The Next Ten Years: Looking Back, Looking Forward

As we near our tenth year as a publication, the journal’s global community continues to grow in ways we could not have imagined when we first started. We now receive over 300 submissions per year. We are proud to be among the top-20 journals in higher education according to GoogleScholar with almost 10,000 active subscribers around the world. As we prepare for the next ten years, we want to share a few updates on where we have been and where we are going. We have five major focus areas as we move forward as a publication: expand our global network of authors, scholars, and leaders; design top-tier journal design and seamless editorial workflow; build international partnerships and diversity editorial team; create mentor pathways for emerging scholars; and develop sustainable funding and support

TruMet: An approach towards computing trust in multi-agent environment.

The growing popularity of multi-agent based approaches towards the formation and operation of virtual organizations (VO) present over the Internet, offer both opportunities and risks. One of the risks involved in such community is in the identification of trustworthy agent partners for transaction. In this paper we aim to describe our trust model which would contribute in measuring trust in the interacting agents. Named as TruMet, the trust metric model works on the basis of the parameters that we have identified as relevant to the features of the community. The model primarily analyses trust value on the basis of the agent¿s reputation, as provided by the agent itself, and the agent¿s aggregate rating as provided by the witness agents. The final computation of the trust value is given by a weighted average of these two components. While computing the aggregate rating, a weight based method has been adopted to discount the contribution of possibly un-fair ratings by the witness agents

The Association Between Coping Strategies, Resilience, and Flourishing Among Students at Large U.S. University During the COVID-19 Pandemic: A Mixed Methods Research Study

Background: Mental illness indicators increased among U.S. university students in recent years; COVID-19 associated disruptions presented additional mental health challenges for students. Aim: This research aimed to assess the relationship between coping strategies identified by university students and scores on resilience and flourishing scales and to identify additional themes that described student experiences during the COVID-19 pandemic. Methods: An online survey was administered to students at a large public Midwestern University. Quantitative data were assessed using nonparametric tests for association and qualitative data were analyzed using cycles of open coding. Results: Most of the 3,473 respondents were female (76.5%) and white (83.6%), with a mean age of 24.67 years (SD = 8.08). The most frequent coping strategy was physical activity participation (n = 712), followed by socializing (n = 507). The highest resilience and flourishing scores were associated with compliance to COVID-19 associated recommendations or spiritual activities. Qualitative themes included the value of focusing on controllable aspects, the need to be strong for others, and the experience of academic overload during transition to online learning. Conclusions: Universities should endeavor to provide ongoing availability of counseling during university disruptions. Universities might also consider proactive efforts to guide students toward proficiency in strategies that improve coping skills, including some that do not center around technology

Intraarticular versus intravenous tranexemic acid in reducing blood loss after primary total knee arthroplasty

Background: One of the substantial complications of total knee arthroplasty is major blood loss. Postoperative blood loss can range up to 2000 ml and 10-38% of patients may require blood transfusion. Among the sundry methods of preventing this prob, tranexamic acid, an anti-fibrinolytic, is one of the most effective options. It can be administered directly into the blood or injected locally. The purpose of this study was to compare the hemostatic effects of intraarticular versus intravenous administration of tranexamic acid in primary total knee arthroplasty. Methods: A prospective comparative observational study was done from done September 2020 to February 2022 at Civil Service Hospital, Kathmandu. 64 patients randomized into two groups: an intraarticular tranexamic acid group (31 patients who received 3.0 grams of intraarticular tranexamic acid) and intravenous tranexamic acid group (31 patients who received 15 mg/kg intravenous tranexamic acid in two instances). The primary measure was the amount of hemoglobin loss. Secondary outcomes included comparison of hemoglobin level pre- and post- operatively at first and fifth day, drain volume at 48 hours and amount of blood transfusion. There were no significant differences in demographics or preoperative laboratory values between the groups. Results: The baseline data, preoperative hemoglobin, and tourniquet time were similar in both groups. Hemoglobin at first and fifth operative day and drain volume at 48 hours were measured in both categories. There was no significant difference in perioperative blood loss, drain volume, rates of allogeneic blood transfusion between the two groups.  No any thromboembolic complications occurred. Conclusions: Intra-articular administration of tranexamic acid was found to be as effective and safe as intra-venous administration in reducing blood loss in primary total knee arthroplasty

Disulfiram overcomes bortezomib and cytarabine resistance in Down-syndrome-associated acute myeloid leukemia cells

Background Children with Down syndrome (DS) have increased risk for developing AML (DS-AMKL), and they usually experience severe therapy-related toxicities compared to non DS-AMKL. Refractory/relapsed disease has very poor outcome, and patients would benefit from novel, less toxic, therapeutic strategies that overcome resistance. Relapse/resistance are linked to cancer stem cells with high aldehyde dehydrogenase (ALDH) activity. The purpose of the present work was to study less toxic alternative therapeutic agents for relapsed/refractory DS-AMKL. Methods Fourteen AML cell lines including the DS-AMKL CMY and CMK from relapsed/refractory AML were used. Cytarabine (Ara-C), bortezomib (BTZ), disulfiram/copper (DSF/Cu2+) were evaluated for cytotoxicity, depletion of ALDH-positive cells, and resistance. BTZ-resistant CMY and CMK variants were generated by continuous BTZ treatment. Cell viability was assessed using CellTiter-Glo®, ALDH activity by ALDELUORTM, and proteasome inhibition by western blot of ubiquitinated proteins and the Proteasome-Glo™ Chymotrypsin-Like (CT-like) assay, apoptosis by Annexin V Fluos/Propidium iodide staining, and mutations were detected using PCR, cloning and sequencing. Results Ara-C-resistant AML cell lines were sensitive to BTZ and DSF/Cu2+. The Ara-C-resistant DS-AMKL CMY cells had a high percentage of ALDHbright “stem-like” populations that may underlie Ara-C resistance. One percent of these cells were still resistant to BTZ but sensitive to DSF/Cu2+. To understand the mechanism of BTZ resistance, BTZ resistant (CMY-BR) and (CMK-BR) were generated. A novel mutation PSMB5 Q62P underlied BTZ resistance, and was associated with an overexpression of the β5 proteasome subunit. BTZ-resistance conferred increased resistance to Ara-C due to G1 arrest in the CMY-BR cells, which protected the cells from S-phase damage by Ara-C. CMY-BR and CMK-BR cells were cross-resistant to CFZ and MG-132 but sensitive to DSF/Cu2+. In this setting, DSF/Cu2+ induced apoptosis and proteasome inhibition independent of CT-like activity inhibition. Conclusions We provide evidence that DSF/Cu2+ overcomes Ara-C and BTZ resistance in cell lines from DS-AMKL patients. A novel mutation underlying BTZ resistance was detected that may identify BTZ-resistant patients, who may not benefit from treatment with CFZ or Ara-C, but may be responsive to DSF/Cu2+. Our findings support the clinical development of DSF/Cu2+ as a less toxic efficacious treatment approach in patients with relapsed/refractory DS-AMKL

Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53

The destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high-affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery process

The double pendulum

Policy discourses posit an accountability deficit as an underlying cause of a “learning crisis” in many low-income countries. Many studies understand this perceived deficit from a principal-agent perspective, arguing that incentives facing teachers and schools often do not align to the interests of parents and students. Such perspectives underlie many randomized controlled trials, which associate interventions with outcomes, but which also produce varying or inconsistent results across contexts. This paper seeks to study the accountability of schools and teachers more directly, looking at how it varies across public and private schools and how it relates to students’ literacy and numeracy abilities. We report results from a mixed methods study conducted in Mumbai and Kathmandu. Our results show that there are some relationships between accountability and learning outcomes, but these appear to be specific to the context. Quantitative data also show that differences between public and private models of schooling are negligible when students’ social backgrounds and school composition are considered. Qualitative data show that accountability processes create a significant burden on staff time and embed complex power dynamics that are not always productive. Taken together, these results problematize policies that seek to improve learning through “demand-side” approaches such as privatization. They show that the dynamics of accountability are a complex system, like the motion of a “double pendulum,” and therefore simple conceptual approaches such as the principal-agent model are of limited academic and practical utility

Prevalence of the Metabolic Syndrome and its determinants among Nepalese adults: Findings from a nationally representative cross-sectional study

Metabolic syndrome (MetS) increases the risk of cardiovascular diseases and diabetes mellitus. This study is designed to assess the prevalence and determinants of MetS among Nepalese adults from a nationally representative study. This study is based on Stepwise Approach to Surveillance (STEPS) Survey from Nepal. This survey was done among 4200 adults aged 15-69 years from 210 clusters selected proportionately across Nepal's three ecological zones (Mountain, Hill and Terai). Subsequently, using systematic sampling, twenty households per cluster and one participant per household were selected. The overall prevalence of MetS is 15% and 16% according to Adult Treatment Panel III (ATP III) and International Diabetes Federation (IDF) criteria respectively. A triad of low HDL-C, abdominal obesity and high BP was the most prevalent (8.18%), followed by abdominal obesity, low HDL-C cholesterol and high triglycerides (8%). Less than two percent of participants had all the five components of the syndrome and 19% of participants had none. The prevalence steadily rose across the age group with adults aged 45-69 years having the highest prevalence (28-30%) and comparable prevalence across two definitions of MetS. A notably high burden for females, urban, hill or Terai resident were seen among other factors

Effects of climatic factors on diarrheal diseases among children below 5 years of age at national and subnational levels in Nepal: an ecological study

INTRODUCTION: The incidence of diarrhea, a leading cause of morbidity and mortality in low-income countries such as Nepal, is temperature-sensitive, suggesting it could be associated with climate change. With climate change fueled increases in the mean and variability of temperature and precipitation, the incidence of water and food-borne diseases are increasing, particularly in sub-Saharan Africa and South Asia. This national-level ecological study was undertaken to provide evidence linking weather and climate with diarrhea incidence in Nepal. METHOD: We analyzed monthly diarrheal disease count and meteorological data from all districts, spanning 15 eco-development regions of Nepal. Meteorological data and monthly data on diarrheal disease were sourced, respectively, from the Department of Hydrology and Meteorology and Health Management Information System (HMIS) of the Government of Nepal for the period from 2002 to 2014. Time-series log-linear regression models assessed the relationship between maximum temperature, minimum temperature, rainfall, relative humidity, and diarrhea burden. Predictors with p-values < 0.25 were retained in the fitted models. RESULTS: Overall, diarrheal disease incidence in Nepal significantly increased with 1 degrees C increase in mean temperature (4.4%; 95% CI: 3.95, 4.85) and 1 cm increase in rainfall (0.28%; 95% CI: 0.15, 0.41). Seasonal variation of diarrheal incidence was prominent at the national level (11.63% rise in diarrheal cases in summer (95% CI: 4.17, 19.61) and 14.5% decrease in spring (95% CI: -18.81, -10.02) compared to winter season). Moreover, the effects of temperature and rainfall were highest in the mountain region compared to other ecological regions of Nepal. CONCLUSION: Our study provides empirical evidence linking weather factors and diarrheal disease burden in Nepal. This evidence suggests that additional climate change could increase diarrheal disease incidence across the nation. Mountainous regions are more sensitive to climate variability and consequently the burden of diarrheal diseases. These findings can be utilized to allocate necessary resources and envision a weather-based early warning system for the prevention and control of diarrheal diseases in Nepal

Environmental DNA provides higher resolution assessment of riverine biodiversity and ecosystem function via spatio-temporal nestedness and turnover partitioning.

Rapidly assessing biodiversity is essential for environmental monitoring; however, traditional approaches are limited in the scope needed for most ecological systems. Environmental DNA (eDNA) based assessment offers enhanced scope for assessing biodiversity, while also increasing sampling efficiency and reducing processing time, compared to traditional methods. Here we investigated the effects of landuse and seasonality on headwater community richness and functional diversity, via spatio-temporal dynamics, using both eDNA and traditional sampling. We found that eDNA provided greater resolution in assessing biodiversity dynamics in time and space, compared to traditional sampling. Community richness was seasonally linked, peaking in spring and summer, with temporal turnover having a greater effect on community composition compared to localized nestedness. Overall, our assessment of ecosystem function shows that community formation is driven by regional resource availability, implying regional management requirements should be considered. Our findings show that eDNA based ecological assessment is a powerful, rapid and effective assessment strategy that enables complex spatio-temporal studies of community diversity and ecosystem function, previously infeasible using traditional methods