Plasmodium vivax has the largest geographic range of human malaria species and is challenging to manage and eradicate due to its ability to establish a dormant liver stage, the hypnozoite, which can ...reactivate leading to relapse. Until recently, the only treatment approved to kill hypnozoites was the 8-aminoquinoline, primaquine, requiring daily treatment for 14 days. Tafenoquine, an 8-aminoquinoline single-dose treatment with activity against P. vivax hypnozoites, has recently been approved by the US Food and Drug Administration and Australian Therapeutic Goods Administration for the radical cure of P. vivax malaria in patients 16 years and older. We conducted an exploratory pharmacogenetic analysis (GSK Study 208099) to assess the role of host genome-wide variation on tafenoquine efficacy in patients with P. vivax malaria using data from three GSK clinical trials, GATHER and DETECTIVE Part 1 and Part 2. Recurrence-free efficacy at 6 and 4 months and time to recurrence up to 6 months postdosing were analyzed in 438 P. vivax malaria patients treated with tafenoquine. Among the approximately 10.6 million host genetic variants analyzed, two signals reached genome-wide significance (P value ≤ 5 × 10). rs62103056, and variants in a chromosome 12 intergenic region, were associated with recurrence-free efficacy at 6 and 4 months, respectively. Neither of the signals has an obvious biological rationale and would need replication in an independent population. This is the first genome-wide association study to evaluate genetic influence on response to tafenoquine in P. vivax malaria.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized pathologically by progressive neuronal loss, extracellular plaques containing the amyloid-β (Aβ) peptides, and neurofibrillary ...tangles composed of hyperphosphorylated tau proteins. Aβ is thought to act upstream of tau, affecting its phosphorylation and therefore aggregation state. One of the major risk factors for AD is traumatic brain injury (TBI). Acute intra-axonal Aβ and diffuse extracellular plaques occur in ∼30% of human subjects after severe TBI. Intra-axonal accumulations of tau but not tangle-like pathologies have also been found in these patients. Whether and how these acute accumulations contribute to subsequent AD development is not known, and the interaction between Aβ and tau in the setting of TBI has not been investigated. Here, we report that controlled cortical impact TBI in 3xTg-AD mice resulted in intra-axonal Aβ accumulations and increased phospho-tau immunoreactivity at 24 h and up to 7 d after TBI. Given these findings, we investigated the relationship between Aβ and tau pathologies after trauma in this model by systemic treatment of Compound E to inhibit γ-secretase activity, a proteolytic process required for Aβ production. Compound E treatment successfully blocked posttraumatic Aβ accumulation in these injured mice at both time points. However, tau pathology was not affected. Our data support a causal role for TBI in acceleration of AD-related pathologies and suggest that TBI may independently affect Aβ and tau abnormalities. Future studies will be required to assess the behavioral and long-term neurodegenerative consequences of these pathologies.
Vietnam has been experiencing an epidemiologic transition to that of a lower-middle income country with an increasing prevalence of non-communicable diseases. The key risk factors for cardiovascular ...disease (CVD) are either on the rise or at alarming levels in Vietnam, particularly hypertension (HTN). Inasmuch, the burden of CVD will continue to increase in the Vietnamese population unless effective prevention and control measures are put in place. The objectives of the proposed project are to evaluate the implementation and effectiveness of two multi-faceted community and clinic-based strategies on the control of elevated blood pressure (BP) among adults in Vietnam via a cluster randomized trial design.
Sixteen communities will be randomized to either an intervention (8 communities) or a comparison group (8 communities). Eligible and consenting adult study participants with HTN (n = 680) will be assigned to intervention/comparison status based on the community in which they reside. Both comparison and intervention groups will receive a multi-level intervention modeled after the Vietnam National Hypertension Program including education and practice change modules for health care providers, accessible reading materials for patients, and a multi-media community awareness program. In addition, the intervention group only will receive three carefully selected enhancements integrated into routine clinical care: (1) expanded community health worker services, (2) home BP self-monitoring, and (3) a "storytelling intervention," which consists of interactive, literacy-appropriate, and culturally sensitive multi-media storytelling modules for motivating behavior change through the power of patients speaking in their own voices. The storytelling intervention will be delivered by DVDs with serial installments at baseline and at 3, 6, and 9 months after trial enrollment. Changes in BP will be assessed in both groups at several follow-up time points. Implementation outcomes will be assessed as well.
Results from this full-scale trial will provide health policymakers with practical evidence on how to combat a key risk factor for CVD using a feasible, sustainable, and cost-effective intervention that could be used as a national program for controlling HTN in Vietnam.
ClinicalTrials.gov NCT03590691 . Registered on July 17, 2018. Protocol version: 6. Date: August 15, 2019.
Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual ...patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax.
Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval CI 38.7-49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1-12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40-24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48-0.84), p = 0.0013 and 0.83 (0.73-0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99-1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01-0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10-0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01-0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups.
In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis.
(1) Background: The present study measures the fear of COVID-19 among hospital healthcare workers and identifies several factors associated with increasing fear of COVID-19. (2) Methods: A ...cross-sectional, hospital-based survey was conducted on healthcare workforce recruited from the National Hospital of Tropical Diseases from 1 October 2021 and 20 October 2021. We selected the participants who have been directly involved in diagnosing, treating, or providing nursing care to patients with COVID-19. The primary data was collected via sending the invitation directly to the participants, utilizing structured self-completed questionnaires. The seven-item fear of COVID-19 scale was used to measure the data. The responses of 208 hospital healthcare workers were included in the final analysis. (3) Results: Total score of COVID-19 fear was 19.62 (SD = 5.22). The COVID-19 fear score of 7 items ranged from 2.38 (SD = 0.83) to 3.21 (SD = 0.96). The lowest and highest scores were the item '
' and the item '
' was the highest, respectively. Linear regression of the COVID-19 fear showed that the factors positively correlated with the fear of COVID-19 among hospital healthcare workers were: being influenced by the community (
= 0.001), feeling at very high risk of COVID-19 (
= 0.03), and experiencing traumatic stress with an academic event (
= 0.042). (4) Conclusions: Although these findings merit further elaboration, these preliminary findings suggest relatively great fear of the COVID-19 pandemic among Vietnamese hospital healthcare workers and that social and personal connections are necessary for maintaining the mental wellbeing.
Microvascular sequestration was assessed in the brains of 50 Thai and Vietnamese patients who died from severe malaria (
Plasmodium falciparum
, 49;
P. vivax
, 1). Malaria parasites were sequestered ...in 46 cases; in 3 intravascular malaria pigment but no parasites were evident; and in the
P. vivax
case there was no sequestration. Cerebrovascular endothelial expression of the putative cytoadherence receptors ICAM-1, VCAM-1, E-selectin, and chondroitin sulfate and also HLA class II was increased. The median (range) ratio of cerebral to peripheral blood parasitemia was 40 (1.8 to 1500). Within the same brain different vessels had discrete but different populations of parasites, indicating that the adhesion characteristics of cerebrovascular endothelium change asynchronously during malaria and also that significant recirculation of parasitized erythrocytes following sequestration is unlikely. The median (range) ratio of schizonts to trophozoites (0.15:1; 0.0 to 11.7) was significantly lower than predicted from the parasite life cycle (
P
< 0.001). Antimalarial treatment arrests development at the trophozoite stages which remain sequestered in the brain. There were significantly more ring form parasites (age < 26 hours) in the cerebral microvasculature (median range: 19%; 0–90%) than expected from free mixing of these cells in the systemic circulation (median range ring parasitemia: 1.8%; 0–36.2%). All developmental stages of
P. falciparum
are sequestered in the brain in severe malaria.
Lower respiratory tract infections are commonly caused by viruses and cause significant morbidity and mortality among children. Early identification of the pathological agent causing these infections ...is essential to avoid unnecessary antibiotic use and improve patient management. Multiplex PCR techniques were recently developed to detect multiple viral pathogens using a single PCR reaction. In this study, we identify viral pathogens in children with respiratory infections. We collected 194 nasopharyngeal aspirates from infants (2–24 months old) with lower respiratory tract infections treated at the Vietnam National Children’s Hospital between November 2014 and June 2015 and assessed the presence of 16 virus types and subtypes by multiplex PCR using the xTAG Respiratory Viral Panel (RVP) assay. Overall, 73.7% of the samples were positive for at least one virus, and 24.2% corresponded to infections with multiple viruses. The most common viruses were respiratory syncytial virus and enterovirus/rhinovirus. These viruses were more frequent among younger patients (2–5 months old) and caused symptoms similar to those of bronchiolitis and pneumonia. The most common clinical manifestation caused by respiratory tract infection was bronchiolitis. Elevated neutrophils levels were associated with adenovirus infection. Our results showed that the xTAG Respiratory Viral Panel (RVP) can effectively detect multiple viruses causing respiratory infections in children and that the nasopharyngeal aspirates are a good sample choice to detect respiratory viruses in children. Applying this approach in the clinical setting would improve patient management and allow early diagnosis, thus avoiding the unnecessary use of antibiotics.
The role of brain oedema in the pathophysiology of cerebral malaria is controversial. Coma associated with severe Plasmodium falciparum malaria is multifactorial, but associated with histological ...evidence of parasitized erythrocyte sequestration and resultant microvascular congestion in cerebral vessels. To determine whether these changes cause breakdown of the blood-brain barrier and resultant perivascular or parenchymal cerebral oedema, histology, immunohistochemistry and image analysis were used to define the prevalence of histological patterns of oedema and the expression of specific molecular pathways involved in water balance in the brain in adults with fatal falciparum malaria.
The brains of 20 adult Vietnamese patients who died of severe malaria were examined for evidence of disrupted vascular integrity. Immunohistochemistry and image analysis was performed on brainstem sections for activation of the vascular endothelial growth factor (VEGF) receptor 2 and expression of the aquaporin 4 (AQP4) water channel protein. Fibrinogen immunostaining was assessed as evidence of blood-brain barrier leakage and perivascular oedema formation. Correlations were performed with clinical, biochemical and neuropathological parameters of severe malaria infection.
The presence of oedema, plasma protein leakage and evidence of VEGF signalling were heterogeneous in fatal falciparum malaria and did not correlate with pre-mortem coma. Differences in vascular integrity were observed between brain regions with the greatest prevalence of disruption in the brainstem, compared to the cortex or midbrain. There was a statistically non-significant trend towards higher AQP4 staining in the brainstem of cases that presented with coma (P = .02).
Histological evidence of cerebral oedema or immunohistochemical evidence of localised loss of vascular integrity did not correlate with the occurrence of pre-mortem coma in adults with fatal falciparum malaria. Enhanced expression of AQP4 water channels in the brainstem may, therefore, reflect a mix of both neuropathological or attempted neuroprotective responses to oedema formation.
Display omitted
► Incidence of reported malaria cases is highly spatially heterogeneous in Vietnam. ► Poverty and forest cover are associated with malaria incidence in Vietnam. ► The effects of ...climate on malaria vary by socio-ecological zone in Vietnam.
The malaria burden in Viet Nam has been in decline in recent decades, but localised areas of high transmission remain. We used spatiotemporal analytical tools to determine the social and environmental drivers of malaria risk and to identify residual high-risk areas where control and surveillance resources can be targeted. Counts of reported
Plasmodium falciparum and
Plasmodium vivax malaria cases by month (January 2007–December 2008) and by district were assembled. Zero-inflated Poisson regression models were developed in a Bayesian framework. Models had the percentage of the district’s population living below the poverty line, percent of the district covered by forest, median elevation, median long-term average precipitation, and minimum temperature included as fixed effects, and terms for temporal trend and residual district-level spatial autocorrelation. Strong temporal and spatial heterogeneity in counts of malaria cases was apparent. Poverty and forest cover were significantly associated with an increased count of malaria cases but the magnitude and direction of associations between climate and malaria varied by socio-ecological zone. There was a declining trend in counts of malaria cases during the study period. After accounting for the social and environmental fixed effects, substantial spatial heterogeneity was still evident. Unmeasured factors which may contribute to this residual variation include malaria control activities, population migration and accessibility to health care. Forest-related activities and factors encompassed by poverty indicators are major drivers of malaria incidence in Viet Nam.
Indirect clinical measures assessing anti-malarial drug transmission-blocking activity in falciparum malaria include measurement of the duration of gametocytaemia, the rate of gametocyte clearance or ...the area under the gametocytaemia-time curve (AUC). These may provide useful comparative information, but they underestimate dose-response relationships for transmission-blocking activity. Following 8-aminoquinoline administration P. falciparum gametocytes are sterilized within hours, whereas clearance from blood takes days. Gametocytaemia AUC and clearance times are determined predominantly by the more numerous female gametocytes, which are generally less drug sensitive than the minority male gametocytes, whereas transmission-blocking activity and thus infectivity is determined by the more sensitive male forms. In choosing doses of transmission-blocking drugs there is no substitute yet for mosquito-feeding studies.
PDF
