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The Lancet. Oncology Oct 2023PROpel met its primary endpoint showing statistically significant improvement in radiographic progression-free survival with olaparib plus abiraterone versus placebo... (Randomized Controlled Trial)
Randomized Controlled Trial
Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial.
BACKGROUND
PROpel met its primary endpoint showing statistically significant improvement in radiographic progression-free survival with olaparib plus abiraterone versus placebo plus abiraterone in patients with first-line metastatic castration-resistant prostate cancer (mCRPC) unselected by homologous recombination repair mutation (HRRm) status, with benefit observed in all prespecified subgroups. Here we report the final prespecified overall survival analysis.
METHODS
This was a randomised, double-blind, phase 3 trial done at 126 centres in 17 countries worldwide. Patients with mCRPC aged at least 18 years, Eastern Cooperative Oncology Group performance status 0-1, a life expectancy of at least 6 months, with no previous systemic treatment for mCRPC and unselected by HRRm status were randomly assigned (1:1) centrally by means of an interactive voice response system-interactive web response system to abiraterone acetate (orally, 1000 mg once daily) plus prednisone or prednisolone with either olaparib (orally, 300 mg twice daily) or placebo. The patients, the investigator, and study centre staff were masked to drug allocation. Stratification factors were site of metastases and previous docetaxel at metastatic hormone-sensitive cancer stage. Radiographic progression-free survival was the primary endpoint and overall survival was a key secondary endpoint with alpha-control (alpha-threshold at prespecified final analysis: 0·0377 [two-sided]), evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03732820, and is completed and no longer recruiting.
FINDINGS
Between Oct 31, 2018 and March 11, 2020, 1103 patients were screened, of whom 399 were randomly assigned to olaparib plus abiraterone and 397 to placebo plus abiraterone. Median follow-up for overall survival in patients with censored data was 36·6 months (IQR 34·1-40·3) for olaparib plus abiraterone and 36·5 months (33·8-40·3) for placebo plus abiraterone. Median overall survival was 42·1 months (95% CI 38·4-not reached) with olaparib plus abiraterone and 34·7 months (31·0-39·3) with placebo plus abiraterone (hazard ratio 0·81, 95% CI 0·67-1·00; p=0·054). The most common grade 3-4 adverse event was anaemia reported in 64 (16%) of 398 patients in the olaparib plus abiraterone and 13 (3%) of 396 patients in the placebo plus abiraterone group. Serious adverse events were reported in 161 (40%) in the olaparib plus abiraterone group and 126 (32%) in the placebo plus abiraterone group. One death in the placebo plus abiraterone group, from interstitial lung disease, was considered treatment related.
INTERPRETATION
Overall survival was not significantly different between treatment groups at this final prespecified analysis.
FUNDING
Supported by AstraZeneca and Merck Sharp & Dohme.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Double-Blind Method; Phthalazines; Antineoplastic Combined Chemotherapy Protocols; Aged; Piperazines; Middle Aged; Androstenes; Progression-Free Survival; Aged, 80 and over; Neoplasm Metastasis
PubMed: 37714168
DOI: 10.1016/S1470-2045(23)00382-0 -
Cardiovascular Diabetology Sep 2023Pharmacological post-MI treatment is routinely initiated at intensive/cardiac care units. However, solid evidence for an early start of these therapies is only available...
BACKGROUND
Pharmacological post-MI treatment is routinely initiated at intensive/cardiac care units. However, solid evidence for an early start of these therapies is only available for dual platelet therapy and statins, whereas data on beta blockers and RAAS inhibitors are heterogenous and mainly limited to STEMI and heart failure patients. Recently, the EMMY trial provided the first evidence on the beneficial effects of SGLT2 inhibitors (SGLT2i) when initiated early after PCI. In patients with type 2 diabetes mellitus, SGLT2i are considered "sick days drugs" and it, therefore, remains unclear if very early SGLT2i initiation following MI is as safe and effective as delayed initiation.
METHODS AND RESULTS
The EMMY trial evaluated the effect of empagliflozin on NT-proBNP and functional and structural measurements. Within the Empagliflozin group, 22 (9.5%) received early treatment (< 24 h after PCI), 98 (42.2%) within a 24 to < 48 h window (intermediate), and 111 (48.1%) between 48 and 72 h (late). NT-proBNP levels declined by 63.5% (95%CI: - 69.1; - 48.1) in the early group compared to 61.0% (- 76.0; - 41.4) in the intermediate and 61.9% (- 70.8; - 45.7) in the late group (n.s.) within the Empagliflozin group with no significant treatment groups-initiation time interaction (p = 0.96). Secondary endpoints of left ventricular function (LV-EF, e/e`) as well as structure (LVESD and LVEDD) were also comparable between the groups. No significant difference in severe adverse event rate between the initiation time groups was detected.
CONCLUSION
Very early administration of SGLT2i after acute myocardial infarction does not show disadvantageous signals with respect to safety and appears to be as effective in reducing NT-proBNP as well as improving structural and functional LV markers as initiation after 2-3 days.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Percutaneous Coronary Intervention; Myocardial Infarction; Heart Failure
PubMed: 37777743
DOI: 10.1186/s12933-023-02000-5 -
Scientific Reports Jan 2024The association between sarcopenia and OA still presents many uncertainties. We aimed to assess whether sarcopenia is associated with occurrence of OA in US adults. We...
The association between sarcopenia and OA still presents many uncertainties. We aimed to assess whether sarcopenia is associated with occurrence of OA in US adults. We conducted a cross-sectional study consisting of 11,456 participants from National Health and Nutrition Examination Survey 1999-2006. Sarcopenia was defined by a low muscle mass. The skeletal muscle index (SMI) was calculated as the appendicular skeletal muscle mass divided by body mass indexes (BMI) or body weight. OA status was assessed by using self-reported questionnaire. We evaluated the association between sarcopenia and OA using multivariate regression models. In addition, subgroup and interaction analysis were performed. Sarcopenia was associated with OA when it was defined by the BMI-adjusted SMI (OR = 1.23 [95% CI, 1.01, 1.51]; P = 0.038) and defined by the weight-adjusted SMI (OR = 1.30 [95% CI, 1.10, 1.55]; P = 0.003). Subgroup and interaction analysis found that the strongest positive association mainly exists in smoker (OR = 1.54 [95% CI, 1.21, 1.95], Pint = 0.006), and this association is not significant in other groups. In conclusion, we found that sarcopenia was associated with occurrence of OA. Subgroup analysis revealed that the association between sarcopenia and OA was more pronounced in smoker. Further well-designed prospective cohort studies are needed to assess our results.
Topics: Adult; Humans; Sarcopenia; Cross-Sectional Studies; Nutrition Surveys; Prospective Studies; Muscle, Skeletal; Osteoarthritis
PubMed: 38167445
DOI: 10.1038/s41598-023-50528-z -
Journal of Orthopaedic Surgery and... Aug 2023Lumbar disc herniation (LDH) is a complex spinal disease, with multiple genetic polymorphisms being related to its risk. Nevertheless, the role of LINC-PINT...
BACKGROUND
Lumbar disc herniation (LDH) is a complex spinal disease, with multiple genetic polymorphisms being related to its risk. Nevertheless, the role of LINC-PINT polymorphisms in LDH risk has remained unknown. Therefore, this study aimed to investigate the association between LINC-PINT polymorphisms and LDH risk.
METHODS
DNA was extracted from 504 LDH patients and 500 healthy controls. Three single nucleotide polymorphisms (SNPs) in LINC-PINT were selected and genotyped using Agena MassARRAY. We used logistic regression analysis to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) under multiple genetic models to evaluate the association between LINC-PINT polymorphisms and LDH risk. Haploview 4.2 and SNPStats software were used to evaluate the linkage strength of SNPs and the correlation between haplotypes and LDH risk. The impact of SNP-SNP interactions on LDH risk was analyzed using multi-factor dimensionality reduction (MDR).
RESULTS
Results showed that rs157916 (G vs. A: OR = 1.23, FDR-p = 0.029) and rs7801029 (G vs. C: OR = 1.39, FDR-p = 0.006; GG vs. CC: OR = 2.34, FDR-p = 0.038; recessive: OR = 2.13, FDR-p = 0.045; additive: OR = 1.39, FDR-p = 0.030) were associated with an increased risk of LDH. Furthermore, LINC-PINT rs157916 and rs780129 were found to be significantly associated with LDH risk in males. The "GGG" haplotype was associated with increased LDH risk (OR = 1.41, FDR-p = 0.006). MDR analysis indicated that the interaction between rs7801029 and rs16873842 was associated with an increased risk of LDH (OR = 1.47, p = 0.004). Additionally, there were significant differences in C-reactive protein levels among different genotypes of rs157916 and rs780129 (p < 0.05).
CONCLUSION
This study suggests that LINC-PINT gene polymorphisms (rs157916 and rs7801029) are considered risk factors for LDH in the Chinese Han population and provide a scientific basis for early screening, prevention, and diagnosis of LDH.
Topics: Humans; Male; Case-Control Studies; China; East Asian People; Gene Frequency; Genetic Predisposition to Disease; Intervertebral Disc Displacement; Lumbar Vertebrae; Polymorphism, Single Nucleotide; RNA, Long Noncoding
PubMed: 37553573
DOI: 10.1186/s13018-023-04052-5 -
Journal of the American Heart... Aug 2023Background Premature and early menopause are independently associated with greater risk of cardiovascular disease (CVD). However, mechanisms linking age of menopause...
Background Premature and early menopause are independently associated with greater risk of cardiovascular disease (CVD). However, mechanisms linking age of menopause with CVD remain poorly characterized. Methods and Results We measured 71 circulating CVD protein biomarkers in 1565 postmenopausal women enrolled in the FHS (Framingham Heart Study). We examined the association of early menopause with biomarkers and tested whether early menopause modified the association of biomarkers with incident cardiovascular outcomes (heart failure, major CVD, and all-cause death) using multivariable-adjusted linear regression and Cox models, respectively. Among 1565 postmenopausal women included (mean age 62 years), 395 (25%) had a history of early menopause. Of 71 biomarkers examined, we identified 7 biomarkers that were significantly associated with early menopause, of which 5 were higher in women with early menopause including adrenomedullin and resistin, and 2 were higher in women without early menopause including insulin growth factor-1 and CNTN1 (contactin-1) (Benjamini-Hochberg adjusted <0.1 for all). Early menopause also modified the association of specific biomarkers with incident cardiovascular outcomes including adrenomedullin (<0.05). Conclusions Early menopause is associated with circulating levels of CVD protein biomarkers and appears to modify the association between select biomarkers with incident cardiovascular outcomes. Identified biomarkers reflect several distinct biological pathways, including inflammation, adiposity, and neurohormonal regulation. Further investigation of these pathways may provide mechanistic insights into the pathogenesis, prevention, and treatment of early menopause-associated CVD.
Topics: Female; Humans; Middle Aged; Cardiovascular Diseases; Adrenomedullin; Menopause, Premature; Menopause; Biomarkers; Risk Factors
PubMed: 37548169
DOI: 10.1161/JAHA.122.028849 -
Critical Care (London, England) Dec 2023Sepsis is a highly heterogeneous syndrome, which has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine...
BACKGROUND
Sepsis is a highly heterogeneous syndrome, which has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles.
METHODS
The subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses.
RESULTS
Patients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells and less diverse T cell receptor repertoires.
CONCLUSIONS
Two subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences. Trial Registration This is a secondary analysis of data generated as part of the observational CAF-PINT ancillary of the HALF-PINT study (NCT01565941). Registered March 29, 2012.
Topics: Child; Humans; Gene Expression Profiling; Prospective Studies; Sepsis; Shock, Septic; Transcriptome; Randomized Controlled Trials as Topic; Observational Studies as Topic
PubMed: 38066613
DOI: 10.1186/s13054-023-04689-y -
Cardiovascular Diabetology Aug 2023Semaglutide is a glucose-lowering treatment for type 2 diabetes (T2D) with demonstrated cardiovascular benefits; semaglutide may also have kidney-protective effects....
Effect of semaglutide on major adverse cardiovascular events by baseline kidney parameters in participants with type 2 diabetes and at high risk of cardiovascular disease: SUSTAIN 6 and PIONEER 6 post hoc pooled analysis.
BACKGROUND
Semaglutide is a glucose-lowering treatment for type 2 diabetes (T2D) with demonstrated cardiovascular benefits; semaglutide may also have kidney-protective effects. This post hoc analysis investigated the association between major adverse cardiovascular events (MACE) and baseline kidney parameters and whether the effect of semaglutide on MACE risk was impacted by baseline kidney parameters in people with T2D at high cardiovascular risk.
METHODS
Participants from the SUSTAIN 6 and PIONEER 6 trials, receiving semaglutide or placebo, were categorised according to baseline kidney function (estimated glomerular filtration rate [eGFR] < 45 and ≥ 45-<60 versus ≥ 60 mL/min/1.73 m) or damage (urine albumin:creatinine ratio [UACR] ≥ 30-≤300 and > 300 versus < 30 mg/g). Relative risk of first MACE by baseline kidney parameters was evaluated using a Cox proportional hazards model. The same model, adjusted with inverse probability weighting, and a quadratic spline regression were applied to evaluate the effect of semaglutide on risk and event rate of first MACE across subgroups. The semaglutide effects on glycated haemoglobin (HbA), body weight (BW) and serious adverse events (SAEs) across subgroups were also evaluated.
RESULTS
Independently of treatment, participants with reduced kidney function (eGFR ≥ 45-<60 and < 45 mL/min/1.73 m: hazard ratio [95% confidence interval]; 1.36 [1.04;1.76] and 1.52 [1.15;1.99]) and increased albuminuria (UACR ≥ 30-≤300 and > 300 mg/g: 1.53 [1.14;2.04] and 2.52 [1.84;3.42]) had an increased MACE risk versus those without. Semaglutide consistently reduced MACE risk versus placebo across all eGFR and UACR subgroups (interaction p value [p] > 0.05). Semaglutide reduced HbA regardless of baseline eGFR and UACR (p>0.05); reductions in BW were affected by baseline eGFR (p<0.001) but not UACR (p>0.05). More participants in the lower eGFR or higher UACR subgroups experienced SAEs versus participants in reference groups; the number of SAEs was similar between semaglutide and placebo arms in each subgroup.
CONCLUSIONS
MACE risk was greater for participants with kidney impairment or damage than for those without. Semaglutide consistently reduced MACE risk across eGFR and UACR subgroups, indicating that semaglutide provides cardiovascular benefits in people with T2D and at high cardiovascular risk across a broad spectrum of kidney function and damage.
TRIAL REGISTRATIONS
NCT01720446; NCT02692716.
Topics: Humans; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Cardiovascular System; Kidney; Renal Insufficiency
PubMed: 37620807
DOI: 10.1186/s12933-023-01949-7 -
Frontiers in Medicine 2023The association between red blood cell distribution width (RDW) and psoriasis among the US adults is still unknown. We aimed to assess whether RDW is associated with...
INTRODUCTION
The association between red blood cell distribution width (RDW) and psoriasis among the US adults is still unknown. We aimed to assess whether RDW is associated with psoriasis in the US adults.
METHOD
We conducted a cross-sectional study consisting of 14,089 participants from National Health and Nutrition Examination Survey (NHANES) 2009-2014. Psoriasis status were assessed by self-reported questionnaire. We evaluated the association between RDW and risk of psoriasis using multivariate regression models. Subgroup and interaction analysis were performed.
RESULTS
The higher RDW level was associated with an increased risk of psoriasis (OR = 1.10 [95% CI, 1.01, 1.19]; = 0.025) after adjusting for confounders in female. However, there is no significant association between RDW and risk of psoriasis among male (OR = 0.99 [95% CI, 0.87, 1.15]; = 0.992). Subgroup and interaction analysis found that the strongest positive association mainly exists in female participants with BMD greater than 29.9 kg/m (OR = 1.20 [95% CI, 1.09, 1.32], Pint = 0.004).
DISCUSSION
In conclusion, we found that increased RDW levels were associated with an increased risk of psoriasis in females, which could provide clinicians with auxiliary data for the early diagnosis of psoriasis.
PubMed: 38179271
DOI: 10.3389/fmed.2023.1290514 -
Journal of the American College of... Jan 2024In the TRILUMINATE Pivotal (Trial to Evaluate Cardiovascular Outcomes in Patients Treated with the Tricuspid Valve Repair System Pivotal), tricuspid transcatheter...
BACKGROUND
In the TRILUMINATE Pivotal (Trial to Evaluate Cardiovascular Outcomes in Patients Treated with the Tricuspid Valve Repair System Pivotal), tricuspid transcatheter edge-to-edge repair (T-TEER) reduced tricuspid regurgitation (TR) and improved health status compared with medical therapy alone with no benefit on heart failure hospitalizations or survival.
OBJECTIVES
The purpose of this study was to better understand the health status benefits of T-TEER within the TRILUMINATE Pivotal trial.
METHODS
TRILUMINATE randomized patients with severe TR to T-TEER (n = 175) or medical therapy (n = 175). Health status was assessed at baseline and at 1, 6, and 12 months with the Kansas City Cardiomyopathy Questionnaire (KCCQ) (range 0-100; higher = better), which was compared between treatment groups using mixed effects linear regression. Alive and well was defined as KCCQ overall summary score ≥60 and no decline from baseline of >10 points at 1 year.
RESULTS
Compared with medical therapy, T-TEER significantly improved health status at 1 month (mean between-group difference in KCCQ overall summary score 9.4 points; 95% CI: 5.3-13.4 points), with a small additional improvement at 1 year (mean between-group difference 10.4 points; 95% CI: 6.3-14.6 points). T-TEER patients were more likely to be alive and well at 1 year (T-TEER vs medical therapy: 74.8% vs 45.9%; P < 0.001), with a number needed to treat of 3.5. Interaction analyses demonstrated that the benefit of T-TEER diminished as baseline KCCQ overall summary score increased (P < 0.001). Exploratory analyses suggested that much of the health status benefit of T-TEER could be explained by TR reduction and that improvement in health status after T-TEER was strongly correlated with reduced 1-year mortality and heart failure hospitalization.
CONCLUSIONS
T-TEER with the TriClip system resulted in substantial and sustained health status improvement in patients with severe TR compared with medical therapy alone.
Topics: Humans; Tricuspid Valve Insufficiency; Treatment Outcome; Heart Valve Prosthesis Implantation; Health Status; Tricuspid Valve; Heart Failure; Cardiac Catheterization
PubMed: 37898329
DOI: 10.1016/j.jacc.2023.10.008 -
The Plant Cell Sep 2023
Topics: RNA, Long Noncoding
PubMed: 37433057
DOI: 10.1093/plcell/koad194