Safety, immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine: pooled phase 1, 2, 3a and 3b randomized, controlled trials.

Combination of waning immunity and lower effectiveness against new SARS-CoV-2 variants of approved COVID-19 vaccines necessitates new vaccines. We evaluated two doses, 28 days apart, of ARCT-154, a self-amplifying mRNA COVID-19 vaccine, compared with saline placebo in an integrated phase 1/2/3a/3b controlled, observer-blind trial in Vietnamese adults (ClinicalTrial.gov identifier: NCT05012943). Primary safety and reactogenicity outcomes were unsolicited adverse events (AE) 28 days after each dose, solicited local and systemic AE 7 days after each dose, and serious AEs throughout the study. Primary immunogenicity outcome was the immune response as neutralizing antibodies 28 days after the second dose. Efficacy against COVID-19 was assessed as primary and secondary outcomes in phase 3b. ARCT-154 was well tolerated with generally mild-moderate transient AEs. Four weeks after the second dose 94.1% (95% CI: 92.1-95.8) of vaccinees seroconverted for neutralizing antibodies, with a geometric mean-fold rise from baseline of 14.5 (95% CI: 13.6-15.5). Of 640 cases of confirmed COVID-19 eligible for efficacy analysis most were due to the Delta (B.1.617.2) variant. Efficacy of ARCT-154 was 56.6% (95% CI: 48.7- 63.3) against any COVID-19, and 95.3% (80.5-98.9) against severe COVID-19. ARCT-154 vaccination is well tolerated, immunogenic and efficacious, particularly against severe COVID-19 disease.

Rosuvastatin adjunctive therapy for rifampicin-susceptible pulmonary tuberculosis: a phase 2b, randomised, open-label, multicentre trial.

BACKGROUND: Shorter treatments are needed for drug-susceptible tuberculosis. Adjunctive statins increase bactericidal activity in preclinical tuberculosis models. We investigated the safety and efficacy of adjunctive rosuvastatin in people with tuberculosis. We tested the hypothesis that adjunctive rosuvastatin accelerates sputum culture conversion within the first 8 weeks of treatment of rifampicin-susceptible tuberculosis. METHODS: This phase 2b, randomised, open-label, multicentre trial conducted in five hospitals or clinics in three countries with high tuberculosis burden (ie, the Philippines, Viet Nam, and Uganda) enrolled adult participants aged 18-75 years with sputum smear or Xpert MTB/RIF positive, rifampicin-susceptible tuberculosis who had received less than 7 days of previous tuberculosis treatment. Participants were randomly assigned via a web-based system to receive either 10 mg rosuvastatin once per day for 8 weeks plus standard tuberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol; rosuvastatin group) or standard tuberculosis therapy alone (control group). Randomisation was stratified by trial site, history of diabetes, and HIV co-infection. Laboratory staff and central investigators involved in data cleaning and analysis were masked to treatment allocation, but study participants and site investigators were not. Both groups continued standard treatment to week 24. Sputum samples were collected once per week for the first 8 weeks after randomisation, and then at weeks 10, 12, and 24. The primary efficacy outcome was time to culture conversion (TTCC; days) in liquid culture by week 8, assessed in randomised participants who had microbiological confirmation of tuberculosis, took at least one dose of rosuvastatin, and who did not show resistance to rifampicin (modified intention-to-treat population), for which groups were compared with the Cox proportional hazards model. The main safety outcome was grade 3-5 adverse events by week 24, assessed in the intention-to-treat population, for which groups were compared with Fisher's exact test. All participants completed 24 weeks of follow-up. This trial is registered with ClinicalTrials.gov (NCT04504851). FINDINGS: Between Sept 2, 2020, and Jan 14, 2021, 174 participants were screened and 137 were randomly assigned to the rosuvastatin group (70 participants) or control group (67 participants). In the modified intention-to-treat population of 135 participants, 102 (76%) were men and 33 (24%) were women. Median TTCC in liquid media was 42 days (95% CI 35-49) in the rosuvastatin group (68 participants) and 42 days (36-53) in the control group (67 participants; hazard ratio 1·30 [0·88-1·91], p=0·19). Grade 3-5 adverse events occurred in six (9%) of 70 in the rosuvastatin group (none were considered related to rosuvastatin) and four (6%) of 67 in the control group (p=0·75). There were no serious adverse events that were considered to be related to rosuvastatin. INTERPRETATION: Adjunctive rosuvastatin at 10 mg once per day was safe but did not produce substantive benefits on culture conversion in the overall study population. Future trials could explore the safety and efficacy of higher doses of adjunctive rosuvastatin. FUNDING: National Medical Research Council, Singapore.

Safety and immunogenicity of Nanocovax, a SARS-CoV-2 recombinant spike protein vaccine: Interim results of a double-blind, randomised controlled phase 1 and 2 trial.

Background: Nanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminium hydroxide adjuvant. Methods: We conducted a dose-escalation, open label trial (phase 1) and a randomized, double-blind, placebo-controlled trial (phase 2) to evaluate the safety and immunogenicity of the Nanocovax vaccine (in 25 mcg, 50 mcg, and 75 mcg doses, aluminium hydroxide adjuvanted (0·5 mg/dose) in 2-dose regime, 28 days apart (ClinicalTrials.gov number, NCT04683484). In phase 1, 60 participants received two intramuscular injection of the vaccine following dose-escalation procedure. The primary outcomes were reactogenicity and laboratory tests to evaluate the vaccine safety. In phase 2, 560 healthy adults received either vaccine doses similar in phase 1 (25 or 50 or 75 mcg S antigen in 0·5 mg aluminium per dose) or adjuvant (0·5 mg aluminium) in a ratio of 2:2:2:1. One primary outcome was the vaccine safety, including solicited adverse events for 7 day and unsolicited adverse events for 28 days after each injection as well as serious adverse event or adverse events of special interest throughout the study period. Another primary outcome was anti-S IgG antibody response (Index unit/ml). Secondary outcomes were surrogate virus neutralisation (inhibition percentage), wild-type SARS-CoV-2 neutralisation (dilution fold), and T-cell responses by intracellular staining for interferon gamma (IFNg). Anti-S IgG and neutralising antibody levels were compared with convalescent serum samples from symptomatic Covid-19 patients. Findings: For phase 1 study, no serious adverse events were observed for all 60 participants. Most adverse events were grade 1 and disappeared shortly after injection. For phase 2 study, after randomisation, 480 participants were assigned to receive the vaccine with adjuvant, and 80 participants were assigned to receive the placebo (adjuvant only). Reactogenicity was absent or mild in the majority of participants and of short duration (mean ≤3 days). Unsolicited adverse events were mild in most participants. There were no serious adverse events related to Nanocovax. Regarding the immunogenicity, Nanocovax induced robust anti-S antibody responses. In general, there humoral responses were similar among vaccine groups which reached their peaks at day 42 and declined afterward. At day 42, IgG levels of vaccine groups were 60·48 [CI95%: 51·12-71·55], 49·11 [41·26-58·46], 57·18 [48·4-67·5] compared to 7·10 [6·32-13·92] of convalescent samples. IgG levels reported here can be converted to WHO international standard binding antibody unit (BAU/ml) by multiplying them to a conversion factor of 21·8. Neutralising antibody titre of vaccine groups at day 42 were 89·2 [52·2-152·3], 80·0 [50·8-125.9] and 95·1 [63·1-143·6], compared to 55·1 [33·4-91·0] of the convalescent group. Interpretation: Up to day 90, Nanocovax was found to be safe, well tolerated, and induced robust immune responses. Funding: This work was funded by the Coalition for Epidemic Preparedness Innovations (CEPI), the Ministry of Science and Technology of Vietnam, and Nanogen Pharmaceutical Biotechnology JSC.

Perinatal Dioxin Exposure and Attention Deficit Hyperactivity Disorder (ADHD) Symptoms in Children Living in a Dioxin Contamination Hotspot in Vietnam.

We examined children in Da Nang, a dioxin contamination hotspot in Vietnam, twice at 5 and 8 years of age, and investigated sex- and age-dependent differences in the effects of dioxin exposure on attention deficit hyperactivity disorder (ADHD) symptoms. We also studied autistic traits in children with ADHD symptoms. A total of 163 children participated in follow-up surveys at 5 and 8 years of age and were included in the present analysis. ADHD symptoms were assessed using an ADHD rating scale with inattention and hyperactivity-and-impulsivity (hyperactivity) subscales. Autistic behaviors were evaluated using the Autism Spectrum Rating Scale (ASRS). Perinatal dioxin exposure was indicated by dioxin levels in maternal breast milk. In boys, hyperactivity scores were significantly higher in the high 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) group only at 5 years of age. In girls, hyperactivity scores at 8 years of age were significantly higher in the high TCDD group, which was significantly associated with those at 5 years of age. In girls, ASRS unusual behavior scores were significantly higher with higher TCDD exposure and hyperactivity scores at 8 years of age. These results suggest that high perinatal TCDD exposure may increase ADHD likelihood and autistic traits, particularly in girls of 7-8 years of age.

Establishment of an in-house real-time RT-PCR assay for the detection of severe acute respiratory syndrome coronavirus 2 using the first World Health Organization international standard in a resource-limited country.

BACKGROUND: The COVID-19 pandemic caused by SARS-CoV-2 remains public health burdens and many unresolved issues worldwide. Molecular assays based on real-time RT-PCR are critical for the detection of SARS-CoV-2 in clinical specimens from patients suspected of COVID-19. OBJECTIVE: We aimed to establish and validate an in-house real-time RT-PCR for the detection of SARS-CoV-2. METHODOLOGY: Primers and probes sets in our in-house real-time RT-PCR assay were designed in conserved regions of the N and E target genes. Optimized multiplex real-time RT-PCR assay was validated using the first WHO International Standard (NIBSC code: 20/146) and evaluated clinical performance. RESULTS: The limit of detection validated using the first WHO International Standard was 159 IU/ml for both E and N target genes. The evaluation of clinical performance on 170 clinical samples showed a positive percent agreement of 100% and the negative percent agreement of 99.08% for both target genes. The Kappa value of 0.99 was an excellent agreement, the strong correlation of Ct values observed between two tests with r2  = 0.84 for the E gene and 0.87 for the N gene. Notably, we assessed on 60 paired saliva and nasopharyngeal samples. The overall agreement was 91.66%, and Kappa value of 0.74 showed a high agreement between two types of samples. When using nasopharyngeal swabs as the reference standard, positive percent agreement, and negative percent agreement were 91.83% and 90.90%, respectively. CONCLUSION: In the present study, we established and validated an in-house real-time RT-PCR for molecular detection of SARS-CoV-2 in a resource-limited country.

Alterations in Regional Brain Regional Volume Associated with Dioxin Exposure in Men Living in the Most Dioxin-Contaminated Area in Vietnam: Magnetic Resonance Imaging (MRI) Analysis Using Voxel-Based Morphometry (VBM).

To clarify the influence of dioxin exposure on brain morphometry, the present study investigated associations between dioxin exposure at high levels and brain structural irregularities in 32 Vietnamese men. Two exposure markers were used: blood dioxin levels, as a marker of exposure in adulthood, and perinatal dioxin exposure, estimated by maternal residency in a dioxin-contaminated area during pregnancy. All subjects underwent brain magnetic resonance imaging (MRI) scans. We analyzed correlations between regional gray matter volumes and blood dioxin levels, and compared regional volumes between men with and without perinatal dioxin exposure using the voxel-based morphometry (VBM) tool from Statistical Parametric Mapping 12 (SPM12). Blood 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was associated with low volume of the medial temporal pole and fusiform gyrus. Toxic equivalency (TEQ)-PCDDs were correlated with low medial temporal pole volume. However, 1,2,3,4,7,8-HxCDD was associated with high middle frontal gyrus and cerebellum volume. In men with perinatal dioxin exposure, the left inferior frontal gyrus pars orbitalis volume was significantly lower than in those without perinatal exposure. These results suggest that dioxin exposure during the perinatal period and in adulthood may alter regional brain volume, which might lead to cognitive deficits and unusual social emotional behavior in Vietnamese men living in dioxin-contaminated areas.

Low serum prealbumin concentration predicts long-term mortality in maintenance hemodialysis patients with hepatitis B and/or C virus infections.

BACKGROUND AND AIM: A low serum prealbumin concentration is common in maintenance hemodialysis patients with hepatitis B and C and may be associated with mortality. In this study, we assessed Department of Nephrology and Hemodialysis predictive value of a low serum prealbumin concentration on mortality in HD patients using reused low-flux dialyzers who were infected with hepatitis B and/or C virus. METHODS: We used serum prealbumin levels to predict the long-term mortality of 326 hemodialysis patients. The patients were divided into two groups: group 1 (n = 140, with hepatitis B and/or C virus infections), and group 2 (n = 186, without hepatitis virus infections). RESULTS: During a 5-year follow-up, there were 75 deaths due to all-cause mortality (23.0%). Mortality was significantly higher (P < 0.001) in patients with hepatitis B and/or C infection (44%) than in those without hepatitis infection (8%). Serum prealbumin was lower in the hepatitis infected group and mortality group than in non-infected group and survival group. Multivariate Cox regression analysis showed that long duration of HD and lower serum prealbumin and albumin were related to mortality in patients undergoing maintenance HD. Receiver operating characteristic curves showed that serum prealbumin had a good prognostic value in predicting mortality in both groups with hepatitis B and/or C virus infection and without hepatitis infection (AUC = 0.792 [95% confidence interval: 0.714-0.87], P < 0.001; cut-off value = 24.5 mg/dl, sensitivity = 62.3%, and specificity = 88.6%). CONCLUSION: In HD patients, serum prealbumin was a good prognostic biomarker of mortality in both groups of patients with hepatitis B and/or C virus infections and without hepatitis infections.

A new method for synthesis of N,N-diethyl-m-methylbenzamide

RESUMEN Introducción: La N,N-dietil-m-metilbenzamida o N,N-dietil-m-toluamida (DEET), es muy conocida como repelente de insectos. Además, se utiliza para mejorar la administración dérmica y transdérmica de muchos fármacos. Objetivos: Presentar un procedimiento factible para sintetizar DEET a partir de ácido m-toluico y dietilamina. Métodos: El ácido m-toluico fue activado con 1,1'-carbonil-diimidazol, para obtener el producto intermedio 1- (m-toluoil) imidazol que continúa reaccionando con dietilamina, para producir DEET. De este modo, se mejoran los factores que afectan la síntesis de N, N-dietil-m-toluamida. Resultados: Se obtuvo DEET mediante un procedimiento óptimo. Los subproductos de la reacción son solubles en agua; se eliminan fácilmente mediante el método de extracción líquido-líquido con agua y diclorometano. La mayor parte del DEET obtenido tiene gran pureza. Los rendimientos fueron del 94 al 95 %. Conclusiones: Se ha proporcionado una ruta mejorada para una síntesis simple y eficaz de DEET a partir de ácido m-toluico y dietilamina en presencia de 1,1'-carbonil-diimidazol. El procedimiento de síntesis se realizó en un solo reactor y el aislamiento de DEET se logró mediante extracción líquido-líquido. El tiempo total de procedimiento se redujo significativamente. Este método de síntesis es fácilmente escalable y factible industrialmente.

ABSTRACT Introduction: N, N-diethyl-m-methylbenzamide or N, N-diethyl-m-toluamide (DEET), is well known as an insect repellent. In addition, it is used to improve the dermal and transdermal delivery of many drugs. Objectives: To present a feasible procedure to synthesize DEET from m-toluic acid and diethylamine. Methods: The m-toluic acid was activated with 1,1'-carbonyl-diimidazole, to obtain the intermediate product 1- (m-toluoyl) imidazole that continues to react with diethylamine, to produce DEET. In this way, the factors affecting the synthesis of N, N-diethyl-m-toluamide are improved. Results: DEET was obtained through an optimal procedure. The by-products of the reaction are soluble in water; they are easily removed by the liquid-liquid extraction method with water and dichloromethane. Most of the DEET obtained has high purity. The yields were 94 to 95 %. Conclusions: An improved route has been provided for a simple and efficient synthesis of DEET from m-toluic acid and diethylamine in the presence of 1,1'-carbonyl-diimidazole. The synthesis procedure was carried out in one-pot, and the isolation of DEET was achieved by liquid-liquid extraction. The total procedure time was significantly reduced. This synthesis method is easily scalable and industrially feasible.

High Serum Uric Acid and High-Sensitivity C Reactive Protein Concentrations Predict Three-Year Cardiovascular Mortality in Patients Treated With Continuous Ambulatory Peritoneal Dialysis.

AIMS: This study aims to access the predicting value of serum uric acid (UA) and high-sensitivity C reactive protein (hs-CRP) concentration on three-year cardiovascular-related mortality in patients performing continuous ambulatory peritoneal dialysis (CAPD). METHODS: A total of267 CAPD patients [150 male (56.2%); mean age 48.93 ± 13.58 years] were included in our study. All patients had measured serum UA and hs-CRP concentration. A high-sensitivity particle-enhanced immunoturbidimetric assay determined serum hs-CRP; serum UA levels were determined using an enzymatic colorimetric assay. All patients were followed for three years to detect cardiovascular-related mortality by cardiologists and stroke specialists. RESULTS: Mean serum UA level was 415.16 ± 84.28 µmol/L, 58.4% of patients had increased serum UA level. Median serum hs-CRP level was 2 (1-4) mg/L, 12.4% of patients had increased serum hs-CRP level. During 36 months of follow-up, 41 patients (15.4%) had cardiovascular-related mortality. The results of Cox proportional hazards regression showed that hypertension, diabetes, high serum UA and hs-CRP were risk factors that related to cardiovascular-related mortality (p<0.05). The receiver operating characteristic (ROC) curve and Kaplan-Meier analysis results showed that UA and hs-CRP level had predictive value for three-year cardiovascular-related mortality in CAPD patients [uric acid: area under the curve (AUC)=0.822; hs-CRP: AUC=0.834, p < 0.001]. CONCLUSION: High serum UA and hs-CRP levels were predictive factors of cardiovascular-related mortality in CAPD patients.

Association of serum adiponectin and leptin levels with renal function in kidney transplant recipients with or without new-onset diabetes after transplantation.

PURPOSE: To evaluate serum adiponectin and leptin concentration in new-onset diabetes after transplantation (NODAT) and non-NODAT patients and association with renal function in kidney transplant recipients (KTRs). PATIENTS AND METHODS: A study of 314 consecutive adults KTRs divided into four groups: 236 individuals without NODAT who had renal insufficiency (RI; n = 56) or normal renal function (n = 180) and 78 patients with NODAT who had RI (n = 17) or normal renal function (n = 61). NODAT was diagnosed based on venous fasting blood glucose or HbA1c with the criteria of the American Diabetes Association. Renal insufficiency was defined according to KDOQI 2002 guidelines. RESULTS: In the NODAT group, the median level of serum adiponectin was lower than that of non-NODAT one (30 µg/ml vs 37.15 µg/ml, p < 0.001); in contrast, the median leptin concentration was higher (4.27 ng/ml vs 4.05 ng/ml, p = 0.024). In the RI group, both median serum adiponectin and leptin levels were higher than those of non-RI one (Adiponectin: 40.01 µg/ml vs 33.7 µg/ml; Leptin: 4.51 ng/ml vs 3.91 ng/ml, p < 0.001 both). We found that BMI was related to both adiponectin and leptin levels in both NODAT, non-NODAT, and all subject groups, based on univariate and multivariate linear regression analysis. CONCLUSION: New-onset diabetes after transplantation, BMI, and renal insufficiency were affected to the serum level of adiponectin and leptin in KTRs.

Effects of perinatal dioxin exposure on mirror neuron activity in 9-year-old children living in a hot spot of dioxin contamination in Vietnam.

BACKGROUND: For 8 years, we have followed up a birth cohort comprising 241 mother-and-infant pairs living around the Da Nang airbase, a hot spot of dioxin contamination in Vietnam, and have reported the impacts of perinatal dioxin exposure on the neurodevelopment of children at various ages. In the present study, 9 years after birth, we investigated the effects of perinatal dioxin exposure on mu and theta rhythms by analyzing EEG power during the execution and observation of hand movements, which indicate mirror neuron system activity. METHODS: One hundred fifty-five 9-year-old children (86 boys and 69 girls) from the Da Nang birth cohort participated in the EEG examination with free viewing of hand movements. The dioxin levels in their mothers' breast milk, measured 1 month after birth, were used as perinatal dioxin exposure markers. A log transform of the ratio of EEG power during execution or observation of the hand movements relative to the power during observation of a bouncing ball for theta and mu rhythms was used to evaluate mirror neuron activity. RESULTS: In both brain hemispheres, the log power ratio in the theta band was significantly higher (i.e., less reduction of power) during observation of hand movements in girls exposed to high levels of TCDD. In boys, however, dioxin congeners other than TCDD, including HxCDDs and several PCDF congeners, contributed to increased log power ratios in the theta band. Particularly for PCDF congeners, the log power ratios in the lowest group among 4 exposure groups were lowest and significantly increased (i.e., decreasing reduction of power) with increasing dose. CONCLUSION: Perinatal TCDD exposure may influence the mirror neuron system of the brain, which plays an important role for social-emotional behavior in children, particularly in girls living in a hot spot of dioxin contamination in Vietnam.

Serum osteoprotegerin level in hemodialysis patients using low-flux reused dialyzer in relation to atherosclerosis.

AIMS: To assess the relation of high serum OPG level and carotid atherosclerosis in maintenance hemodialysis (MHD) patients using low-flux reused dialyzer. MATERIALS AND METHODS: We examined 209 MHD patients with and without carotid atherosclerosis (83 patients and 126 patients) to establish the relation between OPG and atherosclerosis. RESULTS: The proportion of carotid atherosclerosis was 39.7%. The median serum OPG level was 45.3 pmol/L. Serum OPG had a good predicting value for atherosclerosis in MHD patients using low-flux reused dialyzer (AUC = 0.934, p < 0.001, cutoff value = 43.35 pmol/L, Se = 81.3%, Sp = 90.9%). CONCLUSIONS: In this study, serum OPG had a good predicting value for atherosclerosis in MHD patients using low-flux reused dialyzer.

Serum hs-CRP measured prior transplantation predicts of new-onset diabetes after transplantation in renal transplant recipients.

BACKGROUND: To assess the incidence of new-onset diabetes after transplantation (NODAT) for the first year post-transplantation and the predictive value of high-sensitivity C-reactive Protein (hs-CRP) before transplantation for NODAT prediction in kidney transplantation patients. MATERIAL AND METHODS: A study of 251 consecutive adult end-stage kidney disease patients transplanted kidneys from living donors, follow-up during the first year to find NODAT. We diagnosed NODAT based on blood glucose or HbA1c following to the criteria of the American Diabetes Association. RESULTS: The ratio of NODAT was 12.4%. The mean age, mean BMI, the proportion of arteriosclerosis, and the median hs-CRP level in NODAT group were significantly higher than those of non-NODAT group with p < 0.05. Age, BMI and serum hs-CRP had a predictive value for NODAT (Age: AUC = 0.62, p < 0.05, BMI: AUC = 0.626, hs-CRP: AUC = 0.748, p < 0.001). CONCLUSION: Serum hs-CRP level measured prior transplantation is a good predictor for NODAT in renal transplant recipients.

Nutritional Intervention with Dried Bonito Broth for the Amelioration of Aggressive Behaviors in Children with Prenatal Exposure to Dioxins in Vietnam: A Pilot Study.

Dioxins have been suggested to induce inflammation in the intestine and brain and to induce neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), partly due to deficits in parvalbumin-positive neurons in the brain that are sensitive to inflammatory stress. Previously, we reported ADHD traits with increased aggressiveness in children with prenatal exposure to dioxins in Vietnam, whereas dried bonito broth (DBB) has been reported to suppress inflammation and inhibit aggressive behavior in animal and human studies. In the present study, we investigated the association between dioxin exposure and the prevalence of children with highly aggressive behaviors (Study 1), as well as the effects of DBB on the prevalence of children with highly aggressive behaviors (Study 2). METHODS: In Study 1, we investigated the effects of dioxin exposure on the prevalence of children with high aggression scores, which were assessed using the Children's Scale of Hostility and Aggression: Reactive/Proactive (C-SHARP) in dioxin-contaminated areas. The data were analyzed using a logistic regression model after adjusting for confounding factors. In Study 2, we performed nutritional intervention by administering DBB for 60 days to ameliorate the aggressiveness of children with high scores on the C-SHARP aggression scale. The effects of DBB were assessed by comparing the prevalence of children with high C-SHARP scores between the pre- and post-intervention examinations. RESULTS: In Study 1, only the prevalence of children with high covert aggression was significantly increased with an increase in dioxin exposure. In Study 2, in the full ingestion (>80% of goal ingestion volume) group, the prevalence of children with high covert aggression associated with dioxin exposure was significantly lower in the post-ingestion examination compared with in the pre-ingestion examination. However, in other ingestion (<20% and 20-79%) groups and a reference (no intervention) group, no difference in the prevalence of children with high covert aggression was found between the examinations before and after the same experimental period. CONCLUSIONS: The findings suggest that DBB ingestion may ameliorate children's aggressive behavior, which is associated with perinatal dioxin exposure.

Effects of perinatal dioxin exposure on neonatal electroencephalography (EEG) activity of the quiet sleep stage in the most contaminated area from Agent Orange in Vietnam.

OBJECTIVE: To investigate the effects of perinatal dioxin exposure indicated by dioxins in breast milk on neonatal electroencephalography (EEG) power in the quiet sleep stage, and associations with neurodevelopmental outcomes at 2 years of age. STUDY DESIGN: Fifty-one mother-newborn pairs were enrolled for neonatal EEG analysis in the quiet sleep stage from a birth cohort recruited at a prefecture hospital in Bien Hoa city, Vietnam. Relative EEG power in intra-burst-intervals and high-voltage-bursts in the trace alternant pattern were computed from EEG data during the quiet sleep stage. Forty-three mother-child pairs participated in a 2-year follow-up survey to examine neurodevelopment using the Bayley-III scale and gaze behavior exhibited by fixation duration on the face of a child talking in videos. The general linear model and regression linear model were used for data analysis after adjusting for confounding factors. RESULTS: Perinatal dioxin exposure, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, influenced relative EEG power values mainly in the intra-burst-interval part of the trace alternant pattern in the quiet sleep stage. In intra-burst-intervals, decreased frontal delta power and increased frontal and parietal alpha power values in the left hemisphere and temporal beta power values in the right hemisphere were associated with increased TCDD exposure, with significant dose-response relationships. Almost none of the relative power values in these brain regions were associated with Bayley III scores, but relative delta power values were significantly associated with face fixation duration in left frontal and parietal regions at 2 years of age. CONCLUSION: Perinatal dioxin exposure influences neuronal activity in the quiet sleep stage, leading to poor communication ability indicated by gaze behavior in early childhood.

A Combination of Hemodialysis with Hemoperfusion Helped to Reduce the Cardiovascular-Related Mortality Rate after a 3-Year Follow-Up: A Pilot Study in Vietnam.

AIMS: Moderate to severe hyperparathyroidism (parathyroid hormone [PTH] concentrations ≥600 pg/mL) may increase the risk of cardiovascular problems and bone disease. We assume that a combination of hemodialysis with hemoperfusion may reduce the cardiovascular-related mortality rate in maintenance hemodialysis. SUBJECTS AND METHODS: From 625 maintenance hemodialysis patients, 93 people met with our inclusion criteria. Based on the level of serum PTH, the patients were divided into 2 groups: 46 patients who underwent a combination of hemodialysis and hemoperfusion (HD + HP group) for consecutive 3 years and 47 patients who used hemodialysis only (HD group). RESULTS: During 3 years of follow-up, the ratio of mortality was 4.3% in the HD + HP group which was significantly lower than in the HD group (17%), p = 0.049. Based on Kaplan-Meier analysis of cardiovascular-related mortality, patients in the HD group (red line) exhibited a significantly higher death rate compared to the HD + HP group (violet line) (log-rank test, p = 0.049). CONCLUSION: We demonstrated that a combination of hemodialysis and hemoperfusion for 3 years helped to reduce the cardiovascular-related mortality rate.

Overhydration and low serum prealbumin predict peritoneal dialysis-related peritonitis in continuous ambulatory peritoneal dialysis patients.

BACKGROUND: In this study, we focused on the role of overhydration (OH) and low serum prealbumin concentration in predicting peritonitis in continuous ambulatory peritoneal dialysis (CAPD) patients over a 3-year period. METHODS: We measured serum prealbumin concentration and OH by body composition monitor in 278 CAPD patients (159 males and 119 females) with a mean age of 46 years and a median peritoneal dialysis (PD) duration of 21 months. Cases of PD-related peritonitis were collected over 3 years. RESULTS: After the 3-year follow-up, 44 patients were diagnosed with PD-related peritonitis (15.8%). Low education, serum glucose, prealbumin, and OH were independent risk factors for predicting peritonitis over 36 months in CAPD patients. Based on the ROC curve model and Kaplan-Meier analysis, we realized that low prealbumin and high OH were independent predictors of 3-year peritonitis in CAPD patients (Prealbumin: AUC = 0.838, cut-off value = 32.5 mg/dL, Se = 90.9%, Sp = 32.9%; OH: AUC = 0.851, cut-off value = 1.33 L, Se = 79.5%, Sp = 85.5%; and log-rank test p <  0.001, respectively). CONCLUSION: Overhydration and low serum prealbumin were the independent predictors of PD-related peritonitis in CAPD patients.

Value of multidetector computed tomography angiography before bronchial artery embolization in hemoptysis management and early recurrence prediction: a prospective study.

BACKGROUND: Multidetector computed tomography (MDCT) angiography is a useful examination to detect the source of the bleeding in patients with hemoptysis. The aim of the study was to prospectively evaluate the role and clinical efficacy of MDCT angiography before bronchial artery embolization (BAE) for the management of hemoptysis, and to investigate the predictors of early recurrence. METHODS: It is a double-center study which included 57 hemoptysis patients undergoing MDCT angiography prior to BAE from August 2019 to July 2020. A prospective analysis of culprit arteries detected by MDCT angiography allowed an evaluation of the role of this technique. A follow-up was done to assess the efficacy of BAE with preprocedural MDCT angiography and to explore the risk factors of early recurrent hemoptysis. RESULTS: The accuracy of MDCT angiography in the identification of culprit arteries was as high as 97.5%. The average number of total culprit arteries per patient was 2.75 ± 1.73. Among which, the average numbers of culprit ectopic bronchial arteries (BAs) and non-bronchial systemic arteries (NBSAs) per patient were 0.21 ± 0.41 and 1.04 ± 1.57, respectively. The immediate clinical success rate, total hemoptysis recurrence rate, and early hemoptysis recurrence rate of BAE following MDCT angiography were 94.7, 18.5, 16.7%, respectively. Aspergilloma (HR = 6.63, 95% CI: 1.31-33.60, p = 0.022) was associated with an increase in the risk of early recurrence. CONCLUSIONS: MDCT angiography should be performed before BAE for the management of hemoptysis. Aspergilloma was an independent predictor for early recurrence.

Método modificado para la síntesis de hidrocloruro de amantadina / A modified method for synthesis of amantadine hydrochloride

Introducción: El hidrocloruro de amantadina (I) es conocido como un medicamento antiviral utilizado para prevenir y tratar las infecciones por influenza A. También se utiliza para aliviar los síntomas de la enfermedad de Parkinson en el período inicial. Se han informado varios métodos para la preparación de (I). Estos procedimientos comienzan con adamantano (II) en cuatro o tres pasos de reacción, para producir hidrocloruro de amantadina con rendimientos globales que van del 45 por ciento al 58 por ciento. Objetivo: Mejorar el método para la síntesis de hidrocloruro de amantadina, que puede introducirse a escala industrial. Métodos: La optimización paso a paso para reducir el uso de reactivos, disolventes, así como las condiciones de cada paso, se seleccionaron para ser menos agresivas y más amigables con el medio ambiente. Resultados: Todos los factores relacionados con el rendimiento de la reacción para sintetizar los compuestos intermedios y finales se seleccionaron para obtener el mayor rendimiento de cada etapa. Finalmente, se estableció un procedimiento de dos pasos para la síntesis de (I) a partir de (II), a través de N- (1-adamantil) formamida (III), con un rendimiento global mejorado del 78 por ciento y una pureza del 99,2 por ciento. Se confirmó la estructura del producto por 1H-NMR, 13C-NMR, IR y MS. La síntesis de N- (1-adamantil) formamida (VI) a partir de (II) también se logró con éxito en un solo paso. Este método evita el uso de bromo líquido o ácido sulfúrico gaseoso como reactivos. La conversión posterior de (VI) a (I) se llevó a cabo bajo condiciones de reacción, más suaves sin usar solventes peligrosos. Conclusiones: Se logró la síntesis mejorada del clorhidrato de amantadina (I). Este resultado puede utilizarse en una producción industrialmente conveniente. Las materias primas y reactivos utilizados en esta investigación son baratas y están disponibles. El tiempo total de preparación se redujo significativamente, con ahorro de energía y mano de obra(AU)

Introduction: Amantadine hydrochloride (I) was well-known as an antiviral drug used to prevent and treat influenza A infections. Besides, it also was used to relieve the symptoms of Parkinson's disease in the early period. Several methods for the preparation of I have been reported. These procedures started with adamantane (II) in four or three reaction steps to produce amantadine hydrochloride with overall yields ranging from 45 percent to 58 percent. Objectives: Improving method for synthesis of amantadine hydrochloride could introduce to industrial scale. Methods: Step-by-step optimization to reduce the use of reagents, solvents, as well as the conditions of each step were screened to be milder and more environment-friendly. Results: All factors related to the yield of reaction to synthesize the intermediate and final compounds were screened to give the highest yield of each step. Finally, a two-step procedure for the synthesis of (I) from (II) via N-(1-adamantyl) formamide (III) with improving overall yield of 78 percent and a purity of 99.2 percent was established, and the structure of the product was confirmed by 1H-NMR,13C-NMR, IR and MS. The synthesis of N-(1-adamantyl) formamide (VI) from (II) also was successfully accomplished within only one step. This method avoided the use of liquid bromine or fuming sulfuric acid as reactants. The subsequent conversion of (VI) to (I) was carried out under milder reaction conditions without using hazardous solvents. Conclusions: An improved synthesis for amantadine hydrochloride (I) have been provided. This research can be an industrially convenient production of amantadine hydrochloride. Because the raw materials and reagents used in this research are cheap and available which also were screened to save their use. Moreover, the total preparation time was significantly reduced to save energy as well as labor(AU)

Dioxin exposure and sexual dimorphism of gaze behavior in prepubertal Vietnamese children living in Da Nang, a hot spot for dioxin contamination.

Previous studies have reported that dioxin exposure alters sexual dimorphism of play behavior in pre-pubertal children. We aimed to investigate the effects of perinatal dioxin exposure, indicated by dioxins in breast milk, on sexual dimorphism of gaze behavior after adjusting for salivary testosterone (T). Participants were pre-pubertal children in a hot spot for dioxin contamination originating from herbicide spraying in Vietnam. We used eye tracking to assess gaze behavior in 172 children (100 boys and 72 girls) aged 8-9 years. Two sets of 15 pairs of pictures, one oriented towards boys and one oriented towards girls, containing 5 pairs of toy photos (non-biological stimuli) and 10 pairs of human line drawings (biological stimuli) were shown to all children. The total fixation duration for each picture was extracted using Tobii studio software and a feminine index of gaze behavior was defined as the ratio of the summed fixation duration for the girl- vs boy-oriented versions of each stimuli. When viewing non-biological stimuli, feminine index scores significantly increased with TCDD (ß = 0.294) in girls only. For biological stimuli, however, feminine index scores significantly increased with TEQ-PCDD/Fs (ß = 0.269) in boys and with TCDD in girls (ß = 0.286). These associations were significant even after adjusting for salivary T levels, which were inversely associated with some dioxin congeners in girls. In addition, increased feminine index scores for biological stimuli were associated with lower cognitive scores for hand-movement and word-order tests in boys and for face-recognition tests in girls examined at 5 years of age. In conclusion, these results suggest that perinatal dioxin exposure may increase visual interest in girl-oriented objects through impairment of cognitive abilities in pre-pubertal Vietnamese children. PCDD congeners were associated with gaze behavior independently of T levels in boys, while this was only the case for TCDD levels in girls.