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The Cochrane Database of Systematic... Mar 2023Cystic fibrosis (CF) is a common, life-shortening, genetic disorder in populations of Northern European descent caused by the mutation of a single gene that codes for... (Review)
Review
BACKGROUND
Cystic fibrosis (CF) is a common, life-shortening, genetic disorder in populations of Northern European descent caused by the mutation of a single gene that codes for the production of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This protein coordinates the transport of salt (and bicarbonate) across cell surfaces, and the mutation most notably affects the airways. In the lungs of people with CF, the defective protein compromises mucociliary clearance and makes the airway prone to chronic infection and inflammation, damaging the structure of the airways and eventually leading to respiratory failure. In addition, abnormalities in the truncated CFTR protein lead to other systemic complications, including malnutrition, diabetes and subfertility. Five classes of mutation have been described, depending on the impact of the mutation on the processing of the CFTR protein in the cell. In class I mutations, premature termination codons prevent the production of any functional protein, resulting in severe CF. Therapies targeting class I mutations aim to enable the normal cellular mechanism to read through the mutation, potentially restoring the production of the CFTR protein. This could, in turn, normalise salt transport in the cells and decrease the chronic infection and inflammation that characterises lung disease in people with CF. This is an update of a previously published review.
OBJECTIVES
To evaluate the benefits and harms of ataluren and similar compounds on clinically important outcomes in people with CF with class I mutations (premature termination codons).
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis Trials Register, which is compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles. The last search of the Cochrane Cystic Fibrosis Trials Register was conducted on 7 March 2022. We searched clinical trial registries maintained by the European Medicines Agency, the US National Institutes of Health and the World Health Organization. The last search of the clinical trials registries was conducted on 4 October 2022.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of parallel design comparing ataluren and similar compounds (specific therapies for class I mutations) with placebo in people with CF who have at least one class I mutation.
DATA COLLECTION AND ANALYSIS
For the included trials, the review authors independently extracted data, assessed the risk of bias and evaluated the certainty of the evidence using GRADE; trial authors were contacted for additional data.
MAIN RESULTS
Our searches identified 56 references to 20 trials; of these, 18 trials were excluded. Both the included parallel RCTs compared ataluren to placebo for 48 weeks in 517 participants (males and females; age range six to 53 years) with CF who had at least one nonsense mutation (a type of class I mutation). The certainty of evidence and risk of bias assessments for the trials were moderate overall. Random sequence generation, allocation concealment and blinding of trial personnel were well documented; participant blinding was less clear. Some participant data were excluded from the analysis in one trial that also had a high risk of bias for selective outcome reporting. PTC Therapeutics Incorporated sponsored both trials with grant support from the Cystic Fibrosis Foundation, the US Food and Drug Administration's Office of Orphan Products Development and the National Institutes of Health. The trials reported no difference between treatment groups in terms of quality of life, and no improvement in respiratory function measures. Ataluren was associated with a higher rate of episodes of renal impairment (risk ratio 12.81, 95% confidence interval 2.46 to 66.65; P = 0.002; I = 0%; 2 trials, 517 participants). The trials reported no treatment effect for ataluren for the review's secondary outcomes of pulmonary exacerbation, computed tomography score, weight, body mass index and sweat chloride. No deaths were reported in the trials. The earlier trial performed a post hoc subgroup analysis of participants not receiving concomitant chronic inhaled tobramycin (n = 146). This analysis demonstrated favourable results for ataluren (n = 72) for the relative change in forced expiratory volume in one second (FEV) per cent (%) predicted and pulmonary exacerbation rate. The later trial aimed to prospectively assess the efficacy of ataluren in participants not concomitantly receiving inhaled aminoglycosides, and found no difference between ataluren and placebo in FEV % predicted and pulmonary exacerbation rate. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to determine the effect of ataluren as a therapy for people with CF with class I mutations. One trial reported favourable results for ataluren in a post hoc subgroup analysis of participants not receiving chronic inhaled aminoglycosides, but these were not reproduced in the later trial, suggesting that the earlier results may have occurred by chance. Future trials should carefully assess for adverse events, notably renal impairment, and consider the possibility of drug interactions. Cross-over trials should be avoided, given the potential for the treatment to change the natural history of CF.
Topics: Adolescent; Adult; Child; Female; Humans; Male; Middle Aged; Young Adult; Aminoglycosides; Anti-Bacterial Agents; Codon, Nonsense; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Mutation; Persistent Infection
PubMed: 36866921
DOI: 10.1002/14651858.CD012040.pub3 -
Journal of Medical Virology Mar 2023We assessed the effectiveness of mRNA and viral-vector vaccines in epidemic period led by different SARS-CoV-2 variants. Systematic search of PubMed, EMBASE, and CNKI... (Meta-Analysis)
Meta-Analysis
We assessed the effectiveness of mRNA and viral-vector vaccines in epidemic period led by different SARS-CoV-2 variants. Systematic search of PubMed, EMBASE, and CNKI (China National Knowledge Infrastructure) databases without language restriction for studies published before September 19, 2022. The review was registered with PROSPERO (CRD42022335430) and reported according to PRISMA guidelines. Forty studies met the inclusion criteria for this study, with 62 954 861 participants. The overall vaccine effectiveness (VE) to prevent COVID-19 infection was 0.76 (95% confidence interval [CI] 0.73-0.78), symptomatic infection was 0.87 (95% CI 0.83-0.91), hospital admissions was 0.82 (95% CI 0.75-0.87), and mortality was 0.76 (95% CI 0.48-0.89). Subgroup analysis were performed to characterize the effectiveness of different vaccines. When SARS-CoV-2 variants are taking account, the VE decreased along with the variation of the virus by clinical outcomes and vaccine types. The findings of this systematic review provide the best available evidence that BNT162b2, mRNA-1273, ChAdOx1, and Ad26. COV2.S seems to be approximately effective from predelta to omicron, but only modestly effective in participants aged 65 or older. When SARS-CoV-2 variants are taking account, VE decreased along with the variation of the virus for all mRNA and viral-vector vaccines.
Topics: Humans; Viral Vaccines; SARS-CoV-2; RNA, Messenger; BNT162 Vaccine; COVID-19
PubMed: 36852651
DOI: 10.1002/jmv.28623 -
International Journal of Molecular... Feb 2023Among the most common muscular dystrophies in adults is Myotonic Dystrophy type 1 (DM1), an autosomal dominant disorder characterized by myotonia, muscle wasting and... (Review)
Review
Among the most common muscular dystrophies in adults is Myotonic Dystrophy type 1 (DM1), an autosomal dominant disorder characterized by myotonia, muscle wasting and weakness, and multisystemic dysfunctions. This disorder is caused by an abnormal expansion of the CTG triplet at the gene that, when transcribed to expanded mRNA, can lead to RNA toxic gain of function, alternative splicing impairments, and dysfunction of different signaling pathways, many regulated by protein phosphorylation. In order to deeply characterize the protein phosphorylation alterations in DM1, a systematic review was conducted through PubMed and Web of Science databases. From a total of 962 articles screened, 41 were included for qualitative analysis, where we retrieved information about total and phosphorylated levels of protein kinases, protein phosphatases, and phosphoproteins in DM1 human samples and animal and cell models. Twenty-nine kinases, 3 phosphatases, and 17 phosphoproteins were reported altered in DM1. Signaling pathways that regulate cell functions such as glucose metabolism, cell cycle, myogenesis, and apoptosis were impaired, as seen by significant alterations to pathways such as AKT/mTOR, MEK/ERK, PKC/CUGBP1, AMPK, and others in DM1 samples. This explains the complexity of DM1 and its different manifestations and symptoms, such as increased insulin resistance and cancer risk. Further studies can be done to complement and explore in detail specific pathways and how their regulation is altered in DM1, to find what key phosphorylation alterations are responsible for these manifestations, and ultimately to find therapeutic targets for future treatments.
Topics: Animals; Adult; Humans; Myotonic Dystrophy; Phosphorylation; Alternative Splicing; RNA, Messenger; Muscular Atrophy; Muscle, Skeletal
PubMed: 36834509
DOI: 10.3390/ijms24043091 -
Animal Genetics Jun 2023The FecB mutation in the sheep BMPRIB is strongly correlated with high ovulation traits but its mechanism remains unclear. This study explored differentially expressed... (Meta-Analysis)
Meta-Analysis Review
The FecB mutation in the sheep BMPRIB is strongly correlated with high ovulation traits but its mechanism remains unclear. This study explored differentially expressed genes (DEGs) and their associated molecular mechanisms that may be involved in FecB mutation-induced high ovulation from the perspective of the hypothalamic-pituitary-gonadal (HPG) axis by conducting a systematic review and meta-analysis. The PubMed, EMBASE, CNKI, WanFang, and CBM databases were searched for eligible articles published before August 2022, focusing on mRNA sequencing of different tissues in the HPG axis in sheep with different FecB genotypes. A total of 6555 DEGs were identified from the analysis of six published articles and experimental results from our laboratory. The DEGs were screened by vote-counting rank and robust rank aggregation. Among these, in the follicular phase, FKBP5, CDCA7 and CRABP1 were upregulated in the hypothalamus. INSM2 was upregulated, while LDB3 was downregulated in the pituitary. CLU, SERPINA14, PENK, INHA and STAR were upregulated, while FERMT2 and NPY1R were downregulated in the ovary. On the HPG axis, TAC1 was upregulated and NPNT was downregulated. Many DEGs were found in sheep with different FecB genotypes. The genes FKBP5, CDCA7, CRABP1, INSM2, LDB3, CLU, SERPINA14, PENK, INHA, STAR, FERMT2, NPY1R, TAC1 and NPNT, may be associated with FecB mutation-induced high ovulation in different tissues. These candidate genes will further improve the mechanism of multiple fertility traits induced by the FecB mutation from the perspective of the HPG axis.
Topics: Female; Sheep; Animals; RNA, Messenger; Genotype; Fertility; Ovulation; Phenotype
PubMed: 36811249
DOI: 10.1111/age.13304 -
American Journal of Infection Control Sep 2023We aimed to systematically evaluate the effectiveness of the currently available mRNA vaccines and boosters for the Omicron variant. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
We aimed to systematically evaluate the effectiveness of the currently available mRNA vaccines and boosters for the Omicron variant.
METHODS
We searched for literature published on PubMed, Embase, Web of Science and preprint servers (medRxiv and bioRxiv) from January 1, 2020 to June 20, 2022. The pooled effect estimate was calculated by the random-effects model.
RESULTS
We selected 34 eligible studies in the meta-analysis from 4336 records. For the 2-dose vaccinated group, the mRNA vaccine effectiveness (VE) was 34.74%, 36%, and 63.80% against any Omicron infection, symptomatic infection and severe infection, respectively. For the 3-dose vaccinated group, the mRNA VE was 59.80%, 57.47%, and 87.22% against any infection, symptomatic infection and severe infection. For the 3-dose vaccinated group, the relative mRNA VE was 34.74%, 37.36%, and 63.80% against any infection, symptomatic infection and severe infection. Six months after the 2-dose vaccination, VE with any infection, symptomatic infection, and severe infection decreased to 33.4%, 16.79%, and 60.43%. Three months after the 3-dose vaccination, VE for any infection and severe infection decreased to 55.39% and 73.39%.
CONCLUSIONS
Two-dose mRNA vaccines failed to provide sufficient protection against any Omicron infection and symptomatic infection, while 3-dose mRNA vaccines continued to provide effective protection after 3 months.
Topics: Humans; Immunization, Secondary; RNA, Messenger; Vaccination; mRNA Vaccines
PubMed: 36801346
DOI: 10.1016/j.ajic.2023.02.005 -
Ageing Research Reviews Apr 2023RNA-binding proteins (RBPs), which are conserved proteins comprising multiple intermediate sequences, can interact with proteins, messenger RNA (mRNA) of coding genes,... (Review)
Review
RNA-binding proteins (RBPs), which are conserved proteins comprising multiple intermediate sequences, can interact with proteins, messenger RNA (mRNA) of coding genes, and non-coding RNAs to perform different biological functions, such as the regulation of mRNA stability, selective polyadenylation, and the management of non-coding microRNA (miRNA) synthesis to affect downstream targets. This article will highlight the functions of RBPs, in degenerative joint diseases (intervertebral disc degeneration [IVDD] and osteoarthritis [OA]). It will reviews the latest advancements on the regulatory mechanism of RBPs in degenerative joint diseases, in order to understand the pathophysiology, early diagnosis and treatment of OA and IVDD from a new perspective.
Topics: Humans; Intervertebral Disc Degeneration; RNA, Messenger; RNA-Binding Proteins; Signal Transduction; Joint Diseases
PubMed: 36746279
DOI: 10.1016/j.arr.2023.101870 -
Multiple Sclerosis (Houndmills,... Apr 2023Data are sparse regarding the safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with multiple sclerosis (MS). (Meta-Analysis)
Meta-Analysis
BACKGROUND
Data are sparse regarding the safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with multiple sclerosis (MS).
OBJECTIVE
To estimate (1) the pooled proportion of MS patients experiencing relapse among vaccine recipients; (2) the rate of transient neurological worsening, adverse events, and serious adverse events; (3) the previous outcomes of interest for different SARS-CoV-2 vaccine types.
METHODS
Systematic review and meta-analysis of pharmacovigilance registries and observational studies.
RESULTS
Nineteen observational studies comprising 14,755 MS patients who received 23,088 doses of COVID-19 vaccines were included. Mean age was 43.3 years (95% confidence interval (CI): 40-46.6); relapsing-remitting, secondary-progressive, primary-progressive MS and clinically isolated syndrome were diagnosed in 82.6% (95% CI: 73.9-89.8), 12.6% (95% CI: 6.3-20.8), 6.7% (95% CI: 4.2-9.9), and 2.9% (95% CI: 1-5.9) of cases, respectively. The pooled proportion of MS patients experiencing relapse at a mean time interval of 20 days (95% CI: 12-28.2) from vaccination was 1.9% (95% CI: 1.3%-2.6%; = 78%), with the relapse risk being independent of the type of administered SARS-CoV-2-vaccine ( for subgroup differences = 0.7 for messenger RNA (mRNA), inactivated virus, and adenovector-based vaccines). After vaccination, transient neurological worsening was observed in 4.8% (95% CI: 2.3%-8.1%) of patients. Adverse events and serious adverse events were reported in 52.8% (95% CI: 46.7%-58.8%) and 0.1% (95% CI: 0%-0.2%) of vaccinations, respectively.
CONCLUSION
COVID-19 vaccination does not appear to increase the risk of relapse and serious adverse events in MS. Weighted against the risks of SARS-CoV-2-related complications and MS exacerbations, these safety data provide compelling pro-vaccination arguments for MS patients.
Topics: Adult; Humans; COVID-19; COVID-19 Vaccines; Multiple Sclerosis; SARS-CoV-2; Vaccination
PubMed: 36722184
DOI: 10.1177/13524585221150881 -
International Journal of Infectious... Mar 2023This study aimed to provide guidance for clinical treatment and increase public confidence in COVID-19 vaccines. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
This study aimed to provide guidance for clinical treatment and increase public confidence in COVID-19 vaccines.
METHODS
The Cochrane Library, Embase, PubMed, Web of Science, ClinicalKey, and other COVID-19 datasets were searched from December 2019 to May 2022. Case-control studies and prospective cohort studies of COVID-19 vaccine effectiveness and safety in pregnant women were included.
RESULTS
From day 11 to day 13, after the first dose of the COVID-19 messenger RNA vaccine, the effectiveness was 54% (95% confidence interval: 0.33-0.69). On days 14 to 27, the effectiveness was 59%. There was a 14% increase in vaccine effectiveness 28 days after the first dose was given. The inactivated vaccines showed similar effectiveness. The proportions of placental abruptions, postpartum hemorrhages, miscarriages, stillbirths, premature births, and small for gestational age infants were not significantly different between vaccinated and nonvaccinated pregnant women. Fatigue and fever were also not associated with pregnancy.
CONCLUSION
Our findings affirm that the effectiveness varies for different types of vaccines and is significantly and positively correlated with time in the pregnant population. COVID-19 vaccines have also been deemed safe for pregnant women. Thus, we developed a comprehensive understanding of the role of vaccines in pregnant women.
Topics: Infant; Pregnancy; Female; Humans; COVID-19 Vaccines; Prospective Studies; Placenta; COVID-19; Stillbirth; Vaccination
PubMed: 36707044
DOI: 10.1016/j.ijid.2023.01.018 -
JPEN. Journal of Parenteral and Enteral... May 2023Skeletal muscle wasting is a determinant of physical disability in survivors of critical illness. Intramuscular bioenergetic failure, altered substrate metabolim, and...
BACKGROUND
Skeletal muscle wasting is a determinant of physical disability in survivors of critical illness. Intramuscular bioenergetic failure, altered substrate metabolim, and inflammation are likely underpinning mechanisms. We examined the effect of pioglitazone, a peroxisome proliferator-activated receptor γ agonist, on muscle-related outcomes in adults.
METHODS
We included randomized controlled trials in which pioglitazone was administered (no dose/dosage restrictions) and muscle-related outcomes were reported. We searched MEDLINE, CENTRAL, EMBASE, CINAHL, and trial registries. Risk of bias was assessed using RoB 2. Primary outcomes were physical function and symptoms, muscle mass and function, or body composition and muscular compositional change. Secondary outcomes included muscle insulin sensitivity, mitochondrial effects, and intramuscular inflammation.
RESULTS
Fourteen studies over 19 publications (n = 474 patients) were included. Lean body mass was unaffected in three studies (n = 126) and increased by 1.8-1.92 kg in two studies (P = 0.02 and 0.003, respectively; n = 48). Pioglitazone was associated with increased peripheral insulin sensitivity (+23%-72%, standardized mean difference of 0.97 from trial start point to end point [95% CI, 0.36-1.58; n = 213]). Treatment reduced intramuscular tumor necrosis factor-α (TNF-α) levels (-30%; P = 0.02; n = 29), with mixed effects on serum TNF-α and intramyocellular lipid concentrations. Treatment increased intramuscular markers of adenosine triphosphate (ATP) biosynthesis (ATP5A [+33%, P ≤ 0.05], ETFA [+60%, P ≤ 0.05], and CX6B1 [+ 33%, P = 0.01] [n = 24]), PGC1α and PGC1β messenger RNA expression (P < 0.05; n = 26), and AMPK phosphorylation (+38%, P < 0.05; n = 26). These data have low-quality evidence profiles owing to risk of bias.
CONCLUSIONS
Pioglitazone therapy increases skeletal muscle insulin sensitivity and can decrease intramuscular inflammation.
Topics: Adult; Humans; Pioglitazone; Thiazolidinediones; Hypoglycemic Agents; Insulin Resistance; Critical Illness; Tumor Necrosis Factor-alpha; Inflammation
PubMed: 36700419
DOI: 10.1002/jpen.2481 -
JAMA Pediatrics Apr 2023Evidence of the efficacy and safety of messenger RNA (mRNA) COVID-19 vaccines in children aged 5 to 11 years has been emerging. Collecting these data will inform... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Evidence of the efficacy and safety of messenger RNA (mRNA) COVID-19 vaccines in children aged 5 to 11 years has been emerging. Collecting these data will inform clinicians, families, and policy makers.
OBJECTIVE
To evaluate the efficacy and safety of mRNA COVID-19 vaccines in children aged 5 to 11 years in a systematic review and meta-analysis.
DATA SOURCES
PubMed and Embase databases were searched on September 29, 2022, without language restrictions.
STUDY SELECTION
Randomized clinical trials and observational studies comparing vaccinated vs unvaccinated children aged 5 to 11 years and reporting efficacy or safety outcomes were included. Studies reporting safety outcomes in vaccinated children only (ie, no control group) were also included.
DATA EXTRACTION AND SYNTHESIS
Two investigators independently extracted relevant data from each study. Odds ratios (ORs) for efficacy and safety outcomes and incidences of adverse events (AEs) following vaccination were synthesized using a random-effects model. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology reporting guidelines.
MAIN OUTCOMES AND MEASURES
The primary outcome was SARS-CoV-2 infections with or without symptoms. The secondary outcomes included symptomatic SARS-CoV-2 infections, hospitalizations, and multisystem inflammatory syndrome in children. The incidences of each AE following vaccination were also evaluated.
RESULTS
Two randomized clinical trials and 15 observational studies involving 10 935 541 vaccinated children (median or mean age range, 8.0-9.5 years) and 2 635 251 unvaccinated children (median or mean age range, 7.0-9.5 years) were included. Two-dose mRNA COVID-19 vaccination compared with no vaccination was associated with lower risks of SARS-CoV-2 infections with or without symptoms (OR, 0.47; 95% CI, 0.35-0.64), symptomatic SARS-CoV-2 infections (OR, 0.53; 95% CI, 0.41-0.70), hospitalizations (OR, 0.32; 95% CI, 0.15-0.68), and multisystem inflammatory syndrome in children (OR, 0.05; 95% CI, 0.02-0.10). Two randomized clinical trials and 5 observational studies investigated AEs among vaccinated children. Most vaccinated children experienced at least 1 local AE following the first injection (32 494 of 55 959 [86.3%]) and second injection (28 135 of 46 447 [86.3%]). Vaccination was associated with a higher risk of any AEs compared with placebo (OR, 1.92; 95% CI, 1.26-2.91). The incidence of AEs that prevented normal daily activities was 8.8% (95% CI, 5.4%-14.2%) and that of myocarditis was estimated to be 1.8 per million (95% CI, 0.000%-0.001%) following the second injection.
CONCLUSIONS AND RELEVANCE
In this systematic review and meta-analysis, COVID-19 mRNA vaccines among children aged 5 to 11 years were associated with measures of efficacy in preventing SARS-CoV-2 infection and severe COVID-19-related illnesses. While most children developed local AEs, severe AEs were rare, and most of AEs resolved within several days. These data provide evidence for future recommendations.
Topics: Humans; Child; Child, Preschool; COVID-19; COVID-19 Vaccines; SARS-CoV-2; Parents
PubMed: 36689319
DOI: 10.1001/jamapediatrics.2022.6243