Paclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF melanoma (PACMEL): a multicentre, open-label, randomised, controlled phase II trial.

BACKGROUND: Advanced melanoma treatments often rely on immunotherapy or targeting mutations, with few treatment options for wild-type BRAF (BRAF-wt) melanoma. However, the mitogen-activated protein kinase pathway is activated in most melanoma, including BRAF-wt. We assessed whether inhibiting this pathway by adding kinase inhibitors trametinib or pazopanib to paclitaxel chemotherapy improved outcomes in patients with advanced BRAF-wt melanoma in a phase II, randomised and open-label trial. PATIENTS AND METHODS: Patients were randomised (1 : 1 : 1) to paclitaxel alone or with trametinib or pazopanib. Paclitaxel was given for a maximum of six cycles, while 2 mg trametinib and 800 mg pazopanib were administered orally once daily until disease progression or unacceptable toxicity. Participants and investigators were unblinded. The primary end point was progression-free survival (PFS). Key secondary end points included overall survival (OS) and objective response rate (ORR). RESULTS: Participants were randomised to paclitaxel alone (n = 38), paclitaxel and trametinib (n = 36), or paclitaxel and pazopanib (n = 37). Adding trametinib significantly improved 6-month PFS [time ratio (TR), 1.47; 90% confidence interval (CI) 1.08-2.01, P = 0.04] and ORR (42% versus 13%; P = 0.01) but had no effect on OS (P = 0.25). Adding pazopanib did not benefit 6-month PFS; (TR 1.36; 90% CI 0.96-1.93; P = 0.14), ORR, or OS. Toxicity increased in both combination arms. CONCLUSION: In this phase II trial, adding trametinib to paclitaxel chemotherapy for BRAF-wt melanoma improved PFS and substantially increased ORR but did not impact OS.This study was registered with the EU Clinical Trials Register, EudraCT number 2011-002545-35, and with the ISRCTN registry, number 43327231.

Contemporary genetic structure and postglacial demographic history of the black scorpionfish, Scorpaena porcus, in the Mediterranean and the Black Seas.

Understanding the distribution of genetic diversity in the light of past demographic events linked with climatic shifts will help to forecast evolutionary trajectories of ecosystems within the current context of climate change. In this study, mitochondrial sequences and microsatellite loci were analysed using traditional population genetic approaches together with Bayesian dating and the more recent approximate Bayesian computation scenario testing. The genetic structure and demographic history of a commercial fish, the black scorpionfish, Scorpaena porcus, was investigated throughout the Mediterranean and Black Seas. The results suggest that the species recently underwent population expansions, in both seas, likely concomitant with the warming period following the Last Glacial Maximum, 20 000 years ago. A weak contemporaneous genetic differentiation was identified between the Black Sea and the Mediterranean Sea. However, the genetic diversity was similar for populations of the two seas, suggesting a high number of colonizers entered the Black Sea during the interglacial period and/or the presence of a refugial population in the Black Sea during the glacial period. Finally, within seas, an east/west genetic differentiation in the Adriatic seems to prevail, whereas the Black Sea does not show any structured spatial genetic pattern of its population. Overall, these results suggest that the Black Sea is not that isolated from the Mediterranean, and both seas revealed similar evolutionary patterns related to climate change and changes in sea level.

A simple score to predict survival with dementia in the general population.

BACKGROUND/AIMS: This study was designed to develop a practical risk score for predicting 5-year survival after the diagnosis of dementia. METHODS: Using the Paquid Study (prospective, population-based, long-term cohort study), we created a prognosis score with incident cases of dementia and validated it in another prospective, population-based, long-term cohort study, the Three City Study. - RESULTS: Among the 3,777 subjects enrolled in the Paquid Study, 454 incident cases of dementia were included in this study. After a 5-year follow-up period, 319 (70.3%) were deceased. The score was constructed from three independent prognostic variables (gender, age at diagnosis and number of ADL restricted). The discriminant ability of the score was good with a c index of 0.754. Sensitivity was 64.7% and specificity 76.3%. In the validation cohort, the discriminant ability of the prognostic score with c statistics was 0.700. Sensitivity was 26.3% and specificity 95.4%. CONCLUSIONS: The prognostic factors selected in the predictive model are easily assessable, so this simple score could provide helpful information for the management of dementia, particularly to identify patients with duration of the disease greater than 5 years.

Prevalence of word retrieval complaint and prediction of dementia in a population-based study of elderly subjects.

There is agreement that elderly people complain about word finding difficulties, particularly proper names. However, few studies have focused on the prevalence of this complaint in the general population, nor is it clearly known whether it is predictive of dementia. The aim of this study was to fill this gap using the PAQUID cohort. 1,838 people aged 65 or more completed questionnaires and neuropsychological evaluation regularly during 13 years. Results show that the complaint about proper name retrieval concerns 64% of people aged above 65 years, and the complaint about common names 30%. The complaint was not associated with enhanced risk of dementia, whereas short naming tests were. Only a marginal relation was found between these naming tests and word retrieval complaint. This study emphasizes the importance of proper name retrieval complaint in the general population and suggests that elderly subjects can be reassured in the absence of other symptoms.

Identification of the origin of faecal contamination in estuarine oysters using Bacteroidales and F-specific RNA bacteriophage markers.

AIMS: The aim of this study was to identify the origin of faecal pollution impacting the Elorn estuary (Brittany, France) by applying microbial source tracking (MST) markers in both oysters and estuarine waters. METHODS AND RESULTS: The MST markers used were as follows: (i) human-, ruminant- and pig-associated Bacteroidales markers by real-time PCR and (ii) human genogroup II and animal genogroup I of F-specific RNA bacteriophages (FRNAPH) by culture/genotyping and by direct real-time reverse-transcriptase PCR. The higher occurrence of the human genogroup II of F-specific RNA bacteriophages using a culture/genotyping method, and human-associated Bacteroidales marker by real-time PCR, allowed the identification of human faecal contamination as the predominant source of contamination in oysters (total of 18 oyster batches tested) and waters (total of 24 water samples tested). The importance of using the intravalvular liquids instead of digestive tissues, when applying host-associated Bacteroidales markers in oysters, was also revealed. CONCLUSIONS: This study has shown that the application of a MST toolbox of diverse bacterial and viral methods can provide multiple lines of evidence to identify the predominant source of faecal contamination in shellfish from an estuarine environment. SIGNIFICANCE AND IMPACT OF THE STUDY: Application of this MST toolbox is a useful approach to understand the origin of faecal contamination in shellfish harvesting areas in an estuarine setting.

Co-Occurrence of Geriatric Syndromes and Diseases in the General Population: Assessment of the Dimensions of Aging.

OBJECTIVES: The co-occurrence of multiple medical or psycho-social conditions (geriatric syndromes (GS) and age-related diseases) is a growing concern in older people. Given the diversity of these conditions and their complex interactions, our aim was to determine whether they could be structured into synthetic dimensions in order to facilitate the management of multimorbidity. DESIGN: The underlying structure of 10 GSs and 8 age-related diseases was identified using a multiple correspondence analysis (MCA), and confronted to subjective and objective health outcomes. SETTING: community residents from Bordeaux City (France) older than 75 years in 2010. PARTICIPANTS: 630 adults aged 75+ years who lived in Bordeaux and participated in the 10-year follow-up of the Three-City study. MEASUREMENTS: GSs included physical frailty, cognitive impairment and dementia, dependency, depressive symptoms, polymedication, thinness, falls, sensory deficit, social isolation, incontinence. Age-related diseases were cancer, cardiac diseases, peripheral vascular diseases, diabetes, hypertension, pulmonary diseases, osteoporosis, other chronic diseases. Association of the MCA-derived independent dimensions was assessed with 10-year visit subjective health and well-being, and with incident death and entry into institution during the remaining cohort follow-up. RESULTS: Most of the participants (82%) had at least two age-related syndromes or diseases. The MCA structured the 18 conditions into three major dimensions: Degradation (D) driven by GS, Vascular (V), and Psychosocial (P) representing 68.7%, 7.4%, and 5.7% of the total variance, respectively. Dimension D was a strong predictor of future death and institutionalization. Dimensions D and P were strongly associated with current well-being. CONCLUSIONS: This work confirmed that multimorbidity is very common among older adults, and demonstrated the essential role of GS as manifestations of aging, even more than age-related diseases.

Localisation of opticin in human proliferative retinal disease.

This study sought to determine the distribution of opticin, an extracellular matrix small leucine-rich repeat protein secreted by the non-pigmented ciliary body epithelium (CBE), in pathological eye tissues including posterior hyaloid membranes (PHM) and epiretinal membranes (ERM) from subjects with proliferative diabetic retinopathy (PDR), central retinal vein occlusion (CRVO) and proliferative vitreoretinopathy (PVR). Eight enucleated eyes and eleven surgically excised PHMs/ERMs from patients with PDR, CRVO or PVR were analysed by immunohistochemistry for the presence and distribution of opticin, vitreous (delineated by a type II collagen antibody) and blood vessels (using CD31 and CD34 antibodies as endothelial markers). Opticin was present at the basal surface of the non-pigmented CBE and, in a patchy distribution, within CBE cells in all 8 enucleated globes. It also co-localised with the type II collagen of vitreous, where present, in these eyes. Opticin was present in 16 of the 19 PHMs/ERMs, where it was arranged in layers (10 membranes), diffusely (4 membranes) or in foci (2 membranes). Where in a layered pattern, opticin co-localised with vitreous type II collagen incorporated into the membrane, whereas the other two patterns did not co-localise with type II collagen labelling. We concluded that even in advanced proliferative retinal disease, the CBE continues to express and secrete opticin. Opticin was co-distributed with vitreous type II collagen and was also present in the pre-retinal membranes of proliferative retinopathies, where it could play a role in their development.

[Semantic and letter fluency tasks: normative data in an elderly population of 70 years old and over from the PAQUID cohort]. / Fluences verbales sémantiques et littérales: normes en population générale chez des sujets âgés de 70 ans et plus issus de la cohorte PAQUID.

INTRODUCTION: Verbal fluency tasks are frequently used in neuropsychological examinations. The aim of this study was to produce norms for a normal elderly population in semantic (colors, animals, fruits, city names) and letter fluency (letters "L" and "P") tasks performed in 60 seconds. METHODS: These data were collected as part of the PAQUID cohort, a French population-based study on aging conducted in Gironde and Dordogne. RESULTS: The sub-sample analyzed included 1730 non-institutionalized and non-demented subjects. Norms were calculated according to age (70-74 years, 75-79 years, >or=80 years), sex and educational level (no diploma, primary degree, secondary degree and higher). For each task, the number of correct words produced and repetition errors were analyzed. CONCLUSION: The contribution of this work is to provide clinicians with normative scores for semantic and letter fluency tasks helpful for interpreting the performances of elderly patients consulting for cognitive disorders.

Activity rhythms and adiurnal light-dark control.

The running-wheel activity pattern of mature male rats was successfully synchronized to light-dark cycles as long as 48 hours and as short as 16 hours. Even after 6 months' exposure to "days" longer than the normal 24 hours, the animals returned promptly to circadian rhythmicity when placed under freerunning conditions of continuous dark. That such rhythms also reappeared when the light condition of the 36-hour cycle was reduced from 660 to 33 lumens per square meter suggests that brightness may be the critical factor in the unexpectedly broad range of entrainment demonstrated.

Early post-mortem changes and stages of decomposition in exposed cadavers.

Decomposition of an exposed cadaver is a continuous process, beginning at the moment of death and ending when the body is reduced to a dried skeleton. Traditional estimates of the period of time since death or post-mortem interval have been based on a series of grossly observable changes to the body, including livor mortis, algor mortis, rigor mortis and similar phenomena. These changes will be described briefly and their relative significance discussed. More recently, insects, mites and other arthropods have been increasingly used by law enforcement to provide an estimate of the post-mortem interval. Although the process of decomposition is continuous, it is useful to divide this into a series of five stages: Fresh, Bloated, Decay, Postdecay and Skeletal. Here these stages are characterized by physical parameters and related assemblages of arthropods, to provide a framework for consideration of the decomposition process and acarine relationships to the body.

Forensic acarology: an introduction.

Mites can be found in all imaginable terrestrial habitats, in freshwater, and in salt water. Mites can be found in our houses and furnishings, on our clothes, and even in the pores of our skin-almost every single person carries mites. Most of the time, we are unaware of them because they are small and easily overlooked, and-most of the time-they do not cause trouble. In fact, they may even proof useful, for instance in forensics. The first arthropod scavengers colonising a dead body will be flies with phoretic mites. The flies will complete their life cycle in and around the corpse, while the mites may feed on the immature stages of the flies. The mites will reproduce much faster than their carriers, offering themselves as valuable timeline markers. There are environments where insects are absent or rare or the environmental conditions impede their access to the corpse. Here, mites that are already present and mites that arrive walking, through air currents or material transfer become important. At the end of the ninetieth century, the work of Jean Pierre Mégnin became the starting point of forensic acarology. Mégnin documented his observations in 'La Faune des Cadavres' [The Fauna of Carcasses]. He was the first to list eight distinct waves of arthropods colonising human carcasses. The first wave included flies and mites, the sixth wave was composed of mites exclusively. The scope of forensic acarology goes further than mites as indicators of time of death. Mites are micro-habitat specific and might provide evidential data on movement or relocation of bodies, or locating a suspect at the scene of a crime. Because of their high diversity, wide occurrence, and abundance, mites may be of great value in the analysis of trace evidence.

Towards a characterisation of the wild legume bitter vetch (Lathyrus linifolius L. (Reichard) Bässler): heteromorphic seed germination, root nodule structure and N-fixing rhizobial symbionts.

Lathyrus linifolius L. (Reichard) Bässler (Fabiaceae, bitter vetch) is a nitrogen (N) fixing species. A coloniser of low nutrient (N) soils, it supports biodiversity such as key moth and butterfly species, and its roots are known for their organoleptic and claimed therapeutic properties. Thus, the species has high potential for restoration, conservation, novel cropping and as a model species. The last because of its genetic synteny with important pulse crops. However, regeneration and functional attributes of L. linifolius remain to be characterised. Seeds of L. linifolius were characterised using physical, colorimetric and chemical data. Ultrastructural and functional characterisation of the N-fixing root nodules included immunolabelling with nifH protein antibodies (recognising the N-fixing enzyme, nitrogenase). Endosymbiotic bacteria were isolated from root nodules and characterised phylogenetically using 16S rRNA, nodA and nodD gene sequences. L. linifolius yielded heteromorphic seed of distinct colour classes: green and brown. Seed morphotypes had similar C:N ratios and were equally germinable (ca. 90%) after scarification at differing optimal temperatures (16 and 20 °C). Brown seeds were larger and comprised a larger proportion of the seed batch (69%). L. linifolius root nodules appeared indeterminate in structure, effective (capable of fixing atmospheric N) and having strains very similar to Rhizobium leguminosarum biovar viciae. The findings and rhizobial isolates have potential application for ecological restoration and horticulture using native seeds. Also, the data and rhizobial resources have potential applications in comparative and functional studies with related and socio-economically important crops such as Pisum, Lens and Vicia.

An enhanced postnatal autoimmune profile in 24 week-old C57BL/6 mice developmentally exposed to TCDD.

Developmental exposure of mice to the environmental contaminant and AhR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), causes persistent postnatal suppression of T cell-mediated immune responses. The extent to which prenatal TCDD may induce or exacerbate postnatal autoimmune disease remains unknown. In the present study, time-pregnant high affinity AhR C57BL/6 mice received a single oral administration of 0, 2.5, or 5 microg/kg TCDD on gestation day (gd) 12. Offspring of these mice (n=5/gender/treatment) were evaluated at 24 weeks-of-age and showed considerable immune dysregulation that was often gender-specific. Decreased thymic weight and percentages of CD4(+)CD8(+) thymocytes, and increased CD4(+)CD8(-) thymocytes, were present in the female but not male offspring. Males but not females showed decreased CD4(-)CD8(+) T cells, and increased Vbeta3(+) and Vbeta17a(+) T cells, in the spleen. Males but not females also showed increased percentages of bone marrow CD24(-)B220(+) B cell progenitors. Antibody titers to dsDNA, ssDNA and cardiolipin displayed increasing trends in both male and female mice, reaching significance for anti-dsDNA in both genders and for ssDNA in males at 5 microg/kg TCDD. Immunofluorescent staining of IgG and C3 deposition in kidney glomeruli increased in both genders of prenatal TCDD-exposed mice, suggestive of early stages of autoimmune glomerulonephritis. Collectively, these results show that exposure to TCDD during immune system development causes persistent humoral immune dysregulation as well as altered cell-mediated responses, and induces an adult profile of changes suggestive of increased risk for autoimmune disease.

Zika-Virus-Related Photo Sharing on Pinterest and Instagram.

OBJECTIVE: Pinterest (San Francisco, CA) and Instagram (Menlo Park, CA) are 2 popular photo-sharing social media platforms among young individuals. We assessed differences between Instagram and Pinterest in relaying photographic information regarding Zika virus. Specifically, we investigated whether the percentage of Zika-virus-related photos with Spanish or Portuguese texts embedded therein was higher for Instagram than for Pinterest and whether the contents of Zika-virus-related photos shared on Pinterest were different from those shared on Instagram. METHODS: We retrieved and manually coded 616 Pinterest (key words: "zika" AND "virus") and 616 Instagram (hashtag: #zikavirus) photos. RESULTS: Among the manually coded samples, 47% (290/616) of Pinterest photos and 23% (144/616) of Instagram photos were relevant to Zika virus. Words were embedded in 57% (164/290) of relevant Pinterest photos and all 144 relevant Instagram photos. Among the photos with embedded words, photos in Spanish or Portuguese were more prevalent on Instagram (77/144, 53%) than on Pinterest (14/164, 9%). There were more Zika-virus-related photos on Instagram than on Pinterest pertinent to Zika virus prevention (59/144, 41%, versus 41/290, 14%; P<0.0001), the effects of Zika virus on pregnancy (27/144, 19%, versus 32/290, 11%; P=0.04), and Zika-virus-associated deaths (4/144, 2%, versus 0/290, 0%; P=0.01). CONCLUSIONS: Pinterest and Instagram are similar platforms for Zika virus prevention communication. (Disaster Med Public Health Preparedness. 2017;11:656-659).

The mitochondrial genome of the stramenopile alga Chrysodidymus synuroideus. Complete sequence, gene content and genome organization.

This is the first report of a complete mitochondrial genome sequence from a photosynthetic member of the stramenopiles, the chrysophyte alga Chrysodidymus synuroideus. The circular-mapping mitochondrial DNA (mtDNA) of 34 119 bp contains 58 densely packed genes (all without introns) and five unique open reading frames (ORFs). Protein genes code for components of respiratory chain complexes, ATP synthase and the mitoribosome, as well as one product of unknown function, encoded in many other protist mtDNAs (YMF16). In addition to small and large subunit ribosomal RNAs, 23 tRNAs are mtDNA-encoded, permitting translation of all codons present in protein-coding genes except ACN (Thr) and CGN (Arg). The missing tRNAs are assumed to be imported from the cytosol. Comparison of the C.SYNUROIDEUS: mtDNA with that of other stramenopiles allowed us to draw conclusions about mitochondrial genome organization, expression and evolution. First, we provide evidence that mitochondrial ORFs code for highly derived, unrecognizable versions of ribosomal or respiratory genes otherwise 'missing' in a particular mtDNA. Secondly, the observed constraints in mitochondrial genome rearrangements suggest operon-based, co-ordinated expression of genes functioning in common biological processes. Finally, stramenopile mtDNAs reveal an unexpectedly low variability in genome size and gene complement, testifying to substantial differences in the tempo of mtDNA evolution between major eukaryotic lineages.

Spatial relationships between bone formation and mechanical stress within cancellous bone.

Bone adapts to mechanical stimuli. While in vivo mechanical loading has been shown to increase the density of cancellous bone, theory suggests that the relationship between tissue stress/strain and subsequent bone formation occurs at the scale of individual trabeculae. Here we examine bone formation one week following mechanical stimulus. Three bouts of cyclic loading (300 cycles/day on 3 consecutive days) were applied to caudal vertebrae of female rats (n=7). Bone formation was determined using three-dimensional images of fluorescent markers of bone formation (0.7×0.7×5.0µm(3)) and local tissue stress/strain was determined using high-resolution finite element models. Three days of mechanical stimuli resulted in an increase in mineralizing surface (loaded: 17.68±2.17%; control: 9.05±3.20%; mean±SD) and an increase in the volume of bone formed (loaded: 7.09±1.97%; control: 1.44±0.50%). The number of bone formation sites was greater in loaded animals (650.71±118.54) than pinned not loaded controls (310.71±91.55), a difference that was explained by the number of formation sites at regions with large local tissue strain energy density (SED). In addition, the probability of observing bone formation was greater at locations of the microstructure experiencing greater SED, but did not exceed 32%, consistent with prior work. Our findings demonstrate that bone formation in the week following a short term mechanical stimulus occurs near regions of bone tissue experiencing high tissue SED, although the ability of finite element models to predict the locations of bone formation remains modest and further improvements may require accounting for additional factors such as osteocyte distribution or fluid flow.

Comparative susceptibility of introduced forest-dwelling mosquitoes in Hawai'i to avian malaria, Plasmodium relictum.

To identify potential vectors of avian malaria in Hawaiian native forests, the innate susceptibility of Aedes albopictus, Wyeomyia mitchellii, and Culex quinquefasciatus from 3 geographical sites along an altitudinal gradient was evaluated using local isolates of Plasmodium relictum. Mosquitoes were dissected 5-8 and 9-13 days postinfective blood meal and microscopically examined for oocysts and salivary-gland sporozoites. Sporogony was completed in all 3 species, but prevalence between species varied significantly. Oocysts were detected in 1-2% and sporozoites in 1-7% of Aedes albopictus that fed on infected ducklings. Wyeomyia mitchellii was slightly more susceptible, with 7-19% and 7% infected with oocysts and sporozoites, respectively. In both species, the median oocyst number was 5 or below. This is only the second Wyeomyia species reported to support development of a malarial parasite. Conversely, Culex quinquefasciatus from all 3 sites proved very susceptible. Prevalence of oocysts and sporozoites consistently exceeded 70%, regardless of gametocytemia or origin of the P. relictum isolate. In trials for which a maximum 200 oocysts were recorded, the median number of oocysts ranged from 144 to 200. It was concluded that Culex quinquefasciatus is the primary vector of avian malaria in Hawai'i.

Preliminary observations of arthropods associated with buried carrion on Oahu.

Several studies in Hawaii have focused on arthropod succession and decomposition patterns of surface remains, but the current research presents the first study to focus on shallow burials in this context. Three domestic pig carcasses (Sus scrofa L.) were buried at the depths of 20-40 cm in silty clay loam soil on an exposed ridge on the leeward side of the volcanically formed Koolau Mountain Range. One carcass was exhumed after 3 weeks, another after 6 weeks, and the last carcass was exhumed after 9 weeks. An inventory of arthropod taxa present on the carrion and in the surrounding soil and observations pertaining to decomposition were recorded at each exhumation. The longer the carrion was buried, the greater the diversity of arthropod species that were recovered from the remains. Biomass loss was calculated to be 49% at the 3-week interval, 56% at the 6-week interval, and 59% at the 9-week interval.

Finite element models predict the location of microdamage in cancellous bone following uniaxial loading.

High-resolution finite element models derived from micro-computed tomography images are often used to study the effects of trabecular microarchitecture and loading mode on tissue stress, but the degree to which existing finite element methods correctly predict the location of tissue failure is not well characterized. In the current study, we determined the relationship between the location of highly strained tissue, as determined from high-resolution finite element models, and the location of tissue microdamage, as determined from three-dimensional fluoroscopy imaging, which was performed after the microdamage was generated in-vitro by mechanical testing. Fourteen specimens of human vertebral cancellous bone were assessed (8 male donors, 2 female donors, 47-78 years of age). Regions of stained microdamage, were 50-75% more likely to form in highly strained tissue (principal strains exceeding 0.4%) than elsewhere, and generally the locations of the regions of microdamage were significantly correlated (p<0.05) with the locations of highly strained tissue. This spatial correlation was stronger for the largest regions of microdamage (≥1,000,000µm(3) in volume); 87% of large regions of microdamage were located near highly strained tissue. Together, these findings demonstrate that there is a strong correlation between regions of microdamage and regions of high strain in human cancellous bone, particularly for the biomechanically more important large instances of microdamage.