Untangling the placentome gene network of beef heifers in early gestation.

The cotyledon and caruncle tissues provide a functional bridge between the fetus and the dam. However, the relationship between these tissues and the transcriptomic profile that underlies the tissue functions remains elusive. Herein we investigate the expression profile of cotyledon and caruncle from nulliparous beef heifers carrying female fetuses at day 83 of pregnancy to identify changes occurring across tissues that contribute to placental function and their tissue-specific roles. We identified 2654 differentially expressed genes [padj ≤ 0.05, abs(log2FC) ≥ 1], including nutrient transporters and paternally imprinted genes. We found key regulators of tissue function and differentiation, including FOXO4, GATA2, GATA3, and HAND1, rewired between the tissues. Finally, we shed light on the over-represented pathways related to immune tolerance, tissue differentiation and remodeling. Our findings highlighted the intricate and coordinated cross-talk between fetal-maternal tissues. They provided evidence of a fine-tuned gene regulatory network underlying pregnancy and tissue-specific function in the bovine placenta.

Nutritional Regulation of Embryonic Survival, Growth, and Development.

Maternal nutritional status affects conceptus development and, therefore, embryonic survival, growth, and development. These effects are apparent very early in pregnancy, which is when most embryonic losses occur. Maternal nutritional status has been shown to affect conceptus growth and gene expression throughout the periconceptual period of pregnancy (the period immediately before and after conception). Thus, the periconceptual period may be an important "window" during which the structure and function of the fetus and the placenta are "programmed" by stressors such as maternal malnutrition, which can have long-term consequences for the health and well-being of the offspring, a concept often referred to as Developmental Origins of Health and Disease (DOHaD) or simply developmental programming. In this review, we focus on recent studies, using primarily animal models, to examine the effects of various maternal "stressors," but especially maternal malnutrition and Assisted Reproductive Techniques (ART, including in vitro fertilization, cloning, and embryo transfer), during the periconceptual period of pregnancy on conceptus survival, growth, and development. We also examine the underlying mechanisms that have been uncovered in these recent studies, such as effects on the development of both the placenta and fetal organs. We conclude with our view of future research directions in this critical area of investigation.

Sex-Specific Trends in Acute Myocardial Infarction Within an Integrated Healthcare Network, 2000 Through 2014.

BACKGROUND: In recent decades, the rates of incident acute myocardial infarction (AMI) have declined in the United States, yet disparities by sex remain. In an integrated healthcare delivery system, we examined temporal trends in incident AMI among women and men. METHODS: We identified hospitalized AMI among members ≥35 years of age in Kaiser Permanente Southern California. The first hospitalization for AMI overall, and for ST-segment-elevation MI and non-ST-segment-elevation MI was identified by International Classification of Diseases, Ninth Revision, Clinical Modification primary discharge diagnosis codes in each calendar year from 2000 through 2014. Age- and sex-standardized incidence rates per 100 000 person-years were calculated by using direct adjustment to the 2010 US Census population. Average annual percent changes (AAPCs) and period percent changes were calculated, and trend tests were conducted using Poisson regression. RESULTS: We identified 45 331 AMI hospitalizations between 2000 and 2014. Age- and sex-standardized incidence rates of AMI declined from 322.4 (95% CI, 311.0-333.9) in 2000 to 174.6 (95% CI, 168.2-181.0) in 2014, representing an AAPC of -4.4% (95% CI, -4.2 to -4.6) and a period percent change of -46.6%. The AAPC for AMI in women was -4.6% (95% CI, -4.1 to -5.2) between 2000 and 2009 and declined to -2.3% (95% CI, -1.2 to -3.4) between 2010 and 2014. The AAPC for AMI in men was stable over the study period (-4.7% [95% CI, -4.4 to -4.9]). The AAPC for ST-segment-elevation MI hospitalization overall was -8.3% (95% CI, -8.0% to -8.6%).The AAPC in ST-segment-elevation MI changed among women in 2009 (2000-2009: -10.2% [95% CI, -9.3 to -11.1] and in 2010-2014: -5.2% [95% CI, -3.1 to -7.3]) while remaining stable among men (-8.0% [95% CI, -7.6 to -8.4]). The AAPC for non-ST-segment-elevation MI hospitalization was smaller than for ST-segment-elevation MI among both women and men (-1.9% [95% CI, -1.5 to -2.3] and -2.8% [95% CI, -2.5 to -3.2], respectively). CONCLUSIONS: These results suggest that the incidence of hospitalized AMI declined between 2000 and 2014; however, declines in AMI have slowed among women in comparison with men in recent years. Determining unmet care needs among women may reduce these sex-based AMI disparities.

Statins as a free pass: Body mass index and other cardiovascular risk factors among lipid-lowering medication users and nonusers in the California Men's Health Study.

To lower risk from cardiovascular disease (CVD), national guidelines recommend lifestyle changes followed by use of lipid-lowering medications when appropriate. Previous studies have questioned whether individuals taking these medications are less likely to modify their dietary intake and physical activity, resulting in increased body mass index (BMI). We assessed BMI and CVD clinical risk factors over time between lipid-lowering medication users and nonusers in a diverse cohort of middle-aged and older men. The cohort consisted of 63,357 men who enrolled in the California Men's Health Study between 2002 and 2003 and were not taking lipid-lowering medications at baseline. Lipid-lowering medication use was determined over twelve years of follow-up. BMI and other CVD risk factors were assessed with longitudinal linear mixed effect models adjusting for possible confounders. Overall, lipid-lowering medication users had higher BMI than nonusers (p < .0001); however, there was a decrease over time for both groups (p < .0001). Total cholesterol, LDL-C, and triglycerides decreased for users and nonusers (p < .0001). While HDL-C was higher for nonusers (p < .05), over time this measure increased in both groups (p < .0001). We found no evidence of increases in BMI after initiation of lipid-lowering medication in this cohort. Instead, BMI decreased and several cholesterol-related CVD risk factors improved for lipid-lowering medication users and nonusers. This suggests that men placed on lipid-lowering medications do not view them as a panacea for their increased risk of cardiovascular disease. Instead, they appear to perceive them as one component of a multi-pronged strategy including lifestyle and nutrition as suggested by current guidelines.

Unmet Patient Need in Statin Intolerance: the Clinical Characteristics and Management.

PURPOSE: A substantial percentage of patients report intolerance or side effects of statin treatment leading to treatment changes or discontinuation. The purpose of this study was to examine statin therapy changes and subsequent effects on low-density lipoprotein cholesterol (LDL-C) among patients with statin intolerance (SI). METHODS: We identified 45,037 adults from Kaiser Permanente Southern California with SI documented between 2006 and 2012. Changes in statin therapy in the year before and after the SI index date were examined. We categorized patients into those who initiated statin therapy, discontinued, up-titrated, down-titrated, or did not switch therapy. We calculated the percentage change in LDL-C from the year before to the year after SI, and the percentage of patients attaining LDL-C < 100 and < 70 mg/dL. RESULTS: In the year prior to the SI date, 77.8% of patients filled a statin prescription. Following SI, 44.6% had no treatment change, 25.5% discontinued, and 30.0% altered their statin therapy. Of those who altered statin therapy, 52.6% down-titrated and 17.2% up-titrated their dose. Rhabdomyolysis was documented in < 1% of the cohort. The largest changes in LDL-C were experienced by patients who were on a high-intensity statin then discontinued treatment (35.6% increase) and those who initiated a high-intensity statin (25.5% decrease). The proportion of patients achieving LDL-C < 100 mg/dL and LDL-C < 70 mg/dL was the lowest among those who discontinued therapy. CONCLUSIONS: Although adjustments to the statin dosage may be appropriate upon documentation of SI, many of these patients will have high LDL-C. Strategies for LDL-C reduction in patients with SI may be necessary.

Trends in Statin Use 2009-2015 in a Large Integrated Health System: Pre- and Post-2013 ACC/AHA Guideline on Treatment of Blood Cholesterol.

PURPOSE: Implementation of the 2013 ACC/AHA cholesterol treatment guideline is likely to vary by statin benefit group. The aim of this study was to document trends in statin use before and after introduction of the ACC/AHA guideline. METHODS: We conducted a retrospective study with annual cohorts from 2009 to 2015 among members of Kaiser Permanente Southern California aged ≥ 21 years. Members were categorized into four mutually exclusive statin benefit groups: atherosclerotic cardiovascular disease (ASCVD), LDL-C ≥ 190 mg/dL in the last year, diabetes (aged 40-75 years), and 10-year ASCVD risk ≥ 7.5% (aged 40-75 years). RESULTS: The cohorts ranged from 1,993,755 members in 2009 to 2,440,429 in 2015. Approximately 5% of patients had ASCVD, 1% had LDL-C ≥ 190 mg/dL, 6% had diabetes, and 10% had a 10-year ASCVD risk ≥ 7.5% each year. Trends in statin use were stable for adults with ASCVD (2009 78%; 2015 80%), recent LDL-C ≥ 190 mg/dL (2009 45%; 2015 44%), and diabetes (2009 74%; 2015 73%), but increased for patients with 10-year ASCVD risk ≥ 7.5% (2009 36%; 2015 47%). High-intensity statin use also increased 142% and 54% among patients with LDL-C ≥ 190 mg/dL and those with ASCVD ≤ 75 years of age, respectively. Moderate-to-high intensity statin utilization increased over 50% among those with a 10-year ASCVD risk ≥ 7.5%. CONCLUSIONS: Statin use increased substantially among patients with 10-year ASCVD risk ≥ 7.5% and use of appropriate statin dosage increased in each of the four statin benefit groups between 2009 and 2015; however, there is room for improvement.

Leveraging the electronic medical record to implement an abdominal aortic aneurysm screening program.

OBJECTIVE: Screening for abdominal aortic aneurysms (AAAs) reduces aneurysm-related mortality and has been recommended by the U.S. Preventive Services Task Force and American Heart Association since 2005. Medicare has covered a one-time screening ultrasound for new male enrollees with a familial or smoking history since 2007. Nevertheless, in the U.S., screening has remained underutilized. Review of patients with ruptured AAA in our system in 2007 showed the majority were undiagnosed, yet met U.S. Preventive Services Task Force and American Heart Association screening guidelines. To reduce the number of preventable AAA ruptures and deaths in our patients, we implemented an AAA screening program using our electronic medical record (EMR). This study describes the design, implementation, and early results of that screening program. METHODS: Between March 2012 and June 2013, men aged 65 to 75 years with any history of smoking were targeted for screening. Medical records were reviewed electronically to exclude patients with abdominal imaging studies within 10 years that would have diagnosed an AAA. Best practice alerts (BPA) were created in the EMR so when an appropriate patient is seen, office staff and providers are prompted to order an aortic ultrasound. AAA was defined as aortic diameter ≥3.0 cm or greater, and ultrasound reports contained a standard template providing guidance for patient management when an aneurysm was identified. Newly identified AAAs were triaged for vascular surgery consultation or follow-up with their primary physician. The number of eligible patients, unscreened patients, and AAAs identified were tabulated by our Regional Outpatient Safety Net Program. RESULTS: In a population of 3.6 million, 55,610 patients initially met screening criteria, and 26,837 (48.26%) were excluded from the BPA because of prior abdominal imaging studies. After 15 months, there were 68,164 patients who met screening criteria, 54,356 (79.74%) of whom had undergone an abdominal imaging study. Thus, 27,519 patients underwent an imaging study after the BPA was activated. During the study period, 731 new AAAs were diagnosed, 165 over 4.0 cm in diameter. Screening rates have increased at all medical centers where the BPA was activated, and the percentage of unscreened patients has been reduced from 51.74% to 20.26% system-wide. CONCLUSIONS: In an integrated health care system using an EMR, AAA screening can be implemented with a dramatic reduction in unscreened patients. Further analysis is required to assess the impact of the screening program on AAA rupture rate and cost-effectiveness in our system.

Safety Net Program to Improve Statin Initiation Among Adults With High Low-Density Lipoprotein Cholesterol.

INTRODUCTION: Despite their effectiveness in reducing low-density lipoprotein cholesterol and cardiovascular disease risk, high-intensity statins are underutilized among adults with low-density lipoprotein cholesterol ≥190 mg/dL. This study determined whether a safety net program (SureNet) facilitating medication and laboratory test orders improved statin initiation and laboratory test completions after (SureNet period: April 2019-September 2021) and before implementation (pre-SureNet period: January 2016-September 2018). METHODS: Kaiser Permanente Southern California members aged 20-60 years with low-density lipoprotein cholesterol ≥190 mg/dL and no statin use in previous 2-6 months were included in this retrospective cohort study. Statin orders within 14 days and statin fills, laboratory test completions, and improved low-density lipoprotein cholesterol within 180 days of the high low-density lipoprotein cholesterol (pre-SureNet) or outreach (SureNet period) were compared. Analyses were conducted in 2022. RESULTS: Overall, 3,534 and 3,555 adults were eligible for statin initiation during the pre-SureNet and SureNet periods, respectively. Overall, 759 (21.5%) and 976 (27.5%) had a statin approved by their physician during pre-SureNet and SureNet periods, respectively (p<0.001). After multivariable adjustment for demographics and clinical characteristics, adults during the SureNet period had a higher likelihood of receiving a statin order (prevalence ratio=1.36, 95% CI=1.25, 1.48), filling their statin (prevalence ratio=1.32, 95% CI=1.26, 1.38), completing their laboratories (prevalence ratio=1.41, 95% CI=1.26, 1.58), and improving low-density lipoprotein cholesterol (prevalence ratio=1.21, 95% CI=1.07, 1.37) than in pre-Surenet period. CONCLUSIONS: The SureNet program was able to improve prescription orders, fills, laboratory test completions, and lower low-density lipoprotein cholesterol. Optimizing both physician adherence to treatment guidelines; and patient adherence to the program may improve low-density lipoprotein cholesterol lowering.

Periconceptual Maternal Nutrition Affects Fetal Liver Programming of Energy- and Lipid-Related Genes.

During pregnancy, the fetus relies on the dam for its nutrient supply. Nutritional stimuli during fetal organ development can program hepatic metabolism and function. Herein, we investigated the role of vitamin and mineral supplementation (VTM or NoVTM-at least 71 days pre-breeding to day 83 of gestation) and rate of weight gain (low (LG) or moderate (MG)-from breeding to day 83) on the fetal liver transcriptome and the underlying biological pathways. Crossbred Angus beef heifers (n = 35) were randomly assigned to one of four treatments in a 2 × 2 factorial design (VTM_LG, VTM_MG, NoVTM_LG, and NoVTM_MG). Gene expression was measured with RNA-Seq in fetal livers collected on day 83 ± 0.27 of gestation. Our results show that vitamin and mineral supplementation and rate of weight gain led to the differential expression of hepatic genes in all treatments. We identified 591 unique differentially expressed genes across all six VTM-gain contrasts (FDR ≤ 0.1). Over-represented pathways were related to energy metabolism, including PPAR and PI3K-Akt signaling pathways, as well as lipid metabolism, mineral transport, and amino acid transport. Our findings suggest that periconceptual maternal nutrition affects fetal hepatic function through altered expression of energy- and lipid-related genes.

Fetal Hepatic Lipidome Is More Greatly Affected by Maternal Rate of Gain Compared with Vitamin and Mineral Supplementation at day 83 of Gestation.

Herein, we evaluated the hepatic lipid metabolic profiles of bovine fetuses in response to maternal vitamin and mineral supplementation (VMSUP; supplemented (VTM) or not (NoVTM)) and two different rates of gain (GAIN; low gain (LG), 0.28 kg/d, or moderate gain (MG), 0.79 kg/d). Crossbred Angus heifers (n = 35; initial BW = 359.5 ± 7.1 kg) were randomly assigned to a 2 × 2 factorial arrangement, resulting in the following treatment combinations: NoVTM-LG (n = 9), NoVTM-MG (n = 9), VTM-LG (n = 9), and VTM-MG (n = 8). Heifers received their treatments until d 83 of gestation, when they were ovariohysterectomized. Fetuses were harvested and liver samples were analyzed via ultrahigh-performance liquid chromatography-tandem mass spectroscopy to characterize lipid profiles and abundances. We identified 374 biochemicals/metabolites belonging to 57 sub-pathways of the lipid metabolism super-pathway. The majority of the biochemicals/metabolites (n = 152) were significantly affected by the main effect of GAIN. Maternal moderate rates of gain resulted in greater abundances (p ≤ 0.0001) of ω-3 fatty acids (eicosapentaenoate, docosapentaenoate, and docosahexaenoate) and lower abundances (p ≤ 0.0001) of ω-6 fatty acids. Further, MG resulted in the accumulation of several diacylglycerols and depletion of the majority of the monoacylglycerols. Concentrations of nearly all acylcarnitines (p ≤ 0.03) were decreased in VTM-LG fetal livers compared to all other treatment combinations, indicating a greater rate of complete oxidation of fatty acids. Levels of secondary bile acids were impacted by VMSUP, being greater (p ≤ 0.0048) in NoVTM than in VTM fetal livers. Moreover, NoVTM combined with lower rate of gain resulted in greater concentrations of most secondary bile acid biochemicals/metabolites. These data indicate that maternal diet influenced and altered fetal hepatic lipid composition in the first trimester of gestation. Maternal body weight gain exerted a greater influence on fetal lipid profiles than vitamin and mineral supplementation. Specifically, lower rate of gain (0.28 kg/d) resulted in an increased abundance of the majority of the biochemicals/metabolites identified in this study.

Dataset of RNA-Seq transcriptome of the fetal liver at day 83 of gestation associated with periconceptual maternal nutrition in beef heifers.

Herein, we present a dataset based on the RNA-Seq analysis of liver tissue from bovine female fetuses at day 83 of gestation. The findings were reported in the main article, "Periconceptual maternal nutrition affects fetal liver programming of energy- and lipid-related genes" [1]. These data were generated to investigate the effects of periconceptual maternal vitamin and mineral supplementation and rates of body weight gain on the transcript abundance of genes associated with fetal hepatic metabolism and function. To this end, crossbred Angus beef heifers (n = 35) were randomly assigned to 1 of 4 treatments in a 2 × 2 factorial design. The main effects tested were vitamin and mineral supplementation (VTM or NoVTM - at least 71 days pre-breeding to day 83 of gestation) and rate of weight gain (low (LG - 0.28 kg/d) or moderate (MG - 0.79 kg/d) - from breeding to day 83). The fetal liver was collected on day 83 ± 0.27 of gestation. After total RNA isolation and quality control, strand-specific RNA libraries were prepared and sequenced on the Illumina® NovaSeq 6000 platform to generate paired-end 150-bp reads. After read mapping and counting, differential expression analysis was performed with edgeR. We identified 591 unique differentially expressed genes across all six vitamin-gain contrasts (FDR ≤ 0.1). To our knowledge, this is the first dataset investigating the fetal liver transcriptome in response to periconceptual maternal vitamin and mineral supplementation and/or the rate of weight gain. The data described in this article provides genes and molecular pathways differentially programming liver development and function.

Vitamin and Mineral Supplementation and Rate of Gain in Beef Heifers I: Effects on Dam Hormonal and Metabolic Status, Fetal Tissue and Organ Mass, and Concentration of Glucose and Fructose in Fetal Fluids at d 83 of Gestation.

Thirty-five crossbred Angus heifers (initial BW = 359.5 ± 7.1 kg) were randomly assigned to a 2 × 2 factorial design to evaluate effects of vitamin and mineral supplementation [VMSUP; supplemented (VTM) vs. unsupplemented (NoVTM)] and different rates of gain [GAIN; low gain (LG), 0.28 kg/d, vs. moderate gain (MG), 0.79 kg/d] during the first 83 d of gestation on dam hormone and metabolic status, fetal tissue and organ mass, and concentration of glucose and fructose in fetal fluids. The VMSUP was initiated 71 to 148 d before artificial insemination (AI), allowing time for mineral status of heifers to be altered in advance of breeding. At AI heifers were assigned their GAIN treatment. Heifers received treatments until the time of ovariohysterectomy (d 83 ± 0.27 after AI). Throughout the experiment, serum samples were collected and analyzed for non-esterified fatty acids (NEFA), progesterone (P4), insulin, and insulin-like growth factor 1 (IGF-1). At ovariohysterectomy, gravid reproductive tracts were collected, measurements were taken, samples of allantoic (ALF) and amniotic (AMF) fluids were collected, and fetuses were dissected. By design, MG had greater ADG compared to LG (0.85 vs. 0.34 ± 0.04 kg/d, respectively; p < 0.01). Concentrations of NEFA were greater for LG than MG (p = 0.04) and were affected by a VMSUP × day interaction (p < 0.01), with greater concentrations for NoVTM on d 83. Insulin was greater for NoVTM than VTM (p = 0.01). A GAIN × day interaction (p < 0.01) was observed for IGF-1, with greater concentrations for MG on d 83. At d 83, P4 concentrations were greater for MG than LG (GAIN × day, p < 0.01), and MG had greater (p < 0.01) corpus luteum weights versus LG. Even though fetal BW was not affected (p ≥ 0.27), MG fetuses had heavier (p = 0.01) femurs than LG, and VTM fetuses had heavier (p = 0.05) livers than those from NoVTM. Additionally, fetal liver as a percentage of BW was greater in fetuses from VTM (P = 0.05; 3.96 ± 0.06% BW) than NoVTM (3.79 ± 0.06% BW), and from LG (p = 0.04; 3.96 ± 0.06% BW) than MG (3.78 ± 0.06% BW). A VMSUP × GAIN interaction was observed for fetal small intestinal weight (p = 0.03), with VTM-MG being heavier than VTM-LG. Therefore, replacement heifer nutrition during early gestation can alter the development of organs that are relevant for future offspring performance. These data imply that compensatory mechanisms are in place in the developing conceptus that can alter the growth rate of key metabolic organs possibly in an attempt to increase or decrease energy utilization.

Vitamin and Mineral Supplementation and Rate of Weight Gain during the First Trimester of Gestation in Beef Heifers Alters the Fetal Liver Amino Acid, Carbohydrate, and Energy Profile at Day 83 of Gestation.

The objective of this study was to evaluate the effects of feeding heifers a vitamin and mineral supplement and targeting divergent rates of weight gain during early gestation on the fetal liver amino acid, carbohydrate, and energy profile at d 83 of gestation. Seventy-two crossbred Angus heifers were randomly assigned in a 2 × 2 factorial arrangement to one of four treatments comprising the main effects of vitamin and mineral supplementation (VTM or NOVTM) and feeding to achieve different rates of weight gain (low gain [LG] 0.28 kg/day vs. moderate gain [MG] 0.79 kg/day). Thirty-five gestating heifers with female fetuses were ovariohysterectomized on d 83 of gestation and fetal liver was collected and analyzed by reverse phase UPLC-tandem mass spectrometry with positive and negative ion mode electrospray ionization, as well as by hydrophilic interaction liquid chromatography UPLC-MS/MS with negative ion mode ESI for compounds of known identity. The Glycine, Serine, and Threonine metabolism pathway and the Leucine, Isoleucine, and Valine metabolism pathway had a greater total metabolite abundance in the liver of the NOVTM-LG group and least in the VTM-LG group (p < 0.01). Finally, both the TCA Cycle and Oxidative Phosphorylation pathways within the Energy Metabolism superpathway were differentially affected by the main effect of VTM, where the TCA cycle metabolites were greater (p = 0.04) in the NOVTM fetal livers and the Oxidative Phosphorylation biochemicals were greater (p = 0.02) in the fetal livers of the VTM supplemented heifers. These data demonstrate that the majority of metabolites that are affected by rate of weight gain or vitamin/mineral supplementation are decreased in heifers on a greater rate of weight gain or vitamin/mineral supplementation.

Vitamin and Mineral Supplementation and Rate of Gain in Beef Heifers II: Effects on Concentration of Trace Minerals in Maternal Liver and Fetal Liver, Muscle, Allantoic, and Amniotic Fluids at Day 83 of Gestation.

We evaluated the effects of vitamin and mineral supplementation (from pre-breeding to day 83 of gestation) and two rates of gain (from breeding to day 83 of gestation) on trace mineral concentrations in maternal and fetal liver, fetal muscle, and allantoic (ALF) and amniotic (AMF) fluids. Crossbred Angus heifers (n = 35; BW = 359.5 ± 7.1 kg) were randomly assigned to one of two vitamin and mineral supplementation treatments (VMSUP; supplemented (VTM) vs. unsupplemented (NoVTM)). The VMSUP factor was initiated 71 to 148 d before artificial insemination (AI), allowing time for the mineral status of heifers to be altered in advance of breeding. The VTM supplement (113 g·heifer−1·d−1) provided macro and trace minerals and vitamins A, D, and E to meet 110% of the requirements specified by the NASEM, and the NoVTM supplement was a pelleted product fed at a 0.45 kg·heifer−1·day−1 with no added vitamin and mineral supplement. At AI, heifers were assigned to one of two rates of gain treatments (GAIN; low gain (LG) 0.28 kg/d or moderate gain (MG) 0.79 kg/d) within their respective VMSUP groups. On d 83 of gestation fetal liver, fetal muscle, ALF, and AMF were collected. Liver biopsies were performed prior to VMSUP factor initiation, at the time of AI, and at the time of ovariohysterectomy. Samples were analyzed for concentrations of Se, Cu, Zn, Mo, Mn, and Co. A VMSUP × GAIN × day interaction was present for Se and Cu (p < 0.01 and p = 0.02, respectively), with concentrations for heifers receiving VTM being greater at AI and tissue collection compared with heifers not receiving VTM (p < 0.01). A VMSUP × day interaction (p = 0.01) was present for Co, with greater (p < 0.01) concentrations for VTM than NoVTM at the time of breeding. VTM-MG heifers had greater concentrations of Mn than all other treatments (VMSUP × GAIN, p < 0.01). Mo was greater (p = 0.04) for MG than LG, while Zn concentrations decreased throughout the experiment (p < 0.01). Concentrations of Se (p < 0.01), Cu (p = 0.01), Mn (p = 0.04), and Co (p = 0.01) were greater in fetal liver from VTM than NoVTM. Mo (p ≤ 0.04) and Co (p < 0.01) were affected by GAIN, with greater concentrations in fetal liver from LG than MG. In fetal muscle, Se (p = 0.02) and Zn (p < 0.01) were greater for VTM than NoVTM. Additionally, Zn in fetal muscle was affected by GAIN (p < 0.01), with greater concentrations in LG than MG. The ALF in VTM heifers (p < 0.01) had greater Se and Co than NoVTM. In AMF, trace mineral concentrations were not affected (p ≥ 0.13) by VMSUP, GAIN, or their interaction. Collectively, these data suggest that maternal nutrition pre-breeding and in the first trimester of gestation affects fetal reserves of some trace minerals, which may have long-lasting impacts on offspring performance and health.

Vitamin and mineral supplementation and rate of gain during the first trimester of gestation affect concentrations of amino acids in maternal serum and allantoic fluid of beef heifers.

The objective of this study was to evaluate the effects of feeding vitamin and mineral (VTM) supplement and (or) rate of gain (GAIN) during early gestation on amino acid (AA) concentrations in allantoic fluid (ALF) and amniotic fluid (AMF) and maternal serum. Seventy-two crossbred Angus heifers (initial BW = 359.5 ± 7.1 kg) were randomly assigned to one of four treatments in a 2 × 2 factorial arrangement with main effects of VTM supplement (VTM or NoVTM) and rate of gain (GAIN; low gain [LG], 0.28 kg/d, vs. moderate gain [MG], 0.79 kg/d). The VTM treatment (113 g•heifer-1•d-1, provided macro and trace minerals and vitamins A, D, and E to meet 110% of the requirements specified by the NASEM in Nutrient requirements of beef cattle. Washington, DC: The National Academies Press. doi:10.17226/19014, 2016) was initiated 71 to 148 d before artificial insemination (AI). To complete the factorial arrangement of treatments, at breeding heifers were either maintained on the basal diet (LG), or received MG diet which was implemented by adding a protein/energy supplement to the LG diet. Thirty-five gestating heifers with female fetuses were ovariohysterectomized on d 83 of gestation and maternal serum, ALF, and AMF were collected. Samples were analyzed for concentrations of neutral AA: Ala, Asn, Cys, Gln, Gly, Ile, Leu, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val; cationic AA: Arg, His, and Lys; and anionic AA: Asp and Glu. In serum, a VTM × GAIN interaction (P = 0.02) was observed for Glu, with greater concentrations for VTM-LG than VTM-MG. Concentrations of serum Cys, Met, and Trp were greater (P ≤ 0.03) for MG than LG. In ALF, concentrations of Glu were affected by a VTM × GAIN interaction, where VTM-MG was greater (P < 0.01) than all other treatments. Further, ALF from VTM had increased (P ≤ 0.05) concentrations of His, Asp, and 12 of the 14 neutral AA; whereas GAIN affected concentrations of Arg, Cys, and Asp, with greater concentrations (P ≤ 0.05) in MG heifers. In AMF, AA concentrations were not affected (P ≥ 0.10) by VTM, GAIN, or their interaction. In conclusion, increased concentrations of AA in maternal serum and ALF of beef heifers were observed at d 83 of gestation in response to VTM supplementation and rate of gain of 0.79 kg/d, which raises important questions regarding the mechanisms responsible for AA uptake and balance between the maternal circulation and fetal fluid compartments.

Maternal Vitamin and Mineral Supplementation and Rate of Maternal Weight Gain Affects Placental Expression of Energy Metabolism and Transport-Related Genes.

Maternal nutrients are essential for proper fetal and placental development and function. However, the effects of vitamin and mineral supplementation under two rates of maternal weight gain on placental genome-wide gene expression have not been investigated so far. Furthermore, biological processes and pathways in the placenta that act in response to early maternal nutrition are yet to be elucidated. Herein, we examined the impact of maternal vitamin and mineral supplementation (from pre-breeding to day 83 post-breeding) and two rates of gain during the first 83 days of pregnancy on the gene expression of placental caruncles (CAR; maternal placenta) and cotyledons (COT; fetal placenta) of crossbred Angus beef heifers. We identified 267 unique differentially expressed genes (DEG). Among the DEGs from CAR, we identified ACAT2, SREBF2, and HMGCCS1 that underlie the cholesterol biosynthesis pathway. Furthermore, the transcription factors PAX2 and PAX8 were over-represented in biological processes related to kidney organogenesis. The DEGs from COT included SLC2A1, SLC2A3, SLC27A4, and INSIG1. Our over-representation analysis retrieved biological processes related to nutrient transport and ion homeostasis, whereas the pathways included insulin secretion, PPAR signaling, and biosynthesis of amino acids. Vitamin and mineral supplementation and rate of gain were associated with changes in gene expression, biological processes, and KEGG pathways in beef cattle placental tissues.

Trends in Acute Myocardial Infarction by Race and Ethnicity.

Background Trends in acute myocardial infarction (AMI) incidence rates for diverse races/ethnicities are largely unknown, presenting barriers to understanding the role of race/ethnicity in AMI occurrence. Methods and Results We identified AMI hospitalizations for Kaiser Permanente Southern California members, aged ≥35 years, during 2000 to 2014 using discharge diagnostic codes. We excluded hospitalizations with missing race/ethnicity information. We calculated annual incidence rates (age and sex standardized to the 2010 US census population) for AMI, ST-segment-elevation myocardial infarction, and non-ST-segment-elevation myocardial infarction by race/ethnicity (Hispanic and non-Hispanic racial groups: Asian or Pacific Islander, black, and white). Using Poisson regression, we estimated annual percentage change in AMI, non-ST-segment-elevation myocardial infarction, and ST-segment-elevation myocardial infarction incidence by race/ethnicity and AMI incidence rate ratios between race/ethnicity pairs, adjusting for age and sex. We included 18 630 776 person-years of observation and identified 44 142 AMI hospitalizations. During 2000 to 2014, declines in AMI, non-ST-segment-elevation myocardial infarction, and ST-segment-elevation myocardial infarction were 48.7%, 34.2%, and 69.8%, respectively. Age- and sex-standardized AMI hospitalization rates/100 000 person-years declined for Hispanics (from 307 to 162), Asians or Pacific Islanders (from 271 to 158), blacks (from 347 to 199), and whites (from 376 to 189). Annual percentage changes ranged from -2.99% to -4.75%, except for blacks, whose annual percentage change was -5.32% during 2000 to 2009 and -1.03% during 2010 to 2014. Conclusions During 2000 to 2014, AMI, non-ST-segment-elevation myocardial infarction, and ST-segment-elevation myocardial infarction hospitalization incidence rates declined substantially for each race/ethnic group. Despite narrowing rates among races/ethnicities, differences persist. Understanding these differences can help identify unmet needs in AMI prevention and management to guide targeted interventions.

Molecular analysis of Turkish Gaucher disease patients: identification of novel mutations in glucocerebrosidase (GBA) gene.

Gaucher disease (GD) is the most frequent lysosomal glycolipid storage disorder due to autosomal recessive deficiency of acid beta-glucosidase and is characterized by the accumulation of glucocerebroside. In this work we carried out molecular analysis of the glucocerebrosidase gene (GBA) in 57 unrelated patients and the alleleic frequencies of gene mutations in Turkish patients are reported. The most prevalent are L444P and N370S accounting for 42% and 30% in our patients. We identified three novel genetic alterations: two missense changes S356F, L296V that are associated with the severe phenotype of type 1 GD. 303-305delCAC was identified in a homozygous state in one patient type 1 or type 3.

Trends in Lipid Screening Among Adults in an Integrated Health Care Delivery System, 2009-2015.

BACKGROUND: Lipid screening determines eligibility for statins and other cardiovascular risk reduction interventions. OBJECTIVE: To examine trends in lipid screening among adults aged ≥20 years in a large, multiethnic, integrated health care delivery system in southern California. METHODS: Temporal trends in lipid screening were examined from 2009 to 2015 with an index date of September 30 of each year. Lipid screening was defined as the proportion of eligible members each year who (a) had ever been screened among those aged 20-39 years and (b) had been screened in the previous 6 years for those aged ≥ 40 years. Trends were analyzed by age, gender, and the presence of atherosclerotic cardiovascular disease (ASCVD) or diabetes without ASCVD status. RESULTS: More than 2 million individuals were included each year: 5%-6% had ASCVD (includes those with diabetes), 7%-8% had diabetes without ASCVD, and 87% had neither condition. Among the entire population, lipid screening increased from 79.8% in 2009 to 82.6% in 2015 (P < 0.0001). Among those with ASCVD or diabetes, lipid screening was 99% across all years. Among those without ASCVD or DM, screening increased from 76.9% in 2009 to 80.0% in 2015 (P < 0.0001), with higher screening among women compared with men and lower screening among individuals younger than 55 years. CONCLUSIONS: Consistently high rates of lipid screening were observed among individuals with ASCVD or diabetes. In individuals without these conditions, screening increased over time. However, there is room to further increase screening rates in adults younger than 55 years. DISCLOSURES: This manuscript and research work was supported by a contractual agreement between the Southern California Permanente Medical Group and Regeneron Pharmaceuticals and Sanofi U.S. Researchers from Regeneron and Sanofi collaborated on the study design, interpretation of data, and writing of the manuscript. Ling Grant, Harrison, Chang, Hsu, Cheetham, Wei, and Reynolds are employed by Kaiser Permanente Southern California. Scott is employed by Southern California Permanente Medical Group. Boklage is employed by Regeneron, and Romo-LeTourneau is employed by Sanofi. Preliminary results from this study were presented at the American Heart Association Scientific Sessions; November 12-16, 2016; New Orleans, LA.

All-Cause and Acute Pancreatitis Health Care Costs in Patients With Severe Hypertriglyceridemia.

OBJECTIVE: The aim of this study was to assess health care utilization and costs related to acute pancreatitis (AP) in patients with severe hypertriglyceridemia (sHTG) levels. METHODS: Patients with sHTG levels 1000 mg/dL or higher were identified from January 1, 2007, to June 30, 2013. The first identified incident triglyceride level was labeled as index date. All-cause, AP-related health care visits, and mean total all-cause costs in patients with and without AP were compared during 12 months postindex. A generalized linear model regression was used to compare costs while controlling for patient characteristics and comorbidities. RESULTS: Five thousand five hundred fifty sHTG patients were identified, and 5.4% of these patients developed AP during postindex. Patients with AP had significantly (P < 0.05) more all-cause outpatient visits, hospitalizations, longer length of stays during the hospital visits, and emergency department visits versus patients without AP. Mean (SD) unadjusted all-cause health care costs in the 12 months postindex were $25,343 ($33,139) for patients with AP compared with $15,195 ($24,040) for patients with no AP. The regression showed annual all-cause costs were 49.9% higher (P < 0.01) for patients with AP versus without AP. CONCLUSIONS: Patients who developed AP were associated with higher costs; managing patients with sHTG at risk of developing AP may help reduce unnecessary costs.