Pregnancy enables antibody protection against intracellular infection.

Adaptive immune components are thought to exert non-overlapping roles in antimicrobial host defence, with antibodies targeting pathogens in the extracellular environment and T cells eliminating infection inside cells1,2. Reliance on antibodies for vertically transferred immunity from mothers to babies may explain neonatal susceptibility to intracellular infections3,4. Here we show that pregnancy-induced post-translational antibody modification enables protection against the prototypical intracellular pathogen Listeria monocytogenes. Infection susceptibility was reversed in neonatal mice born to preconceptually primed mothers possessing L. monocytogenes-specific IgG or after passive transfer of antibodies from primed pregnant, but not virgin, mice. Although maternal B cells were essential for producing IgGs that mediate vertically transferred protection, they were dispensable for antibody acquisition of protective function, which instead required sialic acid acetyl esterase5 to deacetylate terminal sialic acid residues on IgG variable-region N-linked glycans. Deacetylated L. monocytogenes-specific IgG protected neonates through the sialic acid receptor CD226,7, which suppressed IL-10 production by B cells leading to antibody-mediated protection. Consideration of the maternal-fetal dyad as a joined immunological unit reveals protective roles for antibodies against intracellular infection and fine-tuned adaptations to enhance host defence during pregnancy and early life.

In situ mapping identifies distinct vascular niches for myelopoiesis.

In contrast to nearly all other tissues, the anatomy of cell differentiation in the bone marrow remains unknown. This is owing to a lack of strategies for examining myelopoiesis-the differentiation of myeloid progenitors into a large variety of innate immune cells-in situ in the bone marrow. Such strategies are required to understand differentiation and lineage-commitment decisions, and to define how spatial organizing cues inform tissue function. Here we develop approaches for imaging myelopoiesis in mice, and generate atlases showing the differentiation of granulocytes, monocytes and dendritic cells. The generation of granulocytes and dendritic cells-monocytes localizes to different blood-vessel structures known as sinusoids, and displays lineage-specific spatial and clonal architectures. Acute systemic infection with Listeria monocytogenes induces lineage-specific progenitor clusters to undergo increased self-renewal of progenitors, but the different lineages remain spatially separated. Monocyte-dendritic cell progenitors (MDPs) map with nonclassical monocytes and conventional dendritic cells; these localize to a subset of blood vessels expressing a major regulator of myelopoiesis, colony-stimulating factor 1 (CSF1, also known as M-CSF)1. Specific deletion of Csf1 in endothelium disrupts the architecture around MDPs and their localization to sinusoids. Subsequently, there are fewer MDPs and their ability to differentiate is reduced, leading to a loss of nonclassical monocytes and dendritic cells during both homeostasis and infection. These data indicate that local cues produced by distinct blood vessels are responsible for the spatial organization of definitive blood cell differentiation.

Mouse models of neutropenia reveal progenitor-stage-specific defects.

Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required; however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes1, aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.

Third-party virus-specific T cells for the treatment of double-stranded DNA viral reactivation and posttransplant lymphoproliferative disease after solid organ transplant.

Reactivation or primary infection with double-stranded DNA viruses is common in recipients of solid organ transplants (SOTs) and is associated with significant morbidity and mortality. Treatment with conventional antiviral medications is limited by toxicities, resistance, and a lack of effective options for adenovirus (ADV) and BK polyomavirus (BKPyV). Virus-specific T cells (VSTs) have been shown to be an effective treatment for infections with ADV, BKPyV, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Most of these studies have been conducted in stem cell recipients, and no large studies have been published in the SOT population to date. In this study, we report on the outcome of quadrivalent third-party VST infusions in 98 recipients of SOTs in the context of an open-label phase 2 trial. The 98 patients received a total of 181 infusions, with a median of 2 infusions per patient. The overall response rate was 45% for BKPyV, 65% for cytomegalovirus, 68% for ADV, and 61% for Epstein-Barr virus. Twenty percent of patients with posttransplant lymphoproliferative disorder had a complete response and 40% of patients had a partial response. All the VST infusions were well tolerated. We conclude that VSTs are safe and effective in the treatment of viral infections in SOT recipients.

Enabling tobacco treatment for gastroenterology patients via a novel low-burden point-of-care model.

BACKGROUND & AIM: Smoking is a major risk factor for multiple gastrointestinal cancers, and adversely affects peptic ulcer disease, gastroesophageal reflux, pancreatitis and Crohn's disease. Despite key recommendations for diagnosing and treating tobacco use disorder in healthcare settings, the degree to which this is implemented in Gastroenterology (GI) clinics is unknown. We aimed to assess our providers' practices, identify barriers for implementing evidence-based smoking cessation treatments, and address these barriers by implementing a novel low-burden point of care Electronic health record-enabled evidence-based tobacco treatment (ELEVATE), in GI clinics. METHODS: An online survey was distributed to clinic gastroenterologists. ELEVATE module training was implemented in 1/2021. Data were evaluated during pre (7/2020-12/2020) and post (1/2021-12/2021) implementation periods to evaluate the reach and effectiveness of ELEVATE. Generalized estimating equations (GEE) were used to generate rate ratios (RR) to evaluate the intervention. RESULTS: 91% (20/22) of GI physicians responded to our survey, and only 20% often assisted patients who smoke with counseling. Lack of a systematic program to offer help to patients was reported by 80% of providers as an extremely/very important barrier limiting their smoking cessation practices. The proportion of current patients who smoke receiving cessation treatment increased from pre-ELEVATE to post-ELEVATE (14.36-27.47%, RR = 1.90, 95% CI 1.60-2.26, p < .001). Post-ELEVATE, 14.4% (38/264) of patients with treatment quit smoking, compared to 7.9% (55/697) of patients without treatment (RR = 1.89, 95% CI 1.26-2.82, p = .0021). CONCLUSION: Smoking practices are frequently assessed in GI clinics but barriers limiting cessation treatment exist. The use of a low burden point of care EHR enabled smoking cessation treatment module has led to a significant improvement in the treatment of smoking and subsequent cessation in our clinics. This study sheds light on an often under-recognized source of morbidity in GI patients and identifies an efficient, effective, and scalable strategy to combat tobacco use and improve clinical outcomes in our patients.

Marine Bromotyrosine Derivatives in Spotlight: Bringing Discoveries and Biological Significance.

The Verongida order comprises several sponge families, such as Aplysinellidae, Aplysinidae, Ianthellidae, and Pseudoceratinidae, reported for producing bromotyrosine-derived compounds. First identified in 1913, bromotyrosine derivatives have since captivated interest notably for their antitumor and antimicrobial properties. To date, over 360 bromotyrosine derivatives have been reported. Our review focuses specifically on bromotyrosine derivatives newly reported from 2004 to 2023, by summarizing current knowledge about their chemical diversity and their biological activities.

Measuring children's sustained selective attention and working memory: validity of new minimally linguistic tasks.

This study introduces visual tasks using nonlinguistic stimuli that measure sustained selective attention (SSA) and working memory (WM), two constructs foundational to learning and associated with developmental disorders in children. Using an argument-based approach to validation, we examine whether each task (a) measures distinct constructs, (b) shows internal consistency, (c) captures a range of performance, and (d) relates to development as indexed by age. Participants included 71 children, ages 4-10, of whom 12 had parental concern for language/learning. The SSA task presented spatial locations within a long and uninteresting task, following the continuous performance task paradigm. The WM task presented paired location sequences of increasing length, incorporating key elements of the n-back and complex span paradigms. Controlling for age, tasks were found to be minimally associated with each other (r = .26), suggesting related but distinct constructs. Internal consistency was high, with split-half reliability of .94 (SSA) and .92 (WM); the stability of these estimates was supported by bootstrapping simulations. Task performance was evenly distributed, with minimal floor or ceiling effects within this age range. Performance was positively related to age (SSA r = .49; WM r = .53). Exploratory correlations with a measure of parental concern were significant for SSA but not WM. The results show that these new tasks can be used to measure children's SSA and WM in a visual domain with minimal linguistic influence. These tasks capture developmental changes in the early school years. Further investigation can examine their utility for classifying children with developmental disorders.

Ran-GTP/-GDP-dependent nuclear accumulation of NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 and TGACG-BINDING FACTOR2 controls salicylic acid-induced leaf senescence.

Leaf senescence is the final stage of leaf development and can be triggered by various external factors, such as hormones and light deprivation. In this study, we demonstrate that the overexpression of the GTP-bound form of Arabidopsis (Arabidopsis thaliana) Ran1 (a Ras-related nuclear small G-protein, AtRan1) efficiently promotes age-dependent and dark-triggered leaf senescence, while Ran-GDP has the opposite effect. Transcriptome analysis comparing AtRan1-GDP- and AtRan1-GTP-overexpressing transgenic plants (Ran1T27Nox and Ran1G22Vox, respectively) revealed that differentially expressed genes (DEGs) related to the senescence-promoting hormones salicylic acid (SA), jasmonic acid, abscisic acid, and ethylene (ET) were significantly upregulated in dark-triggered senescing leaves of Ran1G22Vox, indicating that these hormones are actively involved in Ran-GTP/-GDP-dependent, dark-triggered leaf senescence. Bioinformatic analysis of the promoter regions of DEGs identified diverse consensus motifs, including the bZIP motif, a common binding site for TGACG-BINDING FACTOR (TGA) transcription factors. Interestingly, TGA2 and its interactor, NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 (NPR1), which are two positive transcriptional regulators of SA signaling, differed in their extent of accumulation in the nucleus versus cytoplasm of Ran1T27Nox and Ran1G22Vox plants. Moreover, SA-induced, Ran-GTP-/-GDP-dependent functions of NPR1 included genome-wide global transcriptional reprogramming of genes involved in cell death, aging, and chloroplast organization. Furthermore, the expression of AtRan1-GTP in SA signaling-defective npr1 and SA biosynthesis-deficient SA-induction deficient2 genetic backgrounds abolished the effects of AtRan1-GTP, thus retarding age-promoted leaf senescence. However, ET-induced leaf senescence was not mediated by Ran machinery-dependent nuclear shuttling of ETHYLENE-INSENSITIVE3 and ETHYLENE-INSENSITIVE3-LIKE1 proteins. We conclude that Ran-GTP/-GDP-dependent nuclear accumulation of NPR1 and TGA2 represents another regulatory node for SA-induced leaf senescence.

Assessment of formal tobacco treatment and smoking cessation in dual users of cigarettes and e-cigarettes.

BACKGROUND: The utility of electronic cigarettes ('e-cigarettes') as a smoking cessation adjunct remains unclear. Similarly, it is unclear if formal tobacco treatment (pharmacotherapy and/or behavioural support) augments smoking cessation in individuals who use both cigarettes and e-cigarettes. METHODS: We performed a longitudinal cohort study of adult outpatients evaluated in our tertiary care medical centre (6/2018-6/2020). E-cigarette use, smoking status and formal tobacco treatment (deterrent pharmacotherapy and/or behavioural support) were assessed in 6-month blocks (eg, cohort 1 (C1)=6/2018-12/2018, C2=1/2019-6/2019 and so on) using our electronic health record. We assessed the relationship between e-cigarette use (either with or without formal tobacco treatment) and point prevalence of smoking cessation at 6 and 12 months. RESULTS: 111 823 unique patients were included in the study. The prevalence of dual use of cigarettes and e-cigarettes increased significantly over the study period (C1=0.8%; C2=1.1%; C3=1.8%; C4=2.3%; p<0.001). The prevalence of smoking cessation at 12 months was higher among e-cigarette users (20.8%) compared with non-users (16.8%) (risk difference, 4.0% (95% CI 2.5% to 5.5%); adjusted relative risk (aRR) 1.354, 95% CI 1.252 to 1.464, p<0.0001). Further, among dual users of cigarettes and e-cigarettes, the prevalence of smoking cessation at 12 months was higher among individuals who received tobacco treatment (29.1%) compared with individuals who did not receive tobacco treatment (19.6%) (risk difference, 9.5% (95% CI, 4.6% to 14.4%); aRR 1.238, 95% CI 1.071 to 1.432, p=0.004). INTERPRETATION: These results suggest that dual users of cigarettes and e-cigarettes benefit from formal tobacco treatment. Clinicians should consider offering formal tobacco treatment to such patients, though future trials are needed.

Increased Reach and Effectiveness With a Low-Burden Point-of-Care Tobacco Treatment Program in Cancer Clinics.

BACKGROUND: Tobacco cessation after a cancer diagnosis can extend patient survival by improving outcomes for primary cancer and preventing secondary cancers. However, smoking is often unaddressed in cancer care, highlighting the need for strategies to increase treatment reach and cessation. This study examined a low-burden, point-of-care tobacco treatment program (ELEVATE) featuring an electronic health record-enabled smoking module and decision support tools to increase the reach and effectiveness of evidence-based smoking cessation treatment. METHODS: This study included adult outpatient tobacco smokers (n=13,651) in medical oncology, internal medicine, and surgical oncology clinics from a large midwestern healthcare system. We examined reach and effectiveness of ELEVATE with 2 comparisons: (1) preimplementation versus postimplementation of ELEVATE and (2) ELEVATE versus usual care. Data were evaluated during 2 time periods: preimplementation (January through May 2018) and postimplementation (June through December 2018), with smoking cessation assessed at the last follow-up outpatient encounter during the 6 months after these periods. RESULTS: The proportion of current tobacco smokers receiving cessation treatment increased from pre-ELEVATE to post-ELEVATE (1.6%-27.9%; difference, 26.3%; relative risk, 16.9 [95% CI, 9.8-29.2]; P<.001). Compared with 27.9% treatment reach with ELEVATE in the postimplementation time period, reach within usual care clinics ranged from 11.8% to 12.0% during this same period. The proportion of tobacco smokers who subsequently achieved cessation increased significantly from pre-ELEVATE to post-ELEVATE (12.0% vs 17.2%; difference, 5.2%; relative risk, 1.3 [95% CI, 1.1-1.5]; P=.002). Compared with 17.2% smoking cessation with ELEVATE in the postimplementation time period, achievement of cessation within usual care clinics ranged from 8.2% to 9.9% during this same period. CONCLUSIONS: A low-burden, point-of-care tobacco treatment strategy increased tobacco treatment and cessation, thereby improving access to and the impact of evidence-based cessation treatment. Using implementation strategies to embed tobacco treatment in every healthcare encounter promises to engage more smokers in evidence-based treatment and facilitate smoking cessation, thereby improving care cancer for patients who smoke.

Persistent Zika Virus Clinical Susceptibility despite Reduced Viral Burden in Mice with Expanded Virus-Specific CD8+ T Cells Primed by Recombinant Listeria monocytogenes.

Vaccines against Zika virus (ZIKV) infection that target CD8+ T cells are of considerable interest because Abs may enhance infection susceptibility. However, whether CD8+ T cells are protective or promote susceptibility to clinical infection symptoms remains uncertain. To more precisely investigate ZIKV-specific CD8+ T cells in isolation, we engineered a Listeria monocytogenes-based vector to express a single MHC class I-restricted immune dominant peptide, E294-302, from ZIKV envelope protein. We show accumulation of activated ZIKV-specific CD8+ T cells primed by recombinant L. monocytogenes is associated with reductions in circulating virus levels after ZIKV challenge in type I IFN receptor-deficient mice and wildtype mice administered neutralizing Abs against type I IFN receptor. Interestingly, susceptibility to ZIKV clinical infection including weight loss and mortality each persists and is neither significantly improved nor worsened compared with isogenic L. monocytogenes-primed control mice. These data demonstrating persistent ZIKV clinical susceptibility despite reduced viral burden in mice with expanded virus-specific CD8+ T cells highlights the need for targeting other adaptive immune components in developing vaccines against ZIKV infection.

The Promise of Polygenic Risk Prediction in Smoking Cessation: Evidence From Two Treatment Trials.

INTRODUCTION: Tobacco use disorder is a complex behavior with a strong genetic component. Genome-wide association studies (GWAS) on smoking behaviors allow for the creation of polygenic risk scores (PRSs) to approximate genetic vulnerability. However, the utility of smoking-related PRSs in predicting smoking cessation in clinical trials remains unknown. AIMS AND METHODS: We evaluated the association between polygenic risk scores and bioverified smoking abstinence in a meta-analysis of two randomized, placebo-controlled smoking cessation trials. PRSs of smoking behaviors were created using the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN) consortium summary statistics. We evaluated the utility of using individual PRS of specific smoking behavior versus a combined genetic risk that combines PRS of all four smoking behaviors. Study participants came from the Transdisciplinary Tobacco Use Research Centers (TTURCs) Study (1091 smokers of European descent), and the Genetically Informed Smoking Cessation Trial (GISC) Study (501 smokers of European descent). RESULTS: PRS of later age of smoking initiation (OR [95% CI]: 1.20, [1.04-1.37], p = .0097) was significantly associated with bioverified smoking abstinence at end of treatment. In addition, the combined PRS of smoking behaviors also significantly predicted bioverified smoking abstinence (OR [95% CI] 0.71 [0.51-0.99], p = .045). CONCLUSIONS: PRS of later age at smoking initiation may be useful in predicting smoking cessation at the end of treatment. A combined PRS may be a useful predictor for smoking abstinence by capturing the genetic propensity for multiple smoking behaviors. IMPLICATIONS: There is a potential for polygenic risk scores to inform future clinical medicine, and a great need for evidence on whether these scores predict clinically meaningful outcomes. Our meta-analysis provides early evidence for potential utility of using polygenic risk scores to predict smoking cessation amongst smokers undergoing quit attempts, informing further work to optimize the use of polygenic risk scores in clinical care.

Food parenting topics in social media posts: Development of a coding system, examination of frequency of food parenting concepts, and comparison across Reddit and Facebook.

This study presents development of a coding system to examine food parenting topics presented in posts on social media, and compared topics between two social media platforms (Facebook, Reddit). Publicly available social media posts were gathered from Facebook (2 groups) and Reddit (3 subreddits) and a coding system was developed based on the concept map of food parenting proposed by Vaughn et al. (2016). Based on the developed coding system, we coded posts into overarching food parenting practice constructs (coercive control: attempts to dominate, pressure or impose parents' will on child, structure: organization of child's environment to facilitate competence, autonomy support: supporting child's ability to self-regulate through allowing food choices, conversations about food, and a positive emotional climate) and recipes. We also coded posts dichotomously as including a question or advice-seeking. Differences in frequencies of food parenting constructs presented in posts on Facebook and Reddit were considered using chi-square tests of independence. Of the 2459 posts coded, 900 were related to food parenting (37%). In the subsample of 900, posts related to structure (43%) and recipes (40%) were the most frequent. Close to half of the posts (44%) included questions about food parenting. Frequency of food parenting topics in posts was related to social media platform, with coercive control and structure more frequently discussed on Reddit and recipes more commonly posted on Facebook. Results suggest that food parenting topics discuss on social media differ by platform, which can aid researchers and practitioners in targeting social media-based outreach to the topics of most interest for users. Findings give insight into the everyday food parenting topics and questions that parents and caregivers may be exposed to on social media. TAXONOMY: Development of Feeding; Parenting; Online Information Services.

Isolation of Sesquiterpenoids and Steroids from the Soft Coral Sinularia brassica and Determination of Their Absolute Configuration.

Two undescribed rearranged cadinane-type sesquiterpenoids (1-2), named sinulaketol A-B, together with one new chlorinated steroid (3), one new gorgosterol (4), one known sesquiterpene (5), one known dibromoditerpene (6) and two known polyhydroxylated steroids (7-8) were isolated from the soft coral Sinularia brassica. The structures of these compounds were established by extensive spectroscopic analysis, including HRESIMS, 1D, and 2D NMR spectroscopy. Their absolute configurations were also determined by the ECD calculations and DP4+ probability analysis. Antileishmanial activity of compounds 1-8 was evaluated in vitro against the amastigote forms of Leishmania donovani, in which compounds 3, 6, and 7 inhibited the growth of L. donovani by 58.7, 74.3, 54.7%, respectively, at a concentration of 50 µM. Antimicrobial effect of the isolated compounds were also evaluated against Candida albicans, Staphylococcus aureus, and Escherichia coli. Compound 6, a brominated diterpene, exhibited antimicrobial effect against S. aureus.

ATBS1-INTERACTING FACTOR 2 negatively regulates dark- and brassinosteroid-induced leaf senescence through interactions with INDUCER OF CBF EXPRESSION 1.

ATBS1-INTERACTING FACTOR 2 (AIF2) is a non-DNA-binding basic helix-loop-helix (bHLH) transcription factor. We demonstrated that AIF2 retards dark-triggered and brassinosteroid (BR)-induced leaf senescence in Arabidopsis thaliana. Dark-triggered BR synthesis and the subsequent activation of BRASSINAZOLE RESISTANT 1 (BZR1), a BR signaling positive regulator, result in BZR1 binding to the AIF2 promoter in a dark-dependent manner, reducing AIF2 transcript levels and accelerating senescence. BR-induced down-regulation of AIF2 protein stability partly contributes to the progression of dark-induced leaf senescence. Furthermore, AIF2 interacts with INDUCER OF CBF EXPRESSION 1 (ICE1) via their C-termini. Formation of the AIF2-ICE1 complex and subsequent up-regulation of C-REPEAT BINDING FACTORs (CBFs) negatively regulates dark-triggered, BR-induced leaf senescence. This involves antagonistic down-regulation of PHYTOCHROME INTERACTING FACTOR 4 (PIF4), modulated through AIF2-dependent inhibition of ICE1's binding to the promoter. PIF4-dependent activities respond to dark-induced early senescence and may promote BR synthesis and BZR1 activation to suppress AIF2 and accelerate dark-induced senescence. Taken together, these findings suggest a coordination of AIF2 and ICE1 functions in maintaining stay-green traits.

Patulignans A-C, three structurally unique lignans from the leaves of Melicope patulinervia.

(±)-Patulignans A-C (1-3), three unique pairs of lignan enantiomers were isolated from the leaves of Melicope patulinervia. Patulignan A (1) possesses an unprecedented dimethyloxonane moiety in nature, meanwhile patulignans B (2) and C (3) are epimers carrying a novel dimethyl-1,6-dioxaspiro[4.5]decane skeleton. Their structures were established by spectroscopy methods and electronic circular dichroism (ECD) calculations. Compounds 1-3 showed significant inhibitory activity against α-glucosidase.

Preconceptual Zika virus asymptomatic infection protects against secondary prenatal infection.

Pregnant women, and their fetal offspring, are uniquely susceptible to Zika virus and other microbial pathogens capable of congenital fetal infection. Unavoidable exposure to Zika virus in endemic areas underscores the need for identifying at-risk individuals, and protecting expecting mothers and their fetal offspring against prenatal infection. Here we show that primary Zika virus asymptomatic infection in mice confers protection against re-infection, and that these protective benefits are maintained during pregnancy. Zika virus recovery was sharply reduced in maternal tissues and amongst fetal concepti after prenatal challenge in mothers with resolved subclinical infection prior to pregnancy compared with mice undergoing primary prenatal infection. These benefits coincide with expanded accumulation of viral-specific antibodies in maternal serum and fetal tissues that protect against infection by the identical or heterologous Zika virus genotype strains. Thus, preconceptual infection primes Zika virus-specific antibodies that confer cross-genotype protection against re-infection during pregnancy.

Assessing the efficacy and safety of magnesium sulfate for management of autonomic nervous system dysregulation in Vietnamese children with severe hand foot and mouth disease.

BACKGROUND: Brainstem encephalitis is a serious complication of hand foot and mouth disease (HFMD) in children. Autonomic nervous system (ANS) dysregulation and hypertension may occur, sometimes progressing to cardiopulmonary failure and death. Vietnamese national guidelines recommend use of milrinone if ANS dysregulation with Stage 2 hypertension develops. We wished to investigate whether magnesium sulfate (MgSO4) improved outcomes in children with HFMD if used earlier in the evolution of the ANS dysregulation (Stage 1 hypertension). METHODS: During a regional epidemic we conducted a randomized, double-blind, placebo-controlled trial of MgSO4 in children with HFMD, ANS dysregulation and Stage 1 hypertension, at the Hospital for Tropical Diseases in Ho Chi Minh city. Study participants received an infusion of MgSO4 or matched placebo for 72 h. We also reviewed data from non-trial HFMD patients in whom milrinone failed to control hypertension, some of whom received MgSO4 as second line therapy. The primary outcome for both analyses was a composite of disease progression within 72 h - addition of milrinone (trial participants only), need for ventilation, shock, or death. RESULTS: Between June 2014 and September 2016, 14 and 12 participants received MgSO4 or placebo respectively, before the trial was stopped due to futility. Among 45 non-trial cases with poorly controlled hypertension despite high-dose milrinone, 33 received MgSO4 while 12 did not. There were no statistically significant differences in the composite outcome between the MgSO4 and the placebo/control groups in either study (adjusted relative risk (95%CI) of [6/14 (43%) vs. 6/12 (50%)], 0.84 (0.37, 1.92), p = 0.682 in the trial and [1/33 (3%) vs. 2/12 (17%)], 0.16 (0.01, 1.79), p = 0.132 in the observational cohort). The incidence of adverse events was similar between the groups. Potentially toxic magnesium levels occurred very rarely with the infusion regime used. CONCLUSION: Although we could not demonstrate efficacy in these studies, there were no safety signals associated with use of 30-50 mg/kg/hr. MgSO4 in severe HFMD. Intermittent outbreaks of HFMD are likely to continue across the region, and an adequately powered trial is still needed to evaluate use of MgSO4 in controlling hypertension in severe HFMD, potentially involving a higher dose regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01940250 (Registered 22 AUG 2013). Trial sponsor: University of Oxford.

Evaluation of an Ecohealth Approach to Public Health Intervention in Ha Nam, Vietnam.

CONTEXT: Ecohealth is a transdisciplinary research approach that considers socio-economic, cultural, and environmental factors. Ecohealth program assessment is sometimes unable to capture the process of change, especially when the evidence is not well documented. As such, there is a need to better understand how ecohealth approaches are understood, integrated, and adapted in practice to support the sustainability of the approach. OBJECTIVE: To evaluate the use of an ecohealth approach to a community-based intervention to improve environmental sanitation and draw lessons learned for similar public health initiatives. DESIGN: An iterative evaluation approach involving 27 in-depth interviews and 9 focus group discussions was used to gather feedback on the intervention activities and outcomes from all participants. SETTING AND PARTICIPANTS: The study site was Hoang Tay commune, Kim Bang district, Ha Nam province. The participants included 12 farmers, 4 local policy makers, and 7 researchers from Hanoi University of Public Health. RESULTS: The farmers provided specific shortcomings of the biogas procedure steps, while the local authorities identified new and more effective ways to promote sanitation guidelines. Outcomes, as behavior changes, in 3 participant groups were captured. CONCLUSION: Participation in ecohealth interventions should be collegial to give opportunities for all related stakeholders to build capacity, support, and achieve the transdisciplinary principle. This also helps ensure that the community-based solutions are incorporated in public health interventions. Participatory monitoring and evaluation should support the understanding of the implementation process to capture intervention outcomes.

Community Participatory Interventions to Improve Farmer Knowledge and Practices of Household Biogas Unit Operation in Ha Nam Province, Vietnam.

CONTEXT: The use of biogas systems to treat livestock waste is a common practice in Vietnam. However, farmers' knowledge and practices of the safe and appropriate use of household biogas units (HBUs) are still limited and could negatively impact human, animal, and environmental health. OBJECTIVE: To assess the effectiveness of an intervention to improve knowledge and practices of biogas operation among farmers in 2 communes of Ha Nam Province, Vietnam. DESIGN: A community-based intervention approach. SETTING: This study was conducted from 2015 to 2016 in 2 communes of Ha Nam Province, Vietnam. PARTICIPANTS: Only farmers with HBUs (N = 399) participated in this research. Farmers were assigned to either an intervention group or a control group at a ratio of 1:2. INTERVENTION: Two intervention steps were implemented over a 6-month period as follows: (i) the core farmer group trained in 6 steps of HBU safe handling practice; and (ii) the core farmer group conducted peer-to-peer communication with its neighbors in the commune using the provided material. MAIN OUTCOME MEASURE(S): Farmers' knowledge and practices in biogas operation were assessed by a structured questionnaire. The questionnaire was administered before (baseline) and after the intervention (follow-up) to both the control and intervention groups. RESULTS: There was a significant difference in the knowledge and practices of biogas operation between the 2 groups, in which farmers in the intervention group demonstrated better understanding of the related topic than the control group (P < .05, t test). A linear regression model indicated that baseline and follow-up scores in both knowledge and practices of the intervention group were higher than those of the control group. After the intervention, the mean difference score in knowledge and practices between the intervention and control groups was 5.0 and 2.0 points, respectively (P < .01). CONCLUSION: A community-based intervention approach could be applied to improve knowledge and practices among farmers in using biogas systems. However, further studies should be conducted to assess the sustainability and effectiveness of this model.