A Repurposing Programme Evaluating Repurposing Transdermal Oestradiol Patches for the Treatment of Prostate Cancer Within the PATCH and STAMPEDE Trials: Current Results and Adapting Trial Design

AIMS: Androgen deprivation therapy (ADT), usually achieved with luteinising hormone releasing hormone analogues (LHRHa), is central to prostate cancer management. LHRHa reduce both testosterone and oestrogen and are associated with significant long-term toxicity. Previous use of oral oestrogens as ADT was curtailed because of cardiovascular toxicity. Transdermal oestrogen (tE2) patches are a potential alternative ADT, supressing testosterone without the associated oestrogen-depletion toxicities (osteoporosis, hot flushes, metabolic abnormalities) and avoiding cardiovascular toxicity, and we here describe their evaluation in men with prostate cancer. MATERIALS AND METHODS: The PATCH (NCT00303784) adaptive trials programme (incorporating recruitment through the STAMPEDE [NCT00268476] platform) is evaluating the safety and efficacy of tE2 patches as ADT for men with prostate cancer. An initial randomised (LHRHa versus tE2) phase II study (n = 251) with cardiovascular toxicity as the primary outcome measure has expanded into a phase III evaluation. Those with locally advanced (M0) or metastatic (M1) prostate cancer are eligible. To reflect changes in both management and prognosis, the PATCH programme is now evaluating these cohorts separately. RESULTS: to date: Recruitment is complete, with 1362 and 1128 in the M0 and M1 cohorts, respectively. Rates of androgen suppression with tE2 were equivalent to LHRHa, with improved metabolic parameters, quality of life and bone health indices (mean absolute change in lumbar spine bone mineral density of -3.0% for LHRHa and +7.9% for tE2 with an estimated difference between arms of 9.3% (95% confidence interval 5.3-13.4). Importantly, rates of cardiovascular events were not significantly different between the two arms and the time to first cardiovascular event did not differ between treatment groups (hazard ratio 1.11, 95% confidence interval 0.80-1.53; P = 0.54). Oncological outcomes are awaited. FUTURE: Efficacy results for the M0 cohort (primary outcome measure metastases-free survival) are expected in the final quarter of 2023. For M1 patients (primary outcome measure - overall survival), analysis using restricted mean survival time is being explored. Allied translational work on longitudinal samples is underway

Trends in the prevalence and distribution of HTLV-1 and HTLV-2 infections in Spain

<p>Abstract</p> <p>Background</p> <p>Although most HTLV infections in Spain have been found in native intravenous drug users carrying HTLV-2, the large immigration flows from Latin America and Sub-Saharan Africa in recent years may have changed the prevalence and distribution of HTLV-1 and HTLV-2 infections, and hypothetically open the opportunity for introducing HTLV-3 or HTLV-4 in Spain. To assess the current seroprevalence of HTLV infection in Spain a national multicenter, cross-sectional, study was conducted in June 2009.</p> <p>Results</p> <p>A total of 6,460 consecutive outpatients attending 16 hospitals were examined. Overall, 12% were immigrants, and their main origin was Latin America (4.9%), Africa (3.6%) and other European countries (2.8%). Nine individuals were seroreactive for HTLV antibodies (overall prevalence, 0.14%). Evidence of HTLV-1 infection was confirmed by Western blot in 4 subjects (prevalence 0.06%) while HTLV-2 infection was found in 5 (prevalence 0.08%). Infection with HTLV types 1, 2, 3 and 4 was discarded by Western blot and specific PCR assays in another two specimens initially reactive in the enzyme immunoassay. All but one HTLV-1 cases were Latin-Americans while all persons with HTLV-2 infection were native Spaniards.</p> <p>Conclusions</p> <p>The overall prevalence of HTLV infections in Spain remains low, with no evidence of HTLV-3 or HTLV-4 infections so far.</p

Regulation of Adipocyte 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) by CCAAT/Enhancer-Binding Protein (C/EBP) β Isoforms, LIP and LAP

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses intracellular regeneration of active glucocorticoids, notably in liver and adipose tissue. 11β-HSD1 is increased selectively in adipose tissue in human obesity, a change implicated in the pathogenesis of metabolic syndrome. With high fat (HF)-feeding, adipose tissue 11β-HSD1 is down-regulated in mice, plausibly to counteract metabolic disease. Transcription of 11β-HSD1 is directly regulated by members of the CCAAT/enhancer binding protein (C/EBP) family. Here we show that while total C/EBPβ in adipose tissue is unaltered by HF diet, the ratio of the C/EBPβ isoforms liver-enriched inhibitor protein (LIP) and liver-enriched activator protein (LAP) (C/EBPβ-LIP:LAP) is increased in subcutaneous adipose. This may cause changes in 11β-HSD1 expression since genetically modified C/EBPβ(+/L) mice, with increased C/EBPβ-LIP:LAP ratio, have decreased subcutaneous adipose 11β-HSD1 mRNA levels, whereas C/EBPβΔuORF mice, with decreased C/EBPβ-LIP:LAP ratio, show increased subcutaneous adipose 11β-HSD1. C/EBPβ-LIP:LAP ratio is regulated by endoplasmic reticulum (ER) stress and mTOR signalling, both of which are altered in obesity. In 3T3-L1 adipocytes, 11β-HSD1 mRNA levels were down-regulated following induction of ER stress by tunicamycin but were up-regulated following inhibition of mTOR by rapamycin. These data point to a central role for C/EBPβ and its processing to LIP and LAP in transcriptional regulation of 11β-HSD1 in adipose tissue. Down-regulation of 11β-HSD1 by increased C/EBPβ-LIP:LAP in adipocytes may be part of a nutrient-sensing mechanism counteracting nutritional stress generated by HF diet

Epidemiology of forest malaria in Central Vietnam: the hidden parasite reservoir

BackgroundAfter successfully reducing the malaria burden to pre-elimination levels over the past two decades, the national malaria programme in Vietnam has recently switched from control to elimination. However, in forested areas of Central Vietnam malaria elimination is likely to be jeopardized by the high occurrence of asymptomatic and submicroscopic infections as shown by previous reports. This paper presents the results of a malaria survey carried out in a remote forested area of Central Vietnam where we evaluated malaria prevalence and risk factors for infection.MethodsAfter a full census (four study villages?=?1,810 inhabitants), the study population was screened for malaria infections by standard microscopy and, if needed, treated according to national guidelines. An additional blood sample on filter paper was also taken in a random sample of the population for later polymerase chain reaction (PCR) and more accurate estimation of the actual burden of malaria infections. The risk factor analysis for malaria infections was done using survey multivariate logistic regression as well as the classification and regression tree method (CART).ResultsA total of 1,450 individuals were screened. Malaria prevalence by microscopy was 7.8% (ranging from 3.9 to 10.9% across villages) mostly Plasmodium falciparum (81.4%) or Plasmodium vivax (17.7%) mono-infections; a large majority (69.9%) was asymptomatic. By PCR, the prevalence was estimated at 22.6% (ranging from 16.4 to 42.5%) with a higher proportion of P. vivax mono-infections (43.2%). The proportion of sub-patent infections increased with increasing age and with decreasing prevalence across villages. The main risk factors were young age, village, house structure, and absence of bed net.ConclusionThis study confirmed that in Central Vietnam a substantial part of the human malaria reservoir is hidden. Additional studies are urgently needed to assess the contribution of this hidden reservoir to the maintenance of malaria transmission. Such evidence will be crucial for guiding elimination strategies

Genome sequences of a novel Vietnamese bat bunyavirus

To document the viral zoonotic risks in Vietnam, fecal samples were systematically collected from a number of mammals in southern Vietnam and subjected to agnostic deep sequencing. We describe here novel Vietnamese bunyavirus sequences detected in bat feces. The complete L and S segments from 14 viruses were determined

Prevention of acute kidney injury and protection of renal function in the intensive care unit

Acute renal failure on the intensive care unit is associated with significant mortality and morbidity. To determine recommendations for the prevention of acute kidney injury (AKI), focusing on the role of potential preventative maneuvers including volume expansion, diuretics, use of inotropes, vasopressors/vasodilators, hormonal interventions, nutrition, and extracorporeal techniques. A systematic search of the literature was performed for studies using these potential protective agents in adult patients at risk for acute renal failure/kidney injury between 1966 and 2009. The following clinical conditions were considered: major surgery, critical illness, sepsis, shock, and use of potentially nephrotoxic drugs and radiocontrast media. Where possible the following endpoints were extracted: creatinine clearance, glomerular filtration rate, increase in serum creatinine, urine output, and markers of tubular injury. Clinical endpoints included the need for renal replacement therapy, length of stay, and mortality. Studies are graded according to the international Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) group system Several measures are recommended, though none carries grade 1A. We recommend prompt resuscitation of the circulation with special attention to providing adequate hydration whilst avoiding high-molecular-weight hydroxy-ethyl starch (HES) preparations, maintaining adequate blood pressure using vasopressors in vasodilatory shock. We suggest using vasopressors in vasodilatory hypotension, specific vasodilators under strict hemodynamic control, sodium bicarbonate for emergency procedures administering contrast media, and periprocedural hemofiltration in severe chronic renal insufficiency undergoing coronary intervention

Situation Analysis and Needs Assessment Report for Tra Hat Village, Bac Lieu Province, Vietnam

Bac Lieu Province in Vietnam is mainly agricultural. Rice is the dominant staple food and the main crop in the province. Farmers have changed the farming system from paddy monoculture to diversified agricultural products (cash crops and livestock). Livestock production is in small scale. The province has three ecological zones: rice/fruit and vegetable production in the eastern districts, a mixed rice and rice/shrimp/aquaculture environment in the central districts and an area of saline/acid soil for a wide variety of sea-based product in the western districts. Salinization and shifting land use from cultivation to aquaculture have caused soil degradation in Bac Lieu. Meanwhile, Tra Hat village is in Vinh Loi District in Bac Lieu Province. It is about 25 km distance from Bac Lieu City. Nearly 80% of the total area of 400 ha of the village are paddy fields (316 ha). Livelihood in the village include rice production, livestock, fishpond and garden production. The problems in rice production include the degradation of the traditional rice seed, flooding, lack of freshwater, application of more farm chemicals, and difficult access to market information; for fruits and vegetables, the main problem is the poor market demand; for livestock, the main problems are diseases and lack of market; in fisheries, the main problem is the low catch; and for aquaculture, the main problems are the poor quality of water and the lack of market. Households also earn money from off farm activities and thus can buy other food (meat, egg) at the commune market for daily consumption. Many households in the village are food sufficient. The local production systems are well adapted to the natural seasonal fluctuation in rainfall and flooding regime, but occasional extreme flooding events cause crop damage and food shortage situation, the most recent was in 2011. The main concern is the maintenance of food sufficiency and security, and raising household income. The main challenges are increasing climate shocks, salt-water intrusion, and population growth. Households acknowledged their need to receive support from the government and other organizations to develop their production systems for sustainable and stable income and better living conditions with reduced risks of environmental pollution, natural disasters, and climate variability

Assessing evidence for avian-to-human transmission of influenza A/H9N2 virus in rural farming communities in northern Vietnam

Rural farming communities in northern Vietnam do not routinely practice vaccination for influenza A viruses (IAV) for either humans or poultry, which enables us to study transmission intensity via seroepidemiology. Using samples from a longitudinal cohort of farming households, we determined the number of symptomatic and asymptomatic human infections for seasonal IAV and avian A/H9 over 2 years. As expected, we detected virologically confirmed acute cases of seasonal IAV in humans, as well as large numbers of subclinical seroconversions to A/H1pdm [55/265 (21 %)], A/H3 [95/265 (36 %)] and A/H9 [24/265 (9 %)]. Five of the A/H9 human seroconverters likely represented true infections rather than heterosubtypic immunity, because the individuals seroconverted solely to A/H9. Among co-located poultry, we found significantly higher seroprevalance for A/H5 compared to A/H9 in both chickens and ducks [for northern study sites overall, 337/1105 (30.5 %) seropositive for A/H5 and 123/1105 (11.1 %) seropositive for A/H9]