Citations

Background: Adults with cardiovascular co-morbidities and risk factors are at greater risk of severe COVID-19. These same risk factors may also be associated with an attenuated antibody response to COVID-19 vaccines, although studies in diverse, U.S. population-based cohorts have been limited. Methods: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) conducted a serosurvey for SARS-CoV-2 antibodies via dried blood spot (DBS) in 14 U.S. cohorts. IgG antibodies to SARS-CoV-2 spike subunit 1 (S1) and nucleocapsid (N) were measured from DBS using a semi-quantitative microsphere immunoassay and reported as median fluorescence intensity (MFI). Multivariable adjusted linear models regressed log-transformed anti-S1 MFI on age, sex, race/ethnicity, education attainment, self-reported diabetes, hypertension, cardiovascular disease (CVD), chronic kidney disease, smoking history, body mass index (BMI), asthma, obstructive lung diseases, DBS batch, anti-N MFI, vaccine type, time between vaccine and DBS, and vaccine dose at time of DBS collection. Results are presented as the percent difference in anti-S1 MFI compared with a reference group. Results: There were 6614 vaccinated participants prior to booster regimens and DBS collection (April 2021-July 2022) with 50%, 48%, and 2% of the cohort who received BNT162b2, mRNA-1273, or other vaccines, respectively. The mean (SD) time between vaccination and DBS was 3.8 (1.8) months. Over 10% of the cohort had self-reported a history of diabetes, 55% had hypertension, and 74% had a BMI>25 kg/m 2 . Anti-S1 MFI decreased as the time between vaccine dose and DBS collection increased. Diabetes was associated with a 16.1% lower anti-S1 MFI (95%CI:-22.4,-9.5) whereas neither hypertension (-3.8%;95%CI:-9.3,2.1), nor cardiovascular disease history (-5.3%;95%CI:-16.3,7.4) were associated with anti-S1 MFI. Former and current smoking history were each associated with a lower anti-S1 MFI: (-6.6%;95%CI:-12.1,-0.8) and (-16.1%;95%CI:-24.7,-6.6), respectively. Participants with a BMI 25-29.9 kg/m 2 had a 7.6% higher anti-S1 MFI (95%CI:0.3,15.4) whereas those with a BMI of 30-35 kg/m 2 and >35 kg/m 2 had 6.2% (95%CI:-2.4,15.5) higher and 8.9% lower (95%CI:-17.6,0.7) MFI levels, respectively. Older age and male sex were each associated with a lower anti-S1 MFI and mRNA-1273 vaccine, Asian subgroup, higher anti-N titer, and prior COVID-19 infection were each associated with higher anti-S1 MFI. Chronic kidney disease, education attainment, and lung disease were not associated with anti-S1 MFI. Conclusions: Several traditional cardiovascular disease risk factors were associated with diminished humoral responses to the initial COVID-19 vaccine regimens in a diverse U.S. population-based cohort and may have implications on strategies to improve vaccine responses.

AbstractObjectiveTo analyze the association between preoperative electrodiagnostic (EDX) studies and postoperative pain and functional outcomes following ulnar nerve decompression and/or transposition for ulnar neuropathy at the elbow (UNE).Literature SurveyProtocol was submitted and database search was conducted by an experienced librarian of all available studies in the English language from 1990 to June 8, 2022. Databases included Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, and Scopus.MethodologyInclusion criteria consisted of randomized controlled trials, prospective and retrospective longitudinal studies, and studies involving adults ≥18 years of age who underwent ulnar nerve decompression and/or transposition for UNE. Study quality and risk of bias were assessed using the National Heart, Lung, and Blood Institute (NHLBI) Study Quality of Assessment Tool. Certainty in evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. A meta‐analysis was not performed.SynthesisA total of 289 studies were screened, and 8 retrospective cohort studies met inclusion criteria comprising 762 patients. A decreased or absent preoperative sensory nerve action potential amplitude (SNAP) showed significance with worse postoperative outcomes. The presence of preoperative conduction block showed significance in higher quality studies. There was limited evidence for slow preoperative motor conduction velocities or preoperative electromyography (EMG) abnormalities and postoperative outcomes. Overall quality assessment demonstrated that two studies had “good,” four “fair,” and two “poor” quality of evidence. Certainty in evidence was “low” due to risk of bias.ConclusionsA decreased or absent preoperative ulnar SNAP may predict worse postoperative outcomes. Per higher quality studies, preoperative conduction block at the elbow may also predict worse postoperative outcomes. Careful interpretation is required with a full understanding of the limited evidence, risk of bias, and low certainty in evidence to support the use of preoperative EDX to predict postoperative outcomes in UNE.

Abstract Increased numbers of antral follicles are associated with greater fertility and a uterine environment that is more supportive of early embryonic development in beef heifers. Glucose is a primary energy source for embryos and glucose concentrations are elevated in uterine luminal fluid (ULF) of pregnant heifers. We hypothesized that ULF glucose concentrations and endometrial transcript abundance for glucose transporters at d16 after insemination would be greater in heifers with increased numbers of antral follicles. Heifers classified with either increased (32 ± 1.1) or diminished (14.7 ± 1.1) antral follicle counts were selected and artificially inseminated following the Select Synch protocol (d0). At d16 after insemination, heifers were sent to the abattoir and reproductive tracts were collected to retrieve conceptuses to determine pregnancy. Uterine luminal fluid was collected, the endometrium was biopsied, total RNA was extracted and glucose transporter transcript abundance was determined. Data were analyzed using the MIXED procedure of SAS with antral follicle group, pregnancy status, and the interaction as fixed effects. Glucose concentrations in ULF were greater (P < 0.05) in heifers with increased antral follicle numbers compared to heifers with diminished numbers (122.65 ± 11.91 vs 84.12 ± 12.42 mg/dL). Glucose ULF concentrations were increased (P < 0.05) in pregnant vs. non-pregnant heifers (124.84 ± 12.81 vs 81.93 ± 11.50 mg/dL). Endometrial glucose transporter 1 (GLUT1) transcript abundance was increased in pregnant heifers (P < 0.01) but was not different due to antral follicle number or the interaction. Therefore, differences in glucose concentrations associated with antral follicle number may be due to differences in GLUT1 transcription before d16 or due to differences in protein abundance or functionality. Taken together, heifers with increased number of antral follicles may have increased energy availability in the uterus for trophoblast proliferation and function. USDA is an equal opportunity provider and employer.

Abstract Transcript abundance of two forms of GnRH and its receptor have been characterized in bovine ovaries. The objective was to investigate the relationship of GnRH-1, GnRH-2, GnRH-R, intrafollicular estradiol (E2) and progesterone (P4) during follicular development. Ovaries were collected from beef cows at specific stages of follicular development [pre-selection (PRE, n = 9), post-selection (POST, n = 9), and post-selection 24h after luteal regression (PG, n = 9)]. The largest follicle per stage was aspirated to obtain granulosa cells (GC) and follicular fluid (FF). Total cellular RNA was extracted from GC and RT-PCR was performed for GnRH-1, GnRH-2, GnRH-R and GAPDH. Radioimmunoassays were performed to determine FF concentrations of E2 and P4. Data were analyzed using the MIXED and REG procedures in SAS. There was no difference (P ≥ 0.23) in mRNA abundance of GnRH-2, GnRH-R or FF concentrations of P4 across follicular stages. There was an effect of stage on FF E2 (PRE: 17,925±20,273, POST: 28,458±21,503, and PG: 252,616±21,503 pg/mL; P < 0.01). Stage affected GnRH-1 mRNA abundance (PRE: 2.28±0.55, POST: 0.92±0.55, and PG: 0.11±0.55; P = 0.03). There was no relationship of GnRH-1 and GnRH-2 mRNA abundance or effect of FF P4 on GnRH-R mRNA abundance (P ≥ 0.23). There was no effect of FF P4 on GnRH-1 mRNA abundance (P = 0.68). There was no effect of FF E2 on GnRH-2 mRNA abundance (P = 0.66). As FF E2 increased GnRH-R mRNA abundance tended to increase (P = 0.10;r2=0.13). As FF P4 concentrations increased GnRH-2 mRNA abundance tended to decrease (P = 0.09;r2=0.12). As FF E2 increased GnRH-1 mRNA abundance decreased (P = 0.02;r2=0.20). In conclusion, there were differences in peptide and receptor mRNA abundance of GnRH in relation to FF E2 and P4 at specific stages of follicular development. This is supportive of a regulatory relationship between ovarian GnRH and steroidogenesis. This work is supported by AFRI Grant No.2018-67016-27578 from USDA. USDA is an equal opportunity provider and employer.

Abstract The relationship of ovarian reserve parameters to fertility in mammalian females continues to be debated. We demonstrated improved uterine function, creating an environment that is more supportive of early embryonic development in beef heifers with increased numbers of follicles. In the present study we hypothesized that timing of luteolysis differs between heifers with increased compared to heifers with diminished numbers of follicles. Angus heifers (n = 20/ group) were classified as low (14.7 ± 1.1) or high (32 ± 1.1) antral follicle number based on ovarian ultrasonography, and artificially inseminated (d0) following a Select Synch protocol. At d16 after insemination, heifers were slaughtered, and reproductive tracts collected. Tracts were flushed with 20 mL of physiological saline to determine pregnancy status by presence of a conceptus and endometrial samples from the horn ipsilateral to the CL were frozen for determination of transcript abundance. Real-time RT-PCR was performed to determine relative transcript abundance of oxytocin receptor (OXTR) and interferon-stimulated gene-15 (ISG15) with glyceraldehyde-3-phospate dehydrogenase as the endogenous reference gene. Transcript abundance was analyzed using the MIXED procedure of SAS with follicle group, pregnancy status and the interaction as fixed effects. Transcript abundance of ISG15 was greater in pregnant endometrium than non-pregnant endometrium (2.75 ± 0.25 vs 0.16 ± 0.22-fold; P < 0.0001) with no influence of follicle group or the interaction. The interaction of follicle group and pregnancy status influenced OXTR transcript abundance (P = 0.06). Luteolytic mechanisms were activated in non-pregnant heifers with diminished numbers of follicles (1.46 ± 0.25-fold) and were not activated in pregnant heifers (0.06 ± 0.22-fold) or heifers with increased numbers of follicles that were not pregnant (0.32 ± 0.30-fold). These data indicate a wider window of recognition of pregnancy in beef heifers with increased numbers of ovarian follicles. USDA is an equal opportunity provider and employer.

Background: Levels of the pro-inflammatory cytokines interleukin (IL)-6 and IL-8 and the anti-inflammatory cytokine IL-10 are altered in acute stroke patients compared to controls. However, results for IL-10 are inconsistent (higher in stroke patients compared to controls in some studies and decreased in others) and very few studies have examined associations of these biomarkers with risk of incident stroke. Methods: We examined associations of baseline levels of IL-6, IL-8 and IL-10 with stroke risk factors and risk of incident stroke in 1,572 white and black men and women from the REGARDS Study; an observational cohort of 30,239 adults followed for 5 years. Among those without prebaseline stroke, stroke cases (n=592, 53% men, 59% white, mean age 70 years) were compared to a cohort random sample (n=980, 44% men, 58% white, mean age 65 years). We used Cox proportional hazards models to examine associations of biomarkers with incident stroke. Hazard ratios (HR; 95% confidence intervals) for highest compared to lowest quartile for each biomarker are presented. Results: Baseline IL-6 was significantly higher in incident stroke cases compared to the cohort sample (p<0.001) while IL-8 and IL-10 levels did not vary significantly (p>0.05 for both). Adjusting for age, sex and race, IL-6 was higher in blacks compared to whites and higher in current smokers compared to never/former smokers (all p≤0.01). IL-6 was inversely associated with physical activity, alcohol use and education (all p≤0.01). IL-8 and IL-10 did not vary significantly with the risk factors examined. Adjusting for age, sex and race, the HR for risk of incident stroke in those in the highest compared to lowest quartile of IL-6 was 2.4 (1.6-3.4). HRs for IL-8 and IL-10 were 1.5 (1.0-2.1) and 1.4 (1.0-1.9), respectively. Adjusting for Framingham stroke risk factors and history of coronary heart disease, only IL-6 remained significantly associated with stroke risk (HR 2.0; 1.3-3.2). HRs for IL-8 and IL-10 were 1.1 (0.7-1.6) and 1.2 (0.8-1.8), respectively. IL-6 remained significantly associated with stroke risk when C-reactive protein was added to the model (HR 1.7; 1.1-2.7). Associations did not differ by race. Conclusions: In this population-based sample of US black and white adults, IL-6, but not IL-8 or IL-10, was associated with stroke risk factors and risk of incident stroke. Further study is needed on the clinical utility of IL-6 measurement in stroke risk assessment.

11011 Background: Beyond KRAS status, there are no validated markers for anti-EGFR therapy in mCRC. While expression of genes within the EGF signaling axis has been reported to correlate with benefit, most reports used data from non-randomized trials which cannot distinguish between general prognostic markers and markers that predict for benefit from C. CALGB 80203 was a 238-patient (pt), 4-arm, randomized phase II study of FOLFOX or FOLFIRI +/- C in mCRC pts. Formalin-fixed, paraffin-embedded (FFPE) tumor samples from CALGB 80203 were analyzed for gene expression of HER family ligands, receptors and regulators. Methods: FFPE tumor samples from consenting pts were analyzed for AREG, BTC, CD73, DUSP4, EGF, EGFR, EPGN, EREG, HB-EGF, HER2, HER3, HER4, PHLDA1 and TGFa by RT-qPCR. Interaction between baseline gene expression levels and treatment (C) with respect to progression-free survival (PFS) and overall survival (OS) was modeled using a multiplicative Cox proportional hazards model. Results: Baseline tumor tissue was available from 103 pts; 55% of tumors were KRAS wild type (WT). Two prognostic markers were identified; higher tumor mRNA levels of HER2 (HR=0.64, p=0.002) and EREG (HR=0.89, p=0.016) were associated with longer PFS across all pts. Potential predictive markers of benefit for C were identified. In KRAS WT tumors, lower HER3 expression was associated with longer OS from C treatment while higher HER3 expression was associated with shorter OS from C treatment (chemo + C: HR=1.15; chemo only: HR=0.48, interaction p=0.029). No association was observed for HER3 and outcome in KRAS mutant (MT) tumors. Interestingly, higher CD73 expression was associated with longer PFS in C-treated pts in both KRASWT (chemo + C: HR=0.91; chemo only: HR=1.57, interaction p=0.026) and MT tumors (chemo + C: HR=0.80; chemo only: HR=1.29, p=0.025). Conclusions: In one of the first reports using data from a randomized study, gene expression of HER3 and CD73 were identified as potential predictive markers for C. These data implicate not only HER axis signaling but also immune modulation as potential mechanisms of C action and sensitivity, and warrant confirmation in other large randomized trials.

Orthostatic hypotension (OH) is frequently observed with hypertension treatment, but its contribution to adverse outcomes is unknown. The SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized trial of adults, age ≥50 years at high risk for cardiovascular disease with a seated systolic blood pressure (BP) of 130 to 180 mm Hg and a standing systolic BP ≥110 mm Hg. Participants were randomized to a systolic BP treatment goal of either <120 or <140 mm Hg. OH was defined as a drop in systolic BP ≥20 or diastolic BP ≥10 mm Hg 1 minute after standing from a seated position. We used Cox models to examine the association of OH with cardiovascular disease or adverse study events by randomized BP goal. During the follow-up period (median 3years), there were 1170 (5.7%) instances of OH among those assigned a standard BP goal and 1057 (5.0%) among those assigned the intensive BP goal. OH was not associated with higher risk of cardiovascular disease events (primary outcome: hazard ratio 1.06 [95% CI, 0.78–1.44]). Moreover, OH was not associated with syncope, electrolyte abnormalities, injurious falls, or acute renal failure. OH was associated with hypotension-related hospitalizations or emergency department visits (hazard ratio, 1.77 [95% CI, 1.11–2.82]) and bradycardia (hazard ratio, 1.94 [95% CI, 1.19–3.15]), but these associations did not differ by BP treatment goal. OH was not associated with a higher risk of cardiovascular disease events, and BP treatment goal had no effect on OH’s association with hypotension and bradycardia. Symptomless OH during hypertension treatment should not be viewed as a reason to down-titrate therapy even in the setting of a lower BP goal. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01206062.

AbstractHigher and lower hemoglobin concentrations are associated with coronary heart disease (CHD), but whether this risk is consistent across age, sex, and race is unclear. The Reasons for Geographic And Racial Differences in Stroke (REGARDS) study is an observational cohort study of 30 239 black, and white, adults aged 45 and older recruited 2003‐7. Participants were included if they had hemoglobin measures, were CHD‐free at baseline, and had all baseline variables. The primary outcome was incident CHD. Multivariable Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for incident CHD by hemoglobin concentration. This was expressed as a continuous variable and divided into age‐, sex‐, and race‐specific quintiles. The 16 332 participants were included, contributing 114 362 person‐years of follow‐up and 915 incident CHD events. The mean age was 63 years, 35% were male, 41% were black, and the mean baseline hemoglobin was 13.6 g/dL (SD 1.4). A significant non‐linear association between hemoglobin and CHD was identified (P < .001). This association differed significantly by race (P = .025) but not by sex or age. In whites, the risk for incident CHD was higher in the lowest (HR 2.28, 95% CI 1.61, 3.33) and highest (HR 1.94, 95% CI 1.35, 2.79) hemoglobin quintiles relative to the third quintile. For blacks, only those in the lowest hemoglobin quintile had an increased risk for incident CHD events (HR 1.70, 95% CI 1.20, 2.41). Hemoglobin is an independent risk factor for CHD in whites and blacks but with different hemoglobin concentrations conferring different risks.