Twenty-year economic impacts of deworming.

Estimating the impact of child health investments on adult living standards entails multiple methodological challenges, including the lack of experimental variation in health status, an inability to track individuals over time, and accurately measuring living standards and productivity in low-income settings. This study exploits a randomized school health intervention that provided deworming treatment to Kenyan children, and uses longitudinal data to estimate impacts on economic outcomes up to 20 y later. The effective respondent tracking rate was 84%. Individuals who received two to three additional years of childhood deworming experienced a 14% gain in consumption expenditures and 13% increase in hourly earnings. There are also shifts in sectors of residence and employment: treatment group individuals are 9% more likely to live in urban areas, and experience a 9% increase in nonagricultural work hours. Most effects are concentrated among males and older individuals. The observed consumption and earnings benefits, together with deworming's low cost when distributed at scale, imply that a conservative estimate of its annualized social internal rate of return is 37%, a high return by any standard.

Serotonin type-3 receptor antagonists selectively kill melanoma cells through classical apoptosis, microtubule depolymerisation, ERK activation, and NF-κB downregulation.

Malignant melanoma is a highly metastatic tumour, resistant to treatment. Serotonin type-3 (5-HT3) receptor antagonists, such as tropisetron and ondansetron, are well-tolerated antiemetic drugs commonly used to prevent nausea caused by chemotherapy or radiotherapy. We investigated the anticancer effects of these drugs on melanoma cancer cell lines WM-266-4 and B16F10 with or without paclitaxel. We constructed IC50 curves and performed Chou-Talalay analysis, using data obtained with the MTT assay. Flow cytometry and fluorescent microscopy were used to examine characteristics of the cell cycle, cell death and cytoskeleton changes. Protein levels and activation were analysed by western blotting and molecular docking studies carried out. Data were analysed by one way ANOVA and post hoc testing. Ondansetron and tropisetron showed selective concentration-dependent cytotoxicity in melanoma cell lines WM-266-4 and B16F10. The effect in combination with paclitaxel was synergistic. The drugs did not cause cell cycle arrest but did promote characteristics of classical apoptosis, including accumulation of subG1 DNA, cleaved caspase-3, mitochondrial membrane permeability and phosphatidylserine exposure. As well, the cytosolic calcium level in the melanoma cells was enhanced, phosphorylated ERK1/2 induced and NF-κB inhibited. Finally, the formation of microtubules was shown to be impaired in melanoma cells treated with ondansetron or tropisetron. Docking studies were used to predict that these drugs could bind to the colchicine binding site on the tubulin molecule. Antiemetic drugs, already given in combination with chemotherapy, may enhance the cytotoxic effect of chemotherapy, following successful delivery to the tumour site.

Agency and role models: do they matter for adolescent girls' sexual and reproductive health?

Despite recent declines in early childbearing in Ethiopia, improved sexual and reproductive health continues to elude many adolescent girls, partially due to constrained agency and role models. This study examined the relationship between agency, role models and two sexual and reproductive health outcomes, ideal age at childbirth and attitude towards gender-differentiated parental control, among adolescent girls in Ethiopia. Agency and role model presence were positively associated with ideal age at childbirth (ß = 0.23, p < .01 and ß = 0.77, p < .001, respectively). Having family members, friends or famous individuals as role models was significantly associated with an increase of 1.45 years (p < .01), 1.32 years (p < .05) and 1.01 years (p < .01) in ideal age at childbirth, respectively, compared to having no role model. Agency was positively associated with attitude towards gender-differentiated parental control of adolescent behaviors (OR = 1.18, p < .001). This study highlights the need for interventions aimed at increasing agency and providing role models for adolescent girls.

Women's employment and Children's education: Longitudinal evidence from Nepal.

This study examines how maternal employment is related to children's school enrollment in rural Nepal. Using the Chitwan Valley Family Study we combine over 30 years (1974-2008) of yearly data on mother's employment and their children's education. Results reveal heterogeneity by gender, social status, and type of work. Children from historically disadvantaged social groups were more likely to be in school when their mothers started working. This was largely driven by mothers with jobs that allowed them to more easily combine work and family tasks (i.e., those self-employed in the home). In fact, maternal self-employment outside the home was associated with boys dropping out of school. Additionally, we find evidence that some of the observed relationship between maternal wage labor and children's school enrollment is due to household-level selection effects on mother's work.

Cyclic Imine Pinnatoxin G is Cytotoxic to Cancer Cell Lines via Nicotinic Acetylcholine Receptor-Driven Classical Apoptosis.

Pinnatoxin G is a cyclic imine neurotoxin produced by dinoflagellates that has been reported in shellfish. Like other members of the pinnatoxin family, it has been shown to have its effects via antagonism of the nicotinic acetylcholine receptors, with preferential binding to the α7 subunit often upregulated in cancer. Because increased activity of α7 nicotinic acetylcholine receptors contributes to increased growth and resistance to apoptosis, the effect of pinnatoxin G on cancer cell viability was tested. In a panel of six cancer cell lines, all cell types lost viability, but HT29 colon cancer and LN18 and U373 glioma cell lines were more sensitive than MDA-MB-231 breast cancer cells, PC3 prostate cancer cells, and U87 glioma cells, correlating with expression levels of α7, α4, and α9 nicotinic acetylcholine receptors. Some loss of cell viability could be attributed to cell cycle arrest, but significant levels of classical apoptosis were found, characterized by caspase activity, phosphatidylserine exposure, mitochondrial membrane permeability, and fragmented DNA. Intracellular Ca2+ levels also dropped immediately upon pinnatoxin G treatment, which may relate to antagonism of nicotinic acetylcholine receptor-mediated Ca2+ inflow. In conclusion, pinnatoxin G can decrease cancer cell viability, with both cytostatic and cytotoxic effects.

Facilitators and barriers to antiretroviral therapy adherence among HIV-positive adolescents living in Tanzania.

BACKGROUND: Adolescents living with HIV face substandard outcomes along the continuum of care, including higher rates of poor adherence and virologic failure. Support groups have been identified as a method to improve adherence, but there is insufficient evidence regarding their effectiveness. This study seeks to examine the protective influences for and barriers to antiretroviral therapy (ART) adherence in HIV-positive adolescents living in Tanzania. METHODS: This is a qualitative study conducted in Tanzania from January to March 2018. The sample of adolescents aged 10-19 (n = 33) was purposefully selected based on age, gender, and support group attendance to capture a broad range of experiences. Participants completed an in-depth interview, covering topics such as retention in HIV services, support group experiences, and joys and challenges of adolescent life. Interviews were coded and themes related to ART adherence were identified and summarized. RESULTS: Support groups helped promote adherence by improving adolescents' knowledge and confidence. Participants associated joining support groups with an improvement in health. Almost every participant described the significant positive influence a treatment supporter had on adherence. Adolescents' daily schedules and emotional state served as a barrier to adherence. Furthermore, adherence was negatively impacted by participants' fear of accidental disclosure. CONCLUSION: Logistical and psychosocial factors can hinder adherence. Interventions that provide both education and psychosocial support, such as peer support groups, have the potential to improve health outcomes for this population, but may not address more persistent barriers to adherence rooted in lack of treatment support from family members or friends who have not been disclosed to, or lack of transportation funds/food security.

Multilevel influences of women's empowerment and economic resources on risky sexual behaviour among young women in Zomba district, Malawi.

Gender disparities are pronounced in Zomba district, Malawi. Among women aged 15-49 years, HIV prevalence is 16.8%, compared with 9.3% among men of the same age. Complex structural factors are associated with risky sexual behaviour leading to HIV infection. This study's objective was to explore associations between multilevel measures of economic resources and women's empowerment with risky sexual behaviour among young women in Zomba. Four measures of risky sexual behaviour were examined: ever had sex, condom use and two indices measuring age during sexual activity and partner history. Multilevel regression models and regression models with cluster-robust standard errors were used to estimate associations, stratified by school enrolment status. Among the schoolgirl stratum, the percentage of girls enrolled in school at the community level had protective associations with ever having sex (OR = 0.76; 95% CI: 0.60, 0.96) and condom use (OR = 1.06; 95% CI: 1.01, 1.11). Belief in the right to refuse sex was protective against ever having sex (OR = 0.76; 95% CI: 0.60, 0.96). Participants from households with no secondary school education had higher odds of ever having sex (OR = 1.59; 95% CI: 1.14, 2.22). Among the dropout stratum, participants who had not achieved a secondary school level of education had riskier Age Factor and Partner History Factor scores (ß = 0.51; 95% CI: 0.23, 0.79, and ß = 0.24; 95% CI: 0.07, 0.41, respectively). Participants from households without a secondary school level of education had riskier Age Factor scores (ß = 0.26; 95% CI: 0.03, 0.48). Across strata, the most consistent variables associated with risky sexual behaviour were those related to education, including girl's level of education, highest level of education of her household of origin and the community percentage of girls enrolled in school. These results suggest that programmes seeking to reduce risky sexual behaviour among young women in Malawi should consider the role of improving access to education at multiple levels.

Intersecting barriers to adolescents' educational access during COVID-19: Exploring the role of gender, disability and poverty.

This article explores the social determinants of adolescents' access to education during the COVID-19 pandemic in three diverse urban contexts in Bangladesh, Ethiopia and Jordan. It provides novel empirical data from the Gender and Adolescence: Global Evidence longitudinal study, drawing on phone surveys (4441), qualitative interviews with adolescents aged 12-19 years (500), and key informant interviews conducted between April and October 2020. Findings highlight that the pandemic is compounding pre-existing vulnerabilities to educational disadvantage, and that gender, poverty and disability are intersecting to deepen social inequalities. The paper concludes by reflecting on policy implications for inclusive distance education in emergencies.

Intersecting inequalities, gender and adolescent health in Ethiopia.

BACKGROUND: Until recently, global public health initiatives have tended to overlook the ways that social factors shape adolescent health, and particularly how these dynamics affect the specific needs of adolescents in relation to information about puberty, menstruation and sexual health. This article draws on mixed methods data from rural and urban areas of Ethiopia to explore how access to health information and resources - and subsequently health outcomes - for adolescents are mediated by gender and age norms, living in different geographical locations, poverty, disability and migration. METHODS: Data was collected in 2017-2018 for the Gender and Adolescence: Global Evidence (GAGE) mixed-methods longitudinal research baseline in three regions of Ethiopia (Afar, Amhara and Oromia). Quantitative data was collected from over 6800 adolescents and their caregivers, with qualitative data obtained from a sub-sample of 220 adolescents, their families and communities. Adolescent participants shared their experiences of health, illness and nutrition over the previous year; their knowledge and sources of information about sexual and reproductive health and puberty; and their attitudes toward sexual and reproductive health. Regression analysis was used to explore differences by gender, age, rural/urban residence, and disability status, across a set of adolescents' health knowledge and other outcomes in the quantitative data. Intersectional analysis was used in analysing the qualitative data. RESULTS: Analysis suggested that gender inequality intersects with age, disability and rural/urban differences to shape young people's access to information about puberty, with knowledge about this topic particularly lacking amongst younger adolescents in rural areas. Drought and lack of access to clean water exacerbates health challenges for adolescents in rural areas, where a lack of information and absence of access to preventive healthcare services can lead to permanent disability. The research also found that gaps in both school-based and alternative sources of education about puberty and menstruation reinforce stigma and misinformation, especially in rural areas where adolescents have higher school attrition rates. Gendered cultural norms that place high value on marriage and motherhood generate barriers to contraceptive use, particularly in certain rural communities. CONCLUSIONS: As they progress through adolescence, young people's overall health and access to information about their changing bodies is heavily shaped by intersecting social identities. Structural disadvantages such as poverty, distress migration and differential access to healthcare intersect with gender norms to generate further inequalities in adolescent girls' and boys' health outcomes.

Mesenchymal stem cell homing towards cancer cells is increased by enzyme activity of cathepsin D.

Mesenchymal stem cells home towards inflammatory microenvironments, such as the tumour stroma, where they have been shown to have both pro- and anti-tumorigenic effects. Here, we demonstrate that the aspartic acid protease cathepsin D is part of the chemoattraction process. Using a Boyden chamber co-culture system, the migration of the mesenchymal stem cells and their invasion through Matrigel increased in the presence of breast cancer MDA-MB-231 cells, colon cancer HT29 cells or their conditioned media. Mesenchymal stem cell movement was reduced by protease inhibitors of matrix metalloproteinases and by pepstatin A, an inhibitor of cathepsin D. We confirmed a role for cathepsin D through addition of recombinant protein, upregulation of cathepsin D release using chloroquine and knockdown of cathepsin D expression. While all cell types expressed active cathepsin D, enzymatically inactive precursor procathepsin D was expressed only at low levels by mesenchymal stem cells. Expression in mesenchymal stem cells was increased following co-culture with cancer cells. The chemoattractive effect of cathepsin D required its enzymatic activity, but not changes in mesenchymal stem cell proliferation or adhesion rates. In conclusion, cathepsin D and its precursors enhance mesenchymal stem cell homing towards tumour sites, most likely by enzymatic mechanisms.

ASSOCIATION BETWEEN HIV AWARENESS FACTORS, HEALTH FACILITY CHARACTERISTICS AND RISKY SEXUAL BEHAVIOUR AMONG YOUNG WOMEN IN ZOMBA DISTRICT, MALAWI.

The objective of this study was to examine the association between multilevel factors related to HIV awareness and risky sexual behaviour among young women in Zomba district, Malawi. Secondary analyses of the Schooling, Income, and Health Risk (SIHR) study were undertaken. Four outcomes related to risky sexual behaviour were examined among young women: if participants had ever had sex, consistent condom use and two scores measuring risk related to partner history and age during sexual activity. Independent variables included individual-level factors such as education and rural/urban residence, as well as higher-level factors such as household's highest level of education and health facility characteristics. Regression models with cluster-robust standard errors and multilevel regression models were used to estimate associations; analyses were stratified into two strata by school enrolment status, i.e. whether the women were in school (N=1407) or had dropped out of school (N=407) at baseline of the SIHR study. For both strata, increasing age and residing within 16 km of an urban centre ('near rural' residence) increased the odds of ever having sex; lower educational achievement was associated with lower age during sexual activity. A history of pregnancy was associated with lower odds of condom use and riskier partner history. For women in school at baseline, lower household education was associated with higher odds of ever having sex (OR=1.48; 95% CI: 1.06, 2.07); near-rural and far-rural (≤16 km and >16km from urban centre, respectively) residence were associated with decreased odds of condom use (OR=0.47; 95% CI: 0.28, 0.78; and OR=0.27; 95% CI: 0.11, 0.65, respectively). For those not in school at baseline, lower household education was associated with lower age during sexual activity (ß=0.31, 95% CI: 0.05, 0.58). Also for women not in school, the use of private or non-governmental health facilities was associated with decreased odds of condom use (OR=0.51, 95% CI: 0.39, 0.67) and higher age during sexual activity (ß=-0.30, 95% CI: -0.52, -0.09). While individual factors were associated with risky sexual behaviour in both strata, contextual factors differed.

Native Chinook salmon Oncorhynchus tshawytscha and non-native brook trout Salvelinus fontinalis prefer similar water temperatures.

Preferred water temperatures and acute temperature tolerance limits of two salmonids in California were assessed: juvenile Chinook salmon Oncorhynchus tshawytscha, a native anadromous species, and sub-adult brook trout Salvelinus fontinalis, an introduced game species. These two species preferred similar temperatures across an 18 h temperature preference experiment and showed similar critical thermal tolerance limits, suggesting a substantial thermal habitat overlap in the wild.

Assessment of multiple stressors on the growth of larval green sturgeon Acipenser medirostris: implications for recruitment of early life-history stages.

Early developmental stages of fishes are particularly sensitive to changes in environmental variables that affect physiological processes such as metabolism and growth. Both temperature and food availability have significant effects on the growth and survival of larval and juvenile fishes. As climate change and anthropogenic disturbances influence sensitive rearing environments of fishes it is unlikely that they will experience changes in temperature or food availability in isolation. Therefore, it is critical that we determine the effects of each of these potential stressors on larval growth and development, as well as understand the additive, synergistic or antagonistic effects of both. We reared threatened green sturgeon Acipenser medirostris (initial age ca. 32 days post hatch) at four temperatures (11, 13, 16 and 19°C) and two food availability rates (100% and 40% of optimal) to assess the effects of these stressors and their interactions on larval growth. We compared the overall size (fork length, total length and mass), growth rates (cm day-1 and g day-1 ) and relative condition factor of these larval and juvenile fish at 3 week intervals for up to 12 weeks. Our results indicated that temperature and food availability both had significant effects on growth and condition and that there was a significant interaction between the two. Fish reared with limited food availability exhibited similar patterns in growth rates to those reared with elevated food rates, but the effects of temperature were greatly attenuated when fish were food-limited. Also, the effects of temperature on condition were reversed when fish were reared with restricted food, such that fish reared at 19°C exhibited the highest relative condition when fed optimally, but the lowest relative condition when food was limited. These data are critical for the development of relevant bioenergetics models, which are needed to link the survival of larval sturgeons with historic environmental regimes, pinpoint temperature ranges for optimal survival and help target future restoration sites that will be important for the recovery of sturgeon populations.

Simulations for designing and interpreting intervention trials in infectious diseases.

BACKGROUND: Interventions in infectious diseases can have both direct effects on individuals who receive the intervention as well as indirect effects in the population. In addition, intervention combinations can have complex interactions at the population level, which are often difficult to adequately assess with standard study designs and analytical methods. DISCUSSION: Herein, we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly with regard to emerging infectious diseases, one that more accurately reflects the dynamics of the transmission process. In an increasingly complex world, simulations can explicitly represent transmission dynamics, which are critical for proper trial design and interpretation. Certain ethical aspects of a trial can also be quantified using simulations. Further, after a trial has been conducted, simulations can be used to explore the possible explanations for the observed effects. CONCLUSION: Much is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods, and the conduct of clinical trials.

Programmed death-ligand 1 (PD-L1) characterization of circulating tumor cells (CTCs) in muscle invasive and metastatic bladder cancer patients.

BACKGROUND: While programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) checkpoint inhibitors have activity in a proportion of patients with advanced bladder cancer, strongly predictive and prognostic biomarkers are still lacking. In this study, we evaluated PD-L1 protein expression on circulating tumor cells (CTCs) isolated from patients with muscle invasive (MIBC) and metastatic (mBCa) bladder cancer and explore the prognostic value of CTC PD-L1 expression on clinical outcomes. METHODS: Blood samples from 25 patients with MIBC or mBCa were collected at UCSF and shipped to Epic Sciences. All nucleated cells were subjected to immunofluorescent (IF) staining and CTC identification by fluorescent scanners using algorithmic analysis. Cytokeratin expressing (CK)+ and (CK)-CTCs (CD45-, intact nuclei, morphologically distinct from WBCs) were enumerated. A subset of patient samples underwent genetic characterization by fluorescence in situ hybridization (FISH) and copy number variation (CNV) analysis. RESULTS: CTCs were detected in 20/25 (80 %) patients, inclusive of CK+ CTCs (13/25, 52 %), CK-CTCs (14/25, 56 %), CK+ CTC Clusters (6/25, 24 %), and apoptotic CTCs (13/25, 52 %). Seven of 25 (28 %) patients had PD-L1+ CTCs; 4 of these patients had exclusively CK-/CD45-/PD-L1+ CTCs. A subset of CTCs were secondarily confirmed as bladder cancer via FISH and CNV analysis, which revealed marked genomic instability. Although this study was not powered to evaluate survival, exploratory analyses demonstrated that patients with high PD-L1+/CD45-CTC burden and low burden of apoptotic CTCs had worse overall survival. CONCLUSIONS: CTCs are detectable in both MIBC and mBCa patients. PD-L1 expression is demonstrated in both CK+ and CK-CTCs in patients with mBCa, and genomic analysis of these cells supports their tumor origin. Here we demonstrate the ability to identify CTCs in patients with advanced bladder cancer through a minimally invasive process. This may have the potential to guide checkpoint inhibitor immune therapies that have been established to have activity, often with durable responses, in a proportion of these patients.

Maternity Leave Access and Health: A Systematic Narrative Review and Conceptual Framework Development.

Background Maternity leave is integral to postpartum maternal and child health, providing necessary time to heal and bond following birth. However, the relationship between maternity leave and health outcomes has not been formally and comprehensively assessed to guide public health research and policy in this area. This review aims to address this gap by investigating both the correlates of maternity leave utilization in the US and the related health benefits for mother and child. Methods We searched the peer-reviewed scholarly literature using six databases for the years 1990 to early 2015 and identified 37 studies to be included in the review. We extracted key data for each of the included studies and assessed study quality using the "Weight of the Evidence" approach. Results The literature generally confirms a positive, though limited correlation between maternity leave coverage and utilization. Likewise, longer maternity leaves are associated with improved breastfeeding intentions and rates of initiation, duration and predominance as well as improved maternal mental health and early childhood outcomes. However, the literature points to important disparities in access to maternity leave that carry over into health outcomes, such as breastfeeding. Synthesis We present a conceptual framework synthesizing what is known to date related to maternity leave access and health outcomes.

Integral membrane protease fibroblast activation protein sensitizes fibrosarcoma to chemotherapy and alters cell death mechanisms.

Fibroblast activation protein (FAP), an integral membrane serine protease, is found on fibro- and osteo-sarcoma and on myofibroblasts in epithelial carcinoma, but rarely on other adult tissue. FAP has been demonstrated to be an excellent target for tumor imaging in clinical trials, and antibodies and other FAP-targeting drugs are in development. Here we have shown that FAP overexpression increased the growth of HT1080 fibrosarcoma cells in vitro and in vivo, and found that the expression of FAP affects response to chemotherapy. When treated with doxorubicin, expression of FAP increased susceptibility to the drug. In spite of this, FAP-HT1080 cells had fewer markers of classical apoptosis than HT1080 cells and neither necrosis nor necroptosis were enhanced. However, levels of early mitochondrial and lysosomal membrane permeability markers were increased, and autophagy switched from a protective function in HT1080 cells to part of the cell death mechanism with FAP expression. Therefore, FAP may affect how the tumor responds to chemotherapeutic drugs overall, which should be considered in targeted drug development. The overexpression of FAP also alters cell signaling and responses to the environment in this cell line. This includes cell death mechanisms, changing the response of HT1080 cells to doxorubicin from classical apoptosis to an organelle membrane permeability-dependent form of cell death.

Mesenchymal stem cells inhibit breast cancer cell migration and invasion through secretion of tissue inhibitor of metalloproteinase-1 and -2.

Mesenchymal stem cells (MSCs) form part of tumor stroma, and are typically considered to be pro-tumorigenic, promoting continuing tumor growth and metastasis. Here, we describe a mechanism by which MSCs may be anti-tumorigenic, through inhibition of breast cancer cell migration and invasion, an important part of metastasis. MDA-MB-231 and T47D cells were co-cultured in a Transwell insert above MSCs or MSC conditioned media and their migration or invasion through Matrigel measured. The conditioned media was found to inhibit breast cancer cell movement. TIMP-1 and TIMP-2, inhibitors of matrix metalloproteinases (MMPs), were identified as candidates for this inhibition and enhanced secretion of MMPs was not sufficient to counter the anti-migratory effects of TIMP expression. Inhibition of TIMP activity showed that TIMP-1 and TIMP-2 together were largely responsible for the reduction of migration and invasion by MSCs. Therefore, MSCs may play anti-tumorigenic, anti-metastatic roles in tumor development, with the overall outcome dependent upon the balance of pro-and anti-tumorigenic molecules secreted.