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Background: People frequently experience discomfort with immediate wheal, delayed papules, and pruritus from mosquito bites. A topical cream product containing zinc oxide is commercially available for the management of insect bites, but there has been no published evidence for its effectiveness and safety., Aims: To evaluate the effectiveness and safety of this product in symptoms caused by mosquito bites., Methods: An open-label, controlled study was performed on 41 healthy participants. All subjects received Aedes aegypti mosquito bites on the forearm. Then test product was randomly applied to the bitten areas of the left or right arm. The other arm was left untreated (control). The onset of pruritus relief was noted. The severity of pruritus was assessed using a visual analogue scale (VAS), ranging from 0 mm (no pruritus) to 100 mm (severe pruritus), and a 4-point pruritus score (0 = none; 1 = mild, not affecting normal activities; 2 = moderate, affecting normal activities to some extent; 3 = severe, significantly affecting activities) at four time points: 15 minutes after the mosquito bite (baseline), as well as 1 hour, 24 hours, and 48 hours after initiating treatment. The size of the bite reaction lesion was also measured at all time points. Any local cutaneous adverse reactions observed during the study were documented., Results: The onset of pruritus relief in the treated group (25 ± 21.7 minutes) was significantly faster compared to the untreated group (118.7 ± 304.8 minutes). The reduction in VAS score at 1 hour was significantly greater in the product group (30.5 ± 16.22) compared to the control group (14.9 ± 9.9). Moreover, there was a significant difference in the reduction of pruritus score at 1 hour, with the product group (1.1 ± 0.5) showing a higher reduction compared to the control group (0.3 ± 0.4). However, there was no significant difference in the reduction of bite lesion size between the two groups. Throughout the study, no adverse events were reported., Conclusion: Our preliminary findings indicate that the product effectively reduces pruritus caused by mosquito bites but does not have a significant impact on the size of the bite lesions. The product was found to be safe and may be an option for managing mosquito bites pruritus.

Background: Universal coverage of evidence-based interventions for perinatal health, often part of evidence-based guidelines, could prevent most perinatal deaths, particularly if entire communities were engaged in the implementation. Social innovations may provide creative solutions to the implementation of evidence-based guidelines, but successful use of social innovations relies on the engagement of communities and health system actors. This proof-of-concept study aimed to assess whether an earlier successful social innovation for improved neonatal survival that employed regular facilitated Plan-Do-Study-Act meetings on the commune level was feasible and acceptable when implemented on multiple levels of the health system (52 health units) and resulted in actions with plausibly favourable effects on perinatal health and survival in Cao Bang province, northern Vietnam., Methods: The Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework guided the implementation and evaluation of the Perinatal Knowledge-Into-Practice (PeriKIP) project. Data collection included facilitators' diaries, health workers' knowledge on perinatal care, structured observations of antenatal care, focus group discussions with facilitators, their mentors and representatives of different actors of the initiated stakeholder groups and an individual interview with the Reproductive Health Centre director. Clinical experts assessed the relevance of the identified problems and actions taken based on facilitators' diaries. Descriptive statistics included proportions, means, and t-tests for the knowledge assessment and observations. Qualitative data were analysed by content analysis., Results: The social innovation resulted in the identification of about 500 relevant problems. Also, 75% of planned actions to overcome prioritised problems were undertaken, results presented and a plan for new actions to achieve the group's goals to enhance perinatal health. The facilitators had significant roles, ensuring that the stakeholder groups were established based on principles of mutual respect. Overall, the knowledge of perinatal health and performance of antenatal care improved over the intervention period., Conclusions: The establishment of facilitated local stakeholder groups can remedy the need for tailored interventions and grassroots involvement in perinatal health and provide a scalable structure for focused efforts to reduce preventable deaths and promote health and well-being., (© 2023. The Author(s).)

What Is Known and Objective: Unintentional medication discrepancies (UMDs) are common in geriatric patients during care transitions, resulting in frequent undesirable consequences. Medication reconciliation could be a useful practice to prevent or ameliorate UMD. However, this practice in Vietnamese hospitals has not been well established or standardized. This study aims to determine the effect of pharmacist-initiated educational interventions on improving medication reconciliation practice., Methods: This prospective 6-month pre-and post-study was conducted in two internal medicine wards in a Vietnamese 800-bed public hospital. Pharmacists provided training and short-term support to physicians on medication reconciliation. Primary outcome measures were the proportions of patients with at least one UMD at admission. Secondary outcome measures were the proportions of patients with preventable adverse drug events (pADEs) score ≥0.1 due to these UMDs. Odds ratio and 95% confidence intervals were assessed based on a multivariate logistic regression model., Results and Discussion: One hundred fifty-two patients were recruited in the pre-intervention phase, and 146 in the post-intervention phase. Following the intervention, the proportion of geriatric patients with ≥1 UMD at admission significantly decreased from 55.3 to 25.3 % (ORadj 0.255, 95% CI: 0.151-0.431). Similarly, the proportion of patients with a pADE ≥0.1 at admission reduced from 44.1 to 11.6% [ORadj 0.188, 95% CI: 0.105-0.340] post-intervention., What Is New and Conclusion: Our pharmacist-initiated educational interventions have demonstrated the ability to produce substantial improvement in medication reconciliation practice, reducing UMDs and potential harm. Our approach may provide an alternate option to implement medication reconciliation for jurisdictions with limited healthcare resources., (© 2022 The Authors. Journal of Clinical Pharmacy and Therapeutics published by John Wiley & Sons Ltd.)

Background: Breastfeeding brings benefits to both mothers and children in the short term and long term. Unnecessary cesarean sections can bring risks to both parties. This study was undertaken to examine the relationship between exclusive breastfeeding intention and cesarean delivery., Methods: We analyzed data collected from 554 single mothers who delivered in Dong Anh General District Hospital or Hanoi Obstetrics and Gynecology Hospital, Vietnam, in 2020-2021. The relationship between exclusive breastfeeding intention and cesarean delivery for nonmedical reasons was adjusted for maternal education, maternal age, parity, history of fetal loss, having at least eight antenatal contacts, hospital of delivery, child sex, and birth weight., Results: Antenatally, 34.8% (184/529) of mothers intended to breastfeed exclusively until 6 months and 30.8% (84/274) underwent cesarean section for a nonmedical reason. After adjusting for other factors, mothers who intended to breastfeed exclusively until 6 months were less likely to undergo cesarean delivery for nonmedical reasons (OR = 0.55, 95% CI: 0.31-0.96, p = 0.034)., Conclusions: This study adds to the growing evidence related to unnecessary cesarean sections and routine over-medicalization of normal birth in the urban areas of Vietnam. The association between breastfeeding intentions and a lower rate of cesarean section suggests that education on breastfeeding could be a useful intervention for reducing the rate of cesarean sections and improving maternal and child health.

A multifaceted, relationally focused intervention involving group and individual pre- and postnatal counseling, print resources, and community resources encouraged 390 fathers of newborn infants in Vietnam to responsively support mothers and work with them as a parenting team. Both partners completed questionnaires prebirth and 1-, 4-, and 9-months postbirth on measures of breastfeeding support, exclusive breastfeeding duration, relationship quality, and infant development. Compared to 412 comparison group couples, intervention couples evidenced greater father support, especially in terms of helping and responsiveness to the mother's needs. This support predicted longer exclusive breastfeeding duration, improved relationship quality, and higher levels of infant development at 9 months. Sensitively working together with mothers as a coordinated team enhanced couple's relationship functioning and improved children's developmental outcomes., (© 2019 Society for Research in Child Development.)

Although the benefits of breastfeeding are well-documented, little is known about how best to encourage fathers to support breastfeeding. A quasi-experimental study of a community-based intervention was designed to examine whether health education to promote fathers' involvement in supporting women is associated with early initiation and exclusive breastfeeding practices. At baseline, 802 couples of fathers with pregnant wives from 12 to 27 weeks of gestational age were recruited to either the intervention group (n = 390) or a control group (n = 412) consisting of couples seeking care through routine maternal and child health services. Fathers in the intervention area received breastfeeding education and counselling services in health facilities and at home visits during the antenatal, delivery, and post-partum periods. Peer education and social exchange concerning breastfeeding were organized in fathers' clubs. After 1 year of the intervention, mothers in the intervention group were more likely to initiate early breastfeeding 49.2 and 35.8% in the intervention and control group respectively, P < 0.001. At 1, 4, and 6 months after birth, 34.8, 18.7, and 1.9% of the mothers in the intervention group were exclusively breastfeeding their children because of birth, respectively, compared with 5.7, 4.0, and 0.0% of those in the control group (P < 0.001). Those practices were associated with the intervention in bivariate and multivariate logistic and Cox regression analyses. Intervention targeting fathers at antenatal and postnatal periods may positively influence the breastfeeding practices of mothers, and it should be an important component of breastfeeding programs., (© 2019 John Wiley & Sons Ltd.)

Background: Little is know about whether the effects of community engagement interventions for child survival in low-income and middle-income settings are sustained. Seasonal variation and secular trend may blur the data. Neonatal mortality was reduced in a cluster-randomised trial in Vietnam where laywomen facilitated groups composed of local stakeholders employing a problem-solving approach for 3 years. In this analysis, we aim at disentangling the secular trend, the seasonal variation and the effect of the intervention on neonatal mortality during and after the trial., Methods: In Quang Ninh province, 44 communes were allocated to intervention and 46 to control. Births and neonatal deaths were assessed in a baseline survey in 2005, monitored during the trial in 2008-2011 and followed up by a survey in 2014. Time series analyses were performed on monthly neonatal mortality data., Results: There were 30 187 live births and 480 neonatal deaths. The intervention reduced the neonatal mortality from 19.1 to 11.6 per 1000 live births. The reduction was sustained 3 years after the trial. The control areas reached a similar level at the time of follow-up. Time series decomposition analysis revealed a downward trend in the intervention areas during the trial that was not found in the control areas. Neonatal mortality peaked in the hot and wet summers., Conclusions: A community engagement intervention resulted in a lower neonatal mortality rate that was sustained but not further reduced after the end of the trial. When decomposing time series of neonatal mortality, a clear downward trend was demonstrated in intervention but not in control areas., Trial Registration Number: ISRCTN44599712, Post-results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Obstructive sleep apnea (OSA) is a chronic sleep disorder affecting millions of people worldwide. Individuals with OSA are rarely aware of the condition and are often left untreated, which can lead to some serious health problems. Nowadays, several low-cost wearable health sensors are available that can be used to conveniently and noninvasively collect a wide range of physiological signals. In this paper, we propose a new framework for OSA detection in which we combine the wearable sensor measurement signals with the mathematical models of the cardiorespiratory system. Vector-valued Gaussian processes (GPs) are adopted to model the physiological variations among different individuals. The GP covariance is constructed using the sum of separable kernel functions, and the GP hyperparameters are estimated by maximizing the marginal likelihood function. A likelihood ratio test is proposed to detect OSA using the widely available heart rate and peripheral oxygen saturation (SpO ) measurement signals. We conduct experiments on both synthetic and real data to show the effectiveness of the proposed OSA detection framework compared to purely data-driven approaches.

Background: In a previous trial in Vietnam, a facilitation strategy to secure evidence-based practice in primary care resulted in reduced neonatal mortality over a period of three years. While little is known as to what ensures sustainability in the implementation of community-based strategies, the aim of this study was to investigate factors promoting or hindering implementation, and sustainability of knowledge implementation strategies, by means of the former Neonatal Knowledge Into Practice (NeoKIP) trial., Methods: In 2014 we targeted all levels in the Vietnamese healthcare system: six individual interviews with representatives at national, provincial and district levels, and six focus group discussions with representatives at the commune level. The interviews were transcribed verbatim, translated to English, and analysed using inductive and deductive thematic analysis., Results: To achieve successful implementation and sustained effect of community-based knowledge implementation strategies, engagement of leaders and key stakeholders at all levels of the healthcare system is vital-prior to, during and after a project. Implementation and sustainability require thorough needs assessment, tailoring of the intervention, and consideration of how to attain and manage funds. The NeoKIP trial was characterised by a high degree of engagement at the primary healthcare system level. Further, three years post trial, maternal and neonatal care was still high on the agenda for healthcare workers and leaders, even though primary aspects such as stakeholder engagement at all levels, and funding had been incomplete or lacking., Conclusions: The current study illustrates factors to support successful implementation and sustain effects of community-based strategies in projects in low- and middle-income settings; some but not all factors were represented during the post-NeoKIP era. Most importantly, trials in this and similar contexts require deliberate management throughout and beyond the project lifetime, and engagement of key stakeholders, in order to promote and sustain knowledge implementation.

Analysing child mortality may enhance our perspective on global achievements in child survival. We used data from surveillance sites in Bangladesh, Nicaragua and Vietnam and Demographic Health Surveys in Rwanda to explore the development of neonatal and under-five mortality. The mortality curves showed dramatic reductions over time, but child mortality in the four countries peaked during wars and catastrophes and was rapidly reduced by targeted interventions, multisectorial development efforts and community engagement., Conclusion: Lessons learned from these countries may be useful when tackling future challenges, including persistent neonatal deaths, survival inequalities and the consequences of climate change and migration., (© 2017 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: Neonatal health (NH) remains a major problem in many countries. Children dying before 28 days often suffer from conditions that are preventable or treatable with proven, cost-effective interventions. The knowledge gaps are no longer about what should be done, but to understand why guidelines including these interventions are not followed. Using a behaviour change framework, this study explores neonatal health guidelines use and the role of management in supporting effective usage in two rural settings in China and Vietnam., Methods: Semi-structured interviews with policy makers, health care managers and providers (n = 49) and focus group discussions with women, husbands and grandmothers who had experienced maternal and NH care services within the last year (n = 7) were conducted. Data were analysed using the framework approach., Results: Guidelines are not readily available at county, township and village levels in the study sites in China, whereas, in Vietnam, guidelines are available, accepted and being used at facility level. Improvements in implementation could be made in both settings. Factors influencing guidelines use common to both settings included: lack of equipment and supplies; shortage of staff with NH care experience; and guidelines not in line with patient practices. Factors specific to China included: poor guidelines dissemination; and disagreement with guidelines. There was limited community engagement in NH services in China, whereas in Vietnam, community members were actively involved in decision making and provision of services. Managers have an important role in supporting NH guidelines use through: ensuring guidelines are available; allocating appropriate resources; supporting and monitoring staff in their use; and engaging with local communities to promote effective practices., Conclusions: Engaging managers to support implementation is crucial. Management systems that provide the necessary resources, competent staff, and monitoring, regulatory and incentive frameworks as well as community engagement are needed to promote adoption of guidelines. Further research on how best to strengthen local level management so that they tailor interventions to support guideline use to their specific context is needed. This will ensure that proven interventions to address NH problems are used, and that countries move closer to achieving the new Sustainable Development Goal 3 target.

Fathers have an important but often neglected role in the promotion of healthy breastfeeding practices in developing countries. A community-based education intervention was designed to mobilize fathers' support for early breastfeeding. This study aimed to evaluate an education intervention targeting fathers to increase the proportion of early breastfeeding initiation and to reduce prelacteal feeding. Quasi-experimental study design was used to compare intervention and control areas located in two non-adjacent rural districts that shared similar demographic and health service characteristics in northern Viet Nam. Fathers and expectant fathers with pregnant wives from 7 to 30 weeks gestational age were recruited. Fathers in the intervention area received breastfeeding education materials, counselling services at a commune health centre and household visits. They were also invited to participate in a breastfeeding promotion social event. After intervention, early breastfeeding initiation rate was 81.2% in the intervention area and 39.6% in the control area (P < 0.001). Babies in the intervention area were more likely to be breastfed within the first hour after birth [odds ratio (OR) 7.64, 95% confidence interval (CI) 4.81-12.12] and not to receive any prelacteal feeding (OR 4.43, 95% CI 2.88-6.82) compared with those in the control area. Fathers may positively influence the breastfeeding practices of mothers, and as a resource for early childcare, they can be mobilized in programmes aimed at improving the early initiation of breastfeeding., (© 2015 John Wiley & Sons Ltd.)

Background: Annually, 2.8 million neonatal deaths occur worldwide, despite the fact that three-quarters of them could be prevented if available evidence-based interventions were used. Facilitation of community groups has been recognized as a promising method to translate knowledge into practice. In northern Vietnam, the Neonatal Health - Knowledge Into Practice trial evaluated facilitation of community groups (2008-2011) and succeeded in reducing the neonatal mortality rate (adjusted odds ratio, 0.51; 95 % confidence interval 0.30-0.89). The aim of this paper is to report on the process (implementation and mechanism of impact) of this intervention., Methods: Process data were excerpted from diary information from meetings with facilitators and intervention groups, and from supervisor records of monthly meetings with facilitators. Data were analyzed using descriptive statistics. An evaluation including attributes and skills of facilitators (e.g., group management, communication, and commitment) was performed at the end of the intervention using a six-item instrument. Odds ratios were analyzed, adjusted for cluster randomization using general linear mixed models., Results: To ensure eight active facilitators over 3 years, 11 Women's Union representatives were recruited and trained. Of the 44 intervention groups, composed of health staff and commune stakeholders, 43 completed their activities until the end of the study. In total, 95 % (n = 1508) of the intended monthly meetings with an intervention group and a facilitator were conducted. The overall attendance of intervention group members was 86 %. The groups identified 32 unique problems and implemented 39 unique actions. The identified problems targeted health issues concerning both women and neonates. Actions implemented were mainly communication activities. Communes supported by a group with a facilitator who was rated high on attributes and skills (n = 27) had lower odds of neonatal mortality (odds ratio, 0.37; 95 % confidence interval, 0.19-0.73) than control communes (n = 46)., Conclusions: This evaluation identified several factors that might have influenced the outcomes of the trial: continuity of intervention groups' work, adequate attributes and skills of facilitators, and targeting problems along a continuum of care. Such factors are important to consider in scaling-up efforts., Trial Registration: ISRCTN ISRCTN44599712 .

Background: To operationalize the post-MDG agenda, there is a need to evaluate the effects of health interventions on equity. The aim of this study is to evaluate the effect on equity in neonatal survival of the NeoKIP trial (ISRCTN44599712), a population-based, cluster-randomized intervention trial with facilitated local stakeholder groups for improved neonatal survival in Quang Ninh province in northern Vietnam., Methods: Semi-structured interviews were conducted with all mothers experiencing neonatal mortality and a random sample of 6% of all mothers with a live birth in the study area during the study period (July 2008-June 2011). Multilevel regression analyses were performed, stratifying mothers according to household wealth, maternal education and mother's ethnicity in order to assess impact on equity in neonatal survival., Findings: In the last year of study the risk of neonatal death was reduced by 69% among poor mothers in the intervention area as compared to poor mothers in the control area (OR 0.31, 95% CI 0.15-0.66). This pattern was not evident among mothers from non-poor households. Mothers with higher education had a 50% lower risk of neonatal mortality if living in the intervention area during the same time period (OR 0.50, 95% CI 0.28-0.90), whereas no significant effect was detected among mothers with low education., Interpretation: The NeoKIP intervention promoted equity in neonatal survival based on wealth but increased inequity based on maternal education.

Reducing the disparity in neonatal health among regions to ensure every mother and her newborn receive the health care they need is a priority in Vietnam. This study was conducted to assess the barriers in implementing the National guidelines on newborn care in a rural mountainous province of Vietnam. Qualitative methods were applied with 28 in-depth interviews and 4 focus group discussions in DakNong province. The results showed that there exist many barriers in implementing the national guideline in newborn care services. There is a big gap between health policy development and policy implementation. The Vietnam government had approved a good strategy and guidelines. Efforts now need to focus on implementing the national guideline and improving quality of care.

Background: The gap between what is known and what is practiced results in health service users not benefitting from advances in healthcare, and in unnecessary costs. A supportive context is considered a key element for successful implementation of evidence-based practices (EBP). There were no tools available for the systematic mapping of aspects of organizational context influencing the implementation of EBPs in low- and middle-income countries (LMICs). Thus, this project aimed to develop and psychometrically validate a tool for this purpose., Methods: The development of the Context Assessment for Community Health (COACH) tool was premised on the context dimension in the Promoting Action on Research Implementation in Health Services framework, and is a derivative product of the Alberta Context Tool. Its development was undertaken in Bangladesh, Vietnam, Uganda, South Africa and Nicaragua in six phases: (1) defining dimensions and draft tool development, (2) content validity amongst in-country expert panels, (3) content validity amongst international experts, (4) response process validity, (5) translation and (6) evaluation of psychometric properties amongst 690 health workers in the five countries., Results: The tool was validated for use amongst physicians, nurse/midwives and community health workers. The six phases of development resulted in a good fit between the theoretical dimensions of the COACH tool and its psychometric properties. The tool has 49 items measuring eight aspects of context: Resources, Community engagement, Commitment to work, Informal payment, Leadership, Work culture, Monitoring services for action and Sources of knowledge., Conclusions: Aspects of organizational context that were identified as influencing the implementation of EBPs in high-income settings were also found to be relevant in LMICs. However, there were additional aspects of context of relevance in LMICs specifically Resources, Community engagement, Commitment to work and Informal payment. Use of the COACH tool will allow for systematic description of the local healthcare context prior implementing healthcare interventions to allow for tailoring implementation strategies or as part of the evaluation of implementing healthcare interventions and thus allow for deeper insights into the process of implementing EBPs in LMICs.

Background: Vietnam has achieved great improvements in maternal healthcare outcomes, but there is evidence of increasing inequity. Disadvantaged groups, predominantly ethnic minorities and people living in remote mountainous areas, do not gain access to maternal health improvements despite targeted efforts from policymakers., Objective: This study identifies underlying structural barriers to equitable maternal health care in Nghe An province, Vietnam. Experiences of social inequity and limited access among child-bearing ethnic and minority women are explored in relation to barriers of care provision experienced by maternal health professionals to gain deeper understanding on health outcomes., Design: In 2012, 11 focus group discussions with women and medical care professionals at local community health centers and district hospitals were conducted using a hermeneutic-dialectic method and analyzed for interpretation using framework analysis., Results: The social determinants 'limited negotiation power' and 'limited autonomy' orchestrate cyclical effects of shared marginalization for both women and care professionals within the provincial health system's infrastructure. Under-staffed and poorly equipped community health facilities refer women and create overload at receiving health centers. Limited resources appear diverted away from local community centers as compensation to the district for overloaded facilities. Poor reputation for low care quality exists, and professionals are held in low repute for causing overload and resulting adverse outcomes. Country-wide reforms force women to bear responsibility for limited treatment adherence and health insight, but overlook providers' limited professional development. Ethnic minority women are hindered by relatives from accessing care choices and costs, despite having advanced insight about government reforms to alleviate poverty. Communication challenges are worsened by non-existent interpretation systems., Conclusions: For maternal health policy outcomes to become effective, it is important to understand that limited negotiation power and limited autonomy simultaneously confront childbearing women and health professionals. These two determinants underlie the inequitable economic, social, and political forces in Vietnam's disadvantaged communities, and result in marginalized status shared by both in the poorest sectors.

To determine the extent of exclusive breastfeeding practices among mothers of 4 and 6 month old infants whose fathers received breastfeeding education materials and counseling services. A quasi-experimental design was used. At the baseline, 251 and 241 couples were recruited into the intervention and control sites respectively. Fathers in the intervention area received breastfeeding education materials, counseling services at commune health centers and household visits. In the control site, where mothers routinely receive services on antenatal and postpartum care, fathers did not receive any intervention services on promoting breastfeeding. Primary indicators were exclusive breastfeeding at 4 and 6 months. At 6 months of age, based on 24-hour recall, 16.0% (38/238) of mothers in the intervention group were exclusively breastfeeding their children, compared to 3.9% (10/230) of those mothers in the control group (p < 0.001). Significant differences were found based on last-week recall (8.8% in the intervention group vs. 1.3% in the control group, p < 0.001) and since-birth recall (6.7% in the intervention group vs. 0.9% in the control group, p < 0.01). At 4 months of age, based on since birth recall, the breastfeeding proportion was significantly higher in the intervention group than in control group (20.6% in the intervention group vs. 11.3% in the control group, p < 0.01). An intervention targeting fathers might be effective in increasing exclusive breastfeeding practices at 4 and 6 months. To improve exclusive breastfeeding, health care staff working in maternal and child health units, should consider integrating fathers with services delivered to mothers and children.

This paper introduces an online sleep apnea detection method based on heart rate complexity as measured by recurrence quantification analysis (RQA) statistics of heart rate variability (HRV) data. RQA statistics can capture nonlinear dynamics of a complex cardiorespiratory system during obstructive sleep apnea. In order to obtain a more robust measurement of the nonstationarity of the cardiorespiratory system, we use different fixed amount of neighbor thresholdings for recurrence plot calculation. We integrate a feature selection algorithm based on conditional mutual information to select the most informative RQA features for classification, and hence, to speed up the real-time classification process without degrading the performance of the system. Two types of binary classifiers, i.e., support vector machine and neural network, are used to differentiate apnea from normal sleep. A soft decision fusion rule is developed to combine the results of these classifiers in order to improve the classification performance of the whole system. Experimental results show that our proposed method achieves better classification results compared with the previous recurrence analysis-based approach. We also show that our method is flexible and a strong candidate for a real efficient sleep apnea detection system.

Objective: To investigate changes that took place between 2006 and 2010 in the inequity gap for antenatal care attendance and delivery at health facilities among women in Viet Nam., Methods: Demographic, socioeconomic and obstetric data for women aged 15-49 years were extracted from Viet Nam's Multiple Indicator Cluster Survey for 2006 (MICS3) and 2010-2011 (MICS4). Multivariate logistic regression was performed to determine if antenatal care attendance and place of delivery were significantly associated with maternal education, maternal ethnicity (Kinh/Hoa versus other), household wealth and place of residence (urban versus rural). These independent variables correspond to the analytical framework of the Commission on Social Determinants of Health., Findings: Large discrepancies between urban and rural populations were found in both MICS3 and MICS4. Although antenatal care attendance and health facility delivery rates improved substantially between surveys (from 86.3 to 92.1% and from 76.2 to 89.7%, respectively), inequities increased, especially along ethnic lines. The risk of not giving birth in a health facility increased significantly among ethnic minority women living in rural areas. In 2006 this risk was nearly five times higher than among women of Kinh/Hoa (majority) ethnicity (odds ratio, OR: 4.67; 95% confidence interval, CI: 2.94-7.43); in 2010-2011 it had become nearly 20 times higher (OR: 18.8; 95% CI: 8.96-39.2)., Conclusion: Inequity in maternal health care utilization has increased progressively in Viet Nam, primarily along ethnic lines, and vulnerable groups in the country are at risk of being left behind. Health-care decision-makers should target these groups through affirmative action and culturally sensitive interventions.

Background: Equity in health is a pressing concern and reaching disadvantaged populations is necessary to close the inequity gap. To date, the discourse has predominately focussed on reaching the poor. At the same time and in addition to wealth, other structural determinants that influence health outcomes exist, one of which is ethnicity. Inequities based on group belongings are recognised as 'horizontal', as opposed to the more commonly used notion of 'vertical' inequity based on individual characteristics., Objective: The aim of the present review is to highlight ethnicity as a source of horizontal inequity in health and to expose mechanisms that cause and maintain this inequity in Vietnam., Design: Through a systematic search of available academic and grey literature, 49 publications were selected for review. Information was extracted on: a) quantitative measures of health inequities based on ethnicity and b) qualitative descriptions explaining potential reasons for ethnicity-based health inequities., Results: Five main areas were identified: health-care-seeking and utilization, maternal and child health, nutrition, infectious diseases, and oral health and hygiene. Evidence suggests the presence of severe health inequity in health along ethnic lines in all these areas. Research evidence also offers explanations derived from both external and internal group dynamics to this inequity. It is reported that government policies and programs appear to be lacking in culturally adaptation and sensitivity, and examples of bad attitudes and discrimination from health staff toward minority persons were identified. In addition, traditions and patriarchal structures within ethnic minority groups were seen to contribute to the maintenance of harmful health behaviors within these groups., Conclusion: Better understandings of the scope and pathways of horizontal inequities are required to address ethnic inequities in health. Awareness of ethnicity as a determinant of health, not only as a covariate of poverty or living area, needs to be improved, and research needs to be designed with this in mind.

Background: Facilitation of local women's groups may reportedly reduce neonatal mortality. It is not known whether facilitation of groups composed of local health care staff and politicians can improve perinatal outcomes. We hypothesised that facilitation of local stakeholder groups would reduce neonatal mortality (primary outcome) and improve maternal, delivery, and newborn care indicators (secondary outcomes) in Quang Ninh province, Vietnam., Methods and Findings: In a cluster-randomized design 44 communes were allocated to intervention and 46 to control. Laywomen facilitated monthly meetings during 3 years in groups composed of health care staff and key persons in the communes. A problem-solving approach was employed. Births and neonatal deaths were monitored, and interviews were performed in households of neonatal deaths and of randomly selected surviving infants. A latent period before effect is expected in this type of intervention, but this timeframe was not pre-specified. Neonatal mortality rate (NMR) from July 2008 to June 2011 was 16.5/1,000 (195 deaths per 11,818 live births) in the intervention communes and 18.4/1,000 (194 per 10,559 live births) in control communes (adjusted odds ratio [OR] 0.96 [95% CI 0.73-1.25]). There was a significant downward time trend of NMR in intervention communes (p = 0.003) but not in control communes (p = 0.184). No significant difference in NMR was observed during the first two years (July 2008 to June 2010) while the third year (July 2010 to June 2011) had significantly lower NMR in intervention arm: adjusted OR 0.51 (95% CI 0.30-0.89). Women in intervention communes more frequently attended antenatal care (adjusted OR 2.27 [95% CI 1.07-4.8])., Conclusions: A randomized facilitation intervention with local stakeholder groups composed of primary care staff and local politicians working for three years with a perinatal problem-solving approach resulted in increased attendance to antenatal care and reduced neonatal mortality after a latent period.

Background: There is increasing evidence of an elevated sex ratio at birth (SRB) in many Asian countries, including Vietnam, and that this prenatal gender inequity is related to sex-selective abortion. However, few studies have investigated the relation between the sex of offspring and delivery care utilization., Objective: The aim of the present study was to relate sex of newborns to place and mode of delivery in a province in northern Vietnam., Methods: A population-based surveillance system within the Neonatal Health-Knowledge Into Practice (NeoKIP) project (ISRCTN44599712) recorded all births within eight districts of Quang Ninh province in northern Vietnam from July 2008 to June 2011., Results: In total, there were 22,377 live births within the study area. SRB was 108 boys per 100 girls. There was a large difference in SRB depending on place of delivery, with 94 boys per 100 girls being delivered at home, whereas 113 boys per 100 girls were delivered at a district-level hospital. Cesarean section (CS) rate was 17%, and within the CS group, the SRB was 135:100., Conclusions: We demonstrated an elevated SRB, especially at district hospital level, and that sex of offspring influenced place and mode of delivery. Although mothers to boys were more likely to receive more qualified delivery care, they were at the same time more likely to undergo unnecessary surgery. Correct information to women and family members about CS and stricter implementation of the medical indications for CS are urgently called for., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Background: Inequities in health are a major challenge for health care planners and policymakers globally. In Vietnam, rapid societal development presents a considerable risk for disadvantaged populations to be left behind. The aim of this review is to map the known causes and determinants of inequity in maternal and child health in Vietnam in order to promote policy action., Methods: A review was performed through systematic searches of Pubmed and Proquest and manual searches of "grey literature." A thematic content analysis guided by the conceptual framework suggested by the Commission on Social Determinants of Health was performed., Results: More than thirty different causes and determinants of inequity in maternal and child health were identified. Some determinants worth highlighting were the influence of informal fees and the many testimonies of discrimination and negative attitudes from health staff towards women in general and ethnic minorities in particular. Research gaps were identified, such as a lack of studies investigating the influence of education on health care utilization, informal costs of care, and how psychosocial factors mediate inequity., Conclusions: The evidence of corruption and discrimination as mediators of health inequity in Vietnam calls for attention and indicates a need for more structural interventions such as better governance and anti-discriminatory laws. More research is needed in order to fully understand the pathways of inequities in health in Vietnam and suggest areas for intervention for policy action to reach disadvantaged populations.

Introduction: Vietnam has succeeded in reducing maternal mortality in the last decades. Analysis of survey data however indicate that large inequities exist between different segments of the population. We have analyzed utilization of antenatal care and skilled birth attendance among Vietnamese women of reproductive age in relation to social determinants with the aim to reveal health inequities and identify disadvantaged groups., Method: Data on maternal health care utilization and social determinants were derived from the Multiple Indicator Cluster Survey (MICS) conducted in Vietnam in 2006, and analyzed through stratified logistic regressions and g-computation., Results: Inequities in maternal health care utilization persist in Vietnam. Ethnicity, household wealth and education were all significantly associated with antenatal care coverage and skilled birth attendance, individually and in synergy. Although the structural determinants included in this study were closely related to each other, analysis revealed a significant effect of ethnicity over and above wealth and education. Within the group of mothers from poor households ethnic minority mothers were at a three-fold risk of not attending any antenatal care (OR 3.06, 95% CI 1.27-7.41) and six times more likely not to deliver with skilled birth attendance (OR 6.27, 95% CI 2.37-16.6). The association between ethnicity and lack of antenatal care and skilled birth attendance was even stronger within the non-poor group., Conclusions: In spite of policies to out rule health inequities, ethnic minority women constitute a disadvantaged group in Vietnam. More efficient ways to target disadvantaged groups, taking synergy effects between multiple social determinants into consideration, are needed in order to assure safe motherhood for all.

Aim: To ascertain the causes of neonatal death in a province in northern Vietnam and analyse their distribution over age at death, birth weight and place of delivery., Methods: Verbal autopsy interviews using a questionnaire derived from WHO standard and adapted to Vietnamese conditions was performed on all neonatal deaths occurring in Quang Ninh province from July 2008 to June 2010. Three experienced paediatricians independently reviewed all verbal autopsy records (233) and assigned a main cause of death. In case of disagreement in the allocation of cause of death, a consensus process was initiated to decide on a final cause., Results: Neonatal mortality rate within the study area was 16/1000 (238 neonatal deaths and 14,453 live births) over the study period. Prematurity/low birth-weight (37.8%), intrapartum-related neonatal deaths (birth asphyxia, 33.2%), infections (13.0%) and congenital malformation (6.7%) were the four leading causes of death. Four cases of neonatal tetanus were found. Intrapartum-related deaths dominated in the home delivery group, whereas prematurity was the most prominent cause of death at all facility levels. Most neonatal deaths occurred within the first 24 h after delivery (58.6%)., Conclusion: A high proportion of deaths due to prematurity and intrapartum-related causes, calls for improvements of delivery care and resuscitation practices at health facilities., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

μ-Calpain is a Ca(2+)-activated protease abundant in mammalian tissues. Here, we examined the effects of μ-calpain on three alternatively spliced variants of NCX1 using the giant, excised patch technique. Membrane patches from Xenopus oocytes expressing either heart (NCX1.1), kidney (NCX1.3), or brain (NCX1.4) variants of NCX1 were exposed to μ-calpain and their Na(+)-dependent (I(1)) and Ca(2+)-dependent (I(2)) regulatory phenotypes were assessed. For these exchangers, I(1) inactivation is evident as a Na(+)(i)-dependent decay of peak outward currents whereas I(2) regulation manifests as outward current activation by micromolar Ca(2+)(i) concentrations. Notably, with NCX1.1 and NCX1.4 but not in NCX1.3, higher Ca(2+)(i) levels alleviate I(1) inactivation. Our results show that (i) μ-calpain selectively ablates Ca(2+)-dependent (I(2)) regulation leading to a constitutive activation of exchange current, (ii) μ-calpain has much smaller effects on Na(+)-dependent (I(1)) regulation, produced by a slight destabilization of the I(1) state, and (iii) Ca(2+)-dependent regulation (I(2)) and Ca(2+)-mediated alleviation of I(1) appear to be functionally distinct mechanisms, the latter of which is left largely intact after μ-calpain treatment. The ability of μ-calpain to selectively and constitutively activate Na(+)-Ca(2+) exchange currents may have important pathophysiological implications in tissue where these splice variants are expressed., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Maternal and child mortality rates, the targets for two of the eight Millennium Development Goals, remain unacceptably high in many countries. Some countries have made significant advances in reducing deaths in pregnancy, childbirth, and childhood at the national level. However, on a sub-national basis most countries show wide disparities in health indices which are not necessarily reflected in national figures. This is a sign of inequitable access to and provision of health services. Yet there has been little attention to health equity in relation to the Millennium Development Goals. Instead, countries have focused on achieving national targets. This has led to an emphasis on utilitarian, as opposed to universalist, approaches to public health, which we discuss here. We recommend a policy of "proportionate universalism". In this approach, universal health care and a universal social policy are the ultimate goal, but in the interim actions are carried out with intensities proportionate to disadvantage. We also briefly describe an initiative that aims to promote evidence-based policy and interventions that will reduce inequity in access to maternal and child health care in China, India, Indonesia and Viet Nam., (Copyright © 2011 Reproductive Health Matters. Published by Elsevier Ltd. All rights reserved.)

Background: Globally, almost 4 million newborns die during the first 4 weeks of life every year. By increased use of evidence-based knowledge in the healthcare system a large proportion of these neonatal deaths could be prevented. But there is a severe lack of knowledge on effective methods for successful implementation of evidence into practice, particularly in low- and middle-income countries. Recent studies have demonstrated promising results with increased survival among both mothers and newborns using community-based approaches. In Vietnam evidence-based guidelines on reproductive health were launched in 2003 and revised in 2009. The overall objective of the current project is to evaluate if a facilitation intervention on the community level, with a problem-solving approach involving local representatives if the healthcare system and the community, results in improvements of neonatal health and survival., Methods/design: The study, which has been given the acronym NeoKIP (Neonatal Health - Knowledge Into Practice), took place in 8 districts composed by 90 communes in a province in northern Vietnam, where neonatal mortality rate was 24/1000 in 2005. A cluster randomised design was used, allocating clusters, as defined as a commune and its correponding Commune Health Center (CHC) to either intervention or control arm. The facilitation intervention targeted staff at healthcare centres and key persons in the communes. The facilitator role was performed by lay women (Women's Union representatives) using quality improvement techniques to initiate and sustain improvement processes targeting identified problem areas. The intervention has been running over 3 years and data were collected on the facilitation process, healthcare staff knowledge in neonatal care and their behaviour in clinical practice, and reproductive and perinatal health indicators. Primary outcome is neonatal mortality., Discussion: The intervention is participatory and dynamic, focused on developing a learning process and a problem-solving cycle. The study recognises the vital role of the local community as actors in improving their own and their newborns' health, and applies a bottom-up approach where change will be accomplished by an increasing awareness at and demand from grass root level. By utilising the existing healthcare structure this intervention may, if proven successful, be well suited for scaling up., Trial Registration: Current Controlled Trials ISRCTN44599712.

Background: Nearly four million neonatal deaths occur annually in the world despite existing evidence-based knowledge with the potential to prevent many of these deaths. Effective knowledge translation (KT) could help to bridge this know-do gap in global health. The aim of this study was to explore aspects of KT at the primary healthcare level in a northern province in Vietnam., Methods: Six focus-group discussions were conducted with primary healthcare staff members who provided neonatal care in districts that represented three types of geographical areas existing in the province (urban, rural, and mountainous). Recordings were transcribed verbatim, translated into English, and analyzed using content analysis., Results: We identified three main categories of importance for KT. Healthcare staff used several channels for acquisition and management of knowledge (1), but none appeared to work well. Participants preferred formal training to reading guideline documents, and they expressed interest in interacting with colleagues at higher levels, which rarely happened. In some geographical areas, traditional medicine (2) seemed to compete with evidence-based practices, whereas in other areas it was a complement. Lack of resources, low frequency of deliveries and, poorly paid staff were observed barriers to keeping skills at an adequate level in the healthcare context (3)., Conclusions: This study indicates that primary healthcare staff work in a context that to some extent enables them to translate knowledge into practice. However, the established and structured healthcare system in Vietnam does constitute a base where such processes could be expected to work more effectively. To accelerate the development, thorough considerations over the current situation and carefully targeted actions are required.

Aim: In this study from Quang Ninh province in northern Vietnam (sub-study of the trial Neonatal Health - Knowledge into Practice, NeoKIP, ISRCTN 44599712), we investigated determinants of neonatal mortality through a case-referent design, with special emphasis on socio-economic factors and health system utilization., Methods: From July 2008 until December 2009, we included 183 neonatal mortality cases and 599 referents and their mothers were interviewed., Results: Ethnicity was the main socio-economic determinant for neonatal mortality (OR 2.08, 95% CI 1.39-3.10, adjusted for mothers' education and household economic status). Health system utilization before and at delivery could partly explain the risk elevation, with an increased risk of neonatal mortality for mothers who did not attend antenatal care and who delivered at home (OR 4.79, 95% CI 2.98-7.71). However, even if mothers of an ethnic minority attended antenatal care or delivered at a health facility, the increased risk for this group was sustained., Conclusion: Our study demonstrates inequity in neonatal survival that is related to ethnicity rather than family economy or education level of the mother and highlights the need to include the ethnic dimension in the efforts to reduce neonatal mortality., (© 2010 The Author(s)/Acta Paediatrica © 2010 Foundation Acta Paediatrica.)

Aim: We report baseline results of a community-based randomized trial for improved neonatal survival in Quang Ninh province, Vietnam (NeoKIP; ISRCTN44599712). The NeoKIP trial seeks to evaluate a method of knowledge implementation called facilitation through group meetings at local health centres with health staff and community key persons. Facilitation is a participatory enabling approach that, if successful, is well suited for scaling up within health systems. The aim of this baseline report is to describe perinatal services provided and neonatal outcomes., Methods: Survey of all health facility registers of service utilization, maternal deaths, stillbirths and neonatal deaths during 2005 in the province. Systematic group interviews of village health workers from all communes. A Geographic Information System database was also established., Results: Three quarters of pregnant women had ≥3 visits to antenatal care. Two hundred and five health facilities, including 18 hospitals, provided delivery care, ranging from 1 to 3258 deliveries/year. Totally there were 17 519 births and 284 neonatal deaths in the province. Neonatal mortality rate was 16/1000 live births, ranging from 10 to 44/1000 in the different districts, with highest rates in the mountainous parts of the province. Only 8% had home deliveries without skilled attendance, but those deliveries resulted in one-fifth of the neonatal deaths., Conclusion: A relatively good coverage of perinatal care was found in a Vietnamese province, but neonatal mortality varied markedly with geography and level of care. A remaining small proportion of home deliveries generated a substantial part of mortality., (© 2010 The Author(s)/Journal Compilation © 2010 Foundation Acta Paediatrica.)

Na(+)/Ca(2+) exchangers (NCX) constitute a major Ca(2+) export system that facilitates the re-establishment of cytosolic Ca(2+) levels in many tissues. Ca(2+) interactions at its Ca(2+) binding domains (CBD1 and CBD2) are essential for the allosteric regulation of Na(+)/Ca(2+) exchange activity. The structure of the Ca(2+)-bound form of CBD1, the primary Ca(2+) sensor from canine NCX1, but not the Ca(2+)-free form, has been reported, although the molecular mechanism of Ca(2+) regulation remains unclear. Here, we report crystal structures for three distinct Ca(2+) binding states of CBD1 from CALX, a Na(+)/Ca(2+) exchanger found in Drosophila sensory neurons. The fully Ca(2+)-bound CALX-CBD1 structure shows that four Ca(2+) atoms bind at identical Ca(2+) binding sites as those found in NCX1 and that the partial Ca(2+) occupancy and apoform structures exhibit progressive conformational transitions, indicating incremental regulation of CALX exchange by successive Ca(2+) binding at CBD1. The structures also predict that the primary Ca(2+) pair plays the main role in triggering functional conformational changes. Confirming this prediction, mutagenesis of Glu(455), which coordinates the primary Ca(2+) pair, produces dramatic reductions of the regulatory Ca(2+) affinity for exchange current, whereas mutagenesis of Glu(520), which coordinates the secondary Ca(2+) pair, has much smaller effects. Furthermore, our structures indicate that Ca(2+) binding only enhances the stability of the Ca(2+) binding site of CBD1 near the hinge region while the overall structure of CBD1 remains largely unaffected, implying that the Ca(2+) regulatory function of CBD1, and possibly that for the entire NCX family, is mediated through domain interactions between CBD1 and the adjacent CBD2 at this hinge.

Members of the Na+/Ca2+ exchanger (NCX) family are important regulators of cytosolic Ca2+ in myriad tissues and are highly conserved across a wide range of species. Three distinct NCX genes and numerous splice variants exist in mammals, many of which have been characterized in a variety of heterologous expression systems. Recently, however, we discovered a fourth NCX gene (NCX4), which is found exclusively in teleost, amphibian, and reptilian genomes. Zebrafish (Danio rerio) NCX4a encodes for a protein of 939 amino acids and shows a high degree of identity with known NCXs. Although knockdown of NCX4a activity in zebrafish embryos has been shown to alter left-right patterning, it has not been demonstrated that NCX4a functions as a NCX. In this study, we 1) demonstrated, for the first time, that this gene encodes for a novel NCX; 2) characterized the tissue distribution of zebrafish NCX4a; and 3) evaluated its kinetic and transport properties. While ubiquitously expressed, the highest levels of NCX4a expression occurred in the brain and eyes. NCX4a exhibits modest levels of Na+-dependent inactivation and requires much higher levels of regulatory Ca2+ to activate outward exchange currents. NCX4a also exhibited extremely fast recovery from Na+-dependent inactivation of outward currents, faster than any previously characterized wild-type exchanger. While this result suggests that the Na+-dependent inactive state of NCX4a is far less stable than in other NCX family members, this exchanger was still strongly inhibited by 2 microM exchanger inhibitory peptide. We demonstrated that a new putative member of the NCX gene family, NCX4a, encodes for a NCX with unique functional properties. These data will be useful in understanding the role that NCX4a plays in embryological development as well as in the adult, where it is expressed ubiquitously.

Aim: To examine trends in neonatal, infant and under-five mortality rates in a northern Vietnamese district during 1970-2000, and to analyze socioeconomic differences in child survival over time., Methods: Retrospective interviews with all women aged 15-54 years in Bavi district in Northern Vietnam (n = 14 329) were conducted. Of these women, 13 943 had been pregnant, giving birth to 26 796 children during 1970-2000., Results: There was a dramatic reduction in infant and under-five mortality rate (47%) over time. However, the neonatal mortality rate (NMR) showed a very small reduction, thus causing its proportion of the total child mortality to increase. Mortality trends followed the political and socioeconomic development of Vietnam over war, peace and periods of reforms. There were no differences in under-five and neonatal mortalities associated with family economy, while differentials related to mothers' education and ethnicity were increasing., Conclusion: Interventions to reduce child mortality should be focused on improving neonatal care. In settings with a rapid economic growth and consequent social change, like in Vietnam, it is important that such interventions are targeted at vulnerable groups, in this case, families with low level of education and belonging to ethnic minorities.

The complete cDNA sequence of the tilapia cardiac Na(+)/Ca2+ exchanger (NCX-TL1.0) was determined. The 3.1-kb transcript encodes a protein 957 amino acids in length, with a predicted signal peptide cleaved at residue 31 and two potential N-glycosylation sites in the extracellular N terminus. Hydropathy analysis and sequence comparison predicted a mature protein with nine transmembrane-spanning segments, consistent with the structural topologies of other known mammalian and teleost NCX isoforms. Overall sequence comparison shows high identity to both trout NCX-TR1.0 ( approximately 81%) and mammalian NCX1.1 ( approximately 73%), and phylogenetic analyses confirmed its identity as a member of the NCX1 gene family, expressing exons A, C, D, and F in the alternative splice site. Sequence identity is even higher in the alpha-repeats, the exchanger inhibitory peptide (XIP) site, and Ca(2+)-binding domains, which is reflected in the functional and regulatory properties of tilapia NCX-TL1.0. When NCX-TL1.0 was expressed in Xenopus oocytes and the currents were measured in giant excised patches, they displayed both positive regulation by Ca2+ and Na(+)-dependent inactivation in a manner similar to trout NCX-TR1.0. However, tilapia NCX-TL1.0 exhibited a relatively high sensitivity to temperature compared with trout NCX-TR1.0. Whereas trout NCX-TR1.0 currents displayed activation energies of approximately 7 kJ/mol, tilapia NCX-TL1.0 currents showed mammal-like temperature dependence, with peak and steady-state current activation energies of 53 +/- 9 and 67 +/- 21 kJ/mol, respectively. Using comparative sequence analysis, we highlighted 10 residue positions in the N-terminal domain of the NCX that, in combination, may confer exchanger temperature dependence through subtle changes in protein flexibility. Tilapia NCX-TL1.0 represents the first non-mammalian NCX to exhibit a mammalian temperature dependence phenotype and will prove to be a useful model in defining the interplay between molecular flexibility and stability in NCX function.

Chinese hamster ovary cells expressing the bovine cardiac Na+-Ca2+ exchanger (NCX1.1) accumulated Cd2+ after a lag period of several tens of seconds. The lag period reflects the progressive allosteric activation of exchange activity by Cd2+ as it accumulates within the cytosol. The lag period was greatly reduced in cells expressing a mutant exchanger, Delta(241-680), that does not require allosteric activation by Ca2+ for activity. Non-transfected cells did not show Cd2+ uptake under the same conditions. In cells expressing NCX1.1, the lag period was nearly abolished following an elevation of the cytosolic Ca2+ concentration. Cytosolic Cd2+ concentrations estimated at 0.5-2 pm markedly stimulated the subsequent uptake of Ca2+ by Na+-Ca2+ exchange. Outward exchange currents in membrane patches from Xenopus oocytes expressing the canine NCX1.1 were rapidly and reversibly stimulated by 3 pm Cd2+ applied at the cytosolic membrane surface. Exchange currents activated by 3 pm Cd2+ were 40% smaller than currents activated by 1 mum cytosolic Ca2+. Current amplitudes declined by 30% and the rate of current development fell sharply upon repetitive applications of Na+ in the presence of 3 pm Cd2+. Cd2+ mimicked the anomalous inhibitory effects of Ca2+ on outward exchange currents generated by the Drosophila exchanger CALX1.1. We conclude that the regulatory sites responsible for allosteric Ca2+ activation bind Cd2+ with high affinity and that Cd2+ mimics the regulatory effects of Ca2+ at concentrations 5 orders of magnitude lower than Ca2+.

SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline) has recently been described as a potent and selective inhibitor of Na(+)-Ca(2+) exchange in cardiac, neuronal, and renal preparations. The inhibitory effects of SEA0400 were investigated on the cloned cardiac Na(+)-Ca(2+) exchanger, NCX1.1, expressed in Xenopus laevis oocytes to gain insight into its inhibitory mechanism. Na(+)-Ca(2+) exchange currents were measured using the giant excised patch technique using conditions to evaluate both inward and outward currents. SEA0400 inhibited outward Na(+)-Ca(2+) exchange currents with high affinity (IC(50) = 78 +/- 15 and 23 +/- 4 nM for peak and steady-state currents, respectively). Considerably less inhibitory potency (i.e., micromolar) was observed for inward currents. The inhibitory profile was reexamined after proteolytic treatment of excised patches with alpha-chymotrypsin, a procedure that eliminates ionic regulatory mechanisms. After this treatment, an IC(50) value of 1.2 +/- 0.6 microM was estimated for outward currents, whereas inward currents became almost insensitive to SEA0400. The inhibitory effects of SEA0400 on outward exchange currents were evident at both high and low concentrations of regulatory Ca(2+), although distinct features were noted. SEA0400 accelerated the inactivation rate of outward currents. Based on paired pulse experiments, SEA0400 altered the recovery of exchangers from the Na(+)(i)-dependent inactive state, particularly at higher regulatory Ca(2+)(i) concentrations. Finally, the inhibitory potency of SEA0400 was strongly dependent on the intracellular Na(+) concentration. Our data confirm that SEA0400 is the most potent inhibitor of the cardiac Na(+)-Ca(2+) exchanger described to date and provide a reasonable explanation for its apparent transport mode selectivity.

Neuroblastoma is the most frequent solid childhood malignancy. Despite aggressive therapy, mortality is high due to rapid tumor progression to advanced stages. The molecules and mechanisms underlying poor prognosis are not well understood. Here, we report that cultured human neuroblastoma cells express the hepatocyte growth factor (HGF) and its receptor c-Met. Binding of HGF to c-Met triggers receptor autophosphorylation, indicating functional relevance of this interaction. HGF activates several downstream effectors of c-Met such as the mitogen-activated protein kinases extracellular signal-regulated kinase 1/extracellular signal-regulated kinase 2 and phospholipase C-gamma, whereas signal transducer and activator of transcription 3 is constitutively activated in neuroblastoma cells expressing c-Met. In addition, HGF is able to stimulate expression and proteolytic activity of matrix metalloproteinase-2 and tissue-type plasminogen activator in neuroblastoma cells, thereby promoting degradation of extracellular matrix components. We show that HGF stimulates invasion of neuroblastoma cells in vitro and in vivo, and it promotes the formation of angiogenic neuroblastomas in vivo. These processes can be blocked by specific inhibitors of the mitogen-activated protein kinase cascade, by inhibitors of phospholipase C-gamma, and also by the expression of a dominant negative signal transducer and activator of transcription 3 mutant. Our data provide the first evidence that the HGF/c-Met pathway is essential for invasiveness and malignant progression of human neuroblastomas. They further suggest that specific inhibitors of this pathway may be suitable as therapeutic agents to improve clinical outcome of neuroblastomas.

SEA0400 (SEA) blocks cardiac and neuronal Na+-Ca2+ exchange with the highest affinity of any known inhibitor, yet very little is known about its molecular mechanism of action. Previous data from our lab suggested that SEA stabilizes or modulates the transition of NCX1.1 exchangers into a Na+i-dependent (I1) inactive state. To test this hypothesis, we examined the effects of SEA on mutant exchangers with altered ionic regulatory properties. With mutants where Na+i-dependent inactivation is absent, the effects of SEA were greatly reduced. Conversely, with mutants displaying accelerated Na+i-dependent inactivation, block of NCX1.1 by SEA was either enhanced or unchanged, depending upon the phenotype of the particular mutation. With mutant exchangers where Ca2+i-dependent (I2) inactivation was suppressed, block of exchange currents by SEA was similar to that observed for wild-type NCX1.1. These data strongly support the involvement of I1 inactivation in the inhibitory mechanism of NCX1.1 by SEA, whereas I2 inactivation does not seem to serve an important role. The involvement of processes regulated by intracellular Na+ in the inhibitory mechanism of SEA may prove to be particularly important when considering the potential cardioprotective effects of this agent.

The electrophysiological effects of the benzothiazepine 7-chloro-3,5-dihydro-5-phenyl-1H-4,1-benzothiazepine-2-one (CGP-37157) (CGP) were investigated on the canine (NCX1.1) and Drosophila (CALX1.1) plasmalemmal Na+-Ca2+ exchangers. These exchangers were selected for study because they show opposite responses to cytoplasmic regulatory Ca2+, thereby allowing us to examine the role of this regulatory mechanism in the inhibitory effects of CGP. CGP blocked Na+-Ca2+ exchange current mediated by both transporters with moderate potency (IC50 values = approximately 3-17 microM) compared with other recently reported blockers of Na+-Ca2+ exchange [e.g., 2-[4-[2,5-difluorophenyl) methoxy]phenoxy]phenoxy]-5-ethoxyaniline (KB-R7943) and 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (SEA0400)]. Experiments using alpha-chymotrypsin to remove autoregulation of Na+-Ca2+ exchange showed that block by CGP was reduced, suggesting that part of the effects of this drug may require intact ionic regulatory mechanisms. For NCX1.1, the inhibition produced by CGP was greater for outward Na+-Ca2+ exchange currents compared with inward currents. When CALX1.1 was examined, the extent of inhibition was similar for both inward and outward exchange currents. Although the extent and potency of CGP-mediated inhibition of Na+-Ca2+ exchange are less than those observed with SEA0400 and KB-R7943, our data demonstrate that CGP constitutes a novel class of plasmalemmal Na+-Ca2+ exchange inhibitors. Moreover, the widespread use of CGP as a selective mitochondrial Na+-Ca2+ exchange inhibitor should be reconsidered in light of these additional inhibitory effects.

Aims: Assessment was made of the validity of mortality estimates based on data collected during 1999-2000 by quarterly follow-up visits and compared with other methods (re-census, communal death registration, and neighbourhood survey)., Methods: This study was carried out within a longitudinal epidemiological laboratory in Bavi, District, Vietnam (called FilaBavi), covering a sample of 11,089 households with 51,024 inhabitants. Deaths within FilaBavi during 1999-2000 were collected by four methods and compared: quarterly household follow-ups, the re-census carried out in 2001, the Commune Population Registration System (CPRS), and a neighbourhood survey., Results: Within these four methods, a total of 471 deaths were detected in the FilaBavi sample. Quarterly household follow-ups detected 470 deaths (99.8%). The re-census missed 19 deaths, of which eight were infants, and two-thirds of the missed deaths fell in 1999. The CPRS missed 89 cases (19%), the majority being infant and elderly deaths. The neighbourhood survey over-reported deaths., Conclusions: Quarterly follow-ups were the best method for death registration. The re-census approach was less complete, with problems of recall bias. The completeness and quality of death registration by CPRS was low, especially for infant and elderly mortality.

The Na(+)/Ca(2+) exchanger gene NCX1 undergoes alternative splicing leading to several isoforms that differ in a small portion of the large cytoplasmic loop. This loop is involved in many regulatory processes of NCX1, including ionic regulation by the transported substrates Na(+) and Ca(2+). High intracellular Ca(2+) can alleviate intracellular Na(+)-dependent inactivation in exon A (NCX1.4)-containing isoforms but not in those containing the mutually exclusive exon B (NCX1.3). Giant excised patches from Xenopus oocytes expressing various NCX1 constructs were used to examine the specific amino acids responsible for these observed regulatory differences. Using a chimeric approach, the region responsible was narrowed down to the small central part of exon A (IDDEEYEKNKTF). Replacing the second aspartic acid of this sequence with arginine (the corresponding amino acid in exon B) in an exon A background completely prevented the effect of Ca(2+) on intracellular Na(+)-dependent inactivation. Mutating the second lysine to cysteine (exon B) had a similar, but only partial, effect. The converse double mutant, but neither single mutation alone, introduced into an exon B background (arginine to aspartic acid and cysteine to lysine) was able to restore the NCX1.4 regulatory phenotype. These data demonstrate that aspartic acid 610 and lysine 617 (using the rat NCX1.4 numbering scheme) are critical molecular determinants of the unique Ca(2+) regulatory properties of NCX1.4.

The cardiac Na(+)/Ca(2+) exchanger (NCX) in trout exhibits profoundly lower temperature sensitivity in comparison to the mammalian NCX. In this study, we attempt to characterize the regions of the NCX molecule that are responsible for its temperature sensitivity. Chimeric NCX molecules were constructed using wild-type trout and canine NCX cDNA and expressed in Xenopus oocytes. NCX-mediated currents were measured at 7, 14, and 30 degrees C using the giant excised-patch technique. By using this approach, the differential temperature dependence of NCX was found to reside within the NH(2)-terminal region of the molecule. Specifically, we found that approximately 75% of the Na(+)/Ca(2+) exchange differential energy of activation is attributable to sequence differences in the region that include the first four transmembrane segments, and the remainder is attributable to transmembrane segment five and the exchanger inhibitory peptide site.