Validation of diffuse correlation spectroscopy measurements of rodent cerebral blood flow with simultaneous arterial spin labeling MRI; towards MRI-optical continuous cerebral metabolic monitoring.

Cerebral blood flow (CBF) during stepped hypercapnia was measured simultaneously in the rat brain using near-infrared diffuse correlation spectroscopy (DCS) and arterial spin labeling MRI (ASL). DCS and ASL CBF values agree very well, with high correlation (R=0.86, p< 10(-9)), even when physiological instability perturbed the vascular response. A partial volume effect was evident in the smaller magnitude of the optical CBF response compared to the MRI values (averaged over the cortical area), primarily due to the inclusion of white matter in the optically sampled volume. The 8.2 and 11.7 mm mid-separation channels of the multi-distance optical probe had the lowest partial volume impact, reflecting ~75 % of the MR signal change. Using a multiplicative correction factor, the ASL CBF could be predicted with no more than 10% relative error, affording an opportunity for real-time relative cerebral metabolism monitoring in conjunction with MR measurement of cerebral blood volume using super paramagnetic contrast agents.R01 EB006385 - NIBIB NIH HHS; R01 EB001954 - NIBIB NIH HHS; R01 NS057476 - NINDS NIH HHS; P41 RR014075 - NCRR NIH HHS; R01 HD042908-07 - NICHD NIH HHS; R01 EB002066 - NIBIB NIH HHS; R01 HD042908-06 - NICHD NIH HHS; R01 HD042908 - NICHD NIH HHSPublished versio

Cystatin C and preeclampsia: A case control study

Pregnancy increases plasma cystatin C, but levels are much higher in preeclampsia. Previous studies have not quantified preeclampsia risk with varying cystatin C concentrations or adjusted for confounders. We performed a case-control study of 100 preeclampsia cases and 100 random pregnancies uncomplicated by hypertension (controls). All women were free of pre-existing hypertension, diabetes, and renal disease, and gave birth to singletons. Plasma cystatin C was measured at delivery. Adjusted odds ratios (OR) and 95% confidence intervals (CI) of preeclampsia by quartiles (based on control distribution) of maternal plasma cystatin C were estimated using multivariable logistic regression models. Mean cystatin C levels were elevated in preeclampsia cases compared with controls (1.38 ± 0.04 vs. 1.22 ± 0.03 mg/L, p < 0.01). Compared to the first quartile, the estimated risk of preeclampsia was increased by approximately 12-fold for the fourth quartile, after adjusting for maternal age, body mass index, physical inactivity, smoking, and gestational age. Increased plasma levels of cystatin C were independently associated with preeclampsia. Further studies are required to assess the role of cystatin C levels in preeclampsia severity and maternal and fetal outcomes

Physiological System Identification with the Kalman Filter in Diffuse Optical Tomography

Abstract. Diffuse optical tomography (DOT) is a noninvasive imag-ing technology that is sensitive to local concentration changes in oxy-and deoxyhemoglobin. When applied to functional neuroimaging, DOT measures hemodynamics in the scalp and brain that reflect competing metabolic demands and cardiovascular dynamics. Separating the effects of systemic cardiovascular regulation from the local dynamics is vitally important in DOT analysis. In this paper, we use auxiliary physiological measurements such as blood pressure and heart rate within a Kalman filter framework to model physiological components in DOT. We validate the method on data from a human subject with simulated local hemody-namic responses added to the baseline physiology. The proposed method significantly improved estimates of the local hemodynamics in this test case. Cardiovascular dynamics also affect the blood oxygen dependent (BOLD) signal in functional magnetic resonance imaging (fMRI). This Kalman filter framework for DOT may be adapted for BOLD fMRI anal-ysis and multimodal studies.

Prospective associations of coronary heart disease loci in African Americans using the MetaboChip

Background: Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of publishe

Meta-analysis of exome array data identifies six novel genetic loci for lung function

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10-7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs (SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease

COVAD survey 2 long-term outcomes: unmet need and protocol

Vaccine hesitancy is considered a major barrier to achieving herd immunity against COVID-19. While multiple alternative and synergistic approaches including heterologous vaccination, booster doses, and antiviral drugs have been developed, equitable vaccine uptake remains the foremost strategy to manage pandemic. Although none of the currently approved vaccines are live-attenuated, several reports of disease flares, waning protection, and acute-onset syndromes have emerged as short-term adverse events after vaccination. Hence, scientific literature falls short when discussing potential long-term effects in vulnerable cohorts. The COVAD-2 survey follows on from the baseline COVAD-1 survey with the aim to collect patient-reported data on the long-term safety and tolerability of COVID-19 vaccines in immune modulation. The e-survey has been extensively pilot-tested and validated with translations into multiple languages. Anticipated results will help improve vaccination efforts and reduce the imminent risks of COVID-19 infection, especially in understudied vulnerable groups

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of l