Pathophysiology of non-cystic fibrosis bronchiectasis in children and adolescents with asthma: A protocol for systematic review and meta-analysis.

BACKGROUND: The pathophysiological mechanisms by which asthma and bronchiectasis are associated are still unclear. The association of these two diseases can result in more severe symptoms and a greater number of exacerbations. OBJECTIVE: The aim of this systematic review is to collect evidence of the pathophysiology of non-cystic fibrosis bronchiectasis with associated asthma in children and adolescents, aged 6-18 years old. METHODS: A systematic and comprehensive search will be performed using eight main databases, PubMed, PubMed PMC, BVS/BIREME, Scopus, EMBASE, Cochrane Library, Scielo and Web of Science. Articles will be searched from the earliest available time to July 2023. The studied population will be composed of children and adolescents with asthma and non-cystic fibrosis bronchiectasis. From the data obtained, all articles found will be transferred to the Rayyan platform. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols Checklist (PRISMA P-2015). In addition, if sufficient data are available, a meta-analysis will be conducted. Two independent reviewers will conduct the studies selection, data extraction, and risk of bias assessment. The outcome measures will be to analyze if non-cystic fibrosis bronchiectasis is related to a specific inflammatory profile. DISCUSSION: A systematic review will provide better knowledge about the etiopathogenesis and causes of the association between asthma and bronchiectasis and its role in the severity and control of asthma. Identifying, selecting and critically evaluating studies on asthma and bronchiectasis, would be possible to illuminate the characteristics of children and adolescents with associated diagnoses and provide information to help individualized treatments in order to control and prevent complications. The findings of this study will be published in a peer-reviewed journal. SYSTEMATIC REVIEW REGISTRATION: The systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) in July 2023 (registration number CRD42023440355).

The prevalence of developmental defects of enamel in people with cystic fibrosis: a systematic review.

BACKGROUND: Oral health impacts systemic health, individual well-being, and quality of life. It is important to identify conditions that may exacerbate oral disease to aid public health and policy development and promote targeted patient treatment strategies. Developmental defects can increase an individual's risk of dental caries, hypersensitivity, premature tooth wear, erosion, and poor aesthetics. As part of an ongoing study assessing oral health in adults with cystic fibrosis at Cork University Dental School and Hospital, a systematic review of available literature was conducted to assess the prevalence of enamel defects in people with cystic fibrosis. AIMS: To critically evaluate the literature to determine if the prevalence of developmental defects of enamel is higher in people with cystic fibrosis (PwCF). METHODS: Data Sources: Three online databases were searched Embase, Scopus, and Web of Science Core Collection. Studies that examined an association between cystic fibrosis and developmental defects of enamel were included in this systematic review. RESULTS: The initial search identified 116 publications from the following databases Embase, Web of Science Core Collection, and Scopus. Eleven studies were included for qualitative analysis. Nine studies concluded that PwCF had a higher prevalence of enamel defects than control people and one study found no difference in cystic fibrosis (CF) status. All studies had a risk of bias that may influence study results and their interpretation. CONCLUSIONS: The results of the systematic review show a consistent pattern that PwCF have a higher prevalence of DDE than people without CF. Genetic dysfunction, chronic systemic infections, and long-term antibiotic use are possible aetiological causes. This review highlights the need for future studies to investigate if DDEs are caused by the underlying CFTR mutation or as a consequence of disease manifestations and/or management.

The effect of respiratory muscle training on children and adolescents with cystic fibrosis: a systematic review and meta-analysis.

BACKGROUND: Cystic fibrosis is a chronic genetic disease that can affect the function of the respiratory system. Previous reviews of the effects of respiratory muscle training in people with cystic fibrosis are uncertain and do not consider the effect of age on disease progression. This systematic review aims to determine the effectiveness of respiratory muscle training in the clinical outcomes of children and adolescents with cystic fibrosis. METHODS: Up to July 2023, electronic databases and clinical trial registries were searched. Controlled clinical trials comparing respiratory muscle training with sham intervention or no intervention in children and adolescents with cystic fibrosis. The primary outcomes were respiratory muscle strength, respiratory muscle endurance, lung function, and cough. Secondary outcomes included exercise capacity, quality of life and adverse events. Two review authors independently extracted data and assessed study quality using the Cochrane Risk of Bias Tool 2. The certainty of the evidence was assessed according to the GRADE approach. Meta-analyses where possible; otherwise, take a qualitative approach. RESULTS: Six studies with a total of 151 participants met the inclusion criteria for this review. Two of the six included studies were published in abstract form only, limiting the available information. Four studies were parallel studies and two were cross-over designs. There were significant differences in the methods and quality of the methodology included in the studies. The pooled data showed no difference in respiratory muscle strength, lung function, and exercise capacity between the treatment and control groups. However, subgroup analyses suggest that inspiratory muscle training is beneficial in increasing maximal inspiratory pressure, and qualitative analyses suggest that respiratory muscle training may benefit respiratory muscle endurance without any adverse effects. CONCLUSIONS: This systematic review and meta-analysis indicate that although the level of evidence indicating the benefits of respiratory muscle training is low, its clinical significance suggests that we further study the methodological quality to determine the effectiveness of training. TRIAL REGISTRATION: The protocol for this review was recorded in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42023441829.

Safety of native glucose-dependent insulinotropic polypeptide in humans.

In this systematic review, we assessed the safety and possible safety events of native glucose-dependent insulinotropic polypeptide (GIP)(1-42) in human studies with administration of synthetic human GIP. We searched the PubMed database for all trials investigating synthetic human GIP(1-42) administration. A total of 67 studies were included. Study duration ranged from 30 min to 6 days. In addition to healthy individuals, the studies included individuals with impaired glucose tolerance, type 2 diabetes, type 1 diabetes, chronic pancreatitis and secondary diabetes, latent autoimmune diabetes in adults, diabetes caused by a mutation in the hepatocyte nuclear factor 1-alpha gene, end-stage renal disease, chronic renal insufficiency, critical illness, hypoparathyroidism, or cystic fibrosis-related diabetes. Of the included studies, 78% did not mention safety events, 10% of the studies reported that no safety events were observed in relation to GIP administration, and 15% of the studies reported safety events in relation to GIP administration with most frequently reported event being a moderate and transient increased heart rate. Gastrointestinal safety events, and changes in blood pressure were also reported. Plasma concentration of active GIP(1-42) increased linearly with dose independent of participant phenotype. There was no significant correlation between achieved maximal concentration of GIP(1-42) and reported safety events. Clearance rates of GIP(1-42) were similar between participant groups. In conclusion, the available data indicate that GIP(1-42) in short-term (up to 6 days) infusion studies is generally well-tolerated. The long-term safety of continuous GIP(1-42) administration is unknown.

Safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with Cystic Fibrosis following liver transplantation: A systematic review.

BACKGROUND & AIMS: Cystic Fibrosis (CF) liver disease progresses to liver failure requiring transplantation in about 3 % of patients, 0.7 % of CF patients are post liver transplant. The prognosis of CF has improved with the introduction of elexacaftor/tezacaftor/ivacaftor (ETI). Due to the paucity of data and concerns regarding interactions with immunosuppressive drug regimens, there is no general consensus on use of ETI post liver transplantation. The aim of this review is to report the safety and efficacy of ETI in CF patients who underwent liver transplantation. METHODS: A systematic review was conducted through MEDLINE/Pubmed and EMBASE databases. English-written articles reporting clinical data on liver transplanted CF patients treated with ETI were included. Article quality was evaluated using the Critical Appraisal Checklist for Case Reports. RESULTS: Twenty cases were retrieved from 6 reports. Temporary discontinuation and/or dose reduction due to elevated transaminases was required in 5 cases. ETI restarted on a reduced dose was tolerated in 3 out of 5 patients, 1 patient tolerated full dose. Tacrolimus dose change was required in 14 cases, in 1 case ETI was discontinued due to tacrolimus toxicity. Improvement in percentage predicted FEV1 was noted in 15/19 patients (median +17 %, range 8 %-38 %). CONCLUSIONS: In the majority of liver transplanted patients ETI is well tolerated, although adverse events and liver function abnormalities may occur. Close monitoring of liver function and tacrolimus level is warranted. Significant improvement in lung function after ETI initiation is confirmed, highlighting the importance of accessing this medication for this group of patients.

Early onset of abnormal glucose tolerance in patients with cystic fibrosis: A systematic review and meta-analysis.

BACKGROUND: Despite translational evidences suggesting that cystic fibrosis-related abnormal glucose tolerance (CF-related AGT) may begin early in life and is known to be associated with increased morbidity and mortality, current guidelines recommend screening for AGT only from 10 years of age, thus missing the opportunity for early detection and intervention. METHODS: A systematic review and meta-analysis (PROSPERO number: CRD42021282516) was conducted on studies that reported data on the prevalence of AGT or its subtypes in CF populations. Pooled proportions, risk, and odds ratios with 95 % confidence intervals (CI) were calculated. One-stage dose-response random-effect meta-analysis was used to assess the effect of age on CF-related diabetes (CFRD). RESULTS: The quantitative analysis included 457 studies and data from 520,544 patients. Every third child with CF (chwCF) (0.31 [95 % CI 0.25-0.37]) and every second adult with CF (awCF) (0.51 [95 % CI 0.45-0.57]) were affected by AGT. Even in the 5-10 years of age subgroup, the proportion of AGT was 0.42 [95 % CI 0.34-0.51]. The prevalence of prediabetes remained unchanged (impaired glucose tolerance in chwCF:0.14 [95 % CI 0.10-0.18]) vs. awCF:0.19 [95 % CI 0.14-0.25]), whereas the proportion of CFRD increased with age (0-5: 0.005 [95 % CI 0.0001-0.15]; 5-10: 0.05 [95 % CI 0.01-0.27]; 10-18: 0.11 [95 % CI 0.08-0.14]; >18 years of age: 0.27 [95 % CI 0.24-0.30]). CONCLUSION: CF-related AGT is common under 10 years of age. Our study suggests considering earlier AGT screening, starting from 5 years of age. This highlights the imperative for additional research for guideline adjustments and provides the opportunity for early intervention.

Surgical and medical management of chronic rhinosinusitis in pediatric cystic fibrosis patients: Impact on olfactory symptoms.

BACKGROUND AND PURPOSE: Olfactory dysfunction (OD) commonly occurs in patients with sinonasal dysfunction, but the prevalence and severity of olfactory issues in adolescents with cystic fibrosis (AwCF) is unclear. OD may contribute to dietary deficiencies and exacerbate nutritional challenges. We sought to review literature on the effectiveness of medical and surgical management of sinonasal symptoms in AwCF and the associated impact on olfactory function. METHODS: We performed a systematic literature search of PubMed, Embase, Web of Science, and Ebsco CINAHL from 1980 to 2022 per PRISMA-ScR protocols to conduct a scoping review in an effort to compile data on study design, patient demographics, clinical characteristics and outcomes, along with risk of bias. RESULTS: Of 368 abstracts, 3 articles exclusively evaluated AwCF for a total of 34 patients. Two studies evaluated endoscopic sinus surgery (ESS) and dornase alfa. An additional 6 articles were included for mixed pediatric and adult CF populations totaling 313 patients. Interventions included ESS, elexacaftor-tezacaftor-ivacaftor (ETI), ivacaftor, saline, dornase alfa, hyaluronic acid, and hyaluronic acid-tobramycin combination. Outcome measures included subjective assessment of OD using non-validated (4/9) and validated (4/9) surveys, and psychophysical (1/9) smell testing. Studies evaluating ESS, FESS, dornase alfa, ivacaftor, and both hypertonic and isotonic saline reported statistically significant improvement in OD, whereas ETI failed to improve OD despite improvement in other quality of life measures. CONCLUSIONS: There is limited data regarding the impact of medical and surgical interventions on olfaction for AwCF. Assessment of olfaction was often limited to subjective and qualitative self-report. We suggest that tracking of olfactory outcomes with psychophysical testing is critical in this population with dietary challenges and weight management issues.

Pharmacokinetics of polymyxin B in different populations: a systematic review.

BACKGROUND AND OBJECTIVES: Despite being clinically utilized for the treatment of infections, the limited therapeutic range of polymyxin B (PMB), along with considerable interpatient variability in its pharmacokinetics and frequent occurrence of acute kidney injury, has significantly hindered its widespread utilization. Recent research on the population pharmacokinetics of PMB has provided valuable insights. This study aims to review relevant literature to establish a theoretical foundation for individualized clinical management. METHODS: Follow PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, Pop-PK studies of PMB were searched in PubMed and EMBASE database systems from the inception of the database until March 2023. RESULT: To date, a total of 22 population-based studies have been conducted, encompassing 756 subjects across six different countries. The recruited population in these studies consisted of critically infected individuals with multidrug-resistant bacteria, patients with varying renal functions, those with cystic fibrosis, kidney or lung transplant recipients, patients undergoing extracorporeal membrane oxygenation (ECMO) or continuous renal replacement therapy (CRRT), as well as individuals with obesity or pediatric populations. Among these studies, seven employed a one-compartmental model, with the range of typical clearance (CL) and volume (Vc) being 1.18-2.5L /h and 12.09-47.2 L, respectively. Fifteen studies employed a two-compartmental model, with the ranges of the clearance (CL) and volume of the central compartment (Vc), the volume of the peripheral compartment (Vp), and the intercompartment clearance (Q) were 1.27-8.65 L/h, 5.47-38.6 L, 4.52-174.69 L, and 1.34-24.3 L/h, respectively. Primary covariates identified in these studies included creatinine clearance and body weight, while other covariates considered were CRRT, albumin, age, and SOFA scores. Internal evaluation was conducted in 19 studies, with only one study being externally validated using an independent external dataset. CONCLUSION: We conclude that small sample sizes, lack of multicentre collaboration, and patient homogeneity are the primary reasons for the discrepancies in the results of the current studies. In addition, most of the studies limited in the internal evaluation, which confined the implementation of model-informed precision dosing strategies.

Non-clotting factor therapies for preventing bleeds in people with congenital hemophilia A or B.

BACKGROUND: Management of congenital hemophilia A and B is by prophylactic or on-demand replacement therapy with clotting factor concentrates. The effects of newer non-clotting factor therapies such as emicizumab, concizumab, marstacimab, and fitusiran compared with existing standards of care are yet to be systematically reviewed. OBJECTIVES: To assess the effects (clinical, economic, patient-reported, and adverse outcomes) of non-clotting factor therapies for preventing bleeding and bleeding-related complications in people with congenital hemophilia A or B compared with prophylaxis with clotting factor therapies, bypassing agents, placebo, or no prophylaxis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, electronic databases, conference proceedings, and reference lists of relevant articles and reviews. The date of the last search was 16 August 2023. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating people with congenital hemophilia A or B with and without inhibitors, who were treated with non-clotting factor therapies to prevent bleeds. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed studies for eligibility, assessed risk of bias, and extracted data for the primary outcomes (bleeding rates, health-related quality of life (HRQoL), adverse events) and secondary outcomes (joint health, pain scores, and economic outcomes). We assessed the mean difference (MD), risk ratio (RR), 95% confidence interval (CI) of effect estimates, and evaluated the certainty of the evidence using GRADE. MAIN RESULTS: Six RCTs (including 397 males aged 12 to 75 years) were eligible for inclusion. Prophylaxis versus on-demand therapy in people with inhibitors Four trials (189 participants) compared emicizumab, fitusiran, and concizumab with on-demand therapy in people with inhibitors. Prophylaxis using emicizumab likely reduced annualized bleeding rates (ABR) for all bleeds (MD -22.80, 95% CI -37.39 to -8.21), treated bleeds (MD -20.40, 95% CI -35.19 to -5.61), and annualized spontaneous bleeds (MD -15.50, 95% CI -24.06 to -6.94), but did not significantly reduce annualized joint and target joint bleeding rates (AjBR and AtjBR) (1 trial; 53 participants; moderate-certainty evidence). Fitusiran also likely reduced ABR for all bleeds (MD -28.80, 95% CI -40.07 to -17.53), treated bleeds (MD -16.80, 95% CI -25.80 to -7.80), joint bleeds (MD -12.50, 95% CI -19.91 to -5.09), and spontaneous bleeds (MD -14.80, 95% CI -24.90 to -4.71; 1 trial; 57 participants; moderate-certainty evidence). No evidence was available on the effect of bleed prophylaxis using fitusiran versus on-demand therapy on AtjBR. Concizumab may reduce ABR for all bleeds (MD -12.31, 95% CI -19.17 to -5.45), treated bleeds (MD -10.10, 95% CI -17.74 to -2.46), joint bleeds (MD -9.55, 95% CI -13.55 to -5.55), and spontaneous bleeds (MD -11.96, 95% CI -19.89 to -4.03; 2 trials; 78 participants; very low-certainty evidence), but not target joint bleeds (MD -1.00, 95% CI -3.26 to 1.26). Emicizumab prophylaxis resulted in an 11.31-fold increase, fitusiran in a 12.5-fold increase, and concizumab in a 1.59-fold increase in the proportion of participants with no bleeds. HRQoL measured using the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) physical and total health scores was improved with emicizumab, fitusiran, and concizumab prophylaxis (low-certainty evidence). Non-serious adverse events were higher with non-clotting factor therapies versus on-demand therapy, with injection site reactions being the most frequently reported adverse events. Transient antidrug antibodies were reported for fitusiran and concizumab. Prophylaxis versus on-demand therapy in people without inhibitors Two trials (208 participants) compared emicizumab and fitusiran with on-demand therapy in people without inhibitors. One trial assessed two doses of emicizumab (1.5 mg/kg weekly and 3.0 mg/kg bi-weekly). Fitusiran 80 mg monthly, emicizumab 1.5 mg/kg/week, and emicizumab 3.0 mg/kg bi-weekly all likely resulted in a large reduction in ABR for all bleeds, all treated bleeds, and joint bleeds. AtjBR was not reduced with either of the emicizumab dosing regimens. The effect of fitusiran prophylaxis on target joint bleeds was not assessed. Spontaneous bleeds were likely reduced with fitusiran (MD -20.21, 95% CI -32.12 to -8.30) and emicizumab 3.0 mg/kg bi-weekly (MD -15.30, 95% CI -30.46 to -0.14), but not with emicizumab 1.5 mg/kg/week (MD -14.60, 95% CI -29.78 to 0.58). The percentage of participants with zero bleeds was higher following emicizumab 1.5 mg/kg/week (50% versus 0%), emicizumab 3.0 mg/kg bi-weekly (40% versus 0%), and fitusiran prophylaxis (40% versus 5%) compared with on-demand therapy. Emicizumab 1.5 mg/kg/week did not improve Haem-A-QoL physical and total health scores, EQ-5D-5L VAS, or utility index scores (low-certainty evidence) when compared with on-demand therapy at 25 weeks. Emicizumab 3.0 mg/kg bi-weekly may improve HRQoL measured by the Haem-A-QoL physical health score (MD -15.97, 95% CI -29.14 to -2.80) and EQ-5D-5L VAS (MD 9.15, 95% CI 2.05 to 16.25; 1 trial; 43 participants; low-certainty evidence). Fitusiran may result in improved HRQoL shown as a reduction in Haem-A-QoL total score (MD -7.06, 95% CI -11.50 to -2.62) and physical health score (MD -19.75, 95% CI -25.76 to -11.94; 1 trial; 103 participants; low-certainty evidence). The risk of serious adverse events in participants without inhibitors also likely did not differ following prophylaxis with either emicizumab or fitusiran versus on-demand therapy (moderate-certainty evidence). Transient antidrug antibodies were reported in 4% (3/80) participants to fitusiran, with no observed effect on antithrombin lowering. A comparison of the different dosing regimens of emicizumab identified no differences in bleeding, safety, or patient-reported outcomes. No case of treatment-related cancer or mortality was reported in any study group. None of the included studies assessed our secondary outcomes of joint health, clinical joint function, and economic outcomes. None of the included studies evaluated marstacimab. AUTHORS' CONCLUSIONS: Evidence from RCTs shows that prophylaxis using non-clotting factor therapies compared with on-demand treatment may reduce bleeding events, increase the percentage of individuals with zero bleeds, increase the incidence of non-serious adverse events, and improve HRQoL. Comparative assessments with other prophylaxis regimens, assessment of long-term joint outcomes, and assessment of economic outcomes will improve evidence-based decision-making for the use of these therapies in bleed prevention.

An Updated Review of Exocrine Pancreatic Insufficiency Prevalence finds EPI to be More Common in General Population than Rates of Co-Conditions.

Exocrine pancreatic insufficiency (EPI) is frequently described as underscreened, underdiagnosed, and undertreated. The treatment for EPI is pancreatic enzyme replacement therapy (PERT), which is costly, and provider confidence in prescribing may be one barrier to reducing undertreatment. The lack of interchangeability studies for prescription PERT and/or lack of efficacy studies of over-the-counter enzyme options may be another barrier. This paper reviewed the prevalence of EPI in the general population and in co-conditions. Prevalence of EPI in the general population is commonly estimated around 10-20%, and further research is needed to evaluate EPI across all age groups and to better understand in which age group EPI becomes more prevalent, as an age effect is often seen in EPI prevalence studies. EPI is perceived to be highly correlated with certain co-conditions, and the majority (~65%) of EPI literature is related to a co-condition such as cystic fibrosis, pancreatitis, post-surgery, cancer, or diabetes. It can be estimated that 85% of literature in identified co-conditions, or 56% of total EPI literature, is on rarer co-conditions which only represent <1% of EPI overall. In contrast, there is very little research and literature on EPI in the general population. The highest absolute rates of EPI with co-conditions are likely diabetes and possibly irritable bowel syndrome with diarrhea, yet they are among the least commonly researched in co-condition and EPI studies. A lack of research on EPI in the general population and in the more common co-conditions may be contributing to the rates of underdiagnosis and underscreening, as well as undertreatment for those with low fecal elastase-1 levels.

The effect of Oenothera biennis (Evening primrose) oil on inflammatory diseases: a systematic review of clinical trials.

BACKGROUND: Evening primrose oil (EPO), extracted from the seeds of Oenothera biennis, has gained attention for its therapeutic effects in various inflammatory conditions. METHOD: We performed a systematic search in multiple databases and defined the inclusion criteria based on the following PICOs: P: Patients with a form of inflammatory condition, I: EPO, C: Placebo or other therapeutic interventions, O: changes in inflammatory markers or patients' symptoms; S: randomized controlled trials. The quality of the RCTs was evaluated using Cochrane's RoB tool. RESULTS: Several conditions were investigated in the literature. In rheumatoid arthritis, mixed results were observed, with some studies reporting significant improvements in symptoms while others found no significant impact. EPO showed some results in diabetes mellitus, atopic eczema, menopausal hot flashes, and mastalgia. However, it did not demonstrate effectiveness in chronic hand dermatitis, tardive dyskinesia, psoriatic arthritis, cystic fibrosis, hepatitis B, premenstrual syndrome, contact lens-associated dry eyes, acne vulgaris, breast cyst, pre-eclampsia, psoriasis, or primary Sjogren's syndrome. Some results were reported from multiple sclerosis after EPO consumption. Studies in healthy volunteers indicated no significant effect of EPO on epidermal atrophy, nevertheless, positive effects on the skin regarding hydration and barrier function were achieved. CONCLUSION: Some evidence regarding the potential benefits of EPO in inflammatory disorders were reported however caution is due to the limitations of the current survey. Overall, contemporary literature is highly heterogeneous and fails to provide strong recommendations regarding the efficacy of EPO on inflammatory disorders. Further high-quality studies are necessitated to draw more definite conclusions and establish O. biennis oil effectiveness as an assuring treatment option in alleviating inflammatory conditions.

Macrolide antibiotics (including azithromycin) for cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a life-limiting genetic condition, affecting over 90,000 people worldwide. CF affects several organs in the body, but airway damage has the most profound impact on quality of life (QoL) and survival. Causes of lower airway infection in people with CF are, most notably, Staphylococcus aureus in the early course of the disease and Pseudomonas aeruginosa at a later stage. Macrolide antibiotics, e.g. azithromycin and clarithromycin, are usually taken orally, have a broad spectrum of action against gram-positive (e.g. S aureus) and some gram-negative bacteria (e.g. Haemophilus influenzae), and may have a modifying role in diseases involving airway infection and inflammation such as CF. They are well-tolerated and relatively inexpensive, but widespread use has resulted in the emergence of resistant bacteria. This is an updated review. OBJECTIVES: To assess the potential effects of macrolide antibiotics on clinical status in terms of benefit and harm in people with CF. If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of macrolide therapy. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals, and abstract books of conference proceedings. We last searched the Group's Cystic Fibrosis Trials Register on 2 November 2022. We last searched the trial registries WHO ICTRP and clinicaltrials.gov on 9 November 2022. We contacted investigators known to work in the field, previous authors and pharmaceutical companies manufacturing macrolide antibiotics for unpublished or follow-up data, where possible. SELECTION CRITERIA: We included randomised controlled trials of macrolide antibiotics in adults and children with CF. We compared them to: placebo; another class of antibiotic; another macrolide antibiotic; or the same macrolide antibiotic at a different dose or type of administration. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed risk of bias. We assessed the certainty of evidence using GRADE. MAIN RESULTS: We included 14 studies (1467 participants) lasting 28 days to 36 months. All the studies assessed azithromycin: 11 compared oral azithromycin to placebo (1167 participants); one compared a high dose to a low dose (47 participants); one compared nebulised to oral azithromycin (45 participants); and one looked at weekly versus daily dose (208 participants). Oral azithromycin versus placebo There is a slight improvement in forced expiratory volume (FEV1 % predicted) in one second in the azithromycin group at up to six months compared to placebo (mean difference (MD) 3.97, 95% confidence interval (CI) 1.74 to 6.19; high-certainty evidence), although there is probably no difference at three months, (MD 2.70%, 95% CI -0.12 to 5.52), or 12 months (MD -0.13, 95% CI -4.96 to 4.70). Participants in the azithromycin group are probably at a decreased risk of pulmonary exacerbation with a longer time to exacerbation (hazard ratio (HR) 0.61, 95% CI 0.50 to 0.75; moderate-certainty evidence). Mild side effects were common, but there was no difference between groups (moderate-certainty evidence). There is no difference in hospital admissions at six months (odds ratio (OR) 0.61, 95% CI 0.36 to 1.04; high-certainty evidence), or in new acquisition of P aeruginosa at 12 months (HR 1.00, 95% CI 0.64 to 1.55; moderate-certainty evidence). High-dose versus low-dose azithromycin We are uncertain whether there is any difference in FEV1 % predicted at six months between the two groups (no data available) or in the rate of exacerbations per child per month (MD -0.05 (95% CI -0.20 to 0.10)); very low-certainty evidence for both outcomes. Only children were included in the study and the study did not report on any of our other clinically important outcomes. Nebulised azithromycin versus oral azithromycin We were unable to include any of the data into our analyses and have reported findings directly from the paper; we graded all evidence as being of very low certainty. The authors reported that there was a greater mean change in FEV1 % predicted at one month in the nebulised azithromycin group (P < 0.001). We are uncertain whether there was a change in P aeruginosa count. Weekly azithromycin versus daily azithromycin There is probably a lower mean change in FEV1 % predicted at six months in the weekly group compared to the daily group (MD -0.70, 95% CI -0.95 to -0.45) and probably also a longer period of time until first exacerbation in the weekly group (MD 17.30 days, 95% CI 4.32 days to 30.28 days). Gastrointestinal side effects are probably more common in the weekly group and there is likely no difference in admissions to hospital or QoL. We graded all evidence as moderate certainty. AUTHORS' CONCLUSIONS: Azithromycin therapy is associated with a small but consistent improvement in respiratory function, a decreased risk of exacerbation and longer time to exacerbation at six months; but evidence for treatment efficacy beyond six months remains limited. Azithromycin appears to have a good safety profile (although a weekly dose was associated with more gastrointestinal side effects, which makes it less acceptable for long-term therapy), with a relatively minimal treatment burden for people with CF, and it is inexpensive. A wider concern may be the emergence of macrolide resistance reported in the most recent study which, combined with the lack of long-term data, means we do not feel that the current evidence is strong enough to support azithromycin therapy for all people with CF. Future research should report over longer time frames using validated tools and consistent reporting, to allow for easier synthesis of data. In particular, future trials should report important adverse events such as hearing impairment or liver disease. More data on the effects of azithromycin given in different ways and reporting on our primary outcomes would benefit decision-making on whether and how to give macrolide antibiotics. Finally, it is important to assess azithromycin therapy for people with CF who are established on the relatively new cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies which correct the underlying molecular defect associated with CF (none of the trials included in the review are relevant to this population).

Correction: Assessing the consistency of iPSC and animal models in cystic fibrosis modelling: A meta-analysis.

[This corrects the article DOI: 10.1371/journal.pone.0272091.].

Me, myself, and I: A systematic review of cystic fibrosis and self-concept.

Given extensive pertinent disease factors and evolving medical treatments, this systematic review explores qualitative and quantitative cystic fibrosis (CF) research surrounding self-concept, an overarching perception of self. Research methodologies, self-concept dimensions, prominent self-concept findings and clinical recommendations are identified. Preferred Reporting Items for Systematic Review and Meta-analyses guidelines were applied. PubMed, Scopus, Medline, Psycinfo, CINAHL (ebsco), and CENTRAL Cochrane electronic databases were searched from 2012 to 2022. Methodological quality was assessed using the critical appraisal skills program. Data-based convergent synthesis was applied to analyze and report on qualitative and quantitative studies in parallel. Thirty-seven publications met the inclusion criteria, most of which employed a cross-sectional, single-center design within an adolescent and adult population. Self-efficacy, self-esteem, and self-identity studies were dimensions of self-concept identified, with studies relating to self-efficacy surrounding physical health management most prevalent. All three dimensions were positively associated with improved treatment adherence and psychosocial health. Efficacy tested intervention programs to enhance self-concept are limited; however, an extensive range of clinical recommendations are offered, highlighting the importance of clinician self-concept awareness, quality clinician-patient conversations and online CF peer-support. Self-concept is an important mechanism to optimize patient outcomes. Further CF self-concept research is required, particularly multicenter, longitudinal, and interventional studies. Early childhood, post lung transplant and the older adult CF population in particular, lack research attention. Given the potential impact of rapidly evolving CF transmembrane conductance regulator modulator drugs on many aspects of self, future self-concept research beyond the dimension of self-efficacy may be beneficial.

Biochemical and genetic tools to predict the progression to Cystic Fibrosis in CRMS/CFSPID subjects: A systematic review.

OBJECTIVES: Aim of this study was to identify risk factors for a progression to cystic fibrosis (CF) in individuals detected as CF Screening Positive, Inconclusive Diagnosis (CFSPID). METHODS: This is a systematic review through literature databases (2015-2023). Blood immunoreactive trypsinogen (b-IRT) values, CFTR genotype, sweat chloride (SC) values, isolation of Pseudomonas aeruginosa (Pa) from respiratory samples, Lung Clearance Index (LCI) values in CFSPIDs who converted to CF (CFSPID > CF) and age at CF transition were assessed. RESULTS: Percentage of CFSPID > CF varies from 5.3 % to 44 %. Presence of one CF-causing CFTR variant in trans with a variant with variable clinical consequences (VVCC), an initial SC ≥ 40 mmol/L, an increase of SC > 2.5 mmol/L/year and recurrent isolation of pseudomonas aeruginosa (Pa) from airway samples could allow identification of subjects at risk of progression to CF. CONCLUSIONS: CFSPIDs with CF causing variant/VVCC genotype and first SC in the higher borderline range may require more frequent and prolonged clinical follow-up.

Optimizing sexual reproductive health of men and women with cystic fibrosis: A systematic review.

This systematic review summarizes the impact of cystic fibrosis (CF) on sexual and reproductive health (SRH) in males and females, covering pubertal development, hormonal function, family planning, and fertility. Included articles featured historical CF diagnostic criteria, preclinical or clinical data (retrospective cohorts or open label trials), while excluded articles lacked full text availability, explicit methodology, or comparisons between CF and non-CF patients. Genotype differences in CFTR mutations influenced symptom severity. Males with CF experienced delayed puberty, hypogonadism, infertility from obstructive azoospermia, and semen parameter issues. Female CF patients showed decreased fertility, possibly linked to disrupted ionic balance and ovarian cystic disease. Assistive reproductive technologies addressed fertility issues, but success varied based on disease severity and genotype. CFTR modulators aided pulmonary function and sexual health but require further assessment for fertility benefits.

A systematic review of attention-deficit/hyperactivity disorder in people living with cystic fibrosis.

There is a lack of research that has focused on attention-deficit hyperactivity disorder (ADHD) in people with cystic fibrosis (pwCF). Given ADHD is associated with executive functioning impairments, exploring ADHD in the context of living with cystic fibrosis (CF) is of great importance. The purpose of the current systematic review was to examine ADHD in pwCF across the lifespan in terms of its prevalence, its impact on various health outcomes, and treatments for managing ADHD. This systematic review followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Articles reporting studies of any design that focused on ADHD in pwCF were included. Studies were excluded if they did not meet this criterion and if they were written in languages other than English. PsycINFO, MEDLINE, EMBASE, and CINAHL databases were searched. Search items were based on three concepts: (1) terms related to CF, (2) terms related to ADHD, and (3) terms related to age. Ten studies were included in this systematic review. Reported prevalence rates of ADHD in pwCF ranged from 5.26% to 21.9%. The reported relationships between ADHD and CF and other health outcomes is inconsistent. In terms of treatment considerations, pharmacological interventions and behavioural strategies for managing ADHD in the context of living with CF have been reported as being successful. Additional research is needed to further explore ADHD in the CF population and health variables that may be associated with CF prognosis.

Use of elexacaftor+tezacaftor+ivacaftor in individuals with cystic fibrosis and at least one F508del allele: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of treatment with the combination of three cystic fibrosis transmembrane conductance regulator (CFTR) modulators-elexacaftor+tezacaftor+ivacaftor (ETI)-on important clinical endpoints in individuals with cystic fibrosis. METHODS: This was a systematic review and meta-analysis of randomized clinical trials that compared the use of ETI in individuals with CF and at least one F508del allele with that of placebo or with an active comparator such as other combinations of CFTR modulators, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) methodology. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to December 26th, 2022. The risk of bias was assessed using the Cochrane risk-of-bias tool, and the quality of evidence was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We retrieved 54 studies in the primary search. Of these, 6 met the inclusion criteria and were analyzed (1,127 patients; 577 and 550 in the intervention and control groups, respectively). The meta-analysis revealed that the use of ETI increased FEV1% [risk difference (RD), +10.47%; 95% CI, 6.88-14.06], reduced the number of acute pulmonary exacerbations (RD, -0.16; 95% CI, -0.28 to -0.04), and improved quality of life (RD, +14.93; 95% CI, 9.98-19.89) and BMI (RD, +1.07 kg/m2; 95% CI, 0.90-1.25). Adverse events did not differ between groups (RD, -0.03; 95% CI, -0.08 to 0.01), and none of the studies reported deaths. CONCLUSIONS: Our findings demonstrate that ETI treatment substantially improves clinically significant, patient-centered outcomes.

Vitamin D deficiency in patients with cystic fibrosis: a systematic review and meta-analysis.

AIM: Vitamin D is a prominent modulator of immunity and respiratory function. It plays a vital role in respiratory diseases such as cystic fibrosis (CF). S. However, there is a dearth of information on patients with CF. The purpose of the meta-analysis is to highlight the importance of following the existing guidelines regarding maintenance of Vitamin D serum levels in patients with CF. METHODS: The systematic search was conducted without utilizing any time or language limitations in original database from the beginning until March 2022. The meta-analysis was performed using a random-effects model. Heterogeneity was determined by I2 statistics and Cochrane Q test. RESULTS: Pooled analysis using the random-effects model of the 8 case-control studies with 13 effect sizes revealed that the serum 25-OH-vitamin D in participants with cystic fibrosis was significantly lower than controls in pediatrics and adolescences (WMD: - 3.41 ng/ml, 95% CI - 5.02, - 1.80, p = < 0.001) and adults (WMD: - 2.60 ng/ml, 95% CI - 4.32, - 0.89, p = 0.003). Based on data from 12 studies (21 effect sizes) with a total of 1622 participants, the prevalence of vitamin D levels of 20-30 ng/ml in CF patients was 36% among pediatrics/adolescents and 63% among adults. In addition, 27% of pediatric/adolescent CF patients and 35% of adult CF patients had vitamin D levels of below 20 ng/ml. CONCLUSIONS: As a result, according to the existing guidelines, our results proved the need to pay attention to the level of vitamin D in these patients.