In utero exposure to a maternal high-fat diet alters the epigenetic histone code in a murine model

OBJECTIVE: Data from animal models show that in utero exposure to a maternal high-fat diet (HFD) renders susceptibility of these offspring to the adult onset of metabolic syndrome. We and others have previously shown that epigenetic modifications to histones may serve as a molecular memory of the in utero exposure, rendering the risk of adult disease. Because mice heterozygous for the Glut4 gene (insulin sensitive glucose transporter) born to wild-type (WT) mothers demonstrate exacterbated metabolic syndrome when exposed to an HFD in utero, we sought to analyze the genome-wide epigenetic changes that occur in the fetal liver in susceptible offspring. STUDY DESIGN: WT and Glut4(+/-) (G4(+/-)) offspring of WT mothers that were exposed either to a control or an HFD in utero were studied. Immunoblotting was used to measure hepatic histone modifications of fetal and 5-week animals. Chromatin immunoprecipitation (ChIP) followed by hybridization to chip arrays (ChIP-on-chip) was used to detect genome-wide changes of histone modifications with HFD exposure. RESULTS: We found that levels of hepatic H3K14ac and H3K9me3 significantly increased with HFD exposure in WT and G4(+/-) fetal and 5-week offspring. Pathway analysis of our ChIP-on-chip data revealed differential H3K14ac and H3K9me3 enrichment along pathways that regulate lipid metabolism, specifically in the promoter regions of Pparg, Ppara, Rxra, and Rora. CONCLUSION: We conclude that HFD exposure in utero is associated with functional alterations to fetal hepatic histone modifications in both WT and G4(+/-) offspring, some of which persist up to 5 weeks of age

Obstetric admissions and outcomes in an intensive care unit in Malawi

Background: Despite international commitment to Millennium Development Goal 5, maternal mortality remains high in low- and middle-income countries (LMICs) of sub-Saharan Africa. This is in part due to infrastructure gaps, including availability of intensive care units (ICUs). We sought to use obstetric ICU utilization as a marker of severe maternal morbidity and provide an initial characterization of its relationship with in-hospital mortality. Methods: A prospective observational cohort study of all obstetric subjects admitted to the ICU of Kamuzu Central Hospital in Malawi from September 2016 to March 2018. We reviewed charts at the time of ICU admission to assess the indication for admission, clinical characteristics and laboratory values. Subjects were followed until death or discharge. The primary outcome was in-hospital mortality. Results: One-hundred-and-five obstetric patients were admitted to the study ICU (23% of all admissions). The median age was 26 years. The majority (79%) had undergone recent surgery; 40 (52%) an abdominal postnatal or cesarean hysterectomy and 31 (40%) a cesarean delivery without hysterectomy. Ninety-five percent required mechanical ventilation and 48% required vasopressors. Overall in-hospital mortality was 49%. Conclusions: The proportion of obstetric subjects admitted to the ICU in Malawi is nearly 1 in 4, which exceeds that found in high-income countries by orders of magnitude. Intensive care unit admission was associated with high mortality in this population. Investments in improving infrastructure and care gaps may include addressing available ICU bed and blood-banking needs, and increasing the number of providers trained in managing critical illness among obstetric patients

Influence of acetaminophen and ibuprofen on in vivo patellar tendon adaptations to knee extensor resistance exercise in older adults

Millions of older individuals consume acetaminophen or ibuprofen daily and these same individuals are encouraged to participate in resistance training. Several in vitro studies suggest that cyclooxygenase-inhibiting drugs can alter tendon metabolism and may influence adaptations to resistance training. Thirty-six individuals were randomly assigned to a placebo (67 ± 2 yr old), acetaminophen (64 ± 1 yr old; 4,000 mg/day), or ibuprofen (64 ± 1 yr old; 1,200 mg/day) group in a double-blind manner and completed 12 wk of knee extensor resistance training. Before and after training in vivo patellar tendon properties were assessed with MRI [cross-sectional area (CSA) and signal intensity] and ultrasonography of patellar tendon deformation coupled with force measurements to obtain stiffness, modulus, stress, and strain. Mean patellar tendon CSA was unchanged (P > 0.05) with training in the placebo group, and this response was not influenced with ibuprofen consumption. Mean tendon CSA increased with training in the acetaminophen group (3%, P < 0.05), primarily due to increases in the mid (7%, P < 0.05) and distal (8%, P < 0.05) tendon regions. Correspondingly, tendon signal intensity increased with training in the acetaminophen group at the mid (13%, P < 0.05) and distal (15%, P = 0.07) regions. When normalized to pretraining force levels, patellar tendon deformation and strain decreased 11% (P < 0.05) and stiffness, modulus, and stress were unchanged (P > 0.05) with training in the placebo group. These responses were generally uninfluenced by ibuprofen consumption. In the acetaminophen group, tendon deformation and strain increased 20% (P < 0.05) and stiffness (−17%, P < 0.05) and modulus (−20%, P < 0.05) decreased with training. These data suggest that 3 mo of knee extensor resistance training in older adults induces modest changes in the mechanical properties of the patellar tendon. Over-the-counter doses of acetaminophen, but not ibuprofen, have a strong influence on tendon mechanical and material property adaptations to resistance training. These findings add to a growing body of evidence that acetaminophen has profound effects on peripheral tissues in humans

Optimizing allocation of curricular content across the undergraduate & graduate medical education continuum

BACKGROUND: Medical educators struggle to incorporate socio-cultural topics into crowded curricula. The continuum of learning includes undergraduate and graduate medical education. Utilizing an exemplar socio-cultural topic, we studied the feasibility of achieving expert consensus among two groups of faculty (experts in medical education and experts in social determinants of health) on which aspects of the topic could be taught during undergraduate versus graduate medical education. METHODS: A modified Delphi method was used to generate expert consensus on which learning objectives of social determinants of health are best taught at each stage of medical education. Delphi respondents included experts in medical education or social determinants of health. A survey was created using nationally published criteria for social determinants of health learning objectives. Respondents were asked 1) which learning objectives were necessary for every physician (irrespective of specialty) to develop competence upon completion of medical training and 2) when the learning objective should be taught. Respondents were also asked an open-ended question on how they made the determination of when in the medical education continuum the learning objective should be taught. RESULTS: 26 out of 55 experts (13 social determinants of health and 13 education experts) responded to all 3 Delphi rounds. Experts evaluated a total of 49 learning objectives and were able to achieve consensus for at least one of the two research questions for 45 of 49 (92%) learning objectives. 50% more learning objectives reached consensus for inclusion in undergraduate (n = 21) versus graduate medical education (n = 14). CONCLUSIONS: A modified Delphi technique demonstrated that experts could identify key learning objectives of social determinants of health needed by all physicians and allocate content along the undergraduate and graduate medical education continuum. This approach could serve as a model for similar socio-cultural content. Future work should employ a qualitative approach to capture principles utilized by experts when making these decisions

The OpenCitations Data Model

A variety of schemas and ontologies are currently used for the machine-readable description of bibliographic entities and citations. This diversity, and the reuse of the same ontology terms with different nuances, generates inconsistencies in data. Adoption of a single data model would facilitate data integration tasks regardless of the data supplier or context application. In this paper we present the OpenCitations Data Model (OCDM), a generic data model for describing bibliographic entities and citations, developed using Semantic Web technologies. We also evaluate the effective reusability of OCDM according to ontology evaluation practices, mention existing users of OCDM, and discuss the use and impact of OCDM in the wider open science community.Comment: ISWC 2020 Conference proceeding

Intestinal parasitic infections in schoolchildren in different settings of Côte d'Ivoire : effect of diagnostic approach and implications for control

BACKGROUND: Social-ecological systems govern parasitic infections in humans. Within the frame of assessing the accuracy of a rapid diagnostic test for Schistosoma mansoni in Cote d'Ivoire, three different endemicity settings had to be identified and schoolchildren's intestinal parasitic infection profiles were characterized. METHODS: In September 2010, a rapid screening was conducted in 11 schools in the Azaguie district, south Cote d'Ivoire. In each school, 25 children were examined for S. mansoni and S. haematobium. Based on predefined schistosome endemicity levels, three settings were selected, where schoolchildren aged 8-12 years were asked to provide three stool and three urine samples for an in-depth appraisal of parasitic infections. Triplicate Kato-Katz thick smears were prepared from each stool sample for S. mansoni and soil-transmitted helminth diagnosis, whereas urine samples were subjected to a filtration method for S. haematobium diagnosis. Additionally, a formol-ether concentration method was employed on one stool sample for the diagnosis of helminths and intestinal protozoa. Multivariable logistic regression models were employed to analyse associations between schoolchildren's parasitic infections, age, sex and study setting. RESULTS: The prevalences of S. mansoni and S. haematobium infections in the initial screening ranged from nil to 88% and from nil to 56%, respectively. The rapid screening in the three selected areas revealed prevalences of S. mansoni of 16%, 33% and 78%. Based on a more rigorous diagnostic approach, the respective prevalences increased to 92%, 53% and 33%. S. haematobium prevalences were 0.8%, 4% and 65%. Prevalence and intensity of Schistosoma spp., soil-transmitted helminths and intestinal protozoan infections showed setting-specific patterns. Infections with two or more species concurrently were most common in the rural setting (84%), followed by the peri-urban (28.3%) and urban setting (18.2%). CONCLUSIONS: More sensitive diagnostic tools or rigorous sampling approaches are needed to select endemicity settings with high fidelity. The observed small-scale heterogeneity of helminths and intestinal protozoan infections has important implications for contro

Aneurysm Ostium Angle: A Predictor of the Need for Stent as Assistance for Endovascular Aneurysm Coiling in Internal Carotid Artery Sidewall Aneurysms

BACKGROUND AND PURPOSE: There is no satisfactory parameter that can predict the need for assistant devices for endovascular aneurysm coiling. Our aim was to evaluate the utility of MOA as a predictor of the need for stent-assisted coiling in ICA sidewall aneurysms

Interleukin-2 therapy in patients with HIV infection

BACKGROUND Used in combination with antiretroviral therapy, subcutaneous recombinant interleukin-2 raises CD4+ cell counts more than does antiretroviral therapy alone. The clinical implication of these increases is not known. METHODS We conducted two trials: the Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy (SILCAAT) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). In each, patients infected with the human immunodeficiency virus (HIV) who had CD4+ cell counts of either 50 to 299 per cubic millimeter (SILCAAT) or 300 or more per cubic millimeter (ESPRIT) were randomly assigned to receive interleukin-2 plus antiretroviral therapy or antiretroviral therapy alone. The interleukin-2 regimen consisted of cycles of 5 consecutive days each, administered at 8-week intervals. The SILCAAT study involved six cycles and a dose of 4.5 million IU of interleukin-2 twice daily; ESPRIT involved three cycles and a dose of 7.5 million IU twice daily. Additional cycles were recommended to maintain the CD4+ cell count above predefined target levels. The primary end point of both studies was opportunistic disease or death from any cause. RESULTS In the SILCAAT study, 1695 patients (849 receiving interleukin-2 plus antiretroviral therapy and 846 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 202 cells per cubic millimeter were enrolled; in ESPRIT, 4111 patients (2071 receiving interleukin-2 plus antiretroviral therapy and 2040 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 457 cells per cubic millimeter were enrolled. Over a median follow-up period of 7 to 8 years, the CD4+ cell count was higher in the interleukin-2 group than in the group receiving antiretroviral therapy alone--by 53 and 159 cells per cubic millimeter, on average, in the SILCAAT study and ESPRIT, respectively. Hazard ratios for opportunistic disease or death from any cause with interleukin-2 plus antiretroviral therapy (vs. antiretroviral therapy alone) were 0.91 (95% confidence interval [CI], 0.70 to 1.18; P=0.47) in the SILCAAT study and 0.94 (95% CI, 0.75 to 1.16; P=0.55) in ESPRIT. The hazard ratios for death from any cause and for grade 4 clinical events were 1.06 (P=0.73) and 1.10 (P=0.35), respectively, in the SILCAAT study and 0.90 (P=0.42) and 1.23 (P=0.003), respectively, in ESPRIT. CONCLUSIONS Despite a substantial and sustained increase in the CD4+ cell count, as compared with antiretroviral therapy alone, interleukin-2 plus antiretroviral therapy yielded no clinical benefit in either study. (ClinicalTrials.gov numbers, NCT00004978 [ESPRIT] and NCT00013611 [SILCAAT study].

Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates.

Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection