Combining heart rate and systolic blood pressure to improve risk stratification in older patients with heart failure: Findings from the RICA Registry

Objectives: Heart rate (HR) and systolic blood pressure (SBP) are independent prognostic variables in patients with heart failure (HF). We evaluated if combining HR and SBP could improve prognostic assessment in older patients. Methods: Variables associated with all-cause mortality and readmission for HF during 9 months of follow-up were analyzed from the Spanish Heart Failure Registry (RICA). HR and SBP values were stratified in three combined groups. Results: We evaluated 1551 patients, 82 years and 56% women. Using HR strata of < 70 and ≥ 70 bpm we found mortality rates of 9.8 and 13.6%, respectively (hazard ratio 1.0 and 1.35). For SBP ≥ 140, 120–140 and < 120 mm Hg, mortality rates were 8.2, 10.4 and 20.3%. respectively (hazard ratio 1.0, 1.34 and 2.76). Using combined strata of HR < 70 bpm and SBP ≥ 140 mm Hg (n = 176; low-risk), HR < 70 and SBP < 140 + HR ≥ 70 and SBP < 120 (n = 1089; moderate-risk) and HR ≥ 70 and SBP < 120 (n = 286; high-risk) we found mortality rates of 4.5%, 11.0% and 24.0%, respectively. Multivariate Cox regression for all-cause mortality shows for low-, middle- and high-risk groups was 1 (reference), 1.93 (95% CI: 0.93–3.99, p = 0.077) and 4.32 (95% CI: 2.04–9.14, p < 0.001). BMI, NYHA, MDRD, hypertension and sodium were also independent prognostic factors. Conclusions: The combination provides better risk discrimination than use of HR and SBP alone and may provide a simple and reliable tool for risk assessment for older HF patients in clinical practice

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Combining heart rate and systolic blood pressure to improve risk stratification in older patients with heart failure: Findings from the RICA Registry

Objectives: Heart rate (HR) and systolic blood pressure (SBP) are independent prognostic variables in patients with heart failure (HF). We evaluated if combining HR and SBP could improve prognostic assessment in older patients. Methods: Variables associated with all-cause mortality and readmission for HF during 9 months of follow-up were analyzed from the Spanish Heart Failure Registry (RICA). HR and SBP values were stratified in three combined groups. Results: We evaluated 1551 patients, 82 years and 56% women. Using HR strata of <70 and ≥70 bpm we found mortality rates of 9.8 and 13.6%, respectively (hazard ratio 1.0 and 1.35). For SBP ≥ 140, 120-140 and <120 mm Hg, mortality rates were 8.2, 10.4 and 20.3%. respectively (hazard ratio 1.0, 1.34 and 2.76). Using combined strata of HR < 70 bpm and SBP ≥ 140 mm Hg (n = 176; low-risk), HR < 70 and SBP < 140 + HR ≥ 70 and SBP < 120 (n = 1089; moderate-risk) and HR ≥ 70 and SBP < 120 (n = 286; high-risk) we found mortality rates of 4.5%, 11.0% and 24.0%, respectively. Multivariate Cox regression for all-cause mortality shows for low-, middle- and high-risk groups was 1 (reference), 1.93 (95% CI: 0.93-3.99, p = 0.077) and 4.32 (95% CI: 2.04-9.14, p < 0.001). BMI, NYHA, MDRD, hypertension and sodium were also independent prognostic factors. Conclusions: The combination provides better risk discrimination than use of HR and SBP alone and may provide a simple and reliable tool for risk assessment for older HF patients in clinical practice

Combining heart rate and systolic blood pressure to improve risk stratification in older patients with heart failure: Findings from the RICA Registry

Objectives: Heart rate (HR) and systolic blood pressure (SBP) are independent prognostic variables in patients with heart failure (HF). We evaluated if combining HR and SBP could improve prognostic assessment in older patients. Methods: Variables associated with all-cause mortality and readmission for HF during 9 months of follow-up were analyzed from the Spanish Heart Failure Registry (RICA). HR and SBP values were stratified in three combined groups. Results: We evaluated 1551 patients, 82 years and 56% women. Using HR strata of <70 and ≥70 bpm we found mortality rates of 9.8 and 13.6%, respectively (hazard ratio 1.0 and 1.35). For SBP ≥ 140, 120-140 and <120 mm Hg, mortality rates were 8.2, 10.4 and 20.3%. respectively (hazard ratio 1.0, 1.34 and 2.76). Using combined strata of HR < 70 bpm and SBP ≥ 140 mm Hg (n = 176; low-risk), HR < 70 and SBP < 140 + HR ≥ 70 and SBP < 120 (n = 1089; moderate-risk) and HR ≥ 70 and SBP < 120 (n = 286; high-risk) we found mortality rates of 4.5%, 11.0% and 24.0%, respectively. Multivariate Cox regression for all-cause mortality shows for low-, middle- and high-risk groups was 1 (reference), 1.93 (95% CI: 0.93-3.99, p = 0.077) and 4.32 (95% CI: 2.04-9.14, p < 0.001). BMI, NYHA, MDRD, hypertension and sodium were also independent prognostic factors. Conclusions: The combination provides better risk discrimination than use of HR and SBP alone and may provide a simple and reliable tool for risk assessment for older HF patients in clinical practice

Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies.

BackgroundPrevious studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.MethodsWe pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.ResultsIn case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (&gt;50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.ConclusionsThis study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology

Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial

Background: Additional safe and efficacious vaccines are needed to control the COVID-19 pandemic. We aimed to analyse the efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate. Methods: HERALD is a randomised, observer-blinded, placebo-controlled, phase 2b/3 clinical trial conducted in 47 centres in ten countries in Europe and Latin America. By use of an interactive web response system and stratification by country and age group (18–60 years and ≥61 years), adults with no history of virologically confirmed COVID-19 were randomly assigned (1:1) to receive intramuscularly either two 0·6 mL doses of CVnCoV containing 12 μg of mRNA or two 0·6 mL doses of 0·9% NaCl (placebo) on days 1 and 29. The primary efficacy endpoint was the occurrence of a first episode of virologically confirmed symptomatic COVID-19 of any severity and caused by any strain from 15 days after the second dose. For the primary endpoint, the trial was considered successful if the lower limit of the CI was greater than 30%. Key secondary endpoints were the occurrence of a first episode of virologically confirmed moderate-to-severe COVID-19, severe COVID-19, and COVID-19 of any severity by age group. Primary safety outcomes were solicited local and systemic adverse events within 7 days after each dose and unsolicited adverse events within 28 days after each dose in phase 2b participants, and serious adverse events and adverse events of special interest up to 1 year after the second dose in phase 2b and phase 3 participants. Here, we report data up to June 18, 2021. The study is registered at ClinicalTrials.gov, NCT04652102, and EudraCT, 2020–003998–22, and is ongoing. Findings: Between Dec 11, 2020, and April 12, 2021, 39 680 participants were enrolled and randomly assigned to receive either CVnCoV (n=19 846) or placebo (n=19 834), of whom 19 783 received at least one dose of CVnCoV and 19 746 received at least one dose of placebo. After a mean observation period of 48·2 days (SE 0·2), 83 cases of COVID-19 occurred in the CVnCoV group (n=12 851) in 1735·29 person-years and 145 cases occurred in the placebo group (n=12 211) in 1569·87 person-years, resulting in an overall vaccine efficacy against symptomatic COVID-19 of 48·2% (95·826% CI 31·0–61·4; p=0·016). Vaccine efficacy against moderate-to-severe COVID-19 was 70·7% (95% CI 42·5–86·1; CVnCoV 12 cases in 1735·29 person-years, placebo 37 cases in 1569·87 person-years). In participants aged 18–60 years, vaccine efficacy against symptomatic disease was 52·5% (95% CI 36·2–64·8; CVnCoV 71 cases in 1591·47 person-years, placebo, 136 cases in 1449·23 person-years). Too few cases occurred in participants aged 61 years or older (CVnCoV 12, placebo nine) to allow meaningful assessment of vaccine efficacy. Solicited adverse events, which were mostly systemic, were more common in CVnCoV recipients (1933 [96·5%] of 2003) than in placebo recipients (1344 [67·9%] of 1978), with 542 (27·1%) CVnCoV recipients and 61 (3·1%) placebo recipients reporting grade 3 solicited adverse events. The most frequently reported local reaction after any dose in the CVnCoV group was injection-site pain (1678 [83·6%] of 2007), with 22 grade 3 reactions, and the most frequently reported systematic reactions were fatigue (1603 [80·0%] of 2003) and headache (1541 [76·9%] of 2003). 82 (0·4%) of 19 783 CVnCoV recipients reported 100 serious adverse events and 66 (0·3%) of 19 746 placebo recipients reported 76 serious adverse events. Eight serious adverse events in five CVnCoV recipients and two serious adverse events in two placebo recipients were considered vaccination-related. None of the fatal serious adverse events reported (eight in the CVnCoV group and six in the placebo group) were considered to be related to study vaccination. Adverse events of special interest were reported for 38 (0·2%) participants in the CVnCoV group and 31 (0·2%) participants in the placebo group. These events were considered to be related to the trial vaccine for 14 (<0·1%) participants in the CVnCoV group and for five (<0·1%) participants in the placebo group. Interpretation: CVnCoV was efficacious in the prevention of COVID-19 of any severity and had an acceptable safety profile. Taking into account the changing environment, including the emergence of SARS-CoV-2 variants, and timelines for further development, the decision has been made to cease activities on the CVnCoV candidate and to focus efforts on the development of next-generation vaccine candidates. Funding: German Federal Ministry of Education and Research and CureVac