The Stroke Data Bank: Design, Methods, and Baseline Characteristics

The National Institute of Neurological and Communicative Disorders and Stroke Initiated the Stroke Data Bank, which is a Multicenter Project to Prospectively Collect Data on the Clinical Course and Sequelae of Stroke. Additional Objectives Were to Provide Information that Would Enable a Standard Diagnostic Clinical Evaluation, to Identify Prognostic Factors, and to Provide Planning Data for Future Studies. a Brief Description of the Structure and Methods Precede the Baseline Characterization of 1,805 Patients Enrolled in the Stroke Data Bank between July 1983 and June 1986. Two Thirds of These Patients Were Admitted within 24 Hours after Stroke Onset. Medical History, Neurologic History, and Hospitalization Summaries Are Presented Separately for the Following Stroke Subtypes: Infarction, Unknown Cause; Embolism from Cardiac Source; Infarction Due to Atherosclerosis; Lacune; Parenchy-Matous or Intracerebral Hemorrhage; Subarachnoid Hemorrhage; and Other. the Utility and Limitations of These Data Are Discussed. © 1988 American Heart Association, Inc

Dementia in Stroke Survivors in the Stroke Data Bank Cohort: Prevalence, Incidence, Risk Factors, and Computed Tomographic Findings

We Determined the Prevalence of Dementia in 927 Patients with Acute Ischemic Stroke Aged ≥60 Years in the Stroke Data Bank Cohort based on the Examining Neurologist\u27s Best Judgment Diagnostic Agreement among Examiners Was 68% (K=0.34). of 726 Testable Patients, 116 (16%) Were Demented. Prevalence of Dementia Was Related to Age But Not to Sex, Race, Handedness, Educational Level, or Employment Status Before the Stroke. Previous Stroke and Previous Myocardial Infarction Were Related to Prevalence of Dementia Although Hypertension, Diabetes Mellitus, Atrial Fibrillation, and Previous Use of Antithrombotic Drugs Were Not Prevalence of Dementia Was Most Frequent in Patients with Infarcts Due to Large-Artery Atherosclerosis and in Those with Infarcts of Unknown Cause. Computed Tomographic Findings Related to Prevalence of Dementia Included Infarct Number, Infarct Site, and Cortical Atrophy. among 610 Patients Who Were Not Demented at Stroke Onset, We Used Methods of Survival Analysis to Determine the Incidence of Dementia Occurring during the 2-Year Follow-Up. Incidence of Dementia Was Related to Age But Not Sex. based on Logistic Regression Analysis, the Probability of New-Onset Dementia at 1 Year Was 5.4% for a Patient Aged 60 Years and 10.4% for a Patient Aged 90 Years. with a Multivariate Proportional Hazards Model, the Most Important Predictors of Incidence of Dementia Were a Previous Stroke and the Presence of Cortical Atrophy at Stroke Onset. © 1990 American Heart Association, Inc

Thalamic Stroke: Presentation and Prognosis of Infarcts and Hemorrhages

Thalamic Strokes in 62 Patients Selected from the Stroke Data Bank Were Studied to Determine Differences among 18 Infarctions (INF), 23 Localized Hemorrhages (ICH), and 21 Hematomas with Ventricular Extension (IVH). Stupor or Coma at Onset Occurred More Frequently in the IVH (62%) Than in the INF (6%) or ICH (13%) Groups and Was Reflected in Significantly Lower Median Glasgow Coma Scores in the IVH Group (7) Than in the INF (15) and ICH (14) Groups. Although Ocular Movements Were More Frequently Abnormal in the IVH Group Compared with the ICH and INF Groups, No Significant Differences Were Found in the Frequency of Motor or Sensory Deficits. among the 62 Strokes, 32 Had Restricted Lesions of the Posterolateral (N=9), Anterior (N=3), Paramedian (N=7), and Dorsal (N=13) Portions of the Thalamus. Differences in Consciousness and in Motor, Sensory, and Oculomotor Deficits Were Found among the Topographic Subgroups. Stroke-Related Deaths Occurred in 52% of IVH Cases, 13% of ICH Cases, and No Cases of INF. Median Lesion Volume as Detected with Computed Tomography Was Greater in Hemorrhages (INF, 2 Cm3; ICH, 10 Cm3; IVH, 16 Cm3), with Mortality Related to Increasing Hematoma Size. Coma, Glasgow Coma Score Lower Than 9, Weakness Score Greater Than 15 of a Possible 30, Abnormal Ocular Movements, and Fixed Pupils Were Also Associated with Stroke-Related Mortality. We Conclude that the Initial Neurologic Syndrome Does Not Discriminate Infarcts from Intrathalamic Hemorrhages. Ventricular Extension, However, Causes Significantly More Severe Deficits and Higher Mortality. © 1992 Arch Neurol All Rights Reserved

Morning Increase in Onset of Ischemic Stroke

The Time of Onset of Ischemic Stroke Was Determined for 1,167 of 1,273 Patients during the Collection of Data by Four Academic Hospital Centers between June 30, 1983, and June 30, 1986. More Strokes Occurred in Awake Patients from 10:00 Am to Noon Than during Any Other 2-Hour Interval. the Incidence of Stroke Onset Declined Steadily during the Remainder of the Day and Early Evening. the Onset of Stroke is Least Likely to Occur in the Late Evening, Before Midnight. © 1989 American Heart Association, Inc

Rapid progression of prostate cancer in men with a BRCA2 mutation.

Men with BRCA2 mutations have been found to be at increased risk of developing prostate cancer. There is a recent report that BRCA2 carriers with prostate cancer have poorer survival than noncarrier prostate cancer patients. In this study, we compared survival of men with a BRCA2 mutation and prostate cancer with that of men with a BRCA1 mutation and prostate cancer. We obtained the age at diagnosis, age at death or current age from 182 men with prostate cancer from families with a BRCA2 mutation and from 119 men with prostate cancer from families with a BRCA1 mutation. The median survival from diagnosis was 4.0 years for men with a BRCA2 mutation vs 8.0 years for men with a BRCA1 mutation, and the difference was highly significant (P<0.01). It may be important to develop targeted chemotherapies to treat prostate cancer in men with a BRCA2 mutation

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Antibody correlates of protection from SARS-CoV-2 reinfection prior to vaccination : a nested case-control within the SIREN study

Funding: This study was supported by the U.K. Health Security Agency, the U.K. Department of Health and Social Care (with contributions from the governments in Northern Ireland, Wales, and Scotland), the National Institute for Health Research, and grant from the UK Medical Research Council (grant number MR/W02067X/1). This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (CC2087, CC1283), the UK Medical Research Council (CC2087, CC1283), and the Wellcome Trust (CC2087, CC1283).Objectives To investigate serological differences between SARS-CoV-2 reinfection cases and contemporary controls, to identify antibody correlates of protection against reinfection. Methods We performed a case-control study, comparing reinfection cases with singly infected individuals pre-vaccination, matched by gender, age, region and timing of first infection. Serum samples were tested for anti-SARS-CoV-2 spike (anti-S), anti-SARS-CoV-2 nucleocapsid (anti-N), live virus microneutralisation (LV-N) and pseudovirus microneutralisation (PV-N). Results were analysed using fixed effect linear regression and fitted into conditional logistic regression models. Results We identified 23 cases and 92 controls. First infections occurred before November 2020; reinfections occurred before February 2021, pre-vaccination. Anti-S levels, LV-N and PV-N titres were significantly lower among cases; no difference was found for anti-N levels. Increasing anti-S levels were associated with reduced risk of reinfection (OR 0·63, CI 0·47-0·85), but no association for anti-N levels (OR 0·88, CI 0·73-1·05). Titres >40 were correlated with protection against reinfection for LV-N Wuhan (OR 0·02, CI 0·001–0·31) and LV-N Alpha (OR 0·07, CI 0·009–0·62). For PV-N, titres >100 were associated with protection against Wuhan (OR 0·14, CI 0·03–0·64) and Alpha (0·06, CI 0·008–0·40). Conclusions Before vaccination, protection against SARS-CoV-2 reinfection was directly correlated with anti-S levels, PV-N and LV-N titres, but not with anti-N levels. Detectable LV-N titres were sufficient for protection, whilst PV-N titres >100 were required for a protective effect. Trial registration number ISRCTN11041050Publisher PDFPeer reviewe

BRCA1 and BRCA2 pathogenic sequence variants in women of African origin or ancestry.

BRCA1 and BRCA2 (BRCA1/2) pathogenic sequence variants (PSVs) confer elevated risks of multiple cancers. However, most BRCA1/2 PSVs reports focus on European ancestry individuals. Knowledge of the PSV distribution in African descent individuals is poorly understood. We undertook a systematic review of the published literature and publicly available databases reporting BRCA1/2 PSVs also accessed the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database to identify African or African descent individuals. Using these data, we inferred which of the BRCA PSVs were likely to be of African continental origin. Of the 43,817 BRCA1/2 PSV carriers in the CIMBA database, 469 (1%) were of African descent. Additional African descent individuals were identified in public databases (n = 291) and the literature (n = 601). We identified 164 unique BRCA1 and 173 unique BRCA2 PSVs in individuals of African ancestry. Of these, 83 BRCA1 and 91 BRCA2 PSVs are of likely or possible African origin. We observed numerous differences in the distribution of PSV type and function in African origin versus non-African origin PSVs. Research in populations of African ancestry with BRCA1/2 PSVs is needed to provide the information needed for clinical management and decision-making in African descent individuals worldwide

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors