Physico-electrochemical Characterization of Pluripotent Stem Cells during Self-Renewal or Differentiation by a Multi-modal Monitoring System.

Monitoring pluripotent stem cell behaviors (self-renewal and differentiation to specific lineages/phenotypes) is critical for a fundamental understanding of stem cell biology and their translational applications. In this study, a multi-modal stem cell monitoring system was developed to quantitatively characterize physico-electrochemical changes of the cells in real time, in relation to cellular activities during self-renewal or lineage-specific differentiation, in a non-destructive, label-free manner. The system was validated by measuring physical (mass) and electrochemical (impedance) changes in human induced pluripotent stem cells undergoing self-renewal, or subjected to mesendodermal or ectodermal differentiation, and correlating them to morphological (size, shape) and biochemical changes (gene/protein expression). An equivalent circuit model was used to further dissect the electrochemical (resistive and capacitive) contributions of distinctive cellular features. Overall, the combination of the physico-electrochemical measurements and electrical circuit modeling collectively offers a means to longitudinally quantify the states of stem cell self-renewal and differentiation

The Impact of Health Workers' Strikes on Health Outcomes and Health Service Utilization in Low-and Middle-Income Countries: A Systematic Review

Background The impact of strikes by health workers in low- and middle-income countries (LMIC) is not well described. We systematically reviewed articles on the impact of health workers’ strikes on health outcomes or health service utilization in LMIC. Methods We searched PubMed, SCOPUS, Web of Science, and Google Scholar databases on May 27, 2019. To be included for review, articles met the following criteria: (1) reported on a strike that involved at least one cadre of health worker; (2) reported on a strike in a LMIC; (3) included at least one outcome related to patient or population health or health service utilization; and, (4) included a reference group or time period. There were no date or language restrictions. We modified the Newcastle-Ottawa Tool to appraise study quality. The review is registered with PROSPERO (CRD42019124989). Findings Among 5,123 articles, eleven articles met inclusion criteria. Studies examined 20 strikes in LMIC from 1991 to 2017 (average strike length of 32·9 days), with five studies from Kenya, two each from India and Nigeria, and one each from Malawi and South Africa. The majority of studies reported hospital admissions or inpatient mortality. Generally, health service utilization decreased during strike periods, but changes in patient mortality and other health outcomes varied. Study quality was heterogenous with most studies reporting from a single facility or medical department. Interpretation Compared to high-income settings, our study suggests a more complex picture of the effect of strikes by health workers on health and health service utilization outcomes in LMIC

Improving maternal, newborn and child health outcomes through a community-based women's health education program: a cluster randomised controlled trial in western Kenya

Introduction: Community-based women's health education groups may improve maternal, newborn and child health (MNCH); however, evidence from sub-Saharan Africa is lacking. Chamas for Change (Chamas) is a community health volunteer (CHV)-led, group-based health education programme for pregnant and postpartum women in western Kenya. We evaluated Chamas' effect on facility-based deliveries and other MNCH outcomes. Methods: We conducted a cluster randomised controlled trial involving 74 community health units in Trans Nzoia County. We included pregnant women who presented to health facilities for their first antenatal care visits by 32 weeks gestation. We randomised clusters 1:1 without stratification or matching; we masked data collectors, investigators and analysts to allocation. Intervention clusters were invited to bimonthly, group-based, CHV-led health lessons (Chamas); control clusters had monthly, individual CHV home visits (standard of care). The primary outcome was facility-based delivery at 12-month follow-up. We conducted an intention-to-treat approach with multilevel logistic regression models using individual-level data. Results: Between 27 November 2017 and 8 March 2018, we enrolled 1920 participants from 37 intervention and 37 control clusters. A total of 1550 (80.7%) participants completed the study with 822 (82.5%) and 728 (78.8%) in the intervention and control arms, respectively. Facility-based deliveries improved in the intervention arm (80.9% vs 73.0%; risk difference (RD) 7.4%, 95% CI 3.0 to 12.5, OR=1.58, 95% CI 0.97 to 2.55, p=0.057). Chamas participants also demonstrated higher rates of 48 hours postpartum visits (RD 15.3%, 95% CI 12.0 to 19.6), exclusive breastfeeding (RD 11.9%, 95% CI 7.2 to 16.9), contraceptive adoption (RD 7.2%, 95% CI 2.6 to 12.9) and infant immunisation completion (RD 15.6%, 95% CI 11.5 to 20.9). Conclusion: Chamas participation was associated with significantly improved MNCH outcomes compared with the standard of care. This trial contributes robust data from sub-Saharan Africa to support community-based, women's health education groups for MNCH in resource-limited settings.Trial registration numberNCT03187873

Scalable Purification and Characterization of the Anticancer Lunasin Peptide from Soybean

Lunasin is a peptide derived from the soybean 2S albumin seed protein that has both anticancer and anti-inflammatory activities. Large-scale animal studies and human clinical trials to determine the efficacy of lunasin in vivo have been hampered by the cost of synthetic lunasin and the lack of a method for obtaining gram quantities of highly purified lunasin from plant sources. The goal of this study was to develop a large-scale method to generate highly purified lunasin from defatted soy flour. A scalable method was developed that utilizes the sequential application of anion-exchange chromatography, ultrafiltration, and reversed-phase chromatography. This method generates lunasin preparations of >99% purity with a yield of 442 mg/kg defatted soy flour. Mass spectrometry of the purified lunasin revealed that the peptide is 44 amino acids in length and represents the original published sequence of lunasin with an additional C-terminal asparagine residue. Histone-binding assays demonstrated that the biological activity of the purified lunasin was similar to that of synthetic lunasin. This study provides a robust method for purifying commercial-scale quantities of biologically-active lunasin and clearly identifies the predominant form of lunasin in soy flour. This method will greatly facilitate the development of lunasin as a potential nutraceutical or therapeutic anticancer agent

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Methionine adenosyltransferases in cancers: Mechanisms of dysregulation and implications for therapy

Methionine adenosyltransferase genes encode enzymes responsible for the biosynthesis of S-adenosylmethionine, the principal biological methyl donor and precursor of polyamines and glutathione. Mammalian cells express three genes - MAT1A, MAT2A, and MAT2B - with distinct expression and functions. MAT1A is mainly expressed in the liver and maintains the differentiated states of both hepatocytes and bile duct epithelial cells. Conversely, MAT2A and MAT2B are widely distributed in non-parenchymal cells of the liver and extrahepatic tissues. Increasing evidence suggests that methionine adenosyltransferases play significant roles in the development of cancers. Liver cancers, namely hepatocellular carcinoma and cholangiocarcinoma, involve dysregulation of all three methionine adenosyltransferase genes. MAT1A reduction is associated with increased oxidative stress, progenitor cell expansion, genomic instability, and other mechanisms implicated in tumorigenesis. MAT2A/MAT2B induction confers growth and survival advantage to cancerous cells, enhancing tumor migration. Highlighted examples from colon, gastric, breast, pancreas and prostate cancer studies further underscore methionine adenosyltransferase genes' role beyond the liver in cancer development. In this subset of extra-hepatic cancers, MAT2A and MAT2B are induced via different regulatory mechanisms. Understanding the role of methionine adenosyltransferase genes in tumorigenesis helps identify attributes of these genes that may serve as valuable targets for therapy. While S-adenosylmethionine, and its metabolite, methylthioadenosine, have been largely explored as therapeutic interventions, targets aimed at regulation of MAT gene expression and methionine adenosyltransferase protein-protein interactions are now surfacing as potential effective strategies for treatment and chemoprevention of cancers. Impact statement This review examines the role of methionine adenosyltransferases (MATs) in human cancer development, with a particular focus on liver cancers in which all three MAT genes are implicated in tumorigenesis. An overview of MAT genes, isoenzymes and their regulation provide context for understanding consequences of dysregulation. Highlighting examples from liver, colon, gastric, breast, pancreas and prostate cancers underscore the importance of understanding MAT's tumorigenic role in identifying future targets for cancer therapy

Participation in a Community-Based Women's Health Education Program and At-Risk Child Development in Rural Kenya: Developmental Screening Questionnaire Results Analysis

Background: Over 43% of children living in low- and middle-income countries are at risk for developmental delays; however, access to protective interventions in these settings is limited. We evaluated the effect of maternal participation in Chamas for Change (Chamas)-a community-based women's health education program during pregnancy and postpartum-and risk of developmental delay among their children in rural Kenya. Methods: We analyzed developmental screening questionnaire (DSQ) data from a cluster randomized controlled trial in Trans Nzoia County, Kenya (ClinicalTrials.gov, NCT03187873). Intervention clusters (Chamas) participated in community health volunteer-led, group-based health lessons twice a month during pregnancy and postpartum; controls had monthly home visits (standard of care). We screened all children born during the trial who were alive at 1-year follow-up. We labeled children with any positive item on the DSQ as "at-risk development." We analyzed data using descriptive statistics and multilevel regression models (α=.05); analyses were intention-to-treat using individual-level data. Results: Between November 2017 and March 2018, we enrolled 1,920 pregnant women to participate in the parent trial. At 1-year follow-up, we screened 1,273 (689 intervention, 584 control) children born during the trial with the DSQ. Intervention mothers had lower education levels and higher poverty likelihood scores than controls (P<.001 and P=.007, respectively). The overall rate of at-risk development was 3.5%. Children in Chamas clusters demonstrated significantly lower rates of at-risk development than controls (2.5% vs. 4.8%, P=.025). Adjusted analyses revealed lower odds for at-risk development in the intervention arm (OR=0.50; 95% confidence interval=0.27, 0.94). Conclusions: Maternal participation in a community-based women's health education program was associated with lower rates of at-risk development compared to the standard of care. Overall, rates of at-risk development were lower than expected for this population, warranting further investigation. Chamas may help protect children from developmental delay in rural Kenya and other resource-limited settings

‘It was hell in the community’: a qualitative study of maternal and child health care during health care worker strikes in Kenya

Background Health care workers in Kenya have launched major strikes in the public health sector in the past decade but the impact of strikes on health systems is under-explored. We conducted a qualitative study to investigate maternal and child health care and services during nationwide strikes by health care workers in 2017 from the perspective of pregnant women, community health volunteers (CHVs), and health facility managers. Methods We conducted in-depth interviews and focus group discussions (FGDs) with three populations: women who were pregnant in 2017, CHVs, and health facility managers. Women who were pregnant in 2017 were part of a previous study. All participants were recruited using convenience sampling from a single County in western Kenya. Interviews and FGDs were conducted in English or Kiswahili using semi-structured guides that probed women’s pregnancy experiences and maternal and child health services in 2017. Interviews and FGDs were audio-recorded, translated, and transcribed. Content analysis followed a thematic framework approach using deductive and inductive approaches. Results Forty-three women and 22 CHVs participated in 4 FGDs and 3 FGDs, respectively, and 8 health facility managers participated in interviews. CHVs and health facility managers were majority female (80%). Participants reported that strikes by health care workers significantly impacted the availability and quality of maternal and child health services in 2017 and had indirect economic effects due to households paying for services in the private sector. Participants felt it was the poor, particularly poor women, who were most affected since they were more likely to rely on public services, while CHVs highlighted their own poor working conditions in response to strikes by physicians and nurses. Strikes strained relationships and trust between communities and the health system that were identified as essential to maternal and child health care. Conclusion We found that the impacts of strikes by health care workers in 2017 extended beyond negative health and economic effects and exacerbated fundamental inequities in the health system. While this study was conducted in one County, our findings suggest several potential avenues for strengthening maternal and child health care in Kenya that were highlighted by nationwide strikes in 2017.Medicine, Faculty ofNon UBCObstetrics and Gynaecology, Department ofReviewedFacult

A retrospective study of the impact of health worker strikes on maternal and child health care utilization in western Kenya

Background There have been dozens of strikes by health workers in Kenya in the past decade, but there are few studies of their impact on maternal and child health services and outcomes. We conducted a retrospective survey study to assess the impact of nationwide strikes by health workers in 2017 on utilization of maternal and child health services in western Kenya. Methods We utilized a parent study to enroll women who were pregnant in 2017 when there were prolonged strikes by health workers (“strike group”) and women who were pregnant in 2018 when there were no major strikes (“control group”). Trained research assistants administered a close-ended survey to retrospectively collect demographic and pregnancy-related health utilization and outcomes data. Data were collected between March and July 2019. The primary outcomes of interest were antenatal care (ANC) visits, delivery location, and early child immunizations. Generalized estimating equations were used to estimate risk ratios between the strike and control groups, adjusting for socioeconomic status, health insurance status, and clustering. Adjusted risk ratios (ARR) were calculated with 95% confidence intervals (95%CI). Results Of 1341 women recruited in the parent study in 2017 (strike group), we re-consented 843 women (63%) to participate. Of 924 women recruited in the control arm of the parent study in 2018 (control group), we re-consented 728 women (79%). Women in the strike group were 17% less likely to attend at least four ANC visits during their pregnancy (ARR 0.83, 95%CI 0.74, 0.94) and 16% less likely to deliver in a health facility (ARR 0.84, 95%CI 0.76, 0.92) compared to women in the control group. Whether a child received their first oral polio vaccine did not differ significantly between groups, but children of women in the strike group received their vaccine significantly longer after birth (13 days versus 7 days, p = 0.002). Conclusion We found that women who were pregnant during nationwide strikes by health workers in 2017 were less likely to receive WHO-recommended maternal child health services. Strategies to maintain these services during strikes are urgently needed.Medicine, Faculty ofNon UBCObstetrics and Gynaecology, Department ofReviewedFacult