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BMJ Open Jun 2024In trials, subgroup analyses are used to examine whether treatment effects differ by important patient characteristics. However, which subgroups are most commonly... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
In trials, subgroup analyses are used to examine whether treatment effects differ by important patient characteristics. However, which subgroups are most commonly reported has not been comprehensively described.
DESIGN AND SETTINGS
Using a set of trials identified from the US clinical trials register (ClinicalTrials.gov), we describe every reported subgroup for a range of conditions and drug classes.
METHODS
We obtained trial characteristics from ClinicalTrials.gov via the Aggregate Analysis of ClinicalTrials.gov database. We subsequently obtained all corresponding PubMed-indexed papers and screened these for subgroup reporting. Tables and text for reported subgroups were extracted and standardised using Medical Subject Headings and WHO Anatomical Therapeutic Chemical codes. Via logistic and Poisson regression models we identified independent predictors of result reporting (any vs none) and subgroup reporting (any vs none and counts). We then summarised subgroup reporting by index condition and presented all subgroups for all trials via a web-based interactive heatmap (https://ihwph-hehta.shinyapps.io/subgroup_reporting_app/).
RESULTS
Among 2235 eligible trials, 23% (524 trials) reported subgroups. Follow-up time (OR, 95%CI: 1.13, 1.04-1.24), enrolment (per 10-fold increment, 3.48, 2.25-5.47), trial starting year (1.07, 1.03-1.11) and specific index conditions (eg, hypercholesterolaemia, hypertension, taking asthma as the reference, OR ranged from 0.15 to 10.44), predicted reporting, sponsoring source and number of arms did not. Results were similar on modelling any result reporting (except number of arms, 1.42, 1.15-1.74) and the total number of subgroups. Age (51%), gender (45%), racial group (28%) were the most frequently reported subgroups. Characteristics related to the index condition (severity/duration/types etc) were frequently reported (eg, 69% of myocardial infarction trials reported on its severity/duration/types). However, reporting on comorbidity/frailty (five trials) and mental health (four trials) was rare.
CONCLUSION
Other than age, sex, race ethnicity or geographic location and characteristics related to the index condition, information on variation in treatment effects is sparse.
PROSPERO REGISTRATION NUMBER
CRD42018048202.
Topics: Humans; Chronic Disease; Clinical Trials as Topic; Epidemiologic Studies; Research Design
PubMed: 38908852
DOI: 10.1136/bmjopen-2023-081315 -
Cardiovascular Drugs and Therapy Jun 2024Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the modulation of lipid metabolism as a critical negative regulator of hepatic low-density... (Review)
Review
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the modulation of lipid metabolism as a critical negative regulator of hepatic low-density lipoprotein receptor (LDLR) levels and circulating low-density lipoprotein (LDL) clearance. Numerous gain-of-function (GOF) mutations in PCSK9 have been identified as causing familial hypercholesterolemia (FH) by reducing LDLR levels, and loss-of-function (LOF) mutations associated with a hypercholesterolemia phenotype protective against atherosclerosis. PCSK9 represents an example of successful translational research resulting in the identification of PCSK9 as a major drug target for a lipid-lowering therapy. To explore the genetic constitution of PCSK9 and its biologic role, in this review, we summarize the current evidence of clinically significant PCSK9 genetic variants involved in lipid metabolism as well as emphasize the importance of PCSK9 inhibition for the improvement of cardiovascular outcomes by conducting a meta-analysis of the available data on the incidence of cardiovascular disease events.
PubMed: 38907775
DOI: 10.1007/s10557-024-07599-5 -
Journal of Neurology, Neurosurgery, and... Jun 2024The underlying risk factors for young-onset cryptogenic ischaemic stroke (CIS) remain unclear. This multicentre study aimed to explore the association between heavy...
BACKGROUND
The underlying risk factors for young-onset cryptogenic ischaemic stroke (CIS) remain unclear. This multicentre study aimed to explore the association between heavy alcohol consumption and CIS with subgroup analyses stratified by sex and age.
METHODS
Altogether, 540 patients aged 18-49 years (median age 41; 47.2% women) with a recent CIS and 540 sex-matched and age-matched stroke-free controls were included. Heavy alcohol consumption was defined as >7 (women) and >14 (men) units per week or at least an average of two times per month ≥5 (women) and ≥7 (men) units per instance (binge drinking). A conditional logistic regression adjusting for age, sex, education, hypertension, cardiovascular diseases, diabetes, hypercholesterolaemia, current smoking, obesity, diet and physical inactivity was used to assess the independent association between alcohol consumption and CIS.
RESULTS
Patients were twice as more often heavy alcohol users compared with controls (13.7% vs 6.7%, p<0.001), were more likely to have hypertension and they were more often current smokers, overweight and physically inactive. In the entire study population, heavy alcohol consumption was independently associated with CIS (adjusted OR 2.11; 95% CI 1.22 to 3.63). In sex-specific analysis, heavy alcohol consumption was associated with CIS in men (2.72; 95% CI 1.25 to 5.92), but not in women (1.56; 95% CI 0.71 to 3.41). When exploring the association with binge drinking alone, a significant association was shown in the entire cohort (2.43; 95% CI 1.31 to 4.53) and in men (3.36; 95% CI 1.44 to 7.84), but not in women.
CONCLUSIONS
Heavy alcohol consumption, particularly binge drinking, appears to be an independent risk factor in young men with CIS.
PubMed: 38906694
DOI: 10.1136/jnnp-2024-333759 -
Advances in Food and Nutrition Research 2024Nowadays, the growing knowledge about the high nutritional value and potential functionality of hempseeds, the edible fruits of the Cannabis sativa L. plant, has sparked... (Review)
Review
Nowadays, the growing knowledge about the high nutritional value and potential functionality of hempseeds, the edible fruits of the Cannabis sativa L. plant, has sparked a surge in interest in exploring the worthwhile attributes of hempseed proteins and peptides. This trend aligns with the increasing popularity of hemp-based food, assuming a vital role in the global food chain. This chapter targets the nutritional and chemical composition of hempseed in terms of short- and medium-chain bioactive peptides. The analytical approaches for their characterization and multifunctional properties are summarized in detail. Moreover, the processing, functionality, and application of various hempseed protein products are discussed. In the final part of the chapter-for evaluating their propensity to be transported by intestinal cells-the transepithelial transport of peptides within hempseed protein hydrolysate is highlighted.
Topics: Cannabis; Seeds; Plant Proteins; Peptides; Humans; Nutritive Value
PubMed: 38906589
DOI: 10.1016/bs.afnr.2024.01.002 -
Journal of Medicinal Food Jun 2024Iron supplementation is a common method for alleviating symptoms of iron deficiency, but excessive iron intake may lead to systemic copper deficiencies and...
Iron supplementation is a common method for alleviating symptoms of iron deficiency, but excessive iron intake may lead to systemic copper deficiencies and hypercholesterolemia. In our study, we explored the intricate relationship between dietary iron and copper levels and their impact on cholesterol metabolism. Using a rat model, we conducted dietary interventions with varying iron and copper concentrations and analyzed hepatic transcriptomes. High iron intake coupled with low copper intake induced hypercholesterolemia and altered the expression of genes associated with cholesterol and lipid metabolism, thereby, exacerbating cardiovascular disease risks. Conversely, copper supplementation mitigated these hepatic gene expression alterations, suggesting that dietary copper plays a role in cholesterol regulation. Transcriptomic analysis revealed significant upregulation of genes involved in cholesterol synthesis and antioxidative pathways in response to high iron intake, while genes involved in cholesterol elimination were downregulated. Furthermore, high iron consumption was associated with cellular apoptosis and the activation of cholesterol synthesis. Our findings underscore the importance of balanced iron and copper intake in cholesterol homeostasis and highlight the potential of copper supplementation for mitigating iron-induced hypercholesterolemia.
PubMed: 38905120
DOI: 10.1089/jmf.2024.k.0139 -
Journal of Vascular Surgery Jun 2024Type B intramural hematoma (IMH) is often managed medically, yet may progress to dissection, aneurysmal dilation, or rupture. The aim of this study was to report the...
OBJECTIVE
Type B intramural hematoma (IMH) is often managed medically, yet may progress to dissection, aneurysmal dilation, or rupture. The aim of this study was to report the natural history of medically managed Type B IMH, and factors associated with progression.
METHODS
We reviewed patients with medically managed Type B IMH between January 1995 to December 2022 at a single center. Any patients with immediate surgical or endovascular intervention were excluded. Demographic profiles, comorbidities, imaging, and follow-up details were reviewed. Patients were divided into two groups: Group 1 had isolated IMH, and Group 2 had IMH along with aneurysm or dissection at the time of presentation. On follow-up, progression was defined as degeneration to aneurysm/dissection or increase in the thickness of IMH in Group 1. In Group 2, progression was an increase in the size of aneurysm or development of new dissection.
RESULTS
Of 104 patients with Type B IMH during the study period, 92 were medically managed. The median age was 77 years, and 45 (48.9%) were females. Comorbidities included hypertension (83.7%), hypercholesterolemia (44.6%), and active smoking (47.8%). Mean Society for Vascular Surger comorbidity score was 6.3. Mean IMH thickness and aortic diameter at presentation were 8.9 mm and 38.3 mm, respectively. Median follow-up was 55 months. Overall survival at 1 year and 5 years was 85.8% and 61.9%, respectively. During follow-up, 19 patients (20.7%) required intervention, more common in Group 2 (Group 1, 8/66; 12.3% vs Group 2, 11/26; 42.3%; P = .001). This resulted in higher freedom from intervention in Group 1 at 1 year (93.5% vs 62.7%) and 5 years (87.5% vs 51.1%; P < .001). Indication for intervention was dissection (n = 4), aneurysm (n = 12), and progression of IMH (n = 3). In Group 1, progression was seen in 25 (37.9%), three (4.5%) remained stable, 29 (43.9%) had complete resolution of IMH, and nine patients were lost to follow-up. In Group 2, 11 patients (42.3%) had progression, seven (26.9%) remained stable, and eight were lost to follow-up. IMH thickness at presentation >7.2 mm is associated with both increased odds of progression (odds ratio, 3.3; 95% confidence interval, 1.2-11.1; P = .03) and intervention (odds ratio, 5.5; 95% confidence interval, 1.3-36.9; P = .03) during the follow-up.
CONCLUSIONS
Although many patients with Type B IMH managed medically stabilize or regress, progression or need for intervention can occur in up to 40% of cases. This is associated with the presence of aneurysm, dissection, and IMH thickness. Long-term follow-up is mandatory as late interventions occur, particularly for higher risk patients.
PubMed: 38904581
DOI: 10.1016/j.jvs.2024.04.069 -
Frontiers in Pharmacology 2024Lorlatinib displays marked systemic and intracranial efficacy against anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC). We aimed to establish...
BACKGROUND
Lorlatinib displays marked systemic and intracranial efficacy against anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC). We aimed to establish the safety profile of lorlatinib based on the Food and Drug Administration Adverse Event Reporting System (FAERS).
METHODS
Reports from the FAERS between 2019 and 2023 were collected to conduct the disproportionality analysis. Reporting odds ratio (ROR) was employed to detect the potential adverse events (AEs) related to lorlatinib. The clinical characteristics, age and gender differences, time to onset of AEs were also investigated.
RESULTS
A total of 2,941 AE reports were found to be associated with lorlatinib among the 8,818,870 AE reports obtained from the FAERS database. 167 lorlatinib-related AE signals were identified. The frequently reported AEs including hypercholesterolemia, oedema, and cognitive disorder were in line with those observed in clinical trials and drug instruction. However, AEs such as interstitial lung disease and AV block indicated in the drug label require further evaluation. More attention should be paid to the new potential unexpected AEs including pulmonary arterial hypertension and radiation necrosis. Furthermore, we examined the specific high-risk AEs of different ages and genders. In addition, majority of AEs occurred within the first 2 months after lorlatinib initiation with a median onset time of 51 days.
CONCLUSION
Our study provides valuable insight into the post-marketing safety profile of lorlatinib, which can potentially benefit the rational and safe administration of lorlatinib in the clinic. Further prospective studies are needed to validate the associations between lorlatinib and the identified AEs.
PubMed: 38903993
DOI: 10.3389/fphar.2024.1385036 -
Ugeskrift For Laeger Jun 2024In this case report, a 31-year-old woman with heterozygous familial hypercholesterolaemia (FH) underwent treatment with statins and PCSK9 inhibitor but had to...
In this case report, a 31-year-old woman with heterozygous familial hypercholesterolaemia (FH) underwent treatment with statins and PCSK9 inhibitor but had to discontinue due to elevated creatine kinase levels and neurological and muscular side effects. In 2021, the patient received inclisiran therapy, the first known instance of its application in Denmark. No side effects were reported, and LDL cholesterol levels were significantly reduced. This case report highlights the potential of inclisiran as an effective and well-tolerated treatment for individuals with heterozygous FH.
Topics: Humans; Female; Adult; Hyperlipoproteinemia Type II; PCSK9 Inhibitors; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Anticholesteremic Agents
PubMed: 38903035
DOI: 10.61409/V12230767 -
The British Journal of General Practice... Jun 2024Familial Hypercholesterolaemia (FH) is a greatly underdiagnosed and treatable genetic lipid disorder which significantly increases risk of premature cardiovascular...
BACKGROUND
Familial Hypercholesterolaemia (FH) is a greatly underdiagnosed and treatable genetic lipid disorder which significantly increases risk of premature cardiovascular disease. The prevalence of monogenic FH is thought to be 1 in 250-350. The NHS Long Term Plan aims to increase FH detection to at least 25% over 5 years in collaboration with primary care, supported by the NHS genomics programme.
AIM
This systematic review evaluates systematic screening methods for FH in adults aged ≥18 years in primary care.
METHOD
Seven databases [Cochrane, PubMed, Ovid, CINAHL, ProQuest, Web of Science, Scopus], four clinical trial registries [ISRCTN, ANZCTR, Clinicaltrials.gov, WHO-ICTRP] and relevant grey literature [OpenGrey] from March 2020 to May 2023 were searched. Only studies including adults were eligible. Risk of bias was assessed using ROBINS-I.
RESULTS
831 records were screened. No randomised, controlled studies were identified. From full-text review, five eligible non-randomised studies out of 57 (6.90%) were identified. The included studies all used automated FH case-identification from electronic medical records (EMR) and were high quality studies with a moderate risk of bias. Narrative synthesis reported outcomes which included three algorithmic studies, with a pooled detection rate, DR 14.4% (95%CI 11.67-16.62), one supervised Machine Learning [Ensemble] study, DR 15.5% (95%CI 15.47-15.53) and one study utilising a hybrid diagnostic EMR model and/or FH genotype confirmation DR 25.0% (95%CI 16.30-35.8). No adverse effects were reported in these studies.
CONCLUSION
Incorporating automated case-finding from EMR with clinical follow-up in primary care can enhance FH identification. Pathways incorporating genotyping showed the best detection rate.
Topics: Humans; Hyperlipoproteinemia Type II; Primary Health Care; Mass Screening; Genetic Testing
PubMed: 38902081
DOI: 10.3399/bjgp24X738141 -
The Journal of Nutrition Jun 2024Childbearing increases the risk of weight gain and cardiometabolic disease. The reset hypothesis suggests that lactation has protective cardiometabolic effects in the...
Effects of breastfeeding promotion intervention and dietary treatment in postpartum women with overweight and obesity: Results from a randomized controlled trial on weight and cardiometabolic risk factors.
BACKGROUND
Childbearing increases the risk of weight gain and cardiometabolic disease. The reset hypothesis suggests that lactation has protective cardiometabolic effects in the mother. The hypothesis is based on observational studies and the possible interacting role of weight loss needs to be elucidated.
OBJECTIVE
To examine the individual and interaction effects of a breastfeeding promotion intervention (BPI) and dietary intervention for weight loss postpartum (Diet) on body weight and cardiometabolic risk factors at 6 mo postpartum.
METHODS
Pregnant women (n = 156) with a pre-pregnancy BMI of 25-35 kg/m were randomized to 4 groups in a 2x2 factorial design: BPI, Diet, both treatments or no treatment. BPI consisted of individual counseling by a lactation consultant during pregnancy, at childbirth, and thereafter monthly or more frequently based on individual needs. Diet was initiated at 11 wk postpartum. Body weight, body composition, waist- and hip circumference, markers of lipid and glucose metabolism and blood pressure were measured at 2 wk and 6 mo postpartum.We analyzed main and interaction effects using 2-way ANCOVA adjusted for baseline values.
RESULTS
Among the participants attending both visits (n = 108), 99% practiced any breastfeeding at baseline and 97% at follow-up. The BPI did not affect rates of exclusive or partial breastfeeding, age at introduction of complementary foods or have main effects on body weight or cardiometabolic risk factors. There was a main effect of Diet reducing body weight, fat mass, fat-free mass, percent fat mass, waist- and hip circumference, fasting glucose and insulin (all p ≤ 0.03), with no interactions between the treatments.
CONCLUSIONS
There were no effects of BPI on body weight or cardiometabolic risk factors at 6 mo postpartum. Diet caused weight loss and had favorable effects on risk factors for cardiovascular disease and type 2 diabetes.
TRIAL REGISTRATION
ClinicalTrials.gov (NCT03580057).
PubMed: 38901636
DOI: 10.1016/j.tjnut.2024.06.006