.

ABSTRACT

OBJECTIVE: To observe the effects of Xiaoqinglong Decoction and Qingqi Huatan Pills on interleukin-1β (IL-1β)-induced mucushypersecretion model of human airway epithelial H292 cellsand related molecules of nuclear factor-κB/microRNA-494(NF-κB/miR-494) signaling pathway, and to explore the mechanism of the two medicines in improving pathological airway mucus.

METHODS: Methyl thiazolyl tetrazolium (MTT) colorimetric method was used to detect the effects of different concentrations of Xiaoqinglong Decoction and Qingqi Huatan Pills on the activity of H292 cellsinduced by IL-1β, and the appropriate concentration was selected for subsequent experiments. Cells were randomly divided into blank group, IL-1β model group (5 μg/L IL-1β), NF-κB inhibitor pyrrolidinedithiocarbamate (PDTC) group (5 μg/L IL-1β+100 μmol/L PDTC), Xiaoqinglong Decoction (5 μg/L IL-1β+1 000 mg/L Xiaoqinglong Decoction) and Qingqi Huatan Pill group (5 μg/L IL-1β+1 000 mg/L Qingqi Huatan Pills). 5 μg/L IL-1β was used to induce H292 cells for 24 hours to establish a model of airway epithelial mucus hypersecretion. Enzyme linked immunosorbent assay (ELISA) method was used to detect the levels of mucin 5AC (MUC5AC), tumor necrosis factor-α (TNF-α) and IL-8 and the synthesis of intracellular MUC5AC and cystic fibrosis transmembrane conductance regulator (CFTR). Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression levels of MUC5AC mRNA, CFTR mRNA, miR-494. Western blotting was used to detect protein expression of key proteins (p65) and NF-κB inhibitors (IκB) in NF-κB signaling pathway.

RESULTS: Xiaoqinglong Decoction and Qingqi Huatan Pills with the concentration of 1 000 mg/L were selected for the follow-up experiment. Compared with the blank group, the levels of MUC5AC, TNF-α and IL-8 were significantly increased in the model group, intracellular MUC5AC protein content and mRNA expression were also significantly increased, intracellular CFTR protein content and mRNA expression were significantly decreased, and intracellular p65 protein expression was significantly up-regulated, the expression of IκB protein was significantly down-regulated, and the expression of miR-494 was significantly increased. Compared with the model group, the levels of MUC5AC, TNF-α and IL-8 were significantly reduced in PDTC group, Xiaoqinglong Decoction group and Qingqi Huatan Pill group, intracellular MUC5AC protein content and mRNA expression were also significantly decreased, and intracellular p65 protein expression was significantly down-regulated, and IκB protein expression was significantly up-regulated, miR-494 expression was significantly reduced. Intracellular CFTR protein content and mRNA expression were significantly increased in both PDTC group and Qingqi Huatan Pill group. Compared with the PDTC group, the level of TNF-α in the Xiaoqinglong Decoction group was significantly increased (ng/L: 22.77±3.14 vs. 11.09±3.37, P < 0.05),the content and mRNA expression of CFTR and IκB protein expression was significantly decreased [CFTR protein (ng/L): 97.38±6.62 vs. 227.04±19.48, CFTR mRNA (2-ΔΔCt): 0.99±0.08 vs. 1.21±0.08, IκB/β-actin: 1.69±0.11 vs. 2.00±0.18, all P < 0.05], the level of TNF-α in Qingqi Huatan Pill group was significantly higher (ng/L: 19.08±3.71 vs. 11.09±3.37, P < 0.05). Compared with Xiaoqinglong Decoction group, the protein content and mRNA expression of CFTR and IκB protein expression in Qingqi Huatan Pill group were significantly increased [CFTR protein (ng/L): 235.01±22.71 vs. 97.38±6.62, CFTR mRNA (2-ΔΔCt): 1.32±0.15 vs. 0.99±0.08, IκB/β-actin: 1.94±0.16 vs. 1.69±0.11, all P < 0.05].

CONCLUSIONS: The effect of Xiaoqinglong Decoctionin improving the hypersecretion of mucus in the airway epithelium may be related to the inhibition of NF-κB/miR-494 inflammatory signal-mediated MUC5AC hypersecretion, while the effect of Qingqi Huatan Pills may be related to the inhibition of NF-κB/miR-494 inflammatory signal-mediated MUC5AC hypersecretion and CFTR dysfunction. Therefore, the difference in the mechanism of the two treatments of airway pathological mucus is mainly in the regulation of CFTR mRNA and protein.

PMID:36177926 | DOI:10.3760/cma.j.cn121430-20220310-00234

Front Microbiol. 2022 Sep 13;13:943278. doi: 10.3389/fmicb.2022.943278. eCollection 2022.

ABSTRACT

Cell-to-cell communication is a fundamental process of bacteria to exert communal behaviors. Sputum samples of patients with cystic fibrosis have often been observed with extensive mycobacterial genetic diversity. The emergence of heterogenic mycobacterial populations is observed due to subtle changes in their morphology, gene expression level, and distributive conjugal transfer (DCT). Since each subgroup of mycobacteria has different hetero-resistance, they are refractory against several antibiotics. Such genetically diverse mycobacteria have to communicate with each other to subvert the host immune system. However, it is still a mystery how such heterogeneous strains exhibit synchronous behaviors for the production of quorum sensing (QS) traits, such as biofilms, siderophores, and virulence proteins. Mycobacteria are characterized by division of labor, where distinct sub-clonal populations contribute to the production of QS traits while exchanging complimentary products at the community level. Thus, active mycobacterial cells ensure the persistence of other heterogenic clonal populations through cooperative behaviors. Additionally, mycobacteria are likely to establish communication with neighboring cells in a contact-independent manner through QS signals. Hence, this review is intended to discuss our current knowledge of mycobacterial communication. Understanding mycobacterial communication could provide a promising opportunity to develop drugs to target key pathways of mycobacteria.

PMID:36177463 | PMC:PMC9514802 | DOI:10.3389/fmicb.2022.943278

Cureus. 2022 Aug 27;14(8):e28486. doi: 10.7759/cureus.28486. eCollection 2022 Aug.

ABSTRACT

Distal intestinal obstruction syndrome (DIOS) is a common complication in patients with cystic fibrosis (CF). Patients typically present with right lower quadrant pain, nausea, abdominal distention, and failure to pass stool or flatus. It can be managed conservatively with medical interventions but some cases may require colonoscopy and even surgery. We report a rare instance in which a CF patient with a previous ileostomy developed DIOS and was successfully managed with ileoscopy after medical management failed.

PMID:36176846 | PMC:PMC9512306 | DOI:10.7759/cureus.28486

Allergy. 2022 Sep 29. doi: 10.1111/all.15533. Online ahead of print.

ABSTRACT

Adolescence is a critical stage of rapid biological, emotional and social change and development. Adolescents and young adults (AYA) with asthma and allergies need to develop the knowledge and skills to self-manage their health independently. Healthcare professionals (HCP), parents and their wider network play an essential role in supporting AYA in this process. Previous work showed significant limitations in transition care across Europe. In 2020, the first evidence-based guideline on effective transition for AYA with asthma and allergies was published by EAACI. We herein summarize practical resources to support this guideline's implementation in clinical practice. For this purpose, multi-stakeholder Task Force members searched for resources in peer review journals and grey literature. These resources were included if relevant and of good quality, and were pragmatically rated for their evidence-basis and user friendliness. Resources identified covered a range of topics and targeted healthcare professionals, AYA, parents/carers, schools, workplace, and wider community. Most resources were in English, web-based and had limited evidence-basis. This position paper provides a valuable selection of practical resources for all stakeholders to support effective transitional care for AYA with asthma and allergies. Future research should focus on developing validated, patient-centred tools to further assist evidence-based transition care.

PMID:36176045 | DOI:10.1111/all.15533

Pediatr Pulmonol. 2022 Sep 29. doi: 10.1002/ppul.26169. Online ahead of print.

ABSTRACT

Recently, a cross-talk error with commercial MBWN2 software was discovered, which produced an absolute over-reading of N2 of ~1%, i.e., 2% N2 read as 3%. This caused an extended tail to the washout, and over-estimated lung clearance index (LCI2.5 ) values. Subsequently an updated and corrected software version has been released. Within the field there have been discussions on how to correct legacy data, whether to migrate or completely "rerun" raw data A-files from the old software into the new corrected software. To our knowledge, no research has been published assessing whether either method is equivalent to directly collecting data in the new corrected software. We prospectively recruited 19 participants, 10 adult healthy controls and 9 people with CF. MBWN2 was performed using the Exhalyzer® D first on the old 3.1.6 software and next, directly on corrected 3.3.1 software. MBW data directly collected in 3.3.1 was significantly different from both migrated and rerun data. Seven of the 19 participants (37%; 4 CF) had a relative difference in LCI2.5 >10% for both migrated and rerun data compared to 3.3.1 collected data. Our findings have implications for the Global Lung Initiative MBW project, which is accepting a combination of directly collected, A-file reruns and migrated data to establish normative values. Further, caution must be used in clinical practice when comparing corrected legacy data vs 3.3.1 collected data for clinical interpretation. We recommend that a new baseline is collected directly on 3.3.1. before clinical interpretation and decisions are determined when comparing consecutive MBW tests. This article is protected by copyright. All rights reserved.

PMID:36175005 | DOI:10.1002/ppul.26169

Allergy Asthma Immunol Res. 2022 Sep;14(5):494-504. doi: 10.4168/aair.2022.14.5.494.

ABSTRACT

PURPOSE: Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is rare among non-Caucasians. We aimed to identify the clinical features and CFTR mutations in Korean children.

METHODS: We included 18 pediatric patients with CF diagnosed using sweat chloride test or genetic analysis for 30 years. HEK293 cells were transfected with wild-type CFTR, ΔF508-CFTR, and L441P-CFTR mutant plasmids for 24 hours and treated with CFTR correctors (VX809 and VX661).

RESULTS: The median age at diagnosis was 9.2 years. Eleven patients had growth retardation, and 6 had a respiratory failure at diagnosis. Genetic analysis was used for all patients, while sweat testing was for 8 patients. At diagnosis, the median z scores of forced expiratory volume in one second (FEV1), FEV1/forced vital capacity, and forced expiratory flow at 25%-75% of forced vital capacity were -3.61 (-5.78, 1.78), -3.38 (-4.40, -0.60), and -4.45 (-5.78, 0.54), respectively. Two patients were treated with dornase alfa and only one with CFTR modulator. Patients were followed up for 3.7 years as a median. Four patients died at 10.6 years, with 4.2 years of post-diagnosis survival. The most common mutation was exon 16-17b deletion (19.4%). Among 11 single nucleotide variants, c.1322T>C (p.Leu441Pro, L441P) was detected in 4 patients. In the functional assay, L441P-CFTR correction was well restored by CFTR correctors compared with ΔF508.

CONCLUSIONS: CF is extremely rare in Korean children and is caused by different mutations from those commonly observed in Caucasians. Early diagnosis and treatment availability may improve outcomes. CFTR modulators may be effective for Asian patients with rare CFTR mutations, c.1322T>C (p.Leu441Pro).

PMID:36174992 | DOI:10.4168/aair.2022.14.5.494

ACS Chem Biol. 2022 Sep 29. doi: 10.1021/acschembio.2c00532. Online ahead of print.

ABSTRACT

Multidrug-resistant pathogens such as Burkholderia cenocepacia have become a hazard in the context of healthcare-associated infections, especially for patients admitted with cystic fibrosis or immuno-compromising conditions. Like other opportunistic Gram-negative bacteria, this pathogen establishes virulence and biofilms through lectin-mediated adhesion. In particular, the superlectin BC2L-C is believed to cross-link human epithelial cells to B. cenocepacia during pulmonary infections. We aimed to obtain glycomimetic antagonists able to inhibit the interaction between the N-terminal domain of BC2L-C (BC2L-C-Nt) and its target fucosylated human oligosaccharides. In a previous study, we identified by fragment virtual screening and validated a small set of molecular fragments that bind BC2L-C-Nt in the vicinity of the fucose binding site. Here, we report the rational design and synthesis of bifunctional C- or N-fucosides, generated by connecting these fragments to a fucoside core using a panel of rationally selected linkers. A modular route starting from two key fucoside intermediates was implemented for the synthesis, followed by evaluation of the new compounds as BC2L-C-Nt ligands with a range of techniques (surface plasmon resonance, isothermal titration calorimetry, saturation transfer difference NMR, differential scanning calorimetry, and X-ray crystallography). This study resulted in a hit molecule with an order of magnitude gain over the starting methyl fucoside and in two crystal structures of antagonist/lectin complexes.

PMID:36174276 | DOI:10.1021/acschembio.2c00532

J Am Med Inform Assoc. 2022 Sep 29:ocac176. doi: 10.1093/jamia/ocac176. Online ahead of print.

ABSTRACT

OBJECTIVE: Lung transplant (LTx) saves lives in cystic fibrosis (CF). However, many potential candidates express uncertainty about LTx and die before receiving this treatment. CF guidelines recommend LTx education and clinical discussions well before the need for LTx arises, but limited patient resources exist.

MATERIALS AND METHODS: We engaged people with CF and CF physicians in human-centered design of "Take On Transplant" (TOT), a web-based education tool to prepare patients for LTx discussions. Across 3 phases, needs assessment, design groups, and iterative user testing of TOT, we refined TOT from wireframe prototypes, to an interactive website, to a fully functional intervention ready for clinical trials.

RESULTS: Fifty-five people with CF and 105 physicians identified information needs to prepare for LTx discussions. Design groups (n = 14 participants) then established core requirements: didactic education ("Resource Library"), patient narratives ("CF Stories"), frequently asked questions ("FAQ"), and self-assessment to tailor content ("My CF Stage"). Iterative usability testing (n = 39) optimized the design of CF Stories and prototype layout. We then developed the TOT website and demonstrated feasibility and preliminary efficacy of use through 2-week field testing (n = 9).

DISCUSSION: Our human-centered design process provided guidance for educational tools to serve the evolving needs of potential LTx candidates. Our findings support the process of patient deliberation as a foundation for shared decision-making in CF, and inform educational tools that could potentially translate beyond LTx.

CONCLUSION: TOT fills a critical gap in preparing people with CF for shared decision-making about LTx and may serve as a model for educational tools for other preference-sensitive decisions.

PMID:36173364 | DOI:10.1093/jamia/ocac176

J Antimicrob Chemother. 2022 Sep 29:dkac324. doi: 10.1093/jac/dkac324. Online ahead of print.

ABSTRACT

BACKGROUND: Children with cystic fibrosis (CF) pulmonary exacerbations receive IV tobramycin therapy, with dosing guided by either log-linear regression (LLR) or Bayesian forecasting (BF).

OBJECTIVES: To compare clinical and performance outcomes for LLR and BF.

PATIENTS AND METHODS: A quasi-experimental intervention study was conducted at a tertiary children's hospital. Electronic medical records were extracted (from January 2015 to September 2021) to establish a database consisting of pre-intervention (LLR) and post-intervention (BF) patient admissions and relevant outcomes. All consecutive patients treated with IV tobramycin for CF pulmonary exacerbations guided by either LLR or BF were eligible.

RESULTS: A total of 376 hospital admissions (LLR = 248, BF = 128) for CF pulmonary exacerbations were included. Patient demographics were similar between cohorts. There were no significant differences found in overall hospital length of stay, rates of re-admission within 1 month of discharge or change in forced expiratory volume in the first second (Δ FEV1) at the end of tobramycin treatment. Patients treated with LLR on average had twice the number of therapeutic drug monitoring (TDM) blood samples collected during a single hospital admission. The timeframe for blood sampling was more flexible with BF, with TDM samples collected up to 16 h post-tobramycin dose compared with 10 h for LLR. The tobramycin AUC0-24 target of ≥100 mg/L·h was more frequently attained using BF (72%; 92/128) compared with LLR (50%; 124/248) (P < 0.001). Incidence of acute kidney injury was rare in both groups.

CONCLUSIONS: LLR and BF result in comparable clinical outcomes. However, BF can significantly reduce the number of blood collections required during each admission, improve dosing accuracy, and provide more reliable target concentration attainment in CF children.

PMID:36172897 | DOI:10.1093/jac/dkac324

Front Med (Lausanne). 2022 Sep 12;9:994900. doi: 10.3389/fmed.2022.994900. eCollection 2022.

ABSTRACT

BACKGROUND: Respiratory physiotherapy is reported as safe and feasible in mechanically ventilated patients with severe Coronavirus Disease (COVID-19) admitted to Intensive Care Unit (ICU), but the short-term benefits remain unclear.

METHODS: We performed a retrospective observational study in four ICUs in Northern Italy. All patients with COVID-19 admitted to ICU and under invasive mechanical ventilation (MV) between March 1st and May 30th, 2020, were enrolled into the study. Overlap weighting based on the propensity score was used to adjust for confounding in the comparison of patients who had or had not been treated by physiotherapists. The primary outcome was the number of days alive and ventilator-free (VFDs). The secondary outcomes were arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio (P/F) at ICU discharge, ICU length of stay, ICU and hospital mortality, and survival at 90 days. The trial protocol was registered on clinicaltrials.gov (NCT05067907).

RESULTS: A total of 317 patients were included in the analysis. The median VFDs was 18 days [interquartile range (IQR) 10; 24] in patients performing physiotherapy and 21 days (IQR 0; 26) in the group without physiotherapy [incidence rate ratio (IRR) 0.86, 95% confidence interval (CI): 0.78; 0.95]. The chance of 0 VFDs was lower for patients treated by physiotherapists compared to those who were not [odds ratio (OR) = 0.36, 95% CI: 0.18-0.71]. Survival at 90 days was 96.0% in the physiotherapy group and 70.6% in patients not performing physiotherapy [hazard ratio (HR) = 0.14, 95% CI: 0.03-0.71]. Number of VFDs was not associated with body mass index (BMI), sex, or P/F at ICU admission for individuals with at least 1 day off the ventilator.

CONCLUSION: In patients with COVID-19 admitted to ICU during the first pandemic wave and treated by physiotherapists, the number of days alive and free from MV was lower compared to patients who did not perform respiratory physiotherapy. Survival at 90 days in the physiotherapy group was greater compared to no physiotherapy. These findings may be the starting point for further investigation in this setting.

PMID:36172535 | PMC:PMC9510617 | DOI:10.3389/fmed.2022.994900

Cochrane Database Syst Rev. 2022 Sep 28;9(9):CD012749. doi: 10.1002/14651858.CD012749.pub2.

ABSTRACT

BACKGROUND: Autism spectrum disorder is a neurodevelopmental disorder characterised by social communication difficulties, restricted interests and repetitive behaviours. The clinical pathway for children with a diagnosis of autism spectrum disorder is varied, and current research suggests some children may not continue to meet diagnostic criteria over time.

OBJECTIVES: The primary objective of this review was to synthesise the available evidence on the proportion of preschool children who have a diagnosis of autism spectrum disorder at baseline (diagnosed before six years of age) who continue to meet diagnostic criteria at follow-up one or more years later (up to 19 years of age).

SEARCH METHODS: We searched MEDLINE, Embase, PsycINFO, and eight other databases in October 2017 and ran top-up searches up to July 2021. We also searched reference lists of relevant systematic reviews.

SELECTION CRITERIA: Two review authors independently assessed prospective and retrospective follow-up studies that used the same measure and process within studies to diagnose autism spectrum disorder at baseline and follow-up. Studies were required to have at least one year of follow-up and contain at least 10 participants. Participants were all aged less than six years at baseline assessment and followed up before 19 years of age.

DATA COLLECTION AND ANALYSIS: We extracted data on study characteristics and the proportion of children diagnosed with autism spectrum disorder at baseline and follow-up. We also collected information on change in scores on measures that assess the dimensions of autism spectrum disorder (i.e. social communication and restricted interests and repetitive behaviours). Two review authors independently extracted data on study characteristics and assessed risk of bias using a modified quality in prognosis studies (QUIPS) tool. We conducted a random-effects meta-analysis or narrative synthesis, depending on the type of data available. We also conducted prognostic factor analyses to explore factors that may predict diagnostic outcome.

MAIN RESULTS: In total, 49 studies met our inclusion criteria and 42 of these (11,740 participants) had data that could be extracted. Of the 42 studies, 25 (60%) were conducted in North America, 13 (31%) were conducted in Europe and the UK, and four (10%) in Asia. Most (52%) studies were published before 2014. The mean age of the participants was 3.19 years (range 1.13 to 5.0 years) at baseline and 6.12 years (range 3.0 to 12.14 years) at follow-up. The mean length of follow-up was 2.86 years (range 1.0 to 12.41 years). The majority of the children were boys (81%), and just over half (60%) of the studies primarily included participants with intellectual disability (intelligence quotient < 70). The mean sample size was 272 (range 10 to 8564). Sixty-nine per cent of studies used one diagnostic assessment tool, 24% used two tools and 7% used three or more tools. Diagnosis was decided by a multidisciplinary team in 41% of studies. No data were available for the outcomes of social communication and restricted and repetitive behaviours and interests. Of the 42 studies with available data, we were able to synthesise data from 34 studies (69% of all included studies; n = 11,129) in a meta-analysis. In summary, 92% (95% confidence interval 89% to 95%) of participants continued to meet diagnostic criteria for autism spectrum disorder from baseline to follow-up one or more years later; however, the quality of the evidence was judged as low due to study limitations and inconsistency. The majority of the included studies (95%) were rated at high risk of bias. We were unable to explore the outcomes of change in social communication and restricted and repetitive behaviour and interests between baseline and follow-up as none of the included studies provided separate domain scores at baseline and follow-up. Details on conflict of interest were reported in 24 studies. Funding support was reported by 30 studies, 12 studies omitted details on funding sources and two studies reported no funding support. Declared funding sources were categorised as government, university or non-government organisation or charity groups. We considered it unlikely funding sources would have significantly influenced the outcomes, given the nature of prognosis studies.

AUTHORS' CONCLUSIONS: Overall, we found that nine out of 10 children who were diagnosed with autism spectrum disorder before six years of age continued to meet diagnostic criteria for autism spectrum disorder a year or more later, however the evidence was uncertain. Confidence in the evidence was rated low using GRADE, due to heterogeneity and risk of bias, and there were few studies that included children diagnosed using a current classification system, such as the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) or the eleventh revision of the International Classification of Diseases (ICD-11). Future studies that are well-designed, prospective and specifically assess prognosis of autism spectrum disorder diagnoses are needed. These studies should also include contemporary diagnostic assessment methods across a broad range of participants and investigate a range of relevant prognostic factors.

PMID:36169177 | PMC:PMC9516883 | DOI:10.1002/14651858.CD012749.pub2

J Evol Biol. 2022 Sep 27. doi: 10.1111/jeb.14095. Online ahead of print.

ABSTRACT

Experimental evolution studies have examined coevolutionary dynamics between bacteria and lytic phages, where two models for antagonistic coevolution dominate: arms-race dynamics (ARD) and fluctuating-selection dynamics (FSD). Here, we tested the ability for Pseudomonas aeruginosa to coevolve with phage OMKO1 during 10 passages in the laboratory, whether ARD versus FSD coevolution occurred, and how coevolution affected a predicted phenotypic trade-off between phage resistance and antibiotic sensitivity. We used a unique "deep" sampling design, where 96 bacterial clones per passage were obtained from the three replicate coevolving communities. Next, we examined phenotypic changes in growth ability, susceptibility to phage infection and resistance to antibiotics. Results confirmed that the bacteria and phages coexisted throughout the study with one community undergoing ARD, whereas the other two showed evidence for FSD. Surprisingly, only the ARD bacteria demonstrated the anticipated trade-off. Whole genome sequencing revealed that treatment populations of bacteria accrued more de novo mutations, relative to a control bacterial population. Additionally, coevolved bacteria presented mutations in genes for biosynthesis of flagella, type-IV pilus and lipopolysaccharide, with three mutations fixing contemporaneously with the occurrence of the phenotypic trade-off in the ARD-coevolved bacteria. Our study demonstrates that both ARD and FSD coevolution outcomes are possible in a single interacting bacteria-phage system and that occurrence of predicted phage-driven evolutionary trade-offs may depend on the genetics underlying evolution of phage resistance in bacteria. These results are relevant for the ongoing development of lytic phages, such as OMKO1, in personalized treatment of human patients, as an alternative to antibiotics.

PMID:36168737 | DOI:10.1111/jeb.14095

Open Forum Infect Dis. 2022 Sep 12;9(9):ofac466. doi: 10.1093/ofid/ofac466. eCollection 2022 Sep.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is characterized by recurrent pulmonary exacerbations (PEx) and lung function decline. PEx are frequently treated with antibiotics. However, little is known about the effects of antibiotics on the airway microbiome of persons with CF over time. The purpose of this study was to evaluate changes in the microbiome and lung function in persons with CF over 1 year following an initial study pulmonary exacerbation (iPEx).

METHODS: Twenty children aged ≤18 years with CF were enrolled in the study, which occurred prior to the routine administration of highly effective modulator therapy. Respiratory samples and spirometry were obtained at a minimum of quarterly visits and up to 1 year after an iPEx. Metagenomic sequencing was performed, and bacterial taxa were assigned using MetaPhlAn 2.0. Paired t test, analysis of variance, and generalized least squares regression were used to compare outcome variables.

RESULTS: The mean age of study participants at the time of the iPEx was 10.6 years. There were 3 ± 1.6 PEx treated with antibiotics per person during the study period. Bacterial richness was similar at 1 year compared to iPEx (40.3 vs 39.3, P = .852), whereas the mean Shannon diversity index was significantly higher at 1 year (2.84 vs 1.62, P < .001). The number of PEx treated with antibiotics was not associated with changes in microbial diversity but was associated with changes in lung function.

CONCLUSIONS: In our 1-year prospective study, we found that microbial diversity increased despite decreases in lung function associated with repeated PEx events requiring antibiotic therapy.

PMID:36168550 | PMC:PMC9511275 | DOI:10.1093/ofid/ofac466

Wien Med Wochenschr. 2022 Sep 27. doi: 10.1007/s10354-022-00970-x. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic bacterial infections of the airways are present in most patients with cystic fibrosis (CF). Although most pathogens are acquired from the environment, there is great evidence of patient-to-patient transmission. Therefore, evaluating the genetic variation of strains isolated from CF patients is recommended for the purpose of examining hospital infection.

AIM: The aim of this study was to determine the antibiotic susceptibility pattern and genotyping of Staphylococcus aureus and Pseudomonas aeruginosa strains isolated from sputum samples of children with CF referred to a single pediatric CF center in Tehran, Iran.

METHODS: In this cross-sectional study, the antimicrobial susceptibility profiles of strains isolated from patients with CF during 1 year were determined. Pseudomonas aeruginosa and S. aureus isolates were genotyped using the random amplified polymorphic DNA polymerase chain reaction method and were analyzed using GelCompar II software.

RESULTS: Of 534 patients with CF, 384 had negative sputum cultures (72%), and 94 strains of P. aeruginosa (18%) and 53 strains of S. aureus (10%) were isolated. The mean age of the patients was 8.22 ± 5.7 years (range, 2 months to 18 years). The P. aeruginosa strains showed high sensitivity to ceftazidime (96%), piperacillin/tazobactam (96%), and imipenem (94%). All strains of S. aureus were susceptible to vancomycin, and 13% of the strains were methicillin-resistant S. aureus. High resistance to penicillin (92%) and erythromycin (88.5%) were reported. The results of P. aeruginosa genotyping revealed that there were six major clusters in this hospital. Also, based on the analysis of genotyping results, S. aureus strains were obtained from five clusters, most of which were located in cluster B1 (34 isolates, 64%).

CONCLUSION: The results of this study show the possibility of strains being transferred from one part of the hospital to another (especially from the respiratory ward to other areas). Hence, high attention should be paid to the basic methods of preventing infection.

PMID:36167900 | DOI:10.1007/s10354-022-00970-x

Cell Mol Life Sci. 2022 Sep 27;79(10):530. doi: 10.1007/s00018-022-04554-1.

ABSTRACT

The endoplasmic reticulum exit of some polytopic plasma membrane proteins (PMPs) is controlled by arginin-based retention motifs. PRAF2, a gatekeeper which recognizes these motifs, was shown to retain the GABAB-receptor GB1 subunit in the ER. We report that PRAF2 can interact on a stoichiometric basis with both wild type and mutant F508del Cystic Fibrosis (CF) Transmembrane Conductance Regulator (CFTR), preventing the access of newly synthesized cargo to ER exit sites. Because of its lower abundance, compared to wild-type CFTR, CFTR-F508del recruitment into COPII vesicles is suppressed by the ER-resident PRAF2. We also demonstrate that some pharmacological chaperones that efficiently rescue CFTR-F508del loss of function in CF patients target CFTR-F508del retention by PRAF2 operating with various mechanisms. Our findings open new therapeutic perspectives for diseases caused by the impaired cell surface trafficking of mutant PMPs, which contain RXR-based retention motifs that might be recognized by PRAF2.

PMID:36167862 | DOI:10.1007/s00018-022-04554-1