Metastasis-directed Therapy in Prostate Cancer: Prognostic Significance of the ESTRO/EORTC Classification in Oligometastatic Bone Disease.

AIMS: Oligometastatic disease (OMD) represents a spectrum of clinical scenarios and various classification systems have been proposed. Bone-only OMD can occur in patients with advanced prostate cancer and validated decision-making tools are needed to assist patient selection for metastasis-directed therapy. The aim of the present study was to determine the prognostic utility of a classification system for OMD. MATERIALS AND METHODS: A retrospective review was conducted of all patients with bone-only oligometastatic prostate cancer treated with stereotactic body radiotherapy (SBRT) since November 2011. SBRT was delivered using CyberKnife® and gantry-based linear accelerator platforms. All patients were classified into oligometastatic states based on the European Society for Radiotherapy and Oncology/European Organisation for Research and Treatment of Cancer (ESTRO/EORTC) classification system. Kaplan-Meier and Cox regression analyses were carried out to determine the prognostic utility of this classification system. RESULTS: In total, 105 patients with 145 osseous metastases were treated over 119 sessions. The median follow-up after SBRT was 23 months (interquartile range 10-39.8). Twelve patients had died after a median time of 31 months. The 3-year metastatic progression-free survival was 23% (95% confidence interval 13-32) and the 3-year overall survival was 88% (95% confidence interval 80-96). Patients in a metachronous oligometastatic state were 4.50 (95% confidence interval 1.19-17.10, P = 0.03) times more likely to experience metastatic progression compared with those with synchronous oligometastases, and 6.69 (95% confidence interval 1.05-42.50, P = 0.04) times more likely to experience any failure. Hazard ratio magnitudes increased for patients in a repeat oligometastatic state. The multivariate model for both metastatic progression-free survival and failure-free survival found prostate-specific antigen doubling time <4 months (P = 0.002; P = 0.05) to independently predict for progression. CONCLUSION: The ESTRO/EORTC classification of OMD predicts for progression in patients treated with SBRT for bone-only oligometastatic prostate cancer at our institution. Further validation in prospective series over multiple tumour sites is needed. These characterisation factors should be assessed in patients considered for metastasis-directed therapy together with established prognostic features.

EVIPNet Americas: Overcoming barriers to integrate scientific evidence and health policies in the Americas

In response to the challenges created by the COVID-19 pandemic to the role of evidence in policymaking, the World Health Organization (WHO) in collaboration with the Pan American Health Organization (PAHO) convened the first Global Evidence-to-Policy (E2P) Summit.This summit brought together different stakeholders from all WHO Regions to identify common challenges, share lessons learned, and provide recommendations to support evidence-informed decisionmaking as a catalyst for policy and societal changes

Diel oxygen fluctuation drives the thermal response and metabolic performance of coastal marine ectotherms.

Coastal marine systems are characterized by high levels of primary production that result in diel oxygen fluctuations from undersaturation to supersaturation. Constant normoxia, or 100% oxygen saturation, is therefore rare. Since the thermal sensitivity of invertebrates is directly linked to oxygen availability, we hypothesized that (i) the metabolic response of coastal marine invertebrates would be more sensitive to thermal stress when exposed to oxygen supersaturation rather than 100% oxygen saturation and (ii) natural diel fluctuation in oxygen availability rather than constant 100% oxygen saturation is a main driver of the thermal response. We tested the effects of oxygen regime on the metabolic rate, and haemocyanin and lactate levels, of velvet crabs (Necora puber) and blue mussels (Mytilus edulis), under rising temperatures (up to 24°C) in the laboratory. Oxygen supersaturation and photosynthetically induced diel oxygen fluctuation amplified animal metabolic thermal response significantly in both species, demonstrating that the natural variability of oxygen in coastal environments can provide considerable physiological benefits under ocean warming. Our study highlights the significance of integrating ecologically relevant oxygen variability into experimental assessments of animal physiology and thermal response, and predictions of metabolic performance under climate warming. Given the escalating intensity and frequency of climate anomalies, oxygen variation caused by coastal vegetation will likely become increasingly important in mitigating the effects of higher temperatures on coastal fauna.

Molecular Assessment of Microcirculation Injury in Formalin-Fixed Human Cardiac Allograft Biopsies With Antibody-Mediated Rejection.

Precise diagnosis of antibody-mediated rejection (AMR) in cardiac allograft endomyocardial biopsies (EMBs) remains challenging. This study assessed molecular diagnostics in human EMBs with AMR. A set of 34 endothelial, natural killer cell and inflammatory genes was quantified in 106 formalin-fixed, paraffin-embedded EMBs classified according to 2013 International Society for Heart and Lung Transplantation (ISHLT) criteria. The gene set expression was compared between ISHLT diagnoses and correlated with donor-specific antibody (DSA), endothelial injury by electron microscopy (EM) and prognosis. Findings were validated in an independent set of 57 EMBs. In the training set (n = 106), AMR cases (n = 70) showed higher gene set expression than acute cellular rejection (ACR; n = 21, p < 0.001) and controls (n = 15, p < 0.0001). Anti-HLA DSA positivity was associated with higher gene set expression (p = 0.01). Endothelial injury by electron microscopy strongly correlated with gene set expression, specifically in AMR cases (r = 0.62, p = 0.002). Receiver operating characteristic curve analysis for diagnosing AMR showed greater accuracy with gene set expression (area under the curve [AUC] = 79.88) than with DSA (AUC = 70.47) and C4d (AUC = 70.71). In AMR patients (n = 17) with sequential biopsies, increasing gene set expression was associated with inferior prognosis (p = 0.034). These findings were confirmed in the validation set. In conclusion, biopsy-based molecular assessment of antibody-mediated microcirculation injury has the potential to improve diagnosis of AMR in human cardiac transplants.

Investigating the effects of caffeine on executive functions using traditional Stroop and a new ecologically-valid virtual reality task, the Jansari assessment of Executive Functions (JEF(©)).

OBJECTIVE: Caffeine has been shown to have effects on certain areas of cognition, but in executive functioning the research is limited and also inconsistent. One reason could be the need for a more sensitive measure to detect the effects of caffeine on executive function. This study used a new non-immersive virtual reality assessment of executive functions known as JEF(©) (the Jansari Assessment of Executive Function) alongside the 'classic' Stroop Colour-Word task to assess the effects of a normal dose of caffeinated coffee on executive function. METHOD: Using a double-blind, counterbalanced within participants procedure 43 participants were administered either a caffeinated or decaffeinated coffee and completed the 'JEF(©)' and Stroop tasks, as well as a subjective mood scale and blood pressure pre- and post condition on two separate occasions a week apart. JEF(©) yields measures for eight separate aspects of executive functions, in addition to a total average score. RESULTS: Findings indicate that performance was significantly improved on the planning, creative thinking, event-, time- and action-based prospective memory, as well as total JEF(©) score following caffeinated coffee relative to the decaffeinated coffee. The caffeinated beverage significantly decreased reaction times on the Stroop task, but there was no effect on Stroop interference. CONCLUSION: The results provide further support for the effects of a caffeinated beverage on cognitive functioning. In particular, it has demonstrated the ability of JEF(©) to detect the effects of caffeine across a number of executive functioning constructs, which weren't shown in the Stroop task, suggesting executive functioning improvements as a result of a 'typical' dose of caffeine may only be detected by the use of more real-world, ecologically valid tasks.

Vitrectomy with subretinal tissue plasminogen activator and ranibizumab for submacular haemorrhages secondary to age-related macular degeneration: retrospective case series of 45 consecutive cases.

PurposeTo assess the efficacy of small-gauge vitrectomy with subretinal recombinant tissue plasminogen activator (rtPA) and ranibizumab for submacular haemorrhages secondary to neovascular age-related macular degeneration (nAMD), and to identify the factors associated with visual outcome.MethodsA retrospective case series was performed, including all patients who had small-gauge vitrectomy with subretinal rtPA and ranibizumab for submacular haemorrhages secondary to nAMD. All patients received three consecutive monthly injections of ranibizumab after the surgery, and were reviewed monthly and treated on a pro re nata regime.ResultsA total of 45 eyes of 45 patients were included in the study. Mean age was 77.07±9.67 years, and 32 of 45 patients (71.1%) were women. Surgery was performed on average 6.98±5.70 days after the onset of symptoms, and patients were observed for a follow-up period of 12.9±10.8 months. On average, visual acuity improved -0.59±0.61 LogMAR between presentation and last follow-up. Visual acuity improved in 33 patients (73.3%), remained unchanged in 10 patients (22.2%), and worsened in 2 patients (4.4%). Multiple linear regression showed that patients with smaller haemorrhages (P=0.012) and prompt surgery (P=0.008) had better final visual acuities. A haemorrhage area of ≤30 mm(2) had 91.3% sensitivity and 73.3% specificity for predicting a final visual acuity ≥6/60.ConclusionSmall-gauge vitrectomy with subretinal rtPA and ranibizumab is effective for improving visual acuity in patients with submacular haemorrhages secondary to nAMD. Small haemorrhage area and prompt surgery are associated with better final visual acuity.

Lake and watershed influences on the distribution of elemental contaminants in the Rideau Canal System, a UNESCO world heritage site.

Watershed-specific variables such as sediment particle size distribution, water depth, sedimentation rate, focusing factors, and catchment area to lake area ratio can affect the distribution of trace element contaminants to lakes. The aim of this study was to investigate sources of metals to three headwater lakes and to quantify effects of watershed-specific variables on spatial and temporal trends of trace elements (As, Cd, Co, Cr, Cu, Hg, K, Ni, Pb, Rb, and Zn) in sediments and mercury (Hg) concentrations in fish. Surface sediment and water samples were used to characterize spatial patterns, while sediment cores were collected to portray temporal trends. Historical trends of Hg in northern pike (Esox lucius) were assessed in relation to paleolimnological trends of sediment Hg concentrations. Similarity in timing of sediment peak trace element concentrations for the lakes suggests large-scale, atmospheric sources. The lake with highest catchment area-to-lake area ratio was consistently associated with highest sediment elemental concentrations and displayed significant correlations between increased sediment Hg concentrations and decreased pike tissue concentrations over time. This suggests that catchment area-to-lake area ratio is an important factor influencing the concentration of atmospherically derived contaminants within lake sediments and their transfer through the food web.

A review of metal (Pb and Zn) sensitive and pH tolerant bioassay organisms for risk screening of metal-contaminated acidic soils.

To improve risk estimates at the screening stage of Ecological Risk Assessment (ERA), short duration bioassays tailored to undisturbed soil cores from the contaminated site could be useful. However, existing standardized bioassays use disturbed soil samples and often pH sensitive organisms. This is a problem as naturally acidic soils are widespread. Changing soil properties to suit the test organism may change metal bioavailability, leading to erroneous risk estimates. For bioassays in undisturbed soil cores to be effective, species able to withstand natural soil properties must be identified. This review presents a critical examination of bioassay species' tolerance of acidic soils and sensitivity to metal contaminants such as Pb and Zn. Promising organisms include; Dendrobaena octaedra, Folsomia candida, Caenorhabditis elegans, Oppia nitens, Brassica rapa, Trifolium pratense, Allium cepa, Quercus rubra and Acer rubrum. The MetSTICK test and the Bait lamina test were also identified as suitable microorganism tests.

Putative tumour suppressor gene necdin is hypermethylated and mutated in human cancer.

BACKGROUND: Necdin (NDN) expression is downregulated in telomerase-immortalised normal human urothelial cells. Telomerase-immortalised normal human urothelial cells have no detected genetic alterations. Accordingly, many of the genes whose expression is altered following immortalisation are those for which epigenetic silencing is reported. METHODS: NDN expression was examined in normal tissues and tumour cell lines by quantitative real-time PCR and immunoblotting. Immunohistochemistry was performed on urothelial carcinoma (UC). Urothelial carcinoma and UC cell lines were subject to HumanMethylation27 BeadChip Array-based methylation analyses. Mutation screening was performed. The functional significance of NDN expression was investigated using retroviral-mediated downregulation or overexpression. RESULTS: NDN protein was widely expressed in normal tissues. Loss of expression was observed in 38 out of 44 (86%) of UC cell lines and 19 out of 25 (76%) of non-UC cell lines. Loss of NDN protein was found in the majority of primary UC. Oncomine analysis demonstrated downregulation of expression in multiple tumour types. In UC, tumour-specific hypermethylation of NDN and key CpG sites where hypermethylation correlated with reduced expression were identified. Six novel mutations, including some of predicted functional significance, were identified in colorectal and ovarian cancer cell lines. Functional studies showed that NDN could suppress colony formation at low cell density and affect anchorage-independent growth and anoikis in vitro. CONCLUSION: NDN is a novel tumour suppressor candidate that is downregulated and hypermethylated or mutated in cancer.

Type I leucocyte adhesion deficiency (LAD I). Report of a case

No disponible

Utility of bioassays (lettuce, red clover, red fescue, Microtox, MetSTICK, Hyalella, bait lamina) in ecological risk screening of acid metal (Zn) contaminated soil.

The objective of this study was to assess selected bioassays and ecological screening tools for their suitability in a weight of evidence risk screening process of acidic metal contaminated soil. Intact soil cores were used for the tests, which minimizes changes in pH and metal bioavailability that may result from homogenization and drying of the soil. Soil cores were spiked with ZnCl(2) or CaCl(2). Leachate collected from the soil cores was used to account for the exposure pathways through pore water and groundwater. Tests assessed included MetSTICK in soil cores and Microtox in soil leachate, lettuce (Lactuca sativa), red fescue (Festuca rubra) and red clover (Trifolium pratense) in the soil cores and lettuce and red clover in soil leachate, Hyallella azteca in soil leachate, and an ecological soil function test using Bait Lamina in soil cores. Microtox, H. azteca, lettuce and red fescue showed higher sensitivity to low pH than to Zn concentrations and are therefore not recommended as tests on intact acidic soil cores and soil leachate. The Bait Lamina test appeared sensitive to pH levels below 3.7 but should be investigated further as a screening tool in less acidic soils. Among the bioassays, the MetSTICK and the T. pratense bioassays in soil cores were the most sensitive to Zn, with the lowest nominal NOEC of 200 and 400mg Zn/kg d.w., respectively. These bioassays were also tolerant of low pH, which make them suitable for assessing hazards of metal contaminated acid soils.

Reducción de!la mortalidad materna en Ecuador: opciones de política para mejorar el acceso a atención materna calificada y de calidad

La!muerte!de!una!mujer!durante!el!embarazo,!o!dentro!de!los!42!días!siguientes!a! la! terminación! de! éste,! es! una! tragedia! familiar! y! comunitaria,! con! profundas! consecuencias! sociales! y! económicas.! La! mayoría! de! estas! muertes! pueden! ser!! prevenibles! con! acciones! dirigidas! a! ! evitar! el! embarazo! no! planificado,! con! controles! prenatales! adecuados! para! detección! y! tratamiento! oportuno! de! las! complicaciones!y!una!!adecuada!atención!del!parto!y!puerperio.!

Ecotoxicological risk assessment of undisturbed metal contaminated soil at two remote lighthouse sites.

Ecotoxicological risk assessments of contaminated soil are commonly completed using guideline values based on total concentrations. However, only certain fractions of contaminants are bioavailable and pose a hazard to the environment. This paper investigates the relationship between measured metal concentrations in soil and soil leachate, and the effects in organisms exposed to intact, undisturbed soil cores (wheat, Tricum aestivum) and soil leachate (lettuce, Lactuca sativa, and water flea, Daphnia magna). Despite the samples containing metal concentrations significantly above guideline values, metals of concern (e.g. Pb and Zn) did not have a significant toxic effect on wheat or D. magna. During weeks with low leachate pH, an effect on lettuce root elongation was observed in the most contaminated samples. This study has shown that bioassays with intact soil cores can indicate metal bioavailability and provide a better estimate of ecological risk than total metal concentrations in the soil.

Loss of synaptotagmin IV results in a reduction in synaptic vesicles and a distortion of the Golgi structure in cultured hippocampal neurons.

Fusion of synaptic vesicles with the plasma membrane is mediated by the SNARE (soluble NSF attachment receptor) proteins and is regulated by synaptotagmin (syt). There are at least 17 syt isoforms that have the potential to act as modulators of membrane fusion events. Synaptotagmin IV (syt IV) is particularly interesting; it is an immediate early gene that is regulated by seizures and certain classes of drugs, and, in humans, syt IV maps to a region of chromosome 18 associated with schizophrenia and bipolar disease. Syt IV has recently been found to localize to dense core vesicles in hippocampal neurons, where it regulates neurotrophin release. Here we have examined the ultrastructure of cultured hippocampal neurons from wild-type and syt IV -/- mice using electron tomography. Perhaps surprisingly, we observed a potential synaptic vesicle transport defect in syt IV -/- neurons, with the accumulation of large numbers of small clear vesicles (putative axonal transport vesicles) near the trans-Golgi network. We also found an interaction between syt IV and KIF1A, a kinesin known to be involved in vesicle trafficking to the synapse. Finally, we found that syt IV -/- synapses exhibited reduced numbers of synaptic vesicles and a twofold reduction in the proportion of docked vesicles compared to wild-type. The proportion of docked vesicles in syt IV -/- boutons was further reduced, 5-fold, following depolarization.

Evolutionary transitions among dioecy, androdioecy and hermaphroditism in limnadiid clam shrimp (Branchiopoda: Spinicaudata).

Examinations of breeding system transitions have primarily concentrated on the transition from hermaphroditism to dioecy, likely because of the preponderance of this transition within flowering plants. Fewer studies have considered the reverse transition: dioecy to hermaphroditism. A fruitful approach to studying this latter transition can be sought by studying clades in which transitions between dioecy and hermaphroditism have occurred multiple times. Freshwater crustaceans in the family Limnadiidae comprise dioecious, hermaphroditic and androdioecious (males + hermaphrodites) species, and thus this family represents an excellent model system for the assessment of the evolutionary transitions between these related breeding systems. Herein we report a phylogenetic assessment of breeding system transitions within the family using a total evidence comparative approach. We find that dioecy is the ancestral breeding system for the Limnadiidae and that a minimum of two independent transitions from dioecy to hermaphroditism occurred within this family, leading to (1) a Holarctic, all-hermaphrodite species, Limnadia lenticularis and (2) mixtures of hermaphrodites and males in the genus Eulimnadia. Both hermaphroditic derivatives are essentially females with only a small amount of energy allocated to male function. Within Eulimnadia, we find several all-hermaphrodite populations/species that have been independently derived at least twice from androdioecious progenitors within this genus. We discuss two adaptive (based on the notion of 'reproductive assurance') and one nonadaptive explanations for the derivation of all-hermaphroditism from androdioecy. We propose that L. lenticularis likely represents an all-hermaphrodite species that was derived from an androdioecious ancestor, much like the all-hermaphrodite populations derived from androdioecy currently observed within the Eulimnadia. Finally, we note that the proposed hypotheses for the dioecy to hermaphroditism transition are unable to explain the derivation of a fully functional, outcrossing hermaphroditic species from a dioecious progenitor.