Breast cancer polygenic risk scores derived in White European populations are not calibrated for women of Ashkenazi Jewish descent.

PURPOSE: Polygenic risk scores (PRSs) are a major component of accurate breast cancer (BC) risk prediction but require ethnicity-specific calibration. Ashkenazi Jewish (AJ) population is assumed to be of White European (WE) origin in some commercially available PRSs despite differing effect allele frequencies (EAFs). We conducted a case-control study of WE and AJ women from the Predicting Risk of Cancer at Screening Study. The Breast Cancer in Northern Israel Study provided a separate AJ population-based case-control validation series. METHODS: All women underwent Illumina OncoArray single-nucleotide variation (SNV; formerly single-nucleotide polymorphism [SNP]) analysis. Two PRSs were assessed, SNV142 and SNV78. A total of 221 of 2243 WE women (discovery: cases = 111; controls = 110; validation: cases = 651; controls = 1772) and 221 AJ women (cases = 121; controls = 110) were included from the UK study; the Israeli series consisted of 2045 AJ women (cases = 1331; controls = 714). EAFs were obtained from the Genome Aggregation Database. RESULTS: In the UK study, the mean SNV142 PRS demonstrated good calibration and discrimination in WE population, with mean PRS of 1.33 (95% CI 1.18-1.48) in cases and 1.01 (95% CI 0.89-1.13) in controls. In AJ women from Manchester, the mean PRS of 1.54 (1.38-1.70) in cases and 1.20 (1.08-1.32) in controls demonstrated good discrimination but overestimation of BC relative risk. After adjusting for EAFs for the AJ population, mean risk was corrected (mean SNV142 PRS cases = 1.30 [95% CI 1.16-1.44] and controls = 1.02 [95% CI 0.92-1.12]). This was recapitulated in the larger Israeli data set with good discrimination (area under the curve = 0.632 [95% CI 0.607-0.657] for SNV142). CONCLUSION: AJ women should not be given BC relative risk predictions based on PRSs calibrated to EAFs from the WE population. PRSs need to be recalibrated using AJ-derived EAFs. A simple recalibration using the mean PRS adjustment ratio likely performs well.

The importance of ethnicity: Are breast cancer polygenic risk scores ready for women who are not of White European origin?

Polygenic risk scores (PRS) for disease risk stratification show great promise for application in general populations, but most are based on data from individuals of White European origin. We assessed two well validated PRS (SNP18, SNP143) in the Predicting-Risk-of-Cancer-At-Screening (PROCAS) study in North-West England for breast cancer prediction based on ethnicity. Overall, 9475 women without breast cancer at study entry, including 645 who subsequently developed invasive breast cancer or ductal carcinoma in situ provided DNA. All were genotyped for SNP18 and a subset of 1868 controls were genotyped for SNP143. For White Europeans both PRS discriminated well between individuals with and without cancer. For n = 395 Black (n = 112), Asian (n = 119), mixed (n = 44) or Jewish (n = 120) women without cancer both PRS overestimated breast cancer risk, being most marked for women of Black and Jewish origin (P < .001). SNP143 resulted in a potential mean 40% breast cancer risk overestimation in the combined group of non-White/non-European origin. SNP-PRS that has been normalized based on White European ethnicity for breast cancer should not be used to predict risk in women of other ethnicities. There is an urgent need to develop PRS specific for other ethnicities, in order to widen access of this technology.

The effect of surgical consult in the treatment of abdominal pain in older adults in the ED.

OBJECTIVE: The objective was to determine whether need for surgical consult contributes to delayed or reduced analgesic administration in older adults presenting to the emergency department with abdominal pain. METHODS: Secondary data analyses from a prospective cohort study consisting of adults ≥65 years in age presenting to the emergency department with a chief concern of abdominal pain from November 1, 2012, through October 31, 2014, were performed. Measurements included administration of analgesics, time to administration, type given, and pain score reduction. Covariates for adjusted analyses included age, sex, race/ethnicity, and Emergency Severity Index. RESULTS: A total of 3522 patients were included, of which 281 (8.7%) received any consult. Consult patients were less likely to receive any analgesic medication (53.0%) compared with nonconsult patients (62.5%) (relative risk = 0.80; 95% confidence interval, 0.70-0.91). However, among those patients receiving analgesic medications, there were no differences in likelihood of receiving an opioid, time to administration, or pain score reduction. When analyzing patients who received a surgical consult (n = 154, 4.4%), these associations were notably stronger. Surgical consult patients had a lower rate of analgesic administration (46.8%) compared with nonconsult patients (62.4%) (relative risk = 0.75; 95% confidence interval, 0.63- 0.89). Again, no differences were found in likelihood of receiving any opioid, time to administration, or pain score reduction. CONCLUSION: Need for abdominal surgical consult is associated with decreased administration of analgesics in older patients, possibly indicating a continued need to improve management in this setting. This difference, however, did not impact pain score reductions.

The spatial relationship between neurons and astrocytes in HIV-associated dementia.

Specific neuronal spatial distributional patterns have previously been correlated with increasing severity of HIV-associated dementia (HAD). As astrocytes are also a putative site of neurotoxicity, we investigated the spatial relationships of astrocytes with pyramidal and interneurons in the superior frontal gyrus from 29 patients who died from acquired immunodeficiency syndrome. Frontal cortical brain tissue was taken from diseased HIV patients who had been assessed for the presence and severity of HAD using the Memorial Sloan-Kettering Scale. No correlation was found between neuronal density and severity of dementia. However, the pattern of astrocytes became more clustered as dementia progressed. Bivariate spatial pattern analysis of neuronal populations with astrocytes revealed that, with increasing dementia severity, astrocytes and large pyramidal neurons increasingly "repelled" each other, while astrocytes and interneurons evidenced increasing "attraction." This implies that astrocytes may be more likely to be situated in the vicinity of surviving interneurons but less likely to be situated near surviving large pyramidal neurons in the setting of progressing HAD.

Atrial fibrillation detected after acute ischemic stroke: evidence supporting the neurogenic hypothesis.

BACKGROUND: It is unknown whether atrial fibrillation (AF) detected after acute ischemic stroke is caused by neurogenic or cardiogenic mechanisms. Based on the potential damage to the autonomic nervous system, neurogenic mechanisms could be implicated in the pathophysiology of newly diagnosed AF. To test this hypothesis, we developed a mechanistic approach by comparing a prespecified set of indicators in acute ischemic stroke patients with newly diagnosed AF, known AF, and sinus rhythm. METHODS: We prospectively assessed every acute ischemic stroke patient undergoing continuous electrocardiographic monitoring from 2008 through 2011. We compared newly diagnosed AF, known AF, and sinus rhythm patients by using 20 indicators grouped in 4 domains: vascular risk factors, underlying cardiac disease, burden of neurological injury, and in-hospital outcome. RESULTS: We studied 275 acute ischemic stroke patients, 23 with newly diagnosed AF, 64 with known AF, and 188 with sinus rhythm. Patients with newly diagnosed AF had a lower proportion of left atrial enlargement (60.9% versus 91.2%, P=.001), a smaller left atrial area (22.0 versus 26.0 cm2, P=.021), and a higher frequency of insular involvement (30.4% versus 9.5%, P=.017) than participants with known AF. Compared with patients in sinus rhythm, those with newly diagnosed AF had a higher proportion of brain infarcts of 15 mm or more (60.9% versus 37.2%, P=.029) and a higher frequency of insular involvement (30.4% versus 7.3%, P<.001). CONCLUSIONS: The low frequency of underlying cardiac disease and the strikingly high proportion of concurrent strategic insular infarctions in patients with newly diagnosed AF provide additional evidence supporting the role of neurogenic mechanisms in a subset of AF detected after acute ischemic stroke.

Polygenic risk scores and breast cancer risk prediction.

Polygenic Risk Scores (PRS) are a major component of accurate breast cancer risk prediction and have the potential to improve screening and prevention strategies. PRS combine the risk from Single nucleotide polymorphisms (SNPs) associated with breast cancer in Genome Wide Association Studies (GWAS) and explain over 30% of breast cancer heritability. When incorporated into risk models, the more personalised risk assessment derived from PRS, help identify women at higher risk of breast cancer development and enables the implementation of stratified screening and prevention approaches. This review describes the role of PRS in breast cancer risk prediction including the development of PRS and their clinical application. We have also examined the role of PRS within more well-established risk prediction models which incorporate known classic risk factors and discuss the interaction of PRS with these factors and their capacity to predict breast cancer subtypes. Before PRS can be implemented on a population-wide scale, there are several challenges that must be addressed. Perhaps the most pressing of these is the use of PRS in women of non-White European origin, where PRS have been shown to have attenuated risk prediction both in discrimination and calibration. We discuss progress in developing and applying PRS in non-white European populations. PRS represent a significant advance in breast cancer risk prediction and their further development will undoubtedly enhance personalisation.

Host response and dysfunction in the CNS during chronic simian immunodeficiency virus infection.

CNS abnormalities can be detected during chronic human immunodeficiency virus (HIV) infection, before the development of opportunistic infections or other sequelae of immunodeficiency. However, although end-stage dementia caused by HIV has been linked to the presence of infected and activated macrophages and microglia in the brain, the nature of the changes resulting in the motor and cognitive disorders in the chronic stage is unknown. Using simian immunodeficiency virus-infected rhesus monkeys, we sought the molecular basis for CNS dysfunction. In the chronic stable stage, nearly 2 years after infection, all animals had verified CNS functional abnormalities. Both virus and infiltrating lymphocytes (CD8+ T-cells) were found in the brain. Molecular analysis revealed that the expression of several immune response genes was increased, including CCL5, which has pleiotropic effects on neurons as well as immune cells. CCL5 was significantly upregulated throughout the course of infection, and in the chronic phase was present in the infiltrating lymphocytes. We have identified an altered state of the CNS at an important stage of the viral-host interaction, likely arising to protect against the virus but in the long term leading to damaging processes.

Methamphetamine stimulates interferon inducible genes in HIV infected brain.

OBJECTIVE: To study the synergism of HIV and methamphetamine. DESIGN AND METHODS: We undertook a microarray study using RNA from the frontal cortex of 15 individuals with HIV infection to initially identify genes that are differentially regulated by HIV encephalitis (HIVE). From the analysis of the microarray data, we identified candidate genes to be validated by quantitative real time PCR (qRT-PCR) and to assess if these genes were differentially modulated in individuals with HIVE and documented methamphetamine use. RESULTS: Analysis of microarray data revealed that genes involved in several categories were dysregulated in HIVE. We then chose 15 candidate genes for validation by qRT-PCR and analyzed the tissue concentration of these genes across three groups: those with HIV infection and no brain pathology, those with HIVE, and those with both HIVE and a history of methamphetamine use. We noted that there was upregulation of interferon inducible genes in the HIVE with methamphetamine using group, which together as a gene group was highly statistically significant (p=0.0064). CONCLUSION: These findings indicate that dysregulation of interferon inducible genes may underlie the pathogenic mechanism resulting in greater neurodegenerative and neurocognitive burden that occurs in methamphetamine using HIV infected individuals.

CD163 identifies a unique population of ramified microglia in HIV encephalitis (HIVE).

The idea that CNS ramified microglia are quiescent has been challenged by studies that show that microglia without the classic signs of activation can be phagocytic and appear with shorter, thicker ramifications. These semi-activated cells may constitute a form of microglia that has not been previously recognized in neuropathological conditions and may contribute to the pathology and dysfunction in these disorders. This study investigated the expression of CD 163, a cell surface marker whose normal expression is restricted to monocytes/macrophages, in cases of HIV or SIV encephalitis (HIVE/SIVE), Alzheimer disease, and variant Creutzfeldt-Jakob disease. In HIVE/SIVE, in addition to reacting with CNS macrophages, CD163 antibody staining was shown to highlight ramified microglia. Such reactivity was especially notable in grey matter ramified microglia and was greater than that of another typically used marker, HLA-DR. CD163 expression was only observed in infected/affected tissue, in contrast to that shown with another microglia marker, GLUT5, which has recently been shown to identify all microglia regardless of disease state. Although activated microglia were present in the other disorders, as evidenced by strong HLA-DR expression, there was very little CD163 immunoreactivity. The activation state identified by CD163 has not been previously recognized and may have a positive or negative impact on neuronal damage shown in HIV-associated dementia.

Patterns of gene dysregulation in the frontal cortex of patients with HIV encephalitis.

The neurodegenerative process in HIV encephalitis (HIVE) is associated with extensive damage to the dendritic and synaptic structure that often leads to cognitive impairment. Several mechanisms might be at play, including release of neurotoxins, oxidative stress and decreased activity of neurotrophic factors. Furthermore, HIV-mediated dysregulation of genes involved in neuronal maintenance might play an important role. For this purpose, cRNA was prepared from the brains of 17 AIDS patients for analysis with the Affymetrix Human U95Av2 GeneChip and analyzed with the GeneSpring Expression Analysis Software. Out of 12,625 genes analyzed, 74 were downregulated and 59 were upregulated compared to controls. Initial alternative analysis of RNA was performed by ribonuclease protection assay (RPA). In cases with HIVE, downregulated genes included neuronal molecules involved in synaptic plasticity and transmission (ion channels, synaptogyrin, synapsin II), cell cycle (p35, p39, CDC-L2, CDC42, PAK1) and signaling molecules (PI3K, Ras-Raf-MEK1), transcription factors and cytoskeletal components (MAP-1B, MAP-2, tubulin, adducin-2). Upregulated genes included those involved in neuroimmune (IgG, MHC, beta2microglobulin) and anti-viral responses (interferon-inducible molecules), transcription (STAT1, OLIG2, Pax-6) and signaling modulation (MEK3, EphB1) of the cytoskeleton (myosin, aduccin-3, radixin, dystrobrevin). Taken together, this study suggests that HIV proteins released from infected macrophages might not only induce a neuroinflammatory response, but also may promote neurodegeneration by interfering with neuronal transcription of genes involved in regulating signaling and cytoskeletal molecules important in maintaining synapto-dendritic functioning and integrity.

Acute SIV infection of the brain leads to upregulation of IL6 and interferon-regulated genes: expression patterns throughout disease progression and impact on neuroAIDS.

The virus/host interactions during the acute phase of human immunodeficiency virus (HIV) infection help determine the course of disease. During this time period, virus enters the brain. Here, we report clusters of genes whose transcripts are significantly upregulated in the frontal lobe of the brain during acute simian immunodeficiency virus (SIV) infection of rhesus monkeys. Many of these genes are involved in interferon (IFN) and/or interleukin (IL)-6 pathways. Although neither IFNalpha nor IFNgamma are elevated in the brain, IL6 is increased. Both IFNalpha and IL6 are elevated in plasma during this acute phase. The upregulation of STAT1, verified by immunohistochemical staining, can be due to both central nervous system (CNS) (SIV and IL6) and peripheral (IFNalpha and IL6) causes, and can itself drive the expression of many of these genes. Examination of the levels of expression of the upregulated genes in the post-acute and long-term phases of infection, as well as in SIV encephalitis, reveals increased expression throughout SIV infection, which may serve to protect the brain, but can have untoward long-term consequences.

Newly diagnosed atrial fibrillation linked to wake-up stroke and TIA: hypothetical implications.

BACKGROUND: Based on the higher frequency of paroxysmal atrial fibrillation during night and early morning hours, we sought to analyze the association between newly diagnosed atrial fibrillation and wake-up ischemic cerebrovascular events. METHODS: We prospectively assessed every acute ischemic stroke and TIA patient admitted to our hospital between 2008 and 2011. We used a forward step-by-step multiple logistic regression analysis to assess the relationship between newly diagnosed atrial fibrillation and wake-up ischemic stroke or TIA, after adjusting for significant covariates. RESULTS: The study population comprised 356 patients, 274 (77.0%) with a diagnosis of acute ischemic stroke and 82 (23.0%) with TIA. A total of 41 (11.5%) of these events occurred during night sleep. A newly diagnosed atrial fibrillation was detected in 27 patients of 272 without known atrial fibrillation (9.9%). We found an independent association between newly diagnosed atrial fibrillation and wake-up ischemic stroke and TIA (odds ratio 3.6, 95% confidence interval 1.2-7.7, p = 0.019). CONCLUSIONS: The odds of detecting a newly diagnosed atrial fibrillation were 3-fold higher among wake-up cerebrovascular events than among non-wake-up events. The significance of this independent association between newly diagnosed atrial fibrillation and wake-up ischemic stroke and TIA and the role of other comorbidities should be investigated in future studies.

Induction of pathogenic sets of genes in macrophages and neurons in NeuroAIDS.

The etiology of the central nervous system (CNS) alterations after human immunodeficiency virus (HIV) infection, such as dementia and encephalitis, remains unknown. We have used microarray analysis in a monkey model of neuroAIDS to identify 98 genes, many previously unrecognized in lentiviral CNS pathogenesis, whose expression is significantly up-regulated in the frontal lobe of simian immunodeficiency virus-infected brains. Further, through immunohistochemical illumination, distinct classes of genes were found whose protein products localized to infiltrating macrophages, endothelial cells and resident glia, such as CD163, Glut5, and ISG15. In addition we found proteins induced in cortical neurons (ie, cyclin D3, tissue transglutaminase, alpha1-antichymotrypsin, and STAT1), which have not previously been described as participating in simian immunodeficiency virus or HIV-related CNS pathology. This molecular phenotyping in the infected brains revealed pathways promoting entry of macrophages into the brain and their subsequent detrimental effects on neurons. These data support the hypothesis that in HIV-induced CNS disease products of activated macrophages and astrocytes lead to CNS dysfunction by directly damaging neurons, as well as by induction of altered gene and protein expression profiles in neurons themselves which are deleterious to their function.