Fetal Hypoglycemia Induced by Placental SLC2A3-RNA Interference Alters Fetal Pancreas Development and Transcriptome at Mid-Gestation.

Glucose, the primary energy substrate for fetal oxidative processes and growth, is transferred from maternal to fetal circulation down a concentration gradient by placental facilitative glucose transporters. In sheep, SLC2A1 and SLC2A3 are the primary transporters available in the placental epithelium, with SLC2A3 located on the maternal-facing apical trophoblast membrane and SLC2A1 located on the fetal-facing basolateral trophoblast membrane. We have previously reported that impaired placental SLC2A3 glucose transport resulted in smaller, hypoglycemic fetuses with reduced umbilical artery insulin and glucagon concentrations, in addition to diminished pancreas weights. These findings led us to subject RNA derived from SLC2A3-RNAi (RNA interference) and NTS-RNAi (non-targeting sequence) fetal pancreases to qPCR followed by transcriptomic analysis. We identified a total of 771 differentially expressed genes (DEGs). Upregulated pathways were associated with fat digestion and absorption, particularly fatty acid transport, lipid metabolism, and cholesterol biosynthesis, suggesting a potential switch in energetic substrates due to hypoglycemia. Pathways related to molecular transport and cell signaling in addition to pathways influencing growth and metabolism of the developing pancreas were also impacted. A few genes directly related to gluconeogenesis were also differentially expressed. Our results suggest that fetal hypoglycemia during the first half of gestation impacts fetal pancreas development and function that is not limited to ß cell activity.

The Impact of SLC2A8 RNA Interference on Glucose Uptake and the Transcriptome of Human Trophoblast Cells.

While glucose is the primary fuel for fetal growth, the placenta utilizes the majority of glucose taken up from the maternal circulation. Of the facilitative glucose transporters in the placenta, SLC2A8 (GLUT8) is thought to primarily function as an intracellular glucose transporter; however, its function in trophoblast cells has not been determined. To gain insight into the function of SLC2A8 in the placenta, lentiviral-mediated RNA interference (RNAi) was performed in the human first-trimester trophoblast cell line ACH-3P. Non-targeting sequence controls (NTS RNAi; n = 4) and SLC2A8 RNAi (n = 4) infected ACH-3P cells were compared. A 79% reduction in SLC2A8 mRNA concentration was associated with an 11% reduction (p ≤ 0.05) in ACH-3P glucose uptake. NTS RNAi and SLC2A8 RNAi ACH-3P mRNA were subjected to RNAseq, identifying 1525 transcripts that were differentially expressed (|log2FC| > 1 and adjusted p-value < 0.05), with 273 transcripts derived from protein-coding genes, and the change in 10 of these mRNAs was validated by real-time qPCR. Additionally, there were 147 differentially expressed long non-coding RNAs. Functional analyses revealed differentially expressed genes involved in various metabolic pathways associated with cellular respiration, oxidative phosphorylation, and ATP synthesis. Collectively, these data indicate that SLC2A8 deficiency may impact placental uptake of glucose, but that its likely primary function in trophoblast cells is to support cellular respiration. Since the placenta oxidizes the majority of the glucose it takes up to support its own metabolic needs, impairment of SLC2A8 function could set the stage for functional placental insufficiency.

Increasing maternal glucose concentrations is insufficient to restore placental glucose transfer in chorionic somatomammotropin RNA interference pregnancies.

We previously demonstrated impaired placental nutrient transfer in chorionic somatomammotropin (CSH) RNA interference (RNAi) pregnancies, with glucose transfer being the most impacted. Thus, we hypothesized that despite experimentally elevating maternal glucose, diminished umbilical glucose uptake would persist in CSH RNAi pregnancies, demonstrating the necessity of CSH for adequate placental glucose transfer. Trophectoderm of sheep blastocysts (9 days of gestational age; dGA) were infected with a lentivirus expressing either nontargeting control (CON RNAi; n = 5) or CSH-specific shRNA (CSH RNAi; n = 7) before transfer into recipient sheep. At 126 dGA, pregnancies were fitted with vascular catheters and underwent steady-state metabolic studies (3H2O transplacental diffusion) at 137 ± 0 dGA, before and during a maternal hyperglycemic clamp. Umbilical glucose and oxygen uptakes, as well as insulin and IGF1 concentrations, were impaired (P ≤ 0.01) in CSH RNAi fetuses and were not rescued by elevated maternal glucose. This is partially due to impaired uterine and umbilical blood flow (P ≤ 0.01). However, uteroplacental oxygen utilization was greater (P ≤ 0.05) during the maternal hyperglycemic clamp, consistent with greater placental oxidation of substrates. The relationship between umbilical glucose uptake and the maternal-fetal glucose gradient was analyzed, and while the slope (CON RNAi, Y = 29.54X +74.15; CSH RNAi, Y = 19.05X + 52.40) was not different, the y-intercepts and elevation were (P = 0.003), indicating reduced maximal glucose transport during maternal hyperglycemia. Together, these data suggested that CSH plays a key role in modulating placental metabolism that ultimately promotes maximal placental glucose transfer.NEW & NOTEWORTHY The current study demonstrated a novel, critical autocrine role for chorionic somatomammotropin in augmenting placental glucose transfer and maintaining placental oxidative metabolism. In pregnancies with CSH deficiency, excess glucose in maternal circulation is insufficient to overcome fetal hypoglycemia due to impaired placental glucose transfer and elevated placental metabolic demands. This suggests that perturbations in glucose transfer in CSH RNAi pregnancies are due to compromised metabolic efficiency along with reduced placental mass.

Regular aspirin use among a sample of American Indians/Alaskan Natives in the Upper Midwest region of the United States.

Despite high prevalence of cardiovascular disease (CVD) and CVD risk factors among American Indian or Alaska Native adults (AI/AN), there is little information on aspirin use in this population. This survey-based study seeks to understand prevalence of aspirin use in a sample of AI/AN adults in the Upper Midwestern United States. In-person and telephone based surveys were conducted querying self-reported CVD and CVD risk factors, aspirin use, and aspirin related discussion with clinicians. A total of 237 AI/AN participants were included: mean age (SD) was 60.8 (8.4) years; 143 (60 %) were women; 59 (25 %) reported CVD history. CVD risk factors were common particularly smoking (37 %) and diabetes (37 %). Aspirin use was much higher among those with CVD (secondary prevention, 76 %) than those without (primary prevention, 33 %). Primary prevention aspirin use was significantly associated with age and all CVD risk factors in unadjusted analyses. After adjustment for demographics and CVD risk factors, only age (aRR 1.13 per 5 years, 95 % CI 1.02, 1.25) and diabetes (aRR 2.44, 95 % CI 1.52, 3.92) remained significantly associated with aspirin. Regardless of CVD status, a higher proportion of those taking aspirin reported a conversation about aspirin with their doctor compared to those not taking aspirin. Among participants with no CVD, those who had such a conversation were 2.6 times more likely to use aspirin than those who did not have a conversation (aRR 2.64, 95 % CI 1.58, 4.44). The findings of this study emphasize the importance of the patient-provider relationship for preventive therapy.

Impact of Chorionic Somatomammotropin In Vivo RNA Interference Phenotype on Uteroplacental Expression of the IGF Axis.

While fetal growth is dependent on many factors, optimal placental function is a prerequisite for a normal pregnancy outcome. The majority of fetal growth-restricted (FGR) pregnancies result from placental insufficiency (PI). The insulin-like growth factors (IGF1 and IGF2) stimulate fetal growth and placental development and function. Previously, we demonstrated that in vivo RNA interference (RNAi) of the placental hormone, chorionic somatomammotropin (CSH), resulted in two phenotypes. One phenotype exhibits significant placental and fetal growth restriction (PI-FGR), impaired placental nutrient transport, and significant reductions in umbilical insulin and IGF1. The other phenotype does not exhibit statistically significant changes in placental or fetal growth (non-FGR). It was our objective to further characterize these two phenotypes by determining the impact of CSH RNAi on the placental (maternal caruncle and fetal cotyledon) expression of the IGF axis. The trophectoderm of hatched blastocysts (9 days of gestation, dGA) were infected with a lentivirus expressing either a non-targeting sequence (NTS RNAi) control or CSH-specific shRNA (CSH RNAi) prior to embryo transfer into synchronized recipient ewes. At ≈125 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies. Nutrient uptakes were determined, and tissues were harvested at necropsy. In both CSH RNAi non-FGR and PI-FGR pregnancies, uterine blood flow was significantly reduced (p ≤ 0.05), while umbilical blood flow (p ≤ 0.01), both uterine and umbilical glucose and oxygen uptakes (p ≤ 0.05), and umbilical concentrations of insulin and IGF1 (p ≤ 0.05) were reduced in CSH RNAi PI-FGR pregnancies. Fetal cotyledon IGF1 mRNA concentration was reduced (p ≤ 0.05) in CSH RNAi PI-FGR pregnancies, whereas neither IGF1 nor IGF2 mRNA concentrations were impacted in the maternal caruncles, and either placental tissue in the non-FGR pregnancies. Fetal cotyledon IGF1R and IGF2R mRNA concentrations were not impacted for either phenotype, yet IGF2R was increased (p ≤ 0.01) in the maternal caruncles of CSH RNAi PI-FGR pregnancies. For the IGF binding proteins (IGFBP1, IGFBP2, IGFBP3), only IGFBP2 mRNA concentrations were impacted, with elevated IGFBP2 mRNA in both the fetal cotyledon (p ≤ 0.01) and maternal caruncle (p = 0.08) of CSH RNAi non-FGR pregnancies. These data support the importance of IGF1 in placental growth and function but may also implicate IGFBP2 in salvaging placental growth in non-FGR pregnancies.

Time to Hysterectomy After Transcervical Resection of the Endometrium Based on Age: A Retrospective Cohort Review.

STUDY OBJECTIVE: To determine the rate of hysterectomy over time after transcervical resection of the endometrium (TCRE) based on age. DESIGN: Retrospective audit. SETTING: A single gynecology clinic in regional Victoria, Australia. PATIENTS: A total of 1078 patients who had undergone TCRE for abnormal uterine bleeding. INTERVENTIONS: The likelihood of hysterectomy was compared across age groups using the chi-square test. Time to hysterectomy was summarized as a median with the 25th and 75th percentiles and compared across age groups using the Kaplan-Meier plot (log-rank test) and Cox proportional hazards regression. MEASUREMENTS AND MAIN RESULTS: The overall rate of hysterectomy was 24.2% (261 of 1078, 95% confidence interval [CI] 21.7-26.9). When age was categorized into <40 years, 40 to 44 years, 45 to 49 years, and >50 years, the rate of hysterectomy after TCRE was 32.3% (70 of 217), 29.5% (93 of 315), 19.6% (73 of 372), and 14.4% (25 of 174), respectively (p <.001). The likelihood of hysterectomy at any time point after TCRE among those aged 45 to 49 years and older than 50 years was 43% and 59% lower, respectively, than patients under 40 years (hazard ratio, 0.57; 95% CI, 0.41-0.80, and hazard ratio, 0.41; 95% CI, 0.26-0.65, respectively). The median time to hysterectomy was 1.68 years (25th to 75th percentiles, 0.77-3.76). CONCLUSION: This study demonstrated that patients who underwent a TCRE before the age of 45 years had a higher chance of having a hysterectomy than patients older than 45 years. This information will enable clinicians to inform patients of their chance of undergoing a hysterectomy at any time after TCRE.

Analysis of real-world length of stay data and costs associated with use of autologous skin cell suspension for the treatment of small burns in U.S. centers.

BACKGROUND: Autologous skin cell suspension (ASCS) is a treatment for acute thermal burn injuries associated with significantly lower donor skin requirements than conventional split-thickness skin grafts (STSG). Projections using the BEACON model suggest that among patients with small burns (total body surface area [TBSA]<20 %), use of ASCS± STSG leads to a shorter length of stay (LOS) in hospital and cost savings compared with use of STSG alone. This study evaluated whether data from real-world clinical practice corroborate these findings. MATERIALS AND METHODS: Electronic medical record data were collected from January 2019 through August 2020 from 500 healthcare facilities in the United States. Adult patients receiving inpatient treatment with ASCS± STSG for small burns were identified and matched to patients receiving STSG using baseline characteristics. LOS was assumed to cost $7554/day and to account for 70 % of overall costs. Mean LOS and costs were calculated for the ASCS± STSG and STSG cohorts. RESULTS: A total of 151 ASCS± STSG and 2243 STSG cases were identified; 63.0 % of patients were male and the average age was 44.2 years. Sixty-three matches were made between cohorts. LOS was 18.5 days with ASCS± STSG and 20.6 days with STSG (difference: 2.1 days [10.2 %]). This difference led to bed cost savings of $15,587.62 per ASCS± STSG patient. Overall cost savings with ASCS± STSG were $22,268.03 per patient. CONCLUSIONS: Analysis of real-world data shows that treatment of small burn injuries with ASCS± STSG provides reduced LOS and substantial cost savings compared with STSG, supporting the validity of the BEACON model projections.

Impact of Placental SLC2A3 Deficiency during the First-Half of Gestation.

In the ruminant placenta, glucose uptake and transfer are mediated by facilitative glucose transporters SLC2A1 (GLUT1) and SLC2A3 (GLUT3). SLC2A1 is located on the basolateral trophoblast membrane, whereas SLC2A3 is located solely on the maternal-facing, apical trophoblast membrane. While SLC2A3 is less abundant than SLC2A1, SLC2A3 has a five-fold greater affinity and transport capacity. Based on its location, SLC2A3 likely plays a significant role in the uptake of glucose into the trophoblast. Fetal hypoglycemia is a hallmark of fetal growth restriction (FGR), and as such, any deficiency in SLC2A3 could impact trophoblast glucose uptake and transfer to the fetus, thus potentially setting the stage for FGR. By utilizing in vivo placenta-specific lentiviral-mediated RNA interference (RNAi) in sheep, we were able to significantly diminish (p ≤ 0.05) placental SLC2A3 concentration, and determine the impact at mid-gestation (75 dGA). In response to SLC2A3 RNAi (n = 6), the fetuses were hypoglycemic (p ≤ 0.05), exhibited reduced fetal growth, including reduced fetal pancreas weight (p ≤ 0.05), which was associated with reduced umbilical artery insulin and glucagon concentrations, when compared to the non-targeting sequence (NTS) RNAi controls (n = 6). By contrast, fetal liver weights were not impacted, nor were umbilical artery concentrations of IGF1, possibly resulting from a 70% increase (p ≤ 0.05) in umbilical vein chorionic somatomammotropin (CSH) concentrations. Thus, during the first half of gestation, a deficiency in SLC2A3 results in fetal hypoglycemia, reduced fetal development, and altered metabolic hormone concentrations. These results suggest that SLC2A3 may be the rate-limiting placental glucose transporter during the first-half of gestation in sheep.

Length of Stay and Costs with Autologous Skin Cell Suspension Versus Split-Thickness Skin Grafts: Burn Care Data from US Centers.

INTRODUCTION: Autologous skin cell suspension (ASCS) significantly reduces donor skin requirements versus conventional split-thickness skin grafts (STSG) for thermal burn treatment. In analyses using the Burn-medical counter measure Effectiveness Assessment Cost Outcomes Nexus (BEACON) model, ASCS was associated with shorter hospital length of stay (LOS) and cost savings versus STSG. This study hypothesized that daily practice data from the USA would support these findings. METHODS: Electronic medical record data from 500 healthcare facilities (January 2019-August 2020) were used to match adult patients who received inpatient burn treatment with ASCS (± STSG) to patients treated with STSG alone on the basis of sex, age, percent total body surface area (TBSA), and comorbidities. Based on BEACON analyses, LOS was assumed to represent 70% of total costs and used as a proxy to assess the data. Mean LOS, costs, and the incremental revenue associated with inpatient capacity changes were calculated. RESULTS: A total of 151 ASCS and 2443 STSG patients were identified: 63.0% were male and average age was 44.5 years. Eight-one matches were made between cohorts. LOS was 21.7 days with ASCS and 25.0 days with STSG alone (difference 3.3 days [13.2%]). LOS was lower with ASCS than STSG in four of five TBSA intervals. The LOS difference led to hospital bed cost savings of $25,864 per ASCS patient; overall cost savings were $36,949 per patient. Similar cost savings were observed in TBSA groupings < 20% and ≥ 20%. The reduced LOS with ASCS translated into an increased capacity of 2.2 inpatients/bed annually, which increased hospital revenue by $92,283/burn unit bed annually. CONCLUSIONS: Real-world data show that ASCS (± STSG) is associated with reduced LOS and cost savings versus STSG alone across all burn sizes, supporting the validity of the BEACON analyses. ASCS use may also increase patient capacity and throughput, leading to increased hospital revenue.

Autologous skin cell suspension (ASCS) is a treatment for thermal skin burn injuries that can be used alone or in combination with split-thickness skin grafts (STSG), the conventional standard of care. Projections using the Burn-medical counter measure Effectiveness Assessment Cost Outcomes Nexus (BEACON) model indicate that ASCS leads to shorter hospital length of stay (LOS) and overall cost savings compared with STSG alone. These model findings are supported by benchmarking study data from a limited sample of US burn centers. The current study aimed to understand whether the BEACON projections are supported by daily clinical practice data from US healthcare facilities. Using electronic medical record data, we matched patients who received ASCS ± STSG from January 2019 to August 2020 to those receiving STSG alone on the basis of demographic and clinical factors. Data analysis showed that hospital LOS was shorter (3.3 days) with ASCS ± STSG than STSG alone, a difference associated with a hospital bed cost savings of $25,864 per ASCS patient. Overall cost savings, which included nursing time and other costs, were $36,949 per patient. Analysis of patients with burns comprising total body surface areas less than 20% or at least 20% showed cost savings in both groups. The reduced LOS with ASCS also translated into the ability to treat 2.2 more patients per hospital bed per year, which was projected to increase hospital earnings. These real-world findings support those of modeling analyses, indicating that use of ASCS ± STSG is associated with meaningful clinical and economic benefits compared with use of STSG alone.

Uptake of Phosphate, Calcium, and Vitamin D by the Pregnant Uterus of Sheep in Late Gestation: Regulation by Chorionic Somatomammotropin Hormone.

Minerals are required for the establishment and maintenance of pregnancy and regulation of fetal growth in mammals. Lentiviral-mediated RNA interference (RNAi) of chorionic somatomammotropin hormone (CSH) results in both an intrauterine growth restriction (IUGR) and a non-IUGR phenotype in sheep. This study determined the effects of CSH RNAi on the concentration and uptake of calcium, phosphate, and vitamin D, and the expression of candidate mRNAs known to mediate mineral signaling in caruncles (maternal component of placentome) and cotyledons (fetal component of placentome) on gestational day 132. CSH RNAi Non-IUGR pregnancies had a lower umbilical vein−umbilical artery calcium gradient (p < 0.05) and less cotyledonary calcium (p < 0.05) and phosphate (p < 0.05) compared to Control RNAi pregnancies. CSH RNAi IUGR pregnancies had less umbilical calcium uptake (p < 0.05), lower uterine arterial and venous concentrations of 25(OH)D (p < 0.05), and trends for lower umbilical 25(OH)D uptake (p = 0.059) compared to Control RNAi pregnancies. Furthermore, CSH RNAi IUGR pregnancies had decreased umbilical uptake of calcium (p < 0.05), less uterine venous 25(OH)D (vitamin D metabolite; p = 0.055), lower caruncular expression of SLC20A2 (sodium-dependent phosphate transporter; p < 0.05) mRNA, and lower cotyledonary expression of KL (klotho; p < 0.01), FGFR1 (fibroblast growth factor receptor 1; p < 0.05), FGFR2 (p < 0.05), and TRPV6 (transient receptor potential vanilloid member 6; p < 0.05) mRNAs compared to CSH RNAi Non-IUGR pregnancies. This study has provided novel insights into the regulatory role of CSH for calcium, phosphate, and vitamin D utilization in late gestation.

In vivo investigation of ruminant placenta function and physiology-a review.

The placenta facilitates the transport of nutrients to the fetus, removal of waste products from the fetus, immune protection of the fetus and functions as an endocrine organ, thereby determining the environment for fetal growth and development. Additionally, the placenta is a highly metabolic organ in itself, utilizing a majority of the oxygen and glucose derived from maternal circulation. Consequently, optimal placental function is required for the offspring to reach its genetic potential in utero. Among ruminants, pregnant sheep have been used extensively for investigating pregnancy physiology, in part due to the ability to place indwelling catheters within both maternal and fetal vessels, allowing for steady-state investigation of blood flow, nutrient uptakes and utilization, and hormone secretion, under non-stressed and non-anesthetized conditions. This methodology has been applied to both normal and compromised pregnancies. As such, our understanding of the in vivo physiology of pregnancy in sheep is unrivalled by any other species. However, until recently, a significant deficit existed in determining the specific function or significance of individual genes expressed by the placenta in ruminants. To that end, we developed and have been using in vivo RNA interference (RNAi) within the sheep placenta to examine the function and relative importance of genes involved in conceptus development (PRR15 and LIN28), placental nutrient transport (SLC2A1 and SLC2A3), and placenta-derived hormones (CSH). A lentiviral vector is used to generate virus that is stably integrated into the infected cell's genome, thereby expressing a short-hairpin RNA (shRNA), that when processed within the cell, combines with the RNA Induced Silencing Complex (RISC) resulting in specific mRNA degradation or translational blockage. To accomplish in vivo RNAi, day 9 hatched and fully expanded blastocysts are infected with the lentivirus for 4 to 5 h, and then surgically transferred to synchronized recipient uteri. Only the trophectoderm cells are infected by the replication deficient virus, leaving the inner cell mass unaltered, and we often obtain ~70% pregnancy rates following transfer of a single blastocyst. In vivo RNAi coupled with steady-state study of blood flow and nutrient uptake, transfer and utilization can now provide new insight into the physiological consequences of modifying the translation of specific genes expressed within the ruminant placenta.

Optimal placental function is required for offspring to reach their genetic potential in utero, and functional placental insufficiency not only results in increased offspring morbidity and mortality, but can impact production traits long-term. However, assessing placental function in vivo is technically demanding, and robust assessment of placental function requires cannulating both maternal and fetal vasculature in order to obtain arterial and venous blood samples simultaneously under non-stressed/non-anesthetized conditions. While feasible in cattle, this approach has been used more extensively in sheep, providing a thorough understanding of placental nutrient uptake, transport, and utilization in normal and compromised pregnancies. Previously, it has not been feasible to alter the abundance of specific gene products within the ruminant placenta, impairing the direct assessment of "cause and effect" relationships in vivo. However, recently methods have been developed to facilitate RNA interference (RNAi) within the placenta, effectively generating a deficiency in specific gene products, to examine the impact on pregnancy progression and outcome. While in vivo RNAi is feasible in a variety of species, in sheep it is being coupled with the aforementioned approaches assessing in vivo placental function, thereby providing new insight into the ramification of specific gene function within ruminant placenta.

Association of a Community Population and Clinic Education Intervention Program With Guideline-Based Aspirin Use for Primary Prevention of Cardiovascular Disease: A Nonrandomized Controlled Trial.

Importance: Low-dose aspirin is used for primary prevention of cardiovascular disease in approximately one-third of the US adult population. Overuse and underuse are common and not concordant with guidelines. Objective: To test a community and clinic education intervention to improve guideline-based aspirin use for the primary prevention of cardiovascular disease. Design, Setting, and Participants: The Ask About Aspirin project was a nonrandomized controlled trial conducted from, July 1, 2015, to March 31, 2020, using professional education, traditional media, and digital media to improve guideline-based aspirin use. The adult population (aged 45-79 years for men and 55-79 years for women) and primary care clinics in Minnesota were the education targets. The 4 adjacent states were controls. Interventions: The statewide campaign distributed billboards, newspaper articles and other print material, and radio announcements. An Ask About Aspirin website was heavily promoted. Primary care clinics identified appropriate aspirin candidates, and clinicians received continuing education about aspirin. Main Outcomes and Measures: Guideline-based aspirin use by the target population. Results: Cross-sectional random telephone surveys of 8342 men aged 45 to 79 years and women aged 55 to 79 years were conducted at baseline, 2 years, and 4 years after the intervention. Participation was similar between men and women (baseline: 973 [49%] vs 1001 [51%]; year 4: 912 [50%] vs 930 [50%]). Age during the study also was similar (baseline: 64.7 [IQR, 64.4-65.1] years; year 4: 66.2 [IQR, 65.8-66.5] years). A validated questionnaire evaluated aspirin use. The Ask About Aspirin website had more than 1 million visits; 124 primary care clinics with more than 1000 participating clinicians were part of the education program. Small, nonsignificant increases in discussions with clinicians regarding aspirin resulted (baseline: 341 of 1001 [34%]; year 4: 339 of 930 [36%]; P = .27). Overall aspirin use decreased after the release of new US Preventive Services Task Force guidelines in 2016 and 3 aspirin randomized clinical trials in 2018 suggested reduced aspirin use (baseline: 816 of 1974 [41%]; year 4: 629 of 1842 [34%]; P < .001). Decreases were also noted from year 2 to year 4 in appropriate use (year 2: 597 of 1208 [49%]; year 4: 478 of 1191 [40%]; P < .001) and overuse (year 2: 170 of 602 [28%]; year 4: 151 of 651 [23%]; P = .04). There were no significant differences between Minnesota and the control states. Conclusions and Relevance: In this nonrandomized controlled trial, a multiyear statewide campaign was not associated with increased appropriate aspirin use for cardiovascular disease prevention. Contextual factors during the project, including guideline changes and media controversy following the new trials, undermined study goals. These findings suggest that although education programs using social media for cardiovascular disease prevention can result in millions of hits, the use of this strategy to encourage behavior change is problematic, even with supportive clinical sites. Trial Registration: ClinicalTrials.gov Identifier: NCT02607917.

Trophectoderm Transcriptome Analysis in LIN28 Knockdown Ovine Conceptuses Suggests Diverse Roles of the LIN28-let-7 Axis in Placental and Fetal Development.

The proper conceptus elongation in ruminants is critical for the successful placentation and establishment of pregnancy. We have previously shown that the trophectoderm-specific knockdown of LIN28A/B in day 9 ovine blastocysts resulted in increased let-7 miRNAs and reduced conceptus elongation at day 16 of gestation. In this current study, by transcriptome analysis of LIN28A knockdown (AKD) or LIN28B knockdown (BKD) trophectoderm (TE), we explored the downstream target genes of the LIN28-let-7 axis and their roles in the placental and fetal development. We identified 449 differentially expressed genes (DEGs) in AKD TE and 1214 DEGs in BKD TE compared to non-targeting control (NTC). Our analysis further revealed that 210 downregulated genes in AKD TE and 562 downregulated genes in BKD TE were the potential targets of let-7 miRNAs. Moreover, 16 downregulated genes in AKD TE and 57 downregulated and 7 upregulated genes in BKD TE were transcription factors. The DEGs in AKD and BKD TE showed enrichment in the biological processes and pathways critical for placental development and function, and fetal development and growth. The results of this study suggest the potential roles of the LIN28-let-7 axis in placental and fetal development beyond its involvement in trophoblast proliferation and conceptus elongation.

Association of Cardiovascular Disease Risk Factors With Sociodemographic Characteristics and Health Beliefs Among a Community-Based Sample of African American Adults in Minnesota.

OBJECTIVE: To assess cardiovascular disease (CVD) and CVD risk factors and their association with sociodemographic characteristics and health beliefs among African American (AA) adults in Minnesota. METHODS: A cross-sectional analysis was conducted of a community-based sample of AA adults enrolled in the Minnesota Heart Health Program Ask About Aspirin study from May 2019 to September 2019. Sociodemographic characteristics, health beliefs, and self-reported CVD and CVD risk factors were collected. Prevalence ratio (PR) estimates were calculated using Poisson regression modeling to assess the association between participants' characteristics and age- and sex-adjusted CVD risk factors. RESULTS: The sample included 644 individuals (64% [412] women) with a mean age of 61 years. Risk factors for CVD were common: hypertension (67% [434]), hyperlipidemia (47% [301]), diabetes (34% [219]), and current cigarette smoking (25% [163]); 19% (119) had CVD. Those with greater perceived CVD risk had a higher likelihood of prevalent hyperlipidemia (PR, 1.34; 95% CI, 1.14 to 1.57), diabetes (PR, 1.61; 95% CI, 1.30 to 1.98), and CVD (PR 1.61; 95% CI, 1.16 to 2.23) compared with those with lower perceived risk. Trust in health care provider was high (83% [535]) but was not associated with CVD or CVD risk factors. CONCLUSION: In this community sample of AAs in Minnesota, CVD risk factors were high, as was trust in health care providers. Those with greater CVD risk perceptions had higher CVD prevalence. Consideration of sociodemographic and psychosocial influences on CVD and CVD risk factors could inform development of effective cardiovascular health promotion interventions in the AA Minnesota community.

A quantitative study to explore functional outcomes following laparoscopic ventral mesh rectopexy for rectal prolapse.

INTRODUCTION: Rectal prolapse is a life-altering problem and laparoscopic ventral mesh rectopexy (LVMR) is emerging as the surgical intervention of choice. However, the literature is ambiguous on its effect on bowel function and sparse as regards bladder and sexual function. This study assesses short-term functional outcomes following LVMR. MATERIALS AND METHODS: This quantitative retrospective study with a pretest-post-test design included 130 adults who had undergone LVMR from October 2010 to December 2018 in a tertiary centre. Analysis with paired-samples t-test and Wilcoxon matched pairs test was done using SPSS (v26). RESULTS: The median age was 58 years (interquartile range, 48-74 years); 123 (94.6%) were female. The median length of stay was two days (interquartile range, 1-2 days). A total of 104 (80%) sets of medical notes were reviewed. One patient had recurrence of rectal prolapse. Synthetic mesh was used in 24 patients (23.1%) and biological mesh in 80 (76.9%). One patient had extrusion of a synthetic mesh and required surgery; 31(23.8%) completed the Electronic Patient Assessment Questionnaire for Pelvic Floor. Overall, the improvement in bladder function was not statistically significant (p = 0.670). A statistically significant improvement was seen for all bowel symptoms (p = 0.002) excluding constipation (p = 0.295). Irritable bowel symptoms associated with rectal prolapse improved significantly following LVMR (p = 0.001). Vaginal prolapse (p < 0.0005), dyspareunia (p = 0.001) and bowel symptoms affecting sexual intercourse (p = 0.01) improved, but improvement in overall sexual function was not statistically significant (p = 0.081). CONCLUSIONS: LVMR improves bowel function overall, although it can worsen constipation. It has the potential to improve sexual function but makes negligible difference to bladder function.

The cost-effectiveness of therapeutic drug monitoring for the prescription drug-based treatment of chronic myeloid leukemia.

BACKGROUND: A recent study demonstrating the use of Therapeutic Drug Monitoring (TDM) in patients with chronic myeloid leukemia (CML) resulted in a higher response rate with imatinib (IM) than demonstrated in second-generation tyrosine kinase inhibitor studies. The cost-effectiveness of TDM combined with IM (IM TDM) in first-line CML treatment has not yet been studied. OBJECTIVES: To determine the cost-effectiveness of IM TDM for the first-line treatment of CML compared to tyrosine kinase inhibitor only treatment. METHODS: A recently published cost-effectiveness model of tyrosine kinase inhibitor-treatment in CML was modified to include IM TDM as a first-line tyrosine kinase inhibitor-based CML treatment option. Efficacy inputs for major molecular response (MMR) rates were taken from previously published studies: IM TDM 65%, dasatinib 52%, nilotinib 53%. Annual tyrosine kinase inhibitor drug prices were derived from the Federal Supply Schedule (FSS) and the average and lowest wholesale acquisition costs (WAC) reported in the Red Book; the annual cost of TDM was $228. Other input costs modeled in the original CML CEA model were updated to 2016 US dollars using the medical service component of the Consumer Price Index. A US payer perspective was used with a 5-year time horizon and a 3.0% discount rate. The model compared first-line IM TDM versus IM alone, nilotinib (NIL) or dasatinib (DAS) in terms of the following outcomes: costs, quality-adjusted life-years (QALYs), and cost-effectiveness (total cost/QALY). Deterministic and probabilistic sensitivity analyses were performed using all key clinical and economic parameters. RESULTS: This study found that IM TDM dominates IM alone with $15,452 to $36,940 in savings and 0.25 higher QALYs. Using FSS, per patient total costs for IM and IM TDM were $270,905 and $233,965, respectively.; Using average WAC, these costs were $461,657 and $446,205, and using lowest WAC, these costs were $366,966 and $350,090. The results comparing first line using of IM TDM to NIL/DAS found that TDM IM had higher QALYs and lower costs (0.08 QALYs lower, and $117,006 to $172,420 savings per patient [varying by price basis]). Thus, in terms of cost-effectiveness, IM TDM dominates NIL/DAS with both lower costs and higher QALYs. CONCLUSIONS: IM TDM is a clinically and economically viable first-line treatment option for CML. DISCLOSURES: This study was funded by Saladax Biomedical. Salamone is an employee of Saladax Biomedical. This study was presented at the IATDMCT Congress, September 2018, Brisbane, Australia.

Carepath for overcoming psychosis early (COPE): first 5 years of clinical operation and prospective research in the Cavan-Monaghan early intervention service.

OBJECTIVES: As Ireland confronts the many challenges of broadening the introduction of early intervention services (EIS) for first episode psychosis (FEP) as national policy, this article describes Carepath for Overcoming Psychosis Early (COPE), the EIS of Cavan-Monaghan Mental Health Service, and presents prospective research findings during its first 5 years of operation. METHODS: COPE was launched as a rural EIS with an embedded research protocol in early 2012, following an education programme for general practitioners (GPs). Here, operational activities are documented and research findings presented through to late 2016. RESULTS: During this period, 115 instances of FEP were incepted into COPE, 70.4% via their GP and 29.6% via the Emergency Department. The annual rate of inception was 24.8/100,000 of population aged > 15 years and was 2.1-fold more common among men than women. Mean duration of untreated psychosis was 5.7 months and median time from first psychotic presentation to initiation of antipsychotic treatment was zero days. Assessments of psychopathology, neuropsychology, neurology, premorbid functioning, quality of life, insight, and functionality compared across 10 DSM-IV psychotic diagnoses made at six months following presentation indicated minimal differences between them, other than more prominent negative symptoms in schizophrenia and more prominent mania in bipolar disorder. CONCLUSIONS: COPE illustrates the actuality of introducing and the challenges of operating a rural EIS for FEP. Prospective follow-up studies of the 5-year COPE cohort should inform on the effectiveness of this EIS model in relation to long-term outcome in psychotic illness across what appear to be arbitrary diagnostic boundaries at FEP.