Sustainable Livelihoods

Written as a national policy paper for the Rural Secretariat, this paper provides a succinct and clear overview of several rural trends, challenges, strategies, and policy options for increasing the sustainability of rural communities in Canada. While framed by the focus on sustainable livelihoods, its reach—conceptually and with reference to practice—is relevant to several of the key research interests of the BALTA Social Economy Research Alliance. This paper is an excellent framework and discussion from which to critically reflect on and integrate the learning thus far and prepare for the rich contributions in sections four and five

Effects of ECG Data Length on Heart Rate Variability Among Young Healthy Adults

The relationship between the robustness of HRV derived by linear and nonlinear methods to the required minimum data lengths has yet to be well understood. The normal electrocardiography (ECG) data of 14 healthy volunteers were applied to 34 HRV measures using various data lengths, and compared with the most prolonged (2000 R peaks or 750 s) by using the Mann–Whitney U test, to determine the 0.05 level of significance. We found that SDNN, RMSSD, pNN50, normalized LF, the ratio of LF and HF, and SD1 of the Poincaré plot could be adequately computed by small data size (60–100 R peaks). In addition, parameters of RQA did not show any significant differences among 60 and 750 s. However, longer data length (1000 R peaks) is recommended to calculate most other measures. The DFA and Lyapunov exponent might require an even longer data length to show robust results. Conclusions: Our work suggests the optimal minimum data sizes for different HRV measures which can potentially improve the efficiency and save the time and effort for both patients and medical care providers

Maternity Waiting Homes as an Intervention to Increase Facility Delivery in Rural Zambia

Graduate or above research in rural Zambiahttps://deepblue.lib.umich.edu/bitstream/2027.42/148301/1/BeckPeroskyMunroKramerLockhartMusondaNaggayiLori.pd

Development of subfamily-based consensus PCR assays for the detection of human and animal herpesviruses

Consensus PCR assays that can be used to sensitively detect several herpesvirus (HV) species across the different subfamilies were developed in this study. Primers containing degenerate bases were designed to amplify regions of the DNA polymerase (DPOL) gene of alpha- and gamma-HVs, and the glycoprotein B (gB) gene of beta-HVs in a singleplex, non-nested touchdown PCR format. The singleplex touchdown consensus PCR (STC-PCR) was used to amplify the DNA of eight human and 24 animal HVs. The assay was able to detect the lowest DNA dilution of 10−5 for alpha-HVs and 10−3 for beta- and gamma-HVs. In comparison, lowest detection limits of 10−5, 10−3, and 10−2 were obtained for alpha-, beta-, and gamma-HVs respectively when a nested PCR was used. The findings in this study suggest that the STC-PCR assays can be employed for the molecular surveys and clinical detection of novel and known HVs

Maternity waiting homes as an intervention to increase facility delivery in rural Zambia

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150534/1/ijgo12864_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150534/2/ijgo12864.pd

Effect of preoperative sonographic mapping on vascular access outcomes in hemodialysis patients

Effect of preoperative sonographic mapping on vascular access outcomes in hemodialysis patients.BackgroundCurrent DOQI guidelines encourage placing arteriovenous (AV) fistulas in more hemodialysis patients. However, many new fistulas fail to mature sufficiently to be useable for hemodialysis. Preoperative vascular mapping to identify suitable vessels may improve vascular access outcomes. The present study prospectively evaluated the effect of routine preoperative vascular mapping on the type of vascular accesses placed and their outcomes.MethodsDuring a 17-month period, preoperative sonographic evaluation of the upper extremity arteries and veins was obtained routinely. The surgeons used the information obtained to plan the vascular access procedure. The types of access placed, their initial adequacy for dialysis, and their long-term outcomes were compared to institutional historical controls placed on the basis of physical examination alone.ResultsThe proportion of fistulas placed increased from 34% during the historical control period to 64% with preoperative vascular mapping (P < 0.001). When all fistulas were assessed, the initial adequacy rate for dialysis increased mildly from 46 to 54% (P = 0.34). For the subset of forearm fistulas, the initial adequacy increased substantially from 34 to 54% (P = 0.06); the greatest improvement occurred among women (from 7 to 36%, P = 0.06) and diabetic patients (from 21 to 50%, P = 0.055). In contrast, the initial adequacy rate of upper arm fistulas was not improved by preoperative vascular mapping (59 vs. 56%, P = 0.75). Primary access failure was higher for fistulas than grafts (46.4 vs. 20.6%, P = 0.001), but the subsequent long-term failure rate was higher for grafts than fistulas (P < 0.05). Moreover, grafts required a threefold higher intervention rate (1.67 vs. 0.57 per year, P < 0.001) to maintain their patency. The overall effect of this strategy was to double the proportion of patients dialyzing with a fistula in our population from 16 to 34% (P < 0.001).ConclusionsRoutine preoperative vascular mapping results in a marked increase in placement of AV fistulas, as well as an improvement in the adequacy of forearm fistulas for dialysis. This approach resulted in a substantial increase in the proportion of patients dialyzing with a fistula in our patient population. Fistulas have a higher primary failure rate than grafts, but have a lower subsequent failure rate and require fewer procedures to maintain their long-term patency

Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice

Fabry disease is an X-linked lysosomal storage disorder (LSD) caused by mutations in the gene (GLA) that encodes the lysosomal hydrolase α-galactosidase A (α-Gal A), and is characterized by pathological accumulation of the substrate, globotriaosylceramide (GL-3). Regular infusion of recombinant human α-Gal A (rhα-Gal A), termed enzyme replacement therapy (ERT), is the primary treatment for Fabry disease. However, rhα-Gal A has low physical stability, a short circulating half-life, and variable uptake into different disease-relevant tissues. We hypothesized that coadministration of the orally available, small molecule pharmacological chaperone AT1001 (GR181413A, 1-deoxygalactonojirimycin, migalastat hydrochloride) may improve the pharmacological properties of rhα-Gal A via binding and stabilization. AT1001 prevented rhα-Gal A denaturation and activity loss in vitro at neutral pH and 37 °C. Coincubation of Fabry fibroblasts with rhα-Gal A and AT1001 resulted in up to fourfold higher cellular α-Gal A and ~30% greater GL-3 reduction compared to rhα-Gal A alone. Furthermore, coadministration of AT1001 to rats increased the circulating half-life of rhα-Gal A by >2.5-fold, and in GLA knockout mice resulted in up to fivefold higher α-Gal A levels and fourfold greater GL-3 reduction than rhα-Gal A alone. Collectively, these data highlight the potentially beneficial effects of AT1001 on rhα-Gal A, thus warranting clinical investigation

Circulating adipokines are associated with pre-eclampsia in women with type 1 diabetes

AIMS/HYPOTHESIS: The incidence of pre-eclampsia, a multisystem disorder of pregnancy, is fourfold higher in type 1 diabetic than non-diabetic women; it is also increased in women with features of the metabolic syndrome and insulin resistance. In a prospective study of pregnant women with type 1 diabetes, we measured plasma levels of adipokines known to be associated with insulin resistance: leptin, fatty acid binding protein 4 (FABP4), adiponectin (total and high molecular weight [HMW]; also known as high molecular mass), retinol binding protein 4 (RBP4) and resistin and evaluated associations with the subsequent development of pre-eclampsia. METHODS: From an established prospective cohort of pregnant type 1 diabetic women, we studied 23 who developed pre-eclampsia and 24 who remained normotensive; for reference values we included 19 healthy non-diabetic normotensive pregnant women. Plasma adipokines were measured (by ELISA) in stored samples from three study visits (Visit 1 – Visit 3) at different gestational ages (mean ± SD): Visit 1, 12.4 ± 1.8 weeks; Visit 2, 21.7 ± 1.4 weeks; and Visit 3, 31.4 ± 1.5 weeks. All the women were free of microalbuminuria and hypertension at enrolment. All study visits preceded the clinical onset of pre-eclampsia. RESULTS: In all groups, leptin, the ratio of leptin to total or HMW adiponectin, FABP4 concentration, ratio of FABP4 to total or HMW adiponectin and resistin level increased, while total and HMW adiponectin decreased, with gestational age. At Visit 1, (1) in diabetic women with vs without subsequent pre-eclampsia, leptin, ratio of leptin to total or HMW adiponectin, and ratio of FABP4 to total or HMW adiponectin, were increased (p<0.05), while total adiponectin was decreased (p<0.05); and (2) in normotensive diabetic vs non-diabetic women, total adiponectin was elevated (p<0.05). At Visits 2 and 3, (1) the primary findings in the two diabetic groups persisted, and FABP4 also increased in women with subsequent pre-eclampsia (p<0.05); and (2) there were no differences between the two normotensive groups. By logistic regression analyses after covariate adjustment (HbA(1c), insulin kg(−1) day(−1) and gestational age), the best predictive models for pre-eclampsia were as follows: Visit 1, doubling of leptin, OR 9.0 (p<0.01); Visit 2, doubling of the leptin:total adiponectin ratio, OR 3.7 (p<0.05); and Visit 3, doubling of FABP4 concentration, OR 25.1 (p<0.01). The associations were independent of BMI. CONCLUSIONS/INTERPRETATION: As early as the first trimester in type 1 diabetic women, adipokine profiles that suggest insulin resistance are associated with subsequent pre-eclampsia, possibly reflecting maternal characteristics that precede pregnancy. These associations persist in the second and third trimesters, and are independent of BMI. Insulin resistance may predispose women with type 1 diabetes to pre-eclampsia

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes