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Objective: Multiple single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D) susceptibility have been identified in predominantly European-derived populations. These SNPs have not been extensively investigated for individual and cumulative effects on T2D risk in African Americans.Research Design and Methods: Seventeen index T2D risk variants were genotyped in 2,652 African American case subjects with T2D and 1,393 nondiabetic control subjects. Individual SNPs and cumulative risk allele loads were assessed for association with risk for T2D. Cumulative risk was assessed by counting risk alleles and evaluating the difference in cumulative risk scores between case subjects and control subjects. A second analysis weighted risk scores (ln [OR]) based on previously reported European-derived effect sizes.Results: Frequencies of risk alleles ranged from 8.6 to 99.9%. Eleven SNPs had ORs >1, and 5 from ADAMTS9, WFS1, CDKAL1, JAZF1, and TCF7L2 trended or had nominally significant evidence of T2D association (P < 0.05). Individuals carried between 13 and 29 risk alleles. Association was observed between T2D and increase in risk allele load (unweighted OR 1.04 [95% CI 1.01-1.08], P = 0.010; weighted 1.06 [1.03-1.10], P = 8.10 × 10(-5)). When TCF7L2 SNP rs7903146 was included as a covariate, the risk score was no longer associated with T2D in either model (unweighted 1.02 [0.98-1.05], P = 0.33; weighted 1.02 [0.98-1.06], P = 0.40).Conclusions: The trend of increase in risk for T2D with increasing risk allele load is similar to observations in European-derived populations; however, these analyses indicate that T2D genetic risk is primarily mediated through the effect of TCF7L2 in African Americans. [ABSTRACT FROM AUTHOR]

Abstract: BACKGROUND: Stroke is a medical emergency requiring timely intervention to optimize patient outcomes. The only treatments currently Food and Drug Administration approved for acute stroke are intravenous (IV) thrombolytics, which require obtaining specific medical history to be administered safely. This medical history may be overlooked in the prehospital setting or lost during patient handoff between emergency medical services (EMS) personnel and hospital staff, delaying treatment. We evaluated whether utilization of a "stroke alert sticker" by EMS to capture key information in the field would decrease door-to-needle (DTN) time. METHODS: Bright-orange "stroke alert stickers" were disseminated to our local EMS agency to be placed on all suspected stroke patients in the field prompting documentation of key elements needed for timely treatment decisions. The "stroke alert sticker" included time last known well, contact information, presenting symptoms, and relevant medications. We evaluated the impact of the "stroke alert sticker" on acute stroke metrics, including DTN time. RESULTS: The project included 220 consecutive stroke alert patients brought to our comprehensive stroke center by a single EMS agency from May 2021 through February 2022. Twenty-one patients were treated with an IV thrombolytic. Overall "stroke alert sticker" use compliance was 40%; for the subgroup of patients who were given an IV thrombolytic, the "stroke alert sticker" was used 60% of the time. In patients who received an IV thrombolytic, prehospital EMS notification was 100% with "stroke alert sticker" use, compared with 75% without (P = .13). In addition, with "stroke alert sticker" utilization, DTN time was reduced by 20 minutes (31 [11] minutes with sticker vs 51 [21] minutes without, P = .04). CONCLUSION: Utilization of the "stroke alert sticker" significantly improved DTN times compared with patients without the sticker. This evidence supports continued use of the "stroke alert sticker" to improve DTN times and patient outcomes., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 American Association of Neuroscience Nurses.)

Introduction: Postdischarge patient calls are an effective intervention to decrease unplanned readmissions. Despite its efficacy, calls are time consuming and compete with other clinical obligations. The purpose of this study was to evaluate the viability of intern-led quality improvement (QI) on conducting initial postdischarge calls to filter patients who require clinical or nurse follow-up., Methods: QI interns from an academic medical center's QI program completed postdischarge patient calls within 72 hours of patient discharge from a neurosurgery service between June 2018 and July 2019. QI interns filtered patients who required follow-up calls from a clinical service or nurse department. The departments called patients within 48 hours of requests. Unplanned readmission rate was compared between the cohort of patients who requested and received a follow-up call versus a cohort of patients who requested and did not receive a follow-up call (control)., Results: QI interns completed 83.8% postdischarge patient calls within 72 hours of discharge. Reasons for unsuccessful calls included patient unresponsiveness (74.6%), wrong phone number on file (13.9%), and request to be called at a different time (11.5%). Nurses completed 57.2% follow-up requests within the targeted 48 hours and completed remaining requests within 7 days. QI intern postdischarge follow-up calls, in conjunction with nurse follow-up intervention, showed a significant (risk ratio = -3.31, p = 0.012) preventive effect on unplanned readmission rate., Conclusions: QI interns are a viable alternative to nurses to conduct the first contact of postdischarge patient follow-up calls. This system of QI interns filtering calls to the correct clinical service or nurse department increased postdischarge patient follow-up calls success rate and decreased readmission rates., Competing Interests: Conflict of Interest: None., (© Innovative Healthcare Institute.)

Zinc is a critical component in a number of conserved processes that regulate female germ cell growth, fertility, and pregnancy. During follicle development, a sufficient intracellular concentration of zinc in the oocyte maintains meiotic arrest at prophase I until the germ cell is ready to undergo maturation. An adequate supply of zinc is necessary for the oocyte to form a fertilization-competent egg as dietary zinc deficiency or chelation of zinc disrupts maturation and reduces the oocyte quality. Following sperm fusion to the egg to initiate the acrosomal reaction, a quick release of zinc, known as the zinc spark, induces egg activation in addition to facilitating zona pellucida hardening and reducing sperm motility to prevent polyspermy. Symmetric division, proliferation, and differentiation of the preimplantation embryo rely on zinc availability, both during the oocyte development and post-fertilization. Further, the fetal contribution to the placenta, fetal limb growth, and neural tube development are hindered in females challenged with zinc deficiency during pregnancy. In this review, we discuss the role of zinc in germ cell development, fertilization, and pregnancy with a focus on recent studies in mammalian females. We further detail the fundamental zinc-mediated reproductive processes that have only been explored in non-mammalian species and speculate on the role of zinc in similar mechanisms of female mammals. The evidence collected over the last decade highlights the necessity of zinc for normal fertility and healthy pregnancy outcomes, which suggests zinc supplementation should be considered for reproductive age women at risk of zinc deficiency., (© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To investigate a progressive mobility program in a neurocritical care population with the hypothesis that the benefits and outcomes of the program (e.g., decreased length of stay) would have a significant positive economic impact., Design: Retrospective analysis of economic and clinical outcome data before, immediately following, and 2 years after implementation of the Progressive Upright Mobility Protocol Plus program (UF Health Shands Hospital, Gainesville, FL) involving a series of planned movements in a sequential manner with an additional six levels of rehabilitation in the neuro-ICU at UF Health Shands Hospital., Setting: Thirty-bed neuro-ICU in an academic medical center., Patients: Adult neurologic and neurosurgical patients: 1,118 patients in the pre period, 731 patients in the post period, and 796 patients in the sustained period., Interventions: Implementation of Progressive Upright Mobility Protocol Plus., Measurements and Main Results: ICU length of stay decreased from 6.5 to 5.8 days in the immediate post period and 5.9 days in the sustained period (F(2,2641) = 3.1; p = 0.045). Hospital length of stay was reduced from 11.3 ± 14.1 days to 8.6 ± 8.8 post days and 8.8 ± 9.3 days sustained (F(2,2641) = 13.0; p < 0.001). The impact of the study intervention on ICU length of stay (p = 0.031) and hospital length of stay (p < 0.001) remained after adjustment for age, sex, diagnoses, sedation, and ventilation. Hospital-acquired infections were reduced by 50%. Average total cost per patient after adjusting for inflation was significantly reduced by 16% (post period) and 11% (sustained period) when compared with preintervention (F(2,2641) = 3.1; p = 0.045). Overall, these differences translated to an approximately $12.0 million reduction in direct costs from February 2011 through the end of 2013., Conclusions: An ongoing progressive mobility program in the neurocritical care population has clinical and financial benefits associated with its implementation and should be considered.

Prior studies have identified common genetic variants influencing diabetic and non-diabetic nephropathy, diseases which disproportionately affect African Americans. Recently, exome sequencing techniques have facilitated identification of coding variants on a genome-wide basis in large samples. Exonic variants in known or suspected end-stage kidney disease (ESKD) or nephropathy genes can be tested for their ability to identify association either singly or in combination with known associated common variants. Coding variants in genes with prior evidence for association with ESKD or nephropathy were identified in the NHLBI-ESP GO database and genotyped in 5,045 African Americans (3,324 cases with type 2 diabetes associated nephropathy [T2D-ESKD] or non-T2D ESKD, and 1,721 controls) and 1,465 European Americans (568 T2D-ESKD cases and 897 controls). Logistic regression analyses were performed to assess association, with admixture and APOL1 risk status incorporated as covariates. Ten of 31 SNPs were associated in African Americans; four replicated in European Americans. In African Americans, SNPs in OR2L8, OR2AK2, C6orf167 (MMS22L), LIMK2, APOL3, APOL2, and APOL1 were nominally associated (P = 1.8 × 10(-4)-0.044). Haplotype analysis of common and coding variants increased evidence of association at the OR2L13 and APOL1 loci (P = 6.2 × 10(-5) and 4.6 × 10(-5), respectively). SNPs replicating in European Americans were in OR2AK2, LIMK2, and APOL2 (P = 0.0010-0.037). Meta-analyses highlighted four SNPs associated in T2D-ESKD and all-cause ESKD. Results from this study suggest a role for coding variants in the development of diabetic, non-diabetic, and/or all-cause ESKD in African Americans and/or European Americans.

The use of a murine nonsurgical embryo transfer (NSET) device had been described previously for the transfer of blastocysts, morulae, DNA-microinjected embryos, and embryonic stem cell-containing embryos to create genetically modified mice. However, physiologic effects of the NSET device and traditional surgical methods had not been compared directly. Here we used electrocardiography and fecal corticosterone levels to monitor pseudopregnant mice that underwent anesthesia only, the NSET procedure with or without anesthesia, or surgery. These procedures were performed without the use of actual embryos, to focus on effects of the procedures themselves rather than on any physiologic effects due to the deposition of embryos. As compared with surgery and anesthesia, the NSET procedure was associated with less fluctuation in cardiac rhythm and lower levels of the stress biomarker fecal corticosterone. These results indicate that use of the NSET device avoids these physi- ological perturbations as well as other disadvantages of surgery (for example, postoperative pain and need for postoperative analgesia) and therefore provides a valuable refinement of existing mouse embryo transfer procedures.

Recent genome-wide association studies (GWAS) have identified multiple novel loci associated with obesity in Europeans but results in other ethnicities are less convincing. Here, we report a two-stage GWAS of BMI in African Americans. The GWAS was performed using the Affymetrix 6.0 platform in 816 nondiabetic and 899 diabetic nephropathy subjects. 746,626 single-nucleotide polymorphisms (SNPs) were tested for association with BMI after adjustment for age, gender, disease status, and population structure. Sixty high scoring SNPs that showed nominal association in both GWAS cohorts were further replicated in 3,274 additional subjects in four replication cohorts and a meta-analysis was computed. Meta-analysis of 4,989 subjects revealed five SNPs (rs6794092, rs268972, rs2033195, rs815611, and rs6088887) at four loci showing consistent associations in both GWAS (P < 0.0001) and replication cohorts (P < 0.05) with combined P values range from 2.4 × 10(-6) to 5 × 10(-5). These loci are located near PP13439-TMEM212, CDH12, MFAP3-GALNT10, and FER1L4 and had effect sizes between 0.091 and 0.167 s.d. unit (or 0.67-1.24 kg/m(2)) of BMI for each copy of the effect allele. Our findings suggest the presence of novel loci potentially associated with adiposity in African Americans. Further replication and meta-analysis in African Americans and other populations will shed light on the role of these loci in different ethnic populations.

Objective: Recent genome-wide association studies (GWAS) have identified multiple novel loci associated with adiposity in European-derived study populations. Limited study of these loci has been reported in African Americans. Here we examined the effects of these previously identified adiposity loci in African Americans., Methods: A total of 46 representative single-nucleotide polymorphisms (SNPs) in 19 loci that were previously reported in GWAS in Europeans (including FTO and MC4R) were genotyped in 4992 subjects from six African-American cohorts. These SNPs were tested for association with body mass index (BMI) after adjustment for age, gender, disease status and population structure in each cohort. Meta-analysis was conducted to combine the results., Results: Meta-analysis of 4992 subjects revealed seven SNPs near four loci, including NEGR1, TMEM18, SH2B1 /ATP2A1 and MC4R, showing significant association at 0.005

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

A genome-wide association study was performed using the Affymetrix 6.0 chip to identify genes associated with diabetic nephropathy in African Americans. Association analysis was performed adjusting for admixture in 965 type 2 diabetic African American patients with end-stage renal disease (ESRD) and in 1029 African Americans without type 2 diabetes or kidney disease as controls. The top 724 single nucleotide polymorphisms (SNPs) with evidence of association to diabetic nephropathy were then genotyped in a replication sample of an additional 709 type 2 diabetes-ESRD patients and 690 controls. SNPs with evidence of association in both the original and replication studies were tested in additional African American cohorts consisting of 1246 patients with type 2 diabetes without kidney disease and 1216 with non-diabetic ESRD to differentiate candidate loci for type 2 diabetes-ESRD, type 2 diabetes, and/or all-cause ESRD. Twenty-five SNPs were significantly associated with type 2 diabetes-ESRD in the genome-wide association and initial replication. Although genome-wide significance with type 2 diabetes was not found for any of these 25 SNPs, several genes, including RPS12, LIMK2, and SFI1 are strong candidates for diabetic nephropathy. A combined analysis of all 2890 patients with ESRD showed significant association SNPs in LIMK2 and SFI1 suggesting that they also contribute to all-cause ESRD. Thus, our results suggest that multiple loci underlie susceptibility to kidney disease in African Americans with type 2 diabetes and some may also contribute to all-cause ESRD.

Objective: Variation in the transcription factor 7-like 2 (TCF7L2) locus is associated with type 2 diabetes across multiple ethnicities. The aim of this study was to elucidate which variant in TCF7L2 confers diabetes susceptibility in African Americans., Research Design and Methods: Through the evaluation of tagging single nucleotide polymorphisms (SNPs), type 2 diabetes susceptibility was limited to a 4.3-kb interval, which contains the YRI (African) linkage disequilibrium (LD) block containing rs7903146. To better define the relationship between type 2 diabetes risk and genetic variation we resequenced this 4.3-kb region in 96 African American DNAs. Thirty-three novel and 13 known SNPs were identified: 20 with minor allele frequencies (MAF) >0.05 and 12 with MAF >0.10. These polymorphisms and the previously identified DG10S478 microsatellite were evaluated in African American type 2 diabetic cases (n = 1,033) and controls (n = 1,106)., Results: Variants identified from direct sequencing and databases were genotyped or imputed. Fifteen SNPs showed association with type 2 diabetes (P < 0.05) with rs7903146 being the most significant (P = 6.32 × 10(-6)). Results of imputation, haplotype, and conditional analysis of SNPs were consistent with rs7903146 being the trait-defining SNP. Analysis of the DG10S478 microsatellite, which is outside the 4.3-kb LD block, revealed consistent association of risk allele 8 with type 2 diabetes (odds ratio [OR] = 1.33; P = 0.022) as reported in European populations; however, allele 16 (MAF = 0.016 cases and 0.032 controls) was strongly associated with reduced risk (OR = 0.39; P = 5.02 × 10(-5)) in contrast with previous studies., Conclusions: In African Americans, these observations suggest that rs7903146 is the trait-defining polymorphism associated with type 2 diabetes risk. Collectively, these results support ethnic differences in type 2 diabetes associations.

Age-related changes in circadian rhythms, including attenuation of photic phase shifts, are associated with changes in the central pacemaker in the suprachiasmatic nucleus (SCN). Aging decreases expression of mRNA for vasoactive intestinal peptide (VIP), a key neuropeptide for rhythm generation and photic phase shifts, and increases expression of serotonin transporters and 5-HT(1B) receptors, whose activation inhibits these phase shifts. Here we describe studies in hamsters showing that aging decreases SCN expression of mRNA for gastrin-releasing peptide, which also modulates photic phase resetting. Because serotonin innervation trophically supports SCN VIP mRNA expression, and serotonin transporters decrease extracellular serotonin, we predicted that chronic administration of the serotonin-selective reuptake inhibitor, fluoxetine, would attenuate the age-related changes in SCN VIP mRNA expression and 5-HT(1B) receptors. In situ hybridization studies showed that fluoxetine treatment does not alter SCN VIP mRNA expression, in either age group, at zeitgeber time (ZT)6 or 13 (ZT12 corresponds to lights off). However, receptor autoradiographic studies showed that fluoxetine prevents the age-related increase in SCN 5-HT(1B) receptors at ZT6, and decreases SCN 5-HT(1B) receptors in both ages at ZT13. Therefore, aging effects on SCN VIP mRNA and SCN 5-HT(1B) receptors are differentially regulated; the age-related increase in serotonin transporter sites mediates the latter but not the former. The studies also showed that aging and chronic fluoxetine treatment decrease total daily wheel running without altering the phase of the circadian wheel running rhythm, in contrast to previous reports of phase resetting by acute fluoxetine treatment.

Proliferative lesions of the mammary gland are risk markers and potential precursors for the development of breast cancer in postmenopausal women. In this study we evaluated mammary epithelial proliferation and proliferative lesions in a group of 63 aged postmenopausal macaques randomized by social group to receive one of three experimental diets for 8 months: (1) control; (2) control with 17beta-estradiol (E2) at the human equivalent dose of 1.0 mg per day; and (3) control with the soy phytoestrogen equol (EQ) at the human equivalent dose of 105 mg per day. In normal mammary epithelium, treatment with E2 but not EQ resulted in greater proliferation, epithelial area, and progesterone receptor expression (P<0.05 for all). Mammary lesions included columnar cell change (26/63), columnar cell hyperplasia with and without atypia (13/63), atypical ductal hyperplasia (6/63), and atypical lobular hyperplasia (3/63). Lesions were most common within terminal ductal lobular units. The prevalence of columnar cell hyperplasia (total and atypical cases) was higher in animals treated with E2 compared to control (P<0.05 for both). Compared to normal mammary epithelium, columnar cell lesions (CCLs) showed greater constitutive expression of estrogen receptor-alpha across all groups (P<0.001) and greater expression of progesterone receptor in response to E2 (P<0.01). Independent of treatment, animals with CCLs on histology had greater gene expression of estrogen receptor-alpha and markers of estrogen receptor activity (trefoil factor 1) and proliferation (gene for Ki67 antigen) at a site contralateral to the CCL (P<0.05 for all). These findings demonstrate that the terminal ductal lobular units of the postmenopausal mammary gland contain morphologically distinct cell populations that may hyperrespond to E2 exposure, resulting in specific types of hyperplastic lesions.

Ductal morphogenesis of the mammary gland occurs largely in the early pubertal period under the influence of ovarian sex hormones. In this study we characterized developing ductal structures in breast tissue of 14 female prepubertal or early pubertal rhesus monkeys (average age, 2.6 +/- 0.1 years). Serum estradiol concentrations ranged from < 5.0 to 61.2 pg/ml, while progesterone concentrations were low in all animals (< 0.6 ng/ml). No corpora lutea were seen on ovarian histology. The most immature mammary glands contained multilayered ducts frequently ending in distinctive terminal end bud structures. Transitional ducts had variably stratified columnar epithelium, often with prominent rounded myoepithelial cells and loose periductal stroma. Mature ducts had simple cuboidal luminal epithelium, flattened myoepithelium, and associated lobular development, typical of the premenopausal breast. Expression of estrogen receptor alpha was significantly higher in immature ducts compared to mature ducts, while progesterone receptor expression, epithelial proliferation, and cytokeratin expression did not show a relationship to the maturity of the ducts. These findings identify dynamic morphologic changes occurring in the primate breast during early puberty and suggest that estradiol (rather than progesterone) is the predominant hormonal stimulus for early ductal and lobular development.