The crystal structure of the human smacovirus 1 Rep domain.

Replication initiator proteins (Reps) from the HUH endonuclease family process specific single-stranded DNA sequences to initiate rolling-circle replication in viruses. Here, the first crystal structure of the apo state of a Rep domain from the smacovirus family is reported. The structure of the human smacovirus 1 Rep domain was obtained at 1.33 Šresolution and represents an expansion of the HUH endonuclease superfamily, allowing greater diversity in bioconjugation-tag applications.

Radiosensitizing Pancreatic Cancer via Effective Autophagy Inhibition.

Despite aggressive treatments, pancreatic ductal adenocarcinoma (PDAC) remains an intractable disease, largely because it is refractory to therapeutic interventions. To overcome its nutrient-poor microenvironment, PDAC heavily relies on autophagy for metabolic needs to promote tumor growth and survival. Here, we explore autophagy inhibition as a method to enhance the effects of radiotherapy on PDAC tumors. Hydroxychloroquine is an autophagy inhibitor at the focus of many PDAC clinical trials, including in combination with radiotherapy. However, its acid-labile properties likely reduce its intratumoral efficacy. Here, we demonstrate that EAD1, a synthesized analogue of HCQ, is a more effective therapeutic for sensitizing PDAC tumors of various KRAS mutations to radiotherapy. Specifically, in vitro models show that EAD1 is an effective inhibitor of autophagic flux in PDAC cells, accompanied by a potent inhibition of proliferation. When combined with radiotherapy, EAD1 is consistently superior to HCQ not only as a single agent, but also in radiosensitizing PDAC cells, and perhaps most importantly, in decreasing the self-renewal capacity of PDAC cancer stem cells (PCSC). The more pronounced sensitizing effects of autophagy inhibitors on pancreatic stem over differentiated cells points to a new understanding that PCSCs may be more dependent on autophagy to counter the effects of radiation toxicity, a potential mechanism explaining the resistance of PCSCs to radiotherapy. Finally, in vivo subcutaneous tumor models demonstrate that combination of radiotherapy and EAD1 is the most successful at controlling tumor growth. The models also confirmed a similar toxicity profile between EAD1 and Hydroxychloroquine.

A Substantive Narrative Review on the Usage of Lidocaine in Cataract Surgery.

Cataracts are a disease that causes a gradual decrease in visual prowess and requires surgery when the symptoms progress to an abhorrent state. This disease can be treated through surgical procedures that use anesthetics, such as lidocaine. Through inhibiting sensory nerve propagation to the brain, lidocaine plays an invaluable part in reducing pain for patients that undergo cataract surgery. Current clinical practice commonly utilizes 2% lidocaine with fentanyl as a combination agent. However, recent studies have reported that concentrations higher than 1% can cause substantial alteration to corneal epithelium cells. Additionally, fentanyl is cited as an extremely addictive opioid inappropriate for continual use in cataract surgeries. In this review, the authors examine the application and concentration of lidocaine, along with the various combination agents that were reported in several studies that describe the usage of the anesthetic during cataract surgery. Within the review, it was found that most surgeons generally only use lidocaine gel on the corneal epithelium tissue of patients during cataract surgery. Perhaps this standard could change over time as it is generally known that using intracameral injections in conjunction with topical anesthesia produces better patient outcomes. The authors find that although anesthetics and surgical treatment for cataracts are generally beneficial for patients, there are still many adjustments that could be implemented to enhance patient outcomes.

PK-M2-mediated metabolic changes in breast cancer cells induced by ionizing radiation.

PURPOSE: Radiotherapy (RT) constitutes an important part of breast cancer treatment. However, triple negative breast cancers (TNBC) exhibit remarkable resistance to most therapies, including RT. Developing new ways to radiosensitize TNBC cells could result in improved patient outcomes. The M2 isoform of pyruvate kinase (PK-M2) is believed to be responsible for the re-wiring of cancer cell metabolism after oxidative stress. The aim of the study was to determine the effect of ionizing radiation (IR) on PK-M2-mediated metabolic changes in TNBC cells, and their survival. In addition, we determine the effect of PK-M2 activators on breast cancer stem cells, a radioresistant subpopulation of breast cancer stem cells. METHODS: Glucose uptake, lactate production, and glutamine consumption were assessed. The cellular localization of PK-M2 was evaluated by western blot and confocal microscopy. The small molecule activator of PK-M2, TEPP46, was used to promote its pyruvate kinase function. Finally, effects on cancer stem cell were evaluated via sphere forming capacity. RESULTS: Exposure of TNBC cells to IR increased their glucose uptake and lactate production. As expected, PK-M2 expression levels also increased, especially in the nucleus, although overall pyruvate kinase activity was decreased. PK-M2 nuclear localization was shown to be associated with breast cancer stem cells, and activation of PK-M2 by TEPP46 depleted this population. CONCLUSIONS: Radiotherapy can induce metabolic changes in TNBC cells, and these changes seem to be mediated, at least in part by PK-M2. Importantly, our results show that activators of PK-M2 can deplete breast cancer stem cells in vitro. This study supports the idea of combining PK-M2 activators with radiation to enhance the effect of radiotherapy in resistant cancers, such as TNBC.

Unintentional Injury, Supervision, and Discourses on Childproofing Devices.

Unintentional injury prevention research focuses on parental supervision as critical to reducing toddler injury. We examine how the promotion of childproofing-as a mode of supervision-sells mothers "peace of mind" while also increasing "intensive mothering" and the "privatization of risk." Drawing on the childproofing literature and meaning centered interviews with mothers of toddlers and childproofing business owners, we argue that the connection made by these groups between childproofing and "good parenting" ultimately obscures how this form of harm reduction economically and socially individualizes responsibility for child care.

Mebendazole Potentiates Radiation Therapy in Triple-Negative Breast Cancer.

PURPOSE: The lack of a molecular target in triple-negative breast cancer (TNBC) makes it one of the most challenging breast cancers to treat. Radiation therapy (RT) is an important treatment modality for managing breast cancer; however, we previously showed that RT can also reprogram a fraction of the surviving breast cancer cells into breast cancer-initiating cells (BCICs), which are thought to contribute to disease recurrence. In this study, we characterize mebendazole (MBZ) as a drug with potential to prevent the occurrence of radiation-induced reprogramming and improve the effect of RT in patients with TNBC. METHODS AND MATERIALS: A high-throughput screen was used to identify drugs that prevented radiation-induced conversion of TNBC cells into cells with a cancer-initiating phenotype and exhibited significant toxicity toward TNBC cells. MBZ was one of the drug hits that fulfilled these criteria. In additional studies, we used BCIC markers and mammosphere-forming assays to investigate the effect of MBZ on the BCIC population. Staining with propidium iodide, annexin-V, and γ-H2AX was used to determine the effect of MBZ on cell cycle, apoptosis, and double-strand breaks. Finally, the potential for MBZ to enhance the effect of RT in TNBC was evaluated in vitro and in vivo. RESULTS: MBZ efficiently depletes the BCIC pool and prevents the ionizing radiation-induced conversion of breast cancer cells into therapy-resistant BCICs. In addition, MBZ arrests cells in the G2/M phase of the cell cycle and causes double-strand breaks and apoptosis. MBZ sensitizes TNBC cells to ionizing radiation in vitro and in vivo, resulting in improved tumor control in a human xenograft model of TNBC. CONCLUSIONS: The data presented in this study support the repurposing of MBZ as a combination treatment with RT in patients with TNBC.

Socioeconomic inequalities in self-reported chronic non-communicable diseases in urban Hanoi, Vietnam.

This study measures and decomposes socioeconomic inequalities in the prevalence of self-reported chronic non-communicable diseases (NCDs) in urban Hanoi, Vietnam. A cross-sectional survey of 1211 selected households was carried out in four urban districts in both slum and non-slum areas of Hanoi city in 2013. The respondents were asked if a doctor or health worker had diagnosed any household members with an NCD, such as cardiovascular diseases, chronic respiratory, diabetes or cancer, during last 12 months. Information from 3736 individuals, aged 15 years and over, was used for the analysis. The concentration index (CI) was used to measure inequalities in self-reported NCD prevalence, and it was also decomposed into contributing factors. The prevalence of chronic NCDs in the slum and non-slum areas was 7.9% and 11.6%, respectively. The CIs show gradients disadvantageous to both the slum (CI = -0.103) and non-slum (CI = -0.165) areas. Lower socioeconomic status and aging significantly contributed to inequalities in the self-reported NCDs, particularly for those living in the slum areas. The findings confirm the existence of substantial socioeconomic inequalities linked to NCDs in urban Vietnam. Future policies should target these vulnerable areas.

Socioeconomic inequalities in catastrophic health expenditure and impoverishment associated with non-communicable diseases in urban Hanoi, Vietnam.

BACKGROUND: The catastrophic health expenditure and impoverishment indices offer guidance for developing appropriate health policies and intervention programs to decrease financial inequity. This study assesses socioeconomic inequalities in catastrophic health expenditure and impoverishment in relation to self-reported non-communicable diseases (NCD) in urban Hanoi, Vietnam. METHODS: A cross-sectional survey was conducted from February to March 2013 in Hanoi, the capital city of Vietnam. We estimated catastrophic health expenditure and impoverishment using information from 492 slum household and 528 non-slum households. We calculated concentration indexes to assess socioeconomic inequalities in catastrophic health expenditure and impoverishment. Factors associated with catastrophic health expenditure and impoverishment were modelled using logistic regression analysis. RESULTS: The poor households in both slum and non-slum areas were at higher risk of experiencing catastrophic health expenditure, while only the poor households in slum areas were at higher risk of impoverishment because of healthcare spending. Households with at least one member reporting an NCD were significantly more likely to face catastrophic health expenditure (odds ratio [OR] = 2.4; 95 % confidence interval [CI], 1.8-4.0) and impoverishment (OR = 2.3; 95 % CI, 1.1-6.3) compared to households without NCDs. In addition, households in slum areas, with people age 60 years and above, and belonging to the poorest socioeconomic group were significantly associated with increased catastrophic health expenditure, while only households that lived in slum areas, and belonging to the poor or poorest socioeconomic groups were significantly associated with increased impoverishment because of healthcare spending. CONCLUSION: Financial interventions to prevent catastrophic health expenditure and impoverishment should target poor households, especially those with family members suffering from NCDs, with older members and those located in slum areas in Hanoi Vietnam. Potential interventions derived from this study include targeting and monitoring of health insurance enrolment, and developing a specialized NCD service package for Vietnam's social health insurance program.

The Social Life of Health Insurance in Low- to Middle-income Countries: An Anthropological Research Agenda.

The following article identifies new areas for engaged medical anthropological research on health insurance in low- and middle-income countries (LMICs). Based on a review of the literature and pilot research, we identify gaps in how insurance is understood, administered, used, and abused. We provide a historical overview of insurance as an emerging global health panacea and then offer brief assessments of three high-profile attempts to provide universal health coverage. Considerable research on health insurance in LMICs has been quantitative and focused on a limited set of outcomes. To advance the field, we identify eight productive areas for future ethnographic research that will add depth to our understanding of the social life and impact of health insurance in LMICs. Anthropologists can provide unique insights into shifting health and financial practices that accompany insurance coverage, while documenting insurance programs as they evolve and respond to contingencies.

Toward an Anthropology of Insurance and Health Reform: An Introduction to the Special Issue.

This article introduces a special issue of Medical Anthropology Quarterly on health insurance and health reform. We begin by reviewing anthropological contributions to the study of financial models for health care and then discuss the unique contributions offered by the articles of this collection. The contributors demonstrate how insurance accentuates--but does not resolve tensions between granting universal access to care and rationing limited resources, between social solidarity and individual responsibility, and between private markets and public goods. Insurance does not have a single meaning, logic, or effect but needs to be viewed in practice, in context, and from multiple vantage points. As the field of insurance studies in the social sciences grows and as health reforms across the globe continue to use insurance to restructure the organization of health care, it is incumbent on medical anthropologists to undertake a renewed and concerted study of health insurance and health systems.

Wireless laptop-based phonocardiograph and diagnosis.

Auscultation is used to evaluate heart health, and can indicate when it's needed to refer a patient to a cardiologist. Advanced phonocardiograph (PCG) signal processing algorithms are developed to assist the physician in the initial diagnosis but they are primarily designed and demonstrated with research quality equipment. Therefore, there is a need to demonstrate the applicability of those techniques with consumer grade instrument. Furthermore, routine monitoring would benefit from a wireless PCG sensor that allows continuous monitoring of cardiac signals of patients in physical activity, e.g., treadmill or weight exercise. In this work, a low-cost portable and wireless healthcare monitoring system based on PCG signal is implemented to validate and evaluate the most advanced algorithms. Off-the-shelf electronics and a notebook PC are used with MATLAB codes to record and analyze PCG signals which are collected with a notebook computer in tethered and wireless mode. Physiological parameters based on the S1 and S2 signals and MATLAB codes are demonstrated. While the prototype is based on MATLAB, the later is not an absolute requirement.

Watching as an ordinary affect: Care and mothers' preemption of injury in child supervision.

As unintentional injuries continue to be the leading cause of hospitalization and death for toddlers between the ages of 1 and 4, the Centers for Disease Control has argued that child supervision is a key factor in reducing these injuries and fatalities. This article focuses on the affective relationships in the concept of supervision and practice of watching as an injury prevention method. Three parts frame our argument. First, we describe how watching is an ordinary affect. Second, as part of the ethos of caring, watching is embedded in a temporal frame of anticipation and gives rise to an affectsphere of watching and to a parents' subjectivity as 'good' or 'bad' supervisors. Third, these affective relationships generate seemingly contradictory outcomes wherein children are expected to gain independence and experience injury. The affective qualities of watching provide a critique of the individualizing forces of supervision and an analysis of subjectivities generated by gender and class.

Social science research on HIV in Vietnam: a critical review and future directions.

Social science research can enhance the response to Vietnam's growing HIV epidemic by capturing the country's rapidly changing social and political context. The present paper reviews the published, peer-reviewed and English-language social science literature on HIV in Vietnam in order to identify critical theoretical and substantive gaps, while laying the groundwork for future research. We found four broad foci for work on the social context of HIV and AIDS in Vietnam: the cultural meanings and social relationships that shape Vietnam's HIV epidemic; stigma and discrimination; social inequality and structural violence as contributors to HIV risk; and, finally, how broader global and social systems shape Vietnam's HIV epidemic. We signal the particular need for additional research on the effects of the media on attitudes towards HIV and AIDS, on social movements, and on health systems, as well as on a number of other key areas. Work along these lines, in addition to more effective communication of policy-relevant findings to those responsible for the development and implementation of policies and programmes, will strengthen Vietnam's response to HIV and AIDS.