Single-stranded siRNAs activate RNAi in animals.

The therapeutic utility of siRNAs is limited by the requirement for complex formulations to deliver them to tissues. If potent single-stranded RNAs could be identified, they would provide a simpler path to pharmacological agents. Here, we describe single-stranded siRNAs (ss-siRNAs) that silence gene expression in animals absent lipid formulation. Effective ss-siRNAs were identified by iterative design by determining structure-activity relationships correlating chemically modified single strands and Argonaute 2 (AGO2) activities, potency in cells, nuclease stability, and pharmacokinetics. We find that the passenger strand is not necessary for potent gene silencing. The guide-strand activity requires AGO2, demonstrating action through the RNAi pathway. ss-siRNA action requires a 5' phosphate to achieve activity in vivo, and we developed a metabolically stable 5'-(E)-vinylphosphonate (5'-VP) with conformation and sterioelectronic properties similar to the natural phosphate. Identification of potent ss-siRNAs offers an additional option for RNAi therapeutics and an alternate perspective on RNAi mechanism.

Hepatic Mitochondrial SAB Deletion or Knockdown Alleviates Diet-Induced Metabolic Syndrome, Steatohepatitis, and Hepatic Fibrosis.

BACKGROUND AND AIMS: The hepatic mitogen-activated protein kinase (MAPK) cascade leading to c-Jun N-terminal kinase (JNK) activation has been implicated in the pathogenesis of nonalcoholic fatty liver (NAFL)/NASH. In acute hepatotoxicity, we previously identified a pivotal role for mitochondrial SH3BP5 (SAB; SH3 homology associated BTK binding protein) as a target of JNK, which sustains its activation through promotion of reactive oxygen species production. Therefore, we assessed the role of hepatic SAB in experimental NASH and metabolic syndrome. APPROACH AND RESULTS: In mice fed high-fat, high-calorie, high-fructose (HFHC) diet, SAB expression progressively increased through a sustained JNK/activating transcription factor 2 (ATF2) activation loop. Inducible deletion of hepatic SAB markedly decreased sustained JNK activation and improved systemic energy expenditure at 8 weeks followed by decreased body fat at 16 weeks of HFHC diet. After 30 weeks, mice treated with control-antisense oligonucleotide (control-ASO) developed steatohepatitis and fibrosis, which was prevented by Sab-ASO treatment. Phosphorylated JNK (p-JNK) and phosphorylated ATF2 (p-ATF2) were markedly attenuated by Sab-ASO treatment. After 52 weeks of HFHC feeding, control N-acetylgalactosamine antisense oligonucleotide (GalNAc-Ctl-ASO) treated mice fed the HFHC diet exhibited progression of steatohepatitis and fibrosis, but GalNAc-Sab-ASO treatment from weeks 40 to 52 reversed these findings while decreasing hepatic SAB, p-ATF2, and p-JNK to chow-fed levels. CONCLUSIONS: Hepatic SAB expression increases in HFHC diet-fed mice. Deletion or knockdown of SAB inhibited sustained JNK activation and steatohepatitis, fibrosis, and systemic metabolic effects, suggesting that induction of hepatocyte Sab is an important driver of the interplay between the liver and the systemic metabolic consequences of overfeeding. In established NASH, hepatocyte-targeted GalNAc-Sab-ASO treatment reversed steatohepatitis and fibrosis.

Decentred regulation: The case of private healthcare in India.

In order to progress towards more equitable social welfare systems we need an improved understanding of regulation in social sectors such as health and education. However, research to date has tended to focus on roles for governments and professions, overlooking the broader range of regulatory systems that emerge in contexts of market-based provisioning and partial state regulation. In this article we examine the regulation of private healthcare in India using an analytical approach informed by 'decentred' and 'regulatory capitalism' perspectives. We apply these ideas to qualitative data on private healthcare and its regulation in Maharashtra (review of press media, semi-structured interviews with 43 respondents, and three witness seminars), in order to describe the range of state and non-state actors involved in setting rules and norms in this context, whose interests are represented by these activities, and what problems arise. We show an eclectic set of regulatory systems in operation. Government and statutory councils do perform limited and sporadic regulatory roles, typically organised around legislation, licensing and inspections, and often prompted by the judicial arm of the state. But a range of industry-level actors, private organisations and public insurers are involved too, promoting their own interests in the sector via the offices of regulatory capitalism: accreditation companies, insurers, platform operators and consumer courts. Rules and norms are extensive but diffuse. These are produced not just through laws, licensing and professional codes of conduct, but also through industry influence over standards, practices and market organisation, and through individualised attempts to negotiate exceptions and redressal. Our findings demonstrate regulation in a marketised social sector to be partial, disjointed and decentred to multiple loci, actively representing differing interests. Greater understanding of the different actors and processes at play in such contexts can inform future progress towards universal systems for social welfare.

Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents.

AIMS/HYPOTHESIS: Targeting regulators of adipose tissue lipoprotein lipase could enhance adipose lipid clearance, prevent ectopic lipid accumulation and consequently ameliorate insulin resistance and type 2 diabetes. Angiopoietin-like 8 (ANGPTL8) is an insulin-regulated lipoprotein lipase inhibitor strongly expressed in murine adipose tissue. However, Angptl8 knockout mice do not have improved insulin resistance. We hypothesised that pharmacological inhibition, using a second-generation antisense oligonucleotide (ASO) against Angptl8 in adult high-fat-fed rodents, would prevent ectopic lipid accumulation and insulin resistance by promoting adipose lipid uptake. METHODS: ANGPTL8 expression was assessed by quantitative PCR in omental adipose tissue of bariatric surgery patients. High-fat-fed Sprague Dawley rats and C57BL/6 mice were treated with ASO against Angptl8 and insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamps in rats and glucose tolerance tests in mice. Factors mediating lipid-induced hepatic insulin resistance were assessed, including lipid content, protein kinase Cε (PKCε) activation and insulin-stimulated Akt phosphorylation. Rat adipose lipid uptake was assessed by mixed meal tolerance tests. Murine energy balance was assessed by indirect calorimetry. RESULTS: Omental fat ANGPTL8 mRNA expression is higher in obese individuals with fatty liver and insulin resistance compared with BMI-matched insulin-sensitive individuals. Angptl8 ASO prevented hepatic steatosis, PKCε activation and hepatic insulin resistance in high-fat-fed rats. Postprandial triacylglycerol uptake in white adipose tissue was increased in Angptl8 ASO-treated rats. Angptl8 ASO protected high-fat-fed mice from glucose intolerance. Although there was no change in net energy balance, Angptl8 ASO increased fat mass in high-fat-fed mice. CONCLUSIONS/INTERPRETATION: Disinhibition of adipose tissue lipoprotein lipase is a novel therapeutic modality to enhance adipose lipid uptake and treat non-alcoholic fatty liver disease and insulin resistance. In line with this, adipose ANGPTL8 is a candidate therapeutic target for these conditions.

Demand-side financing for maternal and newborn health: what do we know about factors that affect implementation of cash transfers and voucher programmes?

BACKGROUND: Demand-side financing (DSF) interventions, including cash transfers and vouchers, have been introduced to promote maternal and newborn health in a range of low- and middle-income countries. These interventions vary in design but have typically been used to increase health service utilisation by offsetting some financial costs for users, or increasing household income and incentivising 'healthy behaviours'. This article documents experiences and implementation factors associated with use of DSF in maternal and newborn health. METHODS: A secondary analysis (using an adapted Supporting the Use of Research Evidence framework - SURE) was performed on studies that had previously been identified in a systematic review of evidence on DSF interventions in maternal and newborn health. RESULTS: The article draws on findings from 49 quantitative and 49 qualitative studies. The studies give insights on difficulties with exclusion of migrants, young and multiparous women, with demands for informal fees at facilities, and with challenges maintaining quality of care under increasing demand. Schemes experienced difficulties if communities faced long distances to reach participating facilities and poor access to transport, and where there was inadequate health infrastructure and human resources, shortages of medicines and problems with corruption. Studies that documented improved care-seeking indicated the importance of adequate programme scope (in terms of programme eligibility, size and timing of payments and voucher entitlements) to address the issue of concern, concurrent investments in supply-side capacity to sustain and/or improve quality of care, and awareness generation using community-based workers, leaders and women's groups. CONCLUSIONS: Evaluations spanning more than 15 years of implementation of DSF programmes reveal a complex picture of experiences that reflect the importance of financial and other social, geographical and health systems factors as barriers to accessing care. Careful design of DSF programmes as part of broader maternal and newborn health initiatives would need to take into account these barriers, the behaviours of staff and the quality of care in health facilities. Research is still needed on the policy context for DSF schemes in order to understand how they become sustainable and where they fit, or do not fit, with plans to achieve equitable universal health coverage.

Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice.

Triantennary N-acetyl galactosamine (GalNAc, GN3: ), a high-affinity ligand for the hepatocyte-specific asialoglycoprotein receptor (ASGPR), enhances the potency of second-generation gapmer antisense oligonucleotides (ASOs) 6-10-fold in mouse liver. When combined with next-generation ASO designs comprised of short S-cEt (S-2'-O-Et-2',4'-bridged nucleic acid) gapmer ASOs, ∼ 60-fold enhancement in potency relative to the parent MOE (2'-O-methoxyethyl RNA) ASO was observed. GN3: -conjugated ASOs showed high affinity for mouse ASGPR, which results in enhanced ASO delivery to hepatocytes versus non-parenchymal cells. After internalization into cells, the GN3: -ASO conjugate is metabolized to liberate the parent ASO in the liver. No metabolism of the GN3: -ASO conjugate was detected in plasma suggesting that GN3: acts as a hepatocyte targeting prodrug that is detached from the ASO by metabolism after internalization into the liver. GalNAc conjugation also enhanced potency and duration of the effect of two ASOs targeting human apolipoprotein C-III and human transthyretin (TTR) in transgenic mice. The unconjugated ASOs are currently in late stage clinical trials for the treatment of familial chylomicronemia and TTR-mediated polyneuropathy. The ability to translate these observations in humans offers the potential to improve therapeutic index, reduce cost of therapy and support a monthly dosing schedule for therapeutic suppression of gene expression in the liver using ASOs.

Country experience with strengthening of health systems and deployment of midwives in countries with high maternal mortality.

This paper complements the other papers in the Lancet Series on midwifery by documenting the experience of low-income and middle-income countries that deployed midwives as one of the core constituents of their strategy to improve maternal and newborn health. It examines the constellation of various diverse health-system strengthening interventions deployed by Burkina Faso, Cambodia, Indonesia, and Morocco, among which the scaling up of the pre-service education of midwives was only one element. Efforts in health system strengthening in these countries have been characterised by: expansion of the network of health facilities with increased uptake of facility birthing, scaling up of the production of midwives, reduction of financial barriers, and late attention for improving the quality of care. Overmedicalisation and respectful woman-centred care have received little or no attention.

After surgery: the effects of life-saving caesarean sections in Burkina Faso.

BACKGROUND: In African countries, caesarean sections are usually performed to save mothers and babies' lives, sometimes in extremis and at considerable costs. Little is known about the health and lives of women once discharged after such surgery. We investigated the long-term effects of life-saving caesarean section on health, economic and social outcomes in Burkina Faso. METHODS: We conducted a 4 year prospective cohort study of women and their babies using mixed methods. The quantitative sample was selected in seven hospitals and included 950 women: 100 women with a caesarean section associated with near-miss complication (life-saving caesareans); 173 women with a vaginal birth associated with near-miss complication; and 677 women with uncomplicated vaginal childbirth. Structured interviews were conducted at 3 months, 6 months, 12 months and 3 and 4 years postpartum. These were supplemented by medical record data on delivery and physical examinations at 6 and 12 months postpartum. The lives and experiences of 21 women were documented ethnographically. Data were analysed with multivariable logistic regressions, using survival analysis and thematic analysis. RESULTS: The physical effects of life-saving caesareans appeared to be similar to women who had an uncomplicated childbirth, although 55% of women with life-saving caesareans had another caesarean in their next pregnancy. The negative effects were generally economic, social and reproductive when compared to vaginal births, including increased debts (AOR = 3.91 (1.46-10.48) and sexual violence (AOR = 4.71 (1.04-21.3)) and lower fertility (AOR = 0.44 (0.24-0.80)) 4 years after life-saving caesareans. In the short and medium term, women with life-saving caesareans appeared to suffer increased psychological distress compared to uncomplicated births. They were more likely to use contraceptives (AOR = 5.95 (1.53-23.06); 3 months). Mortality of the index child was increased in both near-miss groups, independent of delivery mode. Ethnographic data suggest that these consequences are significant for Burkinabe women, whose well-being and social standing are mostly determined by their fertility, marriage strength and family links. CONCLUSIONS: Life-saving caesareans have broad consequences beyond clinical sequelae. The recent policy to subsidise emergency obstetric care costs implemented in Burkina Faso should help avoid the majority of catastrophic costs, shown to be problematic for women undergoing emergency caesarean section.

cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) promotes glucagon clearance and hepatic amino acid catabolism to regulate glucose homeostasis.

cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) regulates transcription of gluconeogenic genes by specifying targets for the transcription factor CREB in response to glucagon. We used an antisense oligonucleotide directed against CRTC2 in both normal rodents and in rodent models of increased gluconeogenesis to better understand the role of CRTC2 in metabolic disease. In the context of severe hyperglycemia and elevated hepatic glucose production, CTRC2 knockdown (KD) improved glucose homeostasis by reducing endogenous glucose production. Interestingly, despite the known role of CRTC2 in coordinating gluconeogenic gene expression, CRTC2 KD in a rodent model of type 2 diabetes resulted in surprisingly little alteration of glucose production. However, CRTC2 KD animals had elevated circulating concentrations of glucagon and a ∼80% reduction in glucagon clearance. When this phenomenon was prevented with somatostatin or a glucagon-neutralizing antibody, endogenous glucose production was reduced by CRTC2 KD. Additionally, CRTC2 inhibition resulted in reduced expression of several glucagon-induced pyridoxal 5'-phosphate-dependent enzymes that convert amino acids to gluconeogenic intermediates, suggesting that it may control substrate availability as well as gluconeogenic gene expression. CRTC2 is an important regulator of gluconeogenesis with tremendous impact in models of elevated hepatic glucose production. Surprisingly, it is also part of a previously unidentified negative feedback loop that degrades glucagon and regulates amino acid metabolism to coordinately control glucose homeostasis in vivo.

Effects of demand-side financing on utilisation, experiences and outcomes of maternity care in low- and middle-income countries: a systematic review.

BACKGROUND: Demand-side financing, where funds for specific services are channelled through, or to, prospective users, is now employed in health and education sectors in many low- and middle-income countries. This systematic review aimed to critically examine the evidence on application of this approach to promote maternal health in these settings. Five modes were considered: unconditional cash transfers, conditional cash transfers, short-term payments to offset costs of accessing maternity services, vouchers for maternity services, and vouchers for merit goods. We sought to assess the effects of these interventions on utilisation of maternity services and on maternal health outcomes and infant health, the situation of underprivileged women and the healthcare system. METHODS: The protocol aimed for collection and synthesis of a broad range of evidence from quantitative, qualitative and economic studies. Nineteen health and social policy databases, seven unpublished research databases and 27 websites were searched; with additional searches of Indian journals and websites. Studies were included if they examined demand-side financing interventions to increase consumption of services or goods intended to impact on maternal health, and met relevant quality criteria. Quality assessment, data extraction and analysis used Joanna Briggs Institute standardised tools and software. Outcomes of interest included maternal and infant mortality and morbidity, service utilisation, factors required for successful implementation, recipient and provider experiences, ethical issues, and cost-effectiveness. Findings on Effectiveness, Feasibility, Appropriateness and Meaningfulness were presented by narrative synthesis. RESULTS: Thirty-three quantitative studies, 46 qualitative studies, and four economic studies from 17 countries met the inclusion criteria. Evidence on unconditional cash transfers was scanty. Other demand-side financing modes were found to increase utilisation of maternal healthcare in the index pregnancy or uptake of related merit goods. Evidence of effects on maternal and infant mortality and morbidity outcomes was insufficient. Important implementation aspects include targeting and eligibility criteria, monitoring, respectful treatment of beneficiaries, suitable incentives for providers, quality of care and affordable referral systems. CONCLUSIONS: Demand-side financing schemes can increase utilisation of maternity services, but attention must be paid to supply-side conditions, the fine-grain of implementation and sustainability. Comparative studies and research on health impact and cost-effectiveness are required.

National health policy-makers' views on the clarity and utility of Countdown to 2015 country profiles and reports: findings from two exploratory qualitative studies.

BACKGROUND: The use of sets of indicators to assess progress has become commonplace in the global health arena. Exploratory research has suggested that indicators used for global monitoring purposes can play a role in national policy-making, however, the mechanisms through which this occurs are poorly understood. This article reports findings from two qualitative studies that aimed to explore national policy-makers' interpretation and use of indicators from country profiles and reports developed by Countdown to 2015. METHODS: An initial study aimed at exploring comprehension of Countdown data was conducted at the 2010 joint Women Deliver/Countdown conference. A second study was conducted at the 64th World Health Assembly in 2011, specifically targeting national policy-makers. Semi-structured interviews were carried out with 29 and 22 participants, respectively, at each event. Participants were asked about their understanding of specific graphs and indicators used or proposed for use in Countdown country profiles, and their perception of how such data can inform national policy-making. Responses were categorised using a framework analysis. RESULTS: Respondents in both studies acknowledged the importance of the profiles for tracking progress on key health indicators in and across countries, noting that they could be used to highlight changes in coverage, possible directions for future policy, for lobbying finance ministers to increase resources for health, and to stimulate competition between neighbouring or socioeconomically similar countries. However, some respondents raised questions about discrepancies between global estimates and data produced by national governments, and some struggled to understand the profile graphs shown in the absence of explanatory text. Some respondents reported that use of Countdown data in national policy-making was constrained by limited awareness of the initiative, insufficient detail in the country profiles to inform policy, and the absence of indicators felt to be more appropriate to their own country contexts. CONCLUSIONS: The two studies emphasise the need for country consultations to ensure that national policy-makers understand how to interpret and use tools like the Countdown profile for planning purposes. They make clear the value of qualitative research for refining tools used to promote accountability, and the need for country level Countdown-like processes.

Market making and the production of nurses for export: a case study of India-UK health worker migration.

BACKGROUND: High-income countries increasingly look to the international recruitment of health workers to address domestic shortages, especially from low-income and middle-income countries. We adapt conceptual frameworks from migration studies to examine the networked and commercialised nature of the Indian market for nurse migration to the UK. METHODS: We draw on data from 27 expert interviews conducted with migration intermediaries, healthcare providers and policymakers in India and the UK. FINDINGS: India-UK nurse migration occurs within a complex and evolving market encompassing ways to educate, train and recruit nursing candidates. For-profit actors shape the international orientation of nursing curricula, broker on-the-job training and offer language, exam and specialised clinical training. Rather than merely facilitate travel, these brokers produce both generic, emigratory nurses as well as more customised nurses ready to meet specific shortages in the UK. DISCUSSION: The dialectic of producing emigratory and customised nurses is similar to that seen in the Post-Fordist manufacturing model characterised by flexible specialisation and a networked structure. As the commodity in this case are people attempting to improve their position in life, these markets require attention from health policy makers. Nurse production regimes based on international market opportunities are liable to change, subjecting nurses to the risk of having trained for a market that can no longer accommodate them. The commercial nature of activities further entrenches existing socioeconomic inequalities in the Indian nurse force. Negative repercussions for the source healthcare system can be anticipated as highly qualified, specialised nurses leave to work in healthcare systems abroad.

A national study on nurses' retention in healthcare facilities in underserved areas in Lebanon.

BACKGROUND: Nursing shortages and maldistribution are priority issues for healthcare systems around the globe. Such imbalances are often aggravated in underserved areas, especially in developing countries. Despite the centrality of this issue, there is a dearth of studies that examine the retention of nurses in underserved areas in the Middle East Region. This study investigates the characteristic and the factors associated with the retention of nurses working in rural areas in Lebanon. METHODS: This study uses a non-experimental cross-sectional design to survey nurses working in underserved areas of Lebanon. Underserved areas in Lebanon were identified using WHO definition. A total of 103 health facilities (hospitals and primary healthcare centers) located in these areas were identified and all nurses working at these facilities received a copy of the survey questionnaire. The questionnaire included five sections: demographic, work-life, career plan, job satisfaction, and assessment of work environment. Analysis included univariate and bivariate (chi-square, Student's t-test and ANOVA) tests to describe the respondents and examine the significance between nurses' characteristics and their intent to stay. A logistic regression model was constructed to identify factors associated with nurses' intent to stay in underserved areas. RESULTS: A total of 857 nurses from 63 Primary Healthcare (PHC) centers and hospitals responded to the questionnaire (75.5% response rate). Only 35.1% of nurses indicated their intent to stay in their current job over the coming one to three years. Surveyed nurses were most satisfied with relationship with co-workers and least satisfied with extrinsic rewards. Rural nurses working in PHC centers were more satisfied than their hospital counterparts on all aspects of work and had significantly higher intention to stay (62.5% compared to 31.5% in hospitals, P < 0.001). Regression analysis revealed that nurses less likely to report intent to stay were younger, unmarried, with less years of work experience and were not working towards a higher degree. Analysis reveals a directly proportional relationship between nurses' reported job satisfaction and their intent to stay. CONCLUSION: This study reveals poor retention of nurses in rural and underserved areas in Lebanon, especially in the hospital sector. The status quo is disquieting as it reflects an unstable and dissatisfied nursing workforce. Developing targeted retention strategies for younger nurses and those working in hospitals as well as the offering of professional development opportunities and devising an incentive scheme targeting rural nurses is pivotal to enhance nurses' job satisfaction and retention in rural settings.

'This year I will not put her to work': the production/reproduction nexus in Burkina Faso.

Global advocacy campaigns increasingly highlight the negative impact of reproductive morbidity on economic productivity and development in order to justify donor investment in maternal health. Anthropological approaches nuance such narrow economic estimations of reproductive health. Drawing on ethnographic fieldwork from Burkina Faso in West Africa, this paper analyses the dynamic, and sometimes contradictory, relationship between women's work and reproductive health in impoverished communities. Specifically, it examines the consequences of life-threatening 'near-miss' obstetric complications for women's work across domestic, agricultural and economic spheres over a four-year period. Such events provide a window onto the diverse ways in which production and reproduction are intimately linked within women's everyday lives. Reproduction and production entail sources of potential empowerment and enhancement, as well as potential threats, to health and well-being. In the aftermath of 'near-miss' events, the realms of reproduction and production sometimes jeopardise each other and at other times reinforce each other, while strength in one domain can compensate for weakness in the other. Women's experiences thus reveal how 'production' and 'reproduction' are mutually constituted, challenging the purely instrumental accounts of pregnancy-related 'productivity loss' that dominate current global health discourse.

Understanding India, globalisation and health care systems: a mapping of research in the social sciences.

National and transnational health care systems are rapidly evolving with current processes of globalisation. What is the contribution of the social sciences to an understanding of this field? A structured scoping exercise was conducted to identify relevant literature using the lens of India - a 'rising power' with a rapidly expanding healthcare economy. A five step search and analysis method was employed in order to capture as wide a range of material as possible. Documents published in English that met criteria for a social science contribution were included for review. Via electronic bibliographic databases, websites and hand searches conducted in India, 113 relevant articles, books and reports were identified. These were classified according to topic area, publication date, disciplinary perspective, genre, and theoretical and methodological approaches. Topic areas were identified initially through an inductive approach, then rationalised into seven broad themes. Transnational consumption of health services; the transnational healthcare workforce; the production, consumption and trade in specific health-related commodities, and transnational diffusion of ideas and knowledge have all received attention from social scientists in work related to India. Other themes with smaller volumes of work include new global health governance issues and structures; transnational delivery of health services and the transnational movement of capital. Thirteen disciplines were found represented in our review, with social policy being a clear leader, followed by economics and management studies. Overall this survey of India-related work suggests a young and expanding literature, although hampered by inadequacies in global comparative data, and by difficulties in accessing commercially sensitive information. The field would benefit from further cross-fertilisation between disciplines and greater application of explanatory theory. Literatures around stem cell research and health related commodities provide some excellent examples of illuminating social science. Future research agendas on health systems issues need to include innovative empirical work that captures the dynamics of transnational processes and that links macro-level change to fine-grained observations of social life.

Understanding health systems, health economies and globalization: the need for social science perspectives.

The complex relationship between globalization and health calls for research from many disciplinary and methodological perspectives. This editorial gives an overview of the content trajectory of the interdisciplinary journal 'Globalization and Health' over the first six years of production, 2005 to 2010. The findings show that bio-medical and population health perspectives have been dominant but that social science perspectives have become more evident in recent years. The types of paper published have also changed, with a growing proportion of empirical studies. A special issue on 'Health systems, health economies and globalization: social science perspectives' is introduced, a collection of contributions written from the vantage points of economics, political science, psychology, sociology, business studies, social policy and research policy. The papers concern a range of issues pertaining to the globalization of healthcare markets and governance and regulation issues. They highlight the important contribution that can be made by the social sciences to this field, and also the practical and methodological challenges implicit in the study of globalization and health.

SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats.

Hepatic gluconeogenesis is a major contributing factor to hyperglycemia in the fasting and postprandial states in type 2 diabetes mellitus (T2DM). Because Sirtuin 1 (SirT1) induces hepatic gluconeogenesis during fasting through the induction of phosphoenolpyruvate carboxylase kinase (PEPCK), fructose-1,6-bisphosphatase (FBPase), and glucose-6-phosphatase (G6Pase) gene transcription, we hypothesized that reducing SirT1, by using an antisense oligonucleotide (ASO), would decrease fasting hyperglycemia in a rat model of T2DM. SirT1 ASO lowered both fasting glucose concentration and hepatic glucose production in the T2DM rat model. Whole body insulin sensitivity was also increased in the SirT1 ASO treated rats as reflected by a 25% increase in the glucose infusion rate required to maintain euglycemia during the hyperinsulinemic-euglycemic clamp and could entirely be attributed to increased suppression of hepatic glucose production by insulin. The reduction in basal and clamped rates of glucose production could in turn be attributed to decreased expression of PEPCK, FBPase, and G6Pase due to increased acetylation of signal transducer and activator of transcription 3 (STAT3), forkhead box O1 (FOXO1), and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), known substrates of SirT1. In addition to the effects on glucose metabolism, SirT1 ASO decreased plasma total cholesterol, which was attributed to increased cholesterol uptake and export from the liver. These results indicate that inhibition of hepatic SirT1 may be an attractive approach for treatment of T2DM.

miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting.

Current understanding of microRNA (miRNA) biology is limited, and antisense oligonucleotide (ASO) inhibition of miRNAs is a powerful technique for their functionalization. To uncover the role of the liver-specific miR-122 in the adult liver, we inhibited it in mice with a 2'-O-methoxyethyl phosphorothioate ASO. miR-122 inhibition in normal mice resulted in reduced plasma cholesterol levels, increased hepatic fatty-acid oxidation, and a decrease in hepatic fatty-acid and cholesterol synthesis rates. Activation of the central metabolic sensor AMPK was also increased. miR-122 inhibition in a diet-induced obesity mouse model resulted in decreased plasma cholesterol levels and a significant improvement in liver steatosis, accompanied by reductions in several lipogenic genes. These results implicate miR-122 as a key regulator of cholesterol and fatty-acid metabolism in the adult liver and suggest that miR-122 may be an attractive therapeutic target for metabolic disease.

Evaluation of a domestic violence intervention in the maternity and sexual health services of a UK hospital.

This paper reports on an evaluation of a domestic violence intervention in the maternity and sexual health services of a UK hospital. The intervention encompassed guidelines, staff training, inclusion of routine enquiry for domestic violence with all patients, and referral of women disclosing violence to an on-site advocacy service. An "assumption querying" approach was applied to evaluate the intervention. Programmatic assumptions were identified and tested using interviews with service providers and patients, review of patient records, and pre- and post-training questionnaires. Domestic violence training resulted in changes in health professionals' knowledge and practice in the short-term, but universal routine enquiry was not achieved even in a context of organisational support, guidelines, training and advocacy. Potential and actual harm occurred, including breaches of confidentiality and failure to document evidence, limiting women's ability to access civil and legal remedies. Advocacy support led to positive outcomes for many women, as long as support to maintain positive changes, whether women stayed with or left the violent partner, continued to be given. Maternity and sexual health services were found to be opportune points of intervention for domestic violence services that combine routine enquiry by clinicians, support after disclosure and attention to harm reduction.

The impacts of corporatisation of healthcare on medical practice and professionals in Maharashtra, India.

A heterogeneous private sector dominates healthcare provision in many middle-income countries. In India, the contemporary period has seen this sector undergo corporatisation processes characterised by emergence of large private hospitals and the takeover of medium-sized and charitable hospitals by corporate entities. Little is known about the operations of these private providers and the effects on healthcare professions as employment shifts from practitioner-owned small and medium hospitals to larger corporate settings. This article uses data from a mixed-methods study in two large cities in Maharashtra, India, to consider the implications of these contemporary changes for the medical profession. Data were collected from semistructured interviews with 43 respondents who have detailed knowledge of healthcare in Maharashtra and from a witness seminar on the topic of transformation in Maharashtra's healthcare system. Transcripts from the interviews and witness seminar were analysed thematically through a combination of deductive and inductive approaches. Our findings point to a restructuring of medical practice in Maharashtra as training shifts towards private education and employment to those corporate hospitals. The latter is fuelled by substantial personal indebtedness, dwindling appeal of government employment, reduced opportunities to work in smaller private facilities and the perceived benefits of work in larger providers. We describe a 'reprofessionalisation' of medicine encompassing changes in employment relations, performance targets and constraints placed on professional autonomy within the private healthcare sector that is accompanied by trends in cost inflation, medical malpractice, and distrust in doctor-patient relationships. The accompanying 'restratification' within this part of the profession affords prestige and influence to 'star doctors' while eroding the status and opportunity for young and early career doctors. The research raises important questions about the role that government and medical professionals' bodies can, and should, play in contemporary transformation of private healthcare and the implications of these trends for health systems more broadly.