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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 -
Current Environmental Health Reports Jun 2023Despite increasing awareness of the ubiquity of microplastics (MPs) in our environments, little is known about their risk of developmental toxicity. Even less is known... (Review)
Review
PURPOSE OF REVIEW
Despite increasing awareness of the ubiquity of microplastics (MPs) in our environments, little is known about their risk of developmental toxicity. Even less is known about the environmental distribution and associated toxicity of nanoplastics (NPs). Here, we review the current literature on the capacity for MPs and NPs to be transported across the placental barrier and the potential to exert toxicity on the developing fetus.
RECENT FINDINGS
This review includes 11 research articles covering in vitro, in vivo, and ex vivo models, and observational studies. The current literature confirms the placental translocation of MPs and NPs, depending on physicochemical properties such as size, charge, and chemical modification as well as protein corona formation. Specific transport mechanisms for translocation remain unclear. There is emerging evidence of placental and fetal toxicity due to plastic particles based on animal and in vitro studies. Nine out of eleven studies examined in this review found that plastic particles were capable of placental translocation. In the future, more studies are needed to confirm and quantify the existence of MPs and NPs in human placentas. Additionally, translocation of different plastic particle types and heterogenous mixtures across the placenta, exposure at different periods of gestation, and associations with adverse birth and other developmental outcomes should also be investigated.
Topics: Animals; Pregnancy; Female; Humans; Placenta; Plastics; Microplastics; Water Pollutants, Chemical
PubMed: 36848019
DOI: 10.1007/s40572-023-00391-x -
Seminars in Nuclear Medicine Sep 2023Fibroblast activation protein inhibitor (FAPI) is a promising tracer in oncologic positron emission tomography/computed tomography (PET/CT). Numerous studies have... (Review)
Review
Fibroblast activation protein inhibitor (FAPI) is a promising tracer in oncologic positron emission tomography/computed tomography (PET/CT). Numerous studies have demonstrated the superior sensitivity of FAPI PET/CT over fluorodeoxyglucose (FDG) PET/CT in several types of cancer. However, the cancer specificity of FAPI uptake remains understudied, and several cases of false-positive FAPI PET/CT findings have been reported. A systematic search of PubMed, Embase, and Web of Science was conducted for studies published prior to April 2022 reporting nonmalignant FAPI PET/CT findings. We included original peer-reviewed articles of studies in humans using FAPI tracers radiolabeled with Ga or F that were published in English. Papers without original data and studies with insufficient information were excluded. Nonmalignant findings were presented on a per-lesion basis and grouped according to the type of organ or tissue involved. The search identified a total of 1.178 papers, of which 108 studies were eligible. Eighty studies were case reports (74%), and the remaining 28 were cohort studies (26%). A total of 2.372 FAPI-avid nonmalignant findings were reported, with the most frequent being uptake in the arteries, e.g., related to plaques (n = 1178, 49%). FAPI uptake was also frequently related to degenerative and traumatic bone and joint lesions (n = 147, 6%) or arthritis (n = 92, 4%). For organs, diffuse or focal uptake was often seen in cases of inflammation, infection, fibrosis, and IgG4-related disease (n = 157, 7%). FAPI-avid inflammatory/reactive lymph nodes (n = 121, 5%) and tuberculosis lesions (n = 51, 2%) have been reported and could prove to be potential pitfalls in cancer staging. Periodontitis (n = 76, 3%), hemorrhoids (n = 47, 2%), and scarring/wound healing (n = 35, 2%) also presented as focal uptake on FAPI PET/CT. The present review provides an overview of the reported FAPI-avid nonmalignant PET/CT findings to date. A large number of benign clinical entities may show FAPI uptake and should be kept in mind when interpreting FAPI PET/CT findings in patients with cancer.
Topics: Humans; Biological Transport; Fluorodeoxyglucose F18; Gallium Radioisotopes; Inflammation; Positron Emission Tomography Computed Tomography
PubMed: 36813670
DOI: 10.1053/j.semnuclmed.2023.02.001 -
The Japanese Dental Science Review Dec 2023The mechanisms modulated by periodontal pathogens in atherosclerosis are not fully understood. Aim: to perform an integrative analysis of gene and protein expression... (Review)
Review
UNLABELLED
The mechanisms modulated by periodontal pathogens in atherosclerosis are not fully understood. Aim: to perform an integrative analysis of gene and protein expression modulated by periodontal pathogens in cells and animal models for atherosclerosis.
METHODS
Cochrane, PRISMA and AMSTAR2 guidelines for systematic reviews were followed. Data search was conducted in Pub-med, LILACS and Science Direct databases. Gene and protein expression data were collected from the included papers to perform an overrepresentation analysis using the Reactome Pathway Analysis tool and the KEGG database.
RESULTS
Thirty-two papers were included in the review, they analyzed the effect of , , , , , and or/and their virulent factors on gene and protein expression in human cells and animal models of atherosclerosis. Some of the modulated pathways include the immune system, programmed cell death, cellular responses to external stimuli, transport of small molecules, and signal transduction (p < 0.05). Those pathways are known to be involved in different stages of atherosclerosis progression.
CONCLUSION
Based on the performed analysis, it is possible to state that periodontal pathogens have the potential to be a contributing factor for atherosclerosis even in absence of a high-fat diet or high shear stress.
PubMed: 36654677
DOI: 10.1016/j.jdsr.2022.12.001 -
Journal of Clinical Medicine Dec 2022Fatty acid translocase/cluster of differentiation 36 (FAT/CD36) is a multifunctional membrane protein activated by a high-fat diet, physical exercise, fatty acids (FAs),... (Review)
Review
Fatty acid translocase/cluster of differentiation 36 (FAT/CD36) is a multifunctional membrane protein activated by a high-fat diet, physical exercise, fatty acids (FAs), leptin, and insulin. The principal function of FAT/CD36 is to facilitate the transport of long-chain fatty acids through cell membranes such as myocytes, adipocytes, heart, and liver. Under high-energy expenditure, the different isoforms of FAT/CD36 in the plasma membrane and mitochondria bind to the mobilization and oxidation of FAs. Furthermore, FAT/CD36 is released in its soluble form and becomes a marker of metabolic dysfunction. Studies with healthy animals and humans show that physical exercise and a high-lipid diet increase FAT/CD36 expression and caloric expenditure. However, several aspects such as obesity, diabetes, Single Nucleotide polymorphisms (SNPs), and oxidative stress affect the normal FAs metabolism and function of FAT/CD36, inducing metabolic disease. Through a comprehensive systematic review of primary studies, this work aimed to document molecular mechanisms related to FAT/CD36 in FAs oxidation and trafficking in skeletal muscle under basal conditions, physical exercise, and diet in healthy individuals.
PubMed: 36615118
DOI: 10.3390/jcm12010318 -
Frontiers in Cardiovascular Medicine 2022Gliflozins altering the sodium-glucose transport protein 2 (SGLT2) in the nephron, represent alone or in combination a promising treatment option for patients with type...
BACKGROUND
Gliflozins altering the sodium-glucose transport protein 2 (SGLT2) in the nephron, represent alone or in combination a promising treatment option for patients with type II diabetes mellitus. In addition to glucose control, these drugs provide benefits including reduced risk of long-term cardiovascular (CV) and renal complications. Several trials evaluated gliflozins in patients with various degrees of cardiac dysfunction with heterogeneous results.
OBJECTIVES
We aimed to perform a comprehensive analysis of the effect of gliflozins on CV outcomes.
METHODS
Systematic searches of electronic databases were conducted until September 2022. Multiple treatment network meta-analysis was performed in R. Random-effects model was used to combine risk estimates across trials calculating risk ratio (RR) with 95% confidence intervals as summary statistics. The primary endpoint of interest was the rate of heart failure-related hospitalization (HHF) and the composite of HHF with CV mortality (HHF + CVD). Secondary outcomes included major adverse cardiac events (MACE), CV- and overall mortality, myocardial infarction (MI), and stroke.
RESULTS
Twenty-nine studies randomizing 88,418 patients were identified. Gliflozins reduced the risk of HHF (RR: 0.72 [0.69; 0.76]) and HHF + CVD (RR: 0.78 [0.75; 0.82]). The risk of MACE and its component also improved significantly except for stroke. The network analyses did not explore major differences among the individual substances. The only exception was sotagliflozin which appeared to be more effective regarding HHF + CVD, stroke, and MI compared to ertugliflozin, in HHF + CVD and stroke compared to dapagliflozin, and in stroke endpoint compared to empagliflozin.
CONCLUSION
Our meta-analysis supports a group effect of gliflozins beneficial in a wide spectrum of patients with a risk of heart failure (HF) development. In addition to the improvement of HF-related outcomes, the risk of major adverse events is also reduced with SGLT2 inhibition.
SYSTEMATIC REVIEW REGISTRATION
[www.ClinicalTrials.gov], identifier [CRD42022358078].
PubMed: 36545024
DOI: 10.3389/fcvm.2022.1041200 -
Frontiers in Cardiovascular Medicine 2022To assess whether the current body of accumulated data can give convincing evidence in favor of sodium-glucose transport protein-2 inhibitor (SGLT-2i) in all types of...
UNLABELLED
To assess whether the current body of accumulated data can give convincing evidence in favor of sodium-glucose transport protein-2 inhibitor (SGLT-2i) in all types of heart failure (HF). We searched for randomized controlled trials contrasting the effectiveness of SGLT-2i to placebo or other hypoglycemic medications on clinicaltrials.gov, PubMed, and the Cochrane Library database. To gauge effect size, hazard ratios (HR) were employed as measurements. The composite outcome of cardiovascular death or hospitalization owing to HF was the primary endpoint. Eleven studies were included. In comparison to the control group, the data demonstrated that SGLT-2i is related with a decreased incidence of composite outcome (HR: 0.77, 95% CIs: 0.73-0.81, = 0%, < 0.01), CV death (HR: 0.87, 95% CIs: 0.81-0.94, = 3%, < 0.01), all-cause mortality (HR: 0.90, 95% CIs: 0.84-0.96, = 10%, < 0.01), and hospitalization due to HF (HHF) (HR: 0.70, 95% CIs: 0.66-0.75, = 0%, < 0.01). The trial sequential analysis found strong evidence of a decrease in the incidence of all clinical outcomes with SGLT-2i when compared to the control group. Subgroup analysis demonstrated that the association between SGLT-2i and clinical outcome was independent of population characteristics. We confirm that the present evidence supports the use of SGLT-2i in a wide range of HF patients.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/prospero/#recordDetails], identifier [CRD42022333279].
PubMed: 36531703
DOI: 10.3389/fcvm.2022.1067806 -
Molecular Neurodegeneration Nov 2022The family of VPS10p-Domain (D) receptors comprises five members named SorLA, Sortilin, SorCS1, SorCS2 and SorCS3. While their physiological roles remain incompletely... (Review)
Review
The family of VPS10p-Domain (D) receptors comprises five members named SorLA, Sortilin, SorCS1, SorCS2 and SorCS3. While their physiological roles remain incompletely resolved, they have been recognized for their signaling engagements and trafficking abilities, navigating a number of molecules between endosome, Golgi compartments, and the cell surface. Strikingly, recent studies connected all the VPS10p-D receptors to Alzheimer's disease (AD) development. In addition, they have been also associated with diseases comorbid with AD such as diabetes mellitus and major depressive disorder. This systematic review elaborates on genetic, functional, and mechanistic insights into how dysfunction in VPS10p-D receptors may contribute to AD etiology, AD onset diversity, and AD comorbidities. Starting with their functions in controlling cellular trafficking of amyloid precursor protein and the metabolism of the amyloid beta peptide, we present and exemplify how these receptors, despite being structurally similar, regulate various and distinct cellular events involved in AD. This includes a plethora of signaling crosstalks that impact on neuronal survival, neuronal wiring, neuronal polarity, and synaptic plasticity. Signaling activities of the VPS10p-D receptors are especially linked, but not limited to, the regulation of neuronal fitness and apoptosis via their physical interaction with pro- and mature neurotrophins and their receptors. By compiling the functional versatility of VPS10p-D receptors and their interactions with AD-related pathways, we aim to further propel the AD research towards VPS10p-D receptor family, knowledge that may lead to new diagnostic markers and therapeutic strategies for AD patients.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Depressive Disorder, Major; Protein Transport; Nerve Growth Factors
PubMed: 36397124
DOI: 10.1186/s13024-022-00576-2 -
Cureus Oct 2022Hypertension (HTN) is one of the most prevalent and dangerous cardiovascular diseases worldwide. Recently, its direct or indirect association with gut dysbiosis has been... (Review)
Review
Hypertension (HTN) is one of the most prevalent and dangerous cardiovascular diseases worldwide. Recently, its direct or indirect association with gut dysbiosis has been an interest of study for many. It also includes the metabolomic and functional gene changes in hypertensives compared with healthy individuals. This systematic review aims to study quantitative and qualitative interactions between the two and re-defining the heart-gut axis. We have strictly followed the (PRISMA), 2020, guidelines. We conducted an in-depth search of databases such as PubMed, PubMed Central (PMC), Medline, and ScienceDirect to find relevant studies for our topic of interest. After the final quality check, we included eight articles in the systematic review. A significant difference in richness and diversity in gut microbiota was observed in hypertensive patients compared with healthy controls. There was an increased abundance of many bacteria such as , , , Enterobacteriaceae, , , , , and , while a decreased abundance of , , spp., and . Alteration of the composition also varied based on diet, age, ethnicity, and severity of HTN. Short-chain fatty acids (SCFAs)-producing bacteria are found to be on the lower side in hypertensives owing to the protective property of SCFAs against inflammation, especially butyric acid. From the perspective of metabolomic changes, harmful metabolites for cardiovascular health such as intestinal fatty acid binding protein (I-FABP), lipopolysaccharides (LPSs), zonulin, sphingomyelins, acylcarnitines, and trimethylamine -oxide (TMAO) were found to be increased in hypertensives. Changes in these biomarkers further establish the relation between gut epithelial health and high blood pressure (BP). Participants affected by diseases have an overall lower rate of acquiring new genes, which results in a low richness of genes in them compared with healthy individuals. There is increased expression of the choline utilization () gene and reduced expression of genes associated with biosynthesis and transport of amino acids in high-BP participants. The unique changes in the composition of the microbiota, functional changes in genes, and metabolome collectively help for a better understanding of the pathogenesis of HTN and also suggest the gut as a promising new therapeutic target for HTN. To establish a further causal relationship between the two, more research is required.
PubMed: 36381851
DOI: 10.7759/cureus.29927 -
American Journal of Human Biology : the... Nov 2022Bone is a dynamic organ under continual turnover influenced by life history stage, energy dynamics, diet, climate, and disease. Bone turnover data have enormous...
OBJECTIVES
Bone is a dynamic organ under continual turnover influenced by life history stage, energy dynamics, diet, climate, and disease. Bone turnover data have enormous potential in biological anthropology for testing evolutionary and biocultural hypotheses, yet few studies have integrated these biomarkers. In the present article we systematically review the current availability, future viability, and applicability of measuring bone turnover markers (BTMs) in dried blood spot (DBS) samples obtained from finger prick whole blood.
METHODS
Our review considers clinical and public health relevance, biomarker stability in DBS, assay availability, and cost. We consider biomarkers of bone formation such as osteocalcin (bone matrix protein), PINP (N-terminal propeptide of type I collagen), and alkaline phosphatase (osteoblast enzyme), as well as biomarkers of bone resorption such as CTX (marker of collagen breakdown) and TRACP5b (tartrate-resistant acid phosphatase 5b; osteoclast enzyme).
RESULTS
Two BTMs have been validated for DBS: osteocalcin (formation) and TRACP5b (resorption). Prime candidates for future development are CTX and PINP, the formation and resorption markers used for clinical monitoring of response to osteoporosis treatment.
CONCLUSION
BTMs are a field-friendly technique for longitudinal monitoring of skeletal biology during growth, reproduction and aging, combining minimized risk to study participants with maximized ease of sample storage and transport. This combination allows new insights into the effects of energy availability, disease, and physical activity level on bone, and questions about bone gain and loss across life history and in response to environmental factors; these issues are important in human biology, paleoanthropology, bioarchaeology, and forensic anthropology.
Topics: Humans; Osteocalcin; Tartrate-Resistant Acid Phosphatase; Bone Remodeling; Biomarkers; Anthropology
PubMed: 36214251
DOI: 10.1002/ajhb.23816