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Summary: 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.

Algae encode up to five different types of cryptochrome photoreceptors. So far, relatively little is known about the biological functions of the DASH (Drosophila, Arabidopsis, Synechocystis and Homo)-type cryptochromes. The green alga Chlamydomonas reinhardtii encodes two of them. CRY-DASH1 also called DCRY1 has its maximal absorption peak in the UV-A range. It is localized in the chloroplast and plays an important role in balancing the photosynthetic machinery. Here, we performed a comparative analysis of chloroplast proteins from wild type and a knockout mutant of CRY-DASH1 named cry-dash1 mut , using label-free quantitative proteomics as well as immunoblotting. Our results show upregulation of enzymes involved in specific pathways in the mutant including key enzymes of chlorophyll and carotenoid biosynthesis consistent with increased levels of photosynthetic pigments in cry-dash1 mut . There is also an increase in certain redox as well as photosystem I and II proteins, including D1. Strikingly, CRY-DASH1 is coregulated in a D1 deletion mutant, where its amount is increased. In contrast, key proteins of the central carbon metabolism, including glycolysis/gluconeogenesis, dark fermentation and the oxidative pentose phosphate pathway are downregulated in cry-dash1 mut . Similarly, enzymes of histidine biosynthesis are downregulated in cry-dash1 mut leading to a reduction in the amount of free histidine. Yet, transcripts encoding for several of these proteins are at a similar level in the wild type and cry-dash1 mut or even opposite. We show that CRY-DASH1 can bind to RNA, taking the psbA RNA encoding D1 as target. These data suggest that CRY-DASH1 regulates plastidial metabolic pathways at the posttranscriptional level., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

With the establishment of total mesorectal excision for the treatment of rectal cancer, local recurrence rates have significantly decreased. The addition of preoperative external beam irradiation further reduces this risk to less than 6%. As the local treatment becomes successful and more widely used, the associated treatment-related toxicity is becoming clinically important. If 4 to 6% of the patients are to benefit from neo-adjuvant therapy before total mesorectal excision, the acute and the long-term toxicity burden must be reasonable. With the introduction of better-quality imaging for tumour visualization and treatment planning, a new-targeted radiation treatment was introduced with high dose rate endorectal brachytherapy. The treatment concept was tested in phase I and II studies first in the preoperative setting, then as a boost after external beam radiation therapy as a dose escalation study to achieve higher tumour local control in a radical treatment setting with no surgery. High dose rate endorectal brachytherapy is safe and effective in achieving high tumour regression rate and was well tolerated. It is presently explored in a phase III dose escalation study in the non-operative management of patients with operable rectal cancer., (Copyright © 2022 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Background: Stigmatising attitudes and behaviours by others can have a range of negative effects for population groups and individual people affected by blood borne viruses. The reduction of stigma is a major goal within current Australian national health strategies, however, there is a lack of evidence regarding effective interventions to achieve this goal. Drawing on Allport's (1954) intergroup contact theory, this study aimed to evaluate the effectiveness of an online stigma reduction intervention implemented with the Australian public., Methods: The study was conducted between February and May 2020. Australian adults recruited via Facebook advertising were randomly allocated to a control group (n=316) or one of five intervention groups: people living with HIV (n=320), people living with hepatitis C (n=347), people living with hepatitis B (n=333), people who inject drugs (n=316), or sex workers (n=296). Participants viewed a short video depicting lived experiences of their assigned group. Participants completed attitudinal measures about the group before and immediately after the video, and then at three-month follow-up. These measures related to overall attitudes towards the group, controllability of the stigmatised condition/behaviour, desire to maintain personal distance from the group, and opinions regarding treatment of the group in health care and public policy. Longitudinal changes in attitudes were analysed using a mixed effects regression model with maximum likelihood estimation., Results: Across each of the intervention groups, reductions in negative attitudes were found immediately after watching the videos on almost all outcome measures. By three-month follow-up, the HIV intervention group demonstrated long-term improvements in relation to personal distance compared to the control group, and the hepatitis B intervention group demonstrated long-term improvements in relation to attitudes and personal distance compared to the control group. Across intervention and control groups, long-term reductions in negative attitudes were found in relation to HIV controllability, hepatitis B controllability and opinions, hepatitis C controllability and opinions, and injecting drug use attitudes and opinions., Conclusion: Brief online videos depicting priority populations groups demonstrated positive results in terms of reducing some stigmatising attitudes towards those groups amongst members of the Australian public. Online contact interventions have the potential to be scaled up and rolled out across jurisdictions at national and international levels. These findings suggest that these interventions could be an effective way to contribute to the reduction of stigma and discrimination towards populations affected by blood borne viruses., Competing Interests: Declarations of Interest None., (Copyright © 2021. Published by Elsevier B.V.)

During the last decade, international aid agencies and advocates have been working with Southeast Asian governments to move away from punitive responses towards people who use drugs to more public health, humane approaches. The lack of local scientific evidence about the effectiveness of different treatment approaches has made this advocacy work more challenging. This paper reflects on a generation of treatment research evidence and how it can assist advocacy efforts. The case example is the cost-effectiveness research, comparing centre-based compulsory treatment with community-based voluntary methadone maintenance treatment in Vietnam (2012-2015). Using our long-term and on-going connections with key Vietnamese decision-makers and government agencies, our collective experiences in drug policy advocacy and our unique insight into the working of government in Vietnam, we have used strategies to maximise opportunities for research to inform policy discussions. We have made an assessment here about the extent to which study findings have contributed to policy change in Vietnam and the challenges that impede progressive policy implementation. In doing this, we hope to make a contribution to the research evidence use literature., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: In Vietnam, two dominant approaches for heroin treatment are center-based compulsory rehabilitation (CCT), funded by the Vietnamese government and community-based voluntary methadone maintenance treatment (MMT), funded primarily by international donors. Recent reduction in international funding requires more efficient allocation of government funding for public health programs. A cost-effectiveness analysis comparing two approaches provides a useful source of evidence to inform the government about funding reallocation., Methods: The study was a combined retrospective and prospective, non-randomized cohort comparison over three years of CCT and MMT in Vietnam, conducted between 2012 and 2014, involving 208 CCT participants and 384 MMT participants with heroin dependence. The primary end-point was drug-free days over three years. Total costs, including both program and participant personal costs were measured and cost-effectiveness compared. Mixed effects regression analyses were used to analyze effectiveness data and non-parametric bootstrapping method was used to compare cost-effectiveness., Results: Over three years, MMT costed on average VND85.73 million (US$4108) less than CCT (95% CI: -VND76.88 million, -VND94.59 million). On average, a MMT participant had 344.20 more drug-free days compared to a CCT participant (p<0.001). The incremental cost-effectiveness ratio for MMT was -VND0.25 million (US$11.99) (95% CI: -VND0.34 million, -VND0.19 million) per drug-free day suggesting MMT is the more cost effective alternative., Conclusions: Compared to CCT, MMT is both less expensive and more effective in achieving drug-free days. If the government of Vietnam invests in MMT instead of CCT, it is potentially a cost-saving strategy for reducing illicit drug use among heroin dependent individuals., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The use of wastewater in agriculture and aquaculture has a long tradition throughout Asia. For example, in Hanoi, it creates important livelihood opportunities for >500,000 farmers in peri-urban communities. Discharge of domestic effluents pollute the water streams with potential pathogenic organisms posing a public health threat to farmers and consumers of wastewater-fed foodstuff. We determined the effectiveness of Hanoi's wastewater conveyance system, placing particular emphasis on the quality of wastewater used in agriculture and aquaculture. Between April and June 2014, a total of 216 water samples were obtained from 24 sampling points and the concentrations of total coliforms (TC), Escherichia coli, Salmonella spp. and helminth eggs determined. Despite applied wastewater treatment, agricultural field irrigation water was heavily contaminated with TC (1.3×10(7)colony forming unit (CFU)/100mL), E. coli (1.1×10(6)CFU/100mL) and Salmonella spp. (108 most probable number (MPN)/100mL). These values are 110-fold above Vietnamese discharge limits for restricted agriculture and 260-fold above the World Health Organization (WHO)'s tolerable safety limits for unrestricted agriculture. Mean helminth egg concentrations were below WHO tolerable levels in all study systems (<1egg/L). Hence, elevated levels of bacterial contamination, but not helminth infections, pose a major health risk for farmers and consumers of wastewater fed-products. We propose a set of control measures that might protect the health of exposed population groups without compromising current urban farming activities. This study presents an important example for sanitation safety planning in a rapidly expanding Asian city and can guide public and private entities working towards Sustainable Development Goal target 6.3, that is to improve water quality by reducing pollution, halving the proportion of untreated wastewater and increasing recycling and safe reuse globally., (Copyright © 2016. Published by Elsevier B.V.)

Aim: High-dose-rate brachytherapy (HDRBT) appears to be associated with less treatment-related toxicity compared with external beam radiotherapy in patients with rectal cancer. The present study compared the effect of preoperative treatment strategies on overall survival, cancer-specific deaths, and local recurrences between a Dutch and Canadian expert center with different preoperative treatment strategies., Patients and Methods: We included 145 Dutch and 141 Canadian patients with cT3, non-metastasized rectal cancer. All patients from Canada were preoperatively treated with HDRBT. The preoperative treatment strategy for Dutch patients consisted of either no preoperative treatment, short-course radiotherapy, or chemoradiotherapy. Cox proportional hazards models were used to estimate hazard ratios (HR) with 95% confidence intervals (CIs) comparing overall survival. We adjusted for age, cN stage, (y)pT stage, comorbidity, and type of surgery. Primary endpoint was overall survival. Secondary endpoints were cancer-specific deaths and local recurrences., Results: Five-year overall survival was 70.9% (95% CI 62.6%-77.7%) in Dutch patients compared with 86.9% (80.1%-91.6%) in Canadian patients, resulting in an adjusted HR of 0.70 (95% CI 0.39-1.26; p = 0.233). Of 145 Dutch patients, 6.9% (95% CI 2.8%-11.0%) had a local recurrence and 17.9% (95% CI 11.7%-24.2%) patients died of rectal cancer, compared with 4.3% (95% CI 0.9%-7.5%) local recurrences and 10.6% (95% CI 5.5%-15.7%) rectal cancer deaths out of 141 Canadian patients., Conclusion: We did not detect statistically significant differences in overall survival between a Dutch and Canadian expert center with different treatment strategies. This finding needs to be further investigated in a randomized controlled trial., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Infection with high risk human papillomavirus (HPV) is strongly associated with anal cancer. However, detailed studies on HPV type distribution by gender and age are limited., Methods: Retrospective study of 606 invasive anal cancers diagnosed between 1990 and 2005 in two large urban areas of the province of Québec, Canada. Cases were identified from hospitalization registry. Patient characteristics were collected from medical files. Archived anal squamous cancer specimens were available from 96 patients and were tested for HPV DNA and typing. Variant analysis was performed on 16 consecutive and 24 non-consecutive HPV16-positive samples to assess potential contamination during amplification., Results: Among the 606 patients with anal cancers, 366 (60%) were women. Median age at diagnosis was 63 years. HPV was detected in 88/96 (92%) of cases. HPV16 was the most frequent type detected in 90% of HPV-positive specimens. Other types including 6, 11, 18, 33, 52, 53, 56, 58, 62 and 82 were also found. HPV 97 was not detected. HPV prevalence was associated with female gender and younger age. No contamination occurred during amplification as shown by the subset of 41 HPV16-positive samples, as 37, 2 and 1 isolates were from the European, African and Asian lineages, respectively. The most frequent variants were G1 (n=22) and the prototype (n=12)., Conclusions: Women with anal cancer are at higher risk for anal HPV infection, and HPV infection, especially HPV16, is strongly associated with squamous anal cancer. Therefore, HPV vaccine could potentially prevent the occurrence of anal cancer in both men and women., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Two important challenges in microplate instrumentation are to achieve full well sample coverage and complete mixing. An effective approach of using superhydrophobic rods to accomplish these challenges is reported here. Experiments conducted showed that analytes above 50μl could be made to completely cover the bottom of 96-well standard and transparency microplates. Complete mixing was accomplished by moving the rod parallel to the well bottom while contacting the liquid. The approach is simple and controlled, and it minimizes the problems of spillage and cross-contamination. It works with analytes with varied volumes and of different viscosities present in each well of the microplate., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Driven by the rapid spread of HIV, Vietnam's response to drug use has undergone significant transformation in the past decade. This paper seeks to identify and analyse factors that prompted these changes and to investigate their impact on the lives of people who use drugs., Method: This policy analysis is based on a review of Vietnamese Government documents, peer-reviewed publications and the authors' knowledge of and involvement in drug policy in Vietnam., Results: The last decade has witnessed a progressive change in the mindset of political leaders in Vietnam around illicit drug use and HIV issues. This has led to adoption of evidence-based interventions and the evolution of drug policy that support the scale up of these interventions. However, HIV prevalence among drug users at 31.5% remains high due to limited access to effective interventions and impediments caused by the compulsory treatment centre system., Conclusions: The twin epidemics of HIV and illicit drug use have commanded high-level political attention in Vietnam. Significant policy changes have allowed the implementation of HIV prevention and drug dependence treatment services. Nevertheless, inconsistencies between policies and a continued commitment to compulsory treatment centres remain as major impediments to the provision of effective services to drug users. It is critical that Vietnamese government agencies recognise the social and health consequences of policy conflicts and acknowledge the relative ineffectiveness of centre-based compulsory treatment. In order to facilitate practical changes, the roles of the three ministries directly charged with HIV and illicit drug use need to be harmonised to ensure common goals. The participation of civil society in the policymaking process should also be encouraged. Finally, stronger links between local evidence, policy and practice would increase the impact on HIV prevention and drug addiction treatment programming., (Copyright © 2011 Elsevier B.V. All rights reserved.)

To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC), we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3) emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP)-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq) revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC) and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.

Nonspecific inflammation is associated with primary graft nonfunction (PNF). Inflammatory islet damage is mediated at least partially by pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) produced by resident islet macrophages. The p38 pathway is known to be involved in cytokine production in the cells of the monocyte-macrophage lineage. Therefore, inhibition of the p38 pathway may prevent pro-inflammatory cytokine production by resident islet macrophages and possibly reduce the incidence of PNF. Our present study has demonstrated that inhibition of the p38 pathway by a chemical p38 inhibitor, SB203580, suppresses IL-1beta and TNF-alpha production in human islets exposed to lipopolysaccharide (LPS) and/or inflammatory cytokines. Although IL-1beta is predominantly produced by resident macrophages, ductal cells and islet vascular endothelial cells were found to be another cellular source of IL-1beta in isolated human islets. SB203580 also inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the treated islets. Furthermore, human islets treated with SB203580 for 1 h prior to transplantation showed significantly improved graft function. These results suggest that inhibition of the p38 pathway may become a new therapeutic strategy to improve graft survival in clinical islet transplantation.

Background: Impairment of vasodilation by oxidized low-density lipoprotein has been attributed to lysophosphatidylcholine (LPC). Albumin avidly binds LPC. Therefore, hypoalbuminemia may directly impair vasodilation and thus contribute to increased risk of atherosclerosis in nephrotic syndrome. The addition of albumin reduces LPC in erythrocytes and endothelial cells. We hypothesized that the addition of albumin will salvage vasodilation in aortic rings previously exposed to LPC. LPC increases superoxide production and disturbs L-arginine availability. Therefore, we also decreased superoxide with a superoxide dismutase mimic, MnCl(2), and supplemented L-arginine in an attempt to restore vasodilation., Methods: Rat aorta rings, which had been incubated with various concentrations of LPC and human serum albumin (HSA), were mounted in organ chambers. Relaxation was studied with acetylcholine (0.01 to 100 micromol/L) after precontraction with phenylephrine (CON, 0.3 micromol/L; LPC, 0.03 micromol/L). In some studies MnCl(2) or L-arginine was added to the organ chamber., Results: LPC had time- and dose-dependent inhibitory effects on acetylcholine-mediated vasodilation, but no effect on nitroprusside-mediated vasodilation. Preincubation with albumin (50 or 6 g/L) could protect vasodilation against very high levels of LPC. After preincubation with LPC, the addition of albumin to the incubation salvaged vasodilation. Albumin was more effective after short LPC incubation. MnCl(2) had no specific effect on the LPC-mediated disturbance in vasodilation. L-arginine completely salvaged vasodilation at low concentrations of LPC. However, even high concentrations of L-arginine (1 mmol/L) could not improve vasodilation at LPC levels at which vasodilation was restored by albumin., Conclusions: LPC affects several pathways that inhibit vasodilation, all of which are salvaged by addition of albumin.

Background: A phospholipid, lysophosphatidylcholine (LPC), is the major determinant of the atherosclerotic properties of oxidized low-density lipoprotein (LDL). Under normal circumstances most LPC is bound to albumin. We hypothesized that lipoprotein LPC concentrations are increased in hypoalbuminemic patients with the nephrotic syndrome, irrespective of their lipid levels. To test this hypothesis, we selected nephrotic and control subjects with matched LDL cholesterol levels., Methods: Lipoproteins and the albumin-rich lipoprotein-deficient fractions were separated by ultracentrifugation and their phospholipid composition was analyzed by thin-layer chromatography., Results: Nephrotic subjects (albumin 23 +/- 2 g/liter and LDL cholesterol 3.1 +/- 0.2 mmol/liter) had a LDL LPC concentration that was increased (P < 0.05) to 66 +/- 7 vs. 35 +/- 6 micromol/liter in matched controls (albumin 42 +/- 5 g/liter and LDL cholesterol 3.1 +/- 0.2 mmol/liter). LPC in very low-density lipoprotein plus intermediate-density lipoprotein (VLDL + IDL) in these subjects was also increased to 33 +/- 7 vs. 9 +/- 2 micromol/liter in controls (P < 0.05). Conversely, LPC was decreased to 19 +/- 4 micromol/liter in the albumin-containing fraction of these hypoalbuminemic patients, as compared to 46 +/- 10 micromol/liter in the controls (P < 0.05). LPC was also low (14 +/- 4 micromol/liter) in the albumin-containing fraction of hypoalbuminemic, hypocholesterolemic patients with nonrenal diseases. In hyperlipidemic nephrotic subjects (albumin 21 +/- 2 g/liter and LDL cholesterol 5.7 +/- 0.5 mmol/liter) the LPC levels in LDL and VLDL + IDL were further increased, to 95 +/- 20 and 56 +/- 23 micromol/liter, respectively (P < 0.05)., Conclusion: These findings suggest that in the presence of hypoalbuminemia in combination with proteinuria, LPC shifts from albumin to VLDL, IDL and LDL. This effect is independent of hyperlipidemia. Increased LPC in lipoproteins may be an important factor in the disproportionate increase in cardiovascular disease in nephrotic patients with hypoalbuminemia.