Barriers and enablers to access and utilization of mental health care services across Southeast Asia: A preliminary scoping review.

While the importance of mental health and its impact on overall health and well-being has been widely recognized, there continue to be ongoing barriers to accessing mental health services. This is particularly poignant in countries in Southeast Asia (SEA) where there may be further stigma in accessing mental health services. As no reviews have been undertaken on this topic, this review aims to outline the barriers and enablers to access and utilization of mental health care services in SEA. Searches were undertaken in commercially produced and gray literature sources. Two independent reviewers screened the results. The data were then independently extracted, which was then collated and synthesized, using the Health Belief Model (HMB) as a framework. Twelve studies were included in the review. Under the HBM, barriers were grouped into: stigma, poor health literacy, internalized reasons, cultural beliefs, lack of training of health professionals, quality of service, and poor distribution of resources. Enablers included: social support, outreach services, structural stigma, self-awareness, resources and information, accessibility and affordability, and positive attitudes and beliefs about health professionals. Those accessing mental health care in SEA are confronted by complex barriers and few enablers. Ongoing stigma and a distinct lack of resources pose the greatest challenges, which are even more amplified for those in rural areas and minority groups. A multifaceted strategy that improves the structures, processes, and outcomes of mental health is required within these communities.

Assay Development and Identification of the First Plasmodium falciparum 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase Inhibitors.

In the fight towards eradication of malaria, identifying compounds active against new drug targets constitutes a key approach. Plasmodium falciparum 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase (PfHPPK) has been advanced as a promising target, as being part of the parasite essential folate biosynthesis pathway while having no orthologue in the human genome. However, no drug discovery efforts have been reported on this enzyme. In this study, we conducted a three-step screening of our in-house antifolate library against PfHPPK using a newly designed PfHPPK-GFP protein construct. Combining virtual screening, differential scanning fluorimetry and enzymatic assay, we identified 14 compounds active against PfHPPK. Compounds' binding modes were investigated by molecular docking, suggesting competitive binding with the HMDP substrate. Cytotoxicity and in vitro ADME properties of hit compounds were also assessed, showing good metabolic stability and low toxicity. The most active compounds displayed low micromolar IC50 against drug-resistant parasites. The reported hit compounds constitute a good starting point for inhibitor development against PfHPPK, as an alternative approach to tackle the malaria parasite.

Clinical Course, Associated Factors, and Blood Pressure Profile of Delayed-Onset Postpartum Preeclampsia.

OBJECTIVE: To identify clinical risk factors associated with development of delayed-onset postpartum preeclampsia, and to characterize management and subsequent risk of cardiovascular disease. METHODS: This is a case-control study of women admitted to the hospital with delayed-onset postpartum preeclampsia (defined as a new diagnosis of preeclampsia presenting between 48 hours and 6 weeks postpartum) compared with women with full-term, uncomplicated pregnancies without a hypertensive diagnosis or diabetes. Included women delivered between January 2014 and June 2018 at a single tertiary care center. Women with an antenatal diagnosis of preeclampsia or chronic hypertension were excluded. Univariate analysis was used to identify risk factors associated with delayed-onset postpartum preeclampsia and to compare rates of hypertension and antihypertensive medication use, with follow-up beyond 3 months postpartum among a subset of women in the control group who were matched 2:1 with women in the case group. Multivariable logistic regression was performed and included covariates identified in a backward stepwise approach. RESULTS: Compared with women in the control group (n=26,936), women with delayed-onset postpartum preeclampsia (n=121) were significantly more likely to be of non-Hispanic black race (31.4% vs 18.0%), obese (39.7% vs 20.1%), and deliver by cesarean (40.5% vs 25.8%), all P<.01. For women diagnosed with delayed-onset postpartum preeclampsia, the median postpartum day of presentation was 7.0 (interquartile range 5.0-9.0), with 93.4% presenting secondary to symptoms, which was most commonly a headache. A majority (73.6%) underwent imaging studies, and 49.6% received intravenous antihypertensive agents. A total of 86 (71.0%) women with delayed-onset postpartum preeclampsia and 169 (72.8%) women in the control group had longer term information available, with a median follow-up time of 1.5 years (interquartile range 0.8-2.8). Delayed-onset postpartum preeclampsia was associated with higher blood pressures at 3 months postpartum or later (median systolic 130 mm Hg vs 112 mm Hg and median diastolic 80 mm Hg vs 70 mm Hg, P<.001). CONCLUSION: Delayed-onset postpartum preeclampsia is associated with variable management strategies. There is substantial overlap between the clinical risk factors for delayed-onset postpartum preeclampsia and antepartum preeclampsia. Our findings suggest that delayed-onset postpartum preeclampsia is also associated with an increased risk of progression to chronic hypertension.

Placental findings in non-hypertensive term pregnancies and association with future adverse pregnancy outcomes: a cohort study.

INTRODUCTION: Women with adverse pregnancy outcomes (APOs) have excess risk of later life cardiovascular disease (CVD) perhaps related to an underlying high-risk vascular phenotype. We sought to determine if placental evidence of maternal malperfusion in uncomplicated pregnancies is associated with an increased risk of APOs in subsequent pregnancies. METHODS: 536 women with more than one delivery and an initial uncomplicated pregnancy with placental pathology examination between 2008 and 2012 were included. APOs (small for gestational age, preterm delivery, or preeclampsia) were identified for each delivery. Multivariable log-binomial regression was used to estimate the risk of an APO in a subsequent pregnancy associated with MVM lesions in index pregnancy with adjustment for covariates. RESULTS: Placental pathology from the initial pregnancy was compared between women with no APO in any pregnancy (-APO/-APO; n = 403) and women with an initial uncomplicated pregnancy and a subsequent adverse outcome (-APO/+APO; n = 133). Women with MVM lesions had an increased risk of an APO in a subsequent pregnancy relative to women with no MVM lesions after adjusting for covariates (aOR = 1.61; 95%CI = 1.06-2.46). Decidual vasculopathy was found in 13/133 (9.8%) of -APO/+APO women compared with 16/403 (4.0%) of -APO/-APO women, with an adjusted odds ratio of 2.51 (95% CI = 1.31-4.80). DISCUSSION: MVM lesions found in placentas in uncomplicated pregnancies are associated with an increased risk of an adverse outcome in a subsequent pregnancy. Placental evidence of vascular malperfusion could offer a novel approach to risk stratification for subsequent pregnancy complications and perhaps future CVD.

Role of p90(RSK) in regulating the Crabtree effect: implications for cancer.

High glucose inhibits mitochondrial respiration, known as the 'Crabtree effect', in cancer cells and possibly other cell types. The upstream pathways regulating this phenomenon are poorly understood. In diabetes, where glucose levels are elevated, the p90(RSK) (p90 ribosomal S6 kinase) has received much attention as a potential upstream mediator of the effects of high glucose. Evidence is also emerging that p90(RSK) may play a role in cancer cell signalling, although the role of p90(RSK) in regulating cancer cell metabolism is unclear. In the present paper, we provide an overview of the Crabtree effect and its relationship to mitochondrial metabolism. Furthermore, preliminary data are presented suggesting a role for p90(RSK) and its upstream components, the ERK (extracellular-signal-regulated kinase) family of MAPKs (mitogen-activated protein kinases), in the Crabtree effect.

Cannabidiol enhances consolidation of explicit fear extinction in humans.

RATIONALE: Whilst Cannabidiol (CBD), a non-psychotomimetic cannabinoid, has been shown to enhance extinction learning in rats, its effects on fear memory in humans have not previously been studied. OBJECTIVES: We employed a Pavlovian fear-conditioning paradigm in order to assess the effects of CBD on extinction and consolidation. METHOD: Forty-eight participants were conditioned to a coloured box (CS) with electric shocks (UCS) in one context and were extinguished in a second context. Participants received 32 mg of CBD either following before or after extinction in a double-blind, placebo-controlled design. At recall, 48 h later, participants were exposed to CSs and conditioning contexts before (recall) and after (reinstatement) exposure to the UCS. Skin conductance and shock expectancy measures of conditioned responding were recorded throughout. RESULTS: Successful conditioning, extinction and recall were found in all three treatment groups. CBD given post-extinction enhanced consolidation of extinction learning as assessed by shock expectancy. CBD administered at either time produced trend level reduction in reinstatement of autonomic contextual responding. No acute effects of CBD were found on extinction. CONCLUSIONS: These findings provide the first evidence that CBD can enhance consolidation of extinction learning in humans and suggest that CBD may have potential as an adjunct to extinction-based therapies for anxiety disorders.

Mediterranean diet and cardioprotection: the role of nitrite, polyunsaturated fatty acids, and polyphenols.

The continually increasing rate of myocardial infarction (MI) in the Western world at least partly can be explained by a poor diet lacking in green vegetables, fruits, and fish and enriched in food that contains saturated fat. In contrast, a number of epidemiologic studies provide strong evidence highlighting the cardioprotective benefits of the Mediterranean diet enriched in green vegetables, fruits, fish, and grape wine. Regular consumption of these products leads to an accumulation of nitrate/nitrite/NO, polyunsaturated fatty acids (PUFA), and polyphenolic compounds, such as resveratrol, in the human body. Studies have confirmed that these constituents are bioactive exogenous mediators, which induce strong protection against MI. The aim of this review is to provide a critical, in-depth analysis of the cardioprotective pathways mediated by nitrite/NO, PUFA, and phenolic compounds of grape wines discovered in the recent years, including cross-talk between different mechanisms and compounds. Overall, these findings may facilitate the design and synthesis of novel therapeutic tools for the treatment of MI.

Lysine deacetylation in ischaemic preconditioning: the role of SIRT1.

AIMS: Acute ischaemic preconditioning (IPC) induces protection against cardiac ischaemia-reperfusion (IR) via post-translational modification of key proteins. Lysine (Lys) acetylation is an important regulator of protein function, but this type of modification has not been studied in the context of IPC. We investigated Lys acetylation in IPC and its upstream regulation by SIRT1. METHODS AND RESULTS: Hearts from C57BL/6 mice were Langendorff-perfused and subjected to IPC and IR injury. Mice were exposed to IPC by in vivo coronary artery occlusion. An isolated cardiomyocyte model of IPC was also developed. Lys acetylation was measured by western blotting, and pharmacological modulators of Lys acetylation were tested. More Lys deacetylation was observed in IPC, in the Langendorff, in vivo, and cellular IPC models; this was concurrent with an increase in SIRT1 activity measured by p53 Lys379 deacetylation. IPC was not accompanied by changes in SIRT1 protein level, but evidence was obtained for SIRT1 modification by Small Ubiquitin-like Modifier (SUMOylation) in IPC. Furthermore, the specific SIRT1 inhibitor splitomicin reversed both IPC-mediated Lys deacetylation and IPC-induced cardioprotection. Inhibition of nicotinamide phosphoribosyltransferase (Nampt, an important enzyme which regulates SIRT1 activity by maintaining availability of the substrate NAD(+)) also blocked both IPC-induced deacetylation and cardioprotection. CONCLUSION: Lys deacetylation occurs during IPC and an elevation in SIRT1 activity plays a role in this phenomenon. Inhibition of SIRT1, either directly or by restricting the availability of its substrate NAD(+), inhibits IPC. Together these data suggest a role for SIRT1-mediated Lys deacetylation in the mechanism of acute IPC.

Fungal network responses to grazing.

Mycelial networks operate on scales from microscopic to many m(2) and naturally persist for extended periods. As fungi exhibit highly adaptive development, it is important to test behavioural responses on natural substrata with realistic nutrient levels across a range of spatial scales and extended time periods. Here we quantified network responses over 7.5 months in large (57 x 57cm) microcosms to test whether grazing shifts the network to a more resilient architecture. Resource limitation constrained any ability to respond at all, with both grazed and ungrazed networks gradually thinning out over time. Added resources sustained further exploratory growth, but only transiently increased cross-connectivity and network resilience, when tested by simulated damage in silico. Grazed networks were initially weaker and emergence of new exploratory growth was curtailed. However, increased interstitial proliferation led to new cross-links, consolidating the existing mycelial network and increasing the resilience of the network to further attack.