Gaining momentum: New options and opportunities for the treatment of advanced melanoma.

Before 2011, patients with advanced or metastatic melanoma had a particularly poor long-term prognosis. Since traditional treatments failed to confer a survival benefit, patients were preferentially entered into clinical trials of investigational agents. A greater understanding of the epidemiology and biology of disease has underpinned the development of newer therapies, including six agents that have been approved in the EU, US and/or Japan: a cytotoxic T-lymphocyte antigen-4 inhibitor (ipilimumab), two programmed cell death-1 receptor inhibitors (nivolumab and pembrolizumab), two BRAF inhibitors (vemurafenib and dabrafenib) and a MEK inhibitor (trametinib). The availability of these treatments has greatly improved the outlook for patients with advanced melanoma; however, a major consideration for physicians is now to determine how best to integrate these agents into clinical practice. Therapeutic decisions are complicated by the need to consider patient and disease characteristics, and individual treatment goals, alongside the different efficacy and safety profiles of agents with varying mechanisms of action. Long-term survival, an outcome largely out of reach with traditional systemic therapies, is now a realistic goal, creating the additional need to re-establish how clinical benefit is evaluated. In this review we summarise the current treatment landscape in advanced melanoma and discuss the promise of agents still in development. We also speculate on the future of melanoma treatment and discuss how combination and sequencing approaches may be used to optimise patient care in the future.

Patterns of primary growth increments in otoliths of Sparus aurata larvae in relation to water temperature and food consumption

Sparus aurata larvae reared under controlled water-temperature conditions during the first 24 days after hatching displayed a linear relationship between age (t) and standard length (SL): SL = 2.68 + 0.19 t (r2 = 0.91l). Increments were laid down in the sagittae with daily periodicity starting on day of hatching. Standard length (SL) and sagittae radius (OR) were correlated: SL(mm) = 2.65 + 0.012 OR(mm). The series of measurements of daily growth increment widths (DWI), food density and water temperature were analyzed by means of time series analysis. The DWI series were strongly autocorrelated, the growth on any one day was dependent upon growth on the previous day. Time series of water temperatures showed, as expected, a random pattern of variation, while food consumed daily was a function of food consumed the two previous days. The DWI series and the food density were correlated positively at lags 1 and 2. The results provided evidence of the importance of food intake upon the sagittae growth when temperature is optimal (20ºC). Sagittae growth was correlated with growth on the previous day, so this should be taken into account when fish growth is derived from sagittae growth rates.

Impact of Study Design on Reported Incidences of Acute Mountain Sickness: A Systematic Review.

AIMS: Published incidences of acute mountain sickness (AMS) vary widely. Reasons for this variation, and predictive factors of AMS, are not well understood. We aimed to identify predictive factors that are associated with the occurrence of AMS, and to test the hypothesis that study design is an independent predictive factor of AMS incidence. We did a systematic search (Medline, bibliographies) for relevant articles in English or French, up to April 28, 2013. Studies of any design reporting on AMS incidence in humans without prophylaxis were selected. Data on incidence and potential predictive factors were extracted by two reviewers and crosschecked by four reviewers. Associations between predictive factors and AMS incidence were sought through bivariate and multivariate analyses for different study designs separately. Association between AMS incidence and study design was assessed using multiple linear regression. RESULTS: We extracted data from 53,603 subjects from 34 randomized controlled trials, 44 cohort studies, and 33 cross-sectional studies. In randomized trials, the median of AMS incidences without prophylaxis was 60% (range, 16%-100%); mode of ascent and population were significantly associated with AMS incidence. In cohort studies, the median of AMS incidences was 51% (0%-100%); geographical location was significantly associated with AMS incidence. In cross-sectional studies, the median of AMS incidences was 32% (0%-68%); mode of ascent and maximum altitude were significantly associated with AMS incidence. In a multivariate analysis, study design (p=0.012), mode of ascent (p=0.003), maximum altitude (p<0.001), population (p=0.002), and geographical location (p<0.001) were significantly associated with AMS incidence. Age, sex, speed of ascent, duration of exposure, or history of AMS were inconsistently reported and therefore not further analyzed. CONCLUSIONS: Reported incidences and identifiable predictive factors of AMS depend on study design.

Roaring lions and chirruping lemurs: How the brain encodes sound objects in space.

The dual-stream model of auditory processing postulates separate processing streams for sound meaning and for sound location. The present review draws on evidence from human behavioral and activation studies as well as from lesion studies to argue for a position-linked representation of sound objects that is distinct both from the position-independent representation within the ventral/What stream and from the explicit sound localization processing within the dorsal/Where stream.

Incidence and Risk Factors of Abdominal Complications After Lung Transplantation.

BACKGROUND: Due to the underlying diseases and the need for immunosuppression, patients after lung transplantation are particularly at risk for gastrointestinal (GI) complications that may negatively influence long-term outcome. The present study assessed the incidences and impact of GI complications after lung transplantation and aimed to identify risk factors. METHODS: Retrospective analysis of all 227 consecutively performed single- and double-lung transplantations at the University hospitals of Lausanne and Geneva was performed between January 1993 and December 2010. Logistic regressions were used to test the effect of potentially influencing variables on the binary outcomes overall, severe, and surgery-requiring complications, followed by a multiple logistic regression model. RESULTS: Final analysis included 205 patients for the purpose of the present study, and 22 patients were excluded due to re-transplantation, multiorgan transplantation, or incomplete datasets. GI complications were observed in 127 patients (62 %). Gastro-esophageal reflux disease was the most commonly observed complication (22.9 %), followed by inflammatory or infectious colitis (20.5 %) and gastroparesis (10.7 %). Major GI complications (Dindo/Clavien III-V) were observed in 83 (40.5 %) patients and were fatal in 4 patients (2.0 %). Multivariate analysis identified double-lung transplantation (p = 0.012) and early (1993-1998) transplantation period (p = 0.008) as independent risk factors for developing major GI complications. Forty-three (21 %) patients required surgery such as colectomy, cholecystectomy, and fundoplication in 6.8, 6.3, and 3.9 % of the patients, respectively. Multivariate analysis identified Charlson comorbidity index of ≥3 as an independent risk factor for developing GI complications requiring surgery (p = 0.015). CONCLUSION: GI complications after lung transplantation are common. Outcome was rather encouraging in the setting of our transplant center.

Low statin use in adults hospitalized with acute coronary syndrome.

OBJECTIVE: To assess recommended and actual use of statins in primary prevention of cardiovascular disease (CVD) based on clinical prediction scores in adults who develop their first acute coronary syndrome (ACS). METHOD: Cross-sectional study of 3172 adults without previous CVD hospitalized with ACS at 4 university centers in Switzerland. The number of participants eligible for statins before hospitalization was estimated based on the European Society of Cardiology (ESC) guidelines and compared to the observed number of participants on statins at hospital entry. RESULTS: Overall, 1171 (37%) participants were classified as high-risk (10-year risk of cardiovascular mortality ≥5% or diabetes); 1025 (32%) as intermediate risk (10-year risk <5% but ≥1%); and 976 (31%) as low risk (10-year risk <1%). Before hospitalization, 516 (16%) were on statins; among high-risk participants, only 236 of 1171 (20%) were on statins. If ESC primary prevention guidelines had been fully implemented, an additional 845 high-risk adults (27% of the whole sample) would have been eligible for statins before hospitalization. CONCLUSION: Although statins are recommended for primary prevention in high-risk adults, only one-fifth of them are on statins when hospitalized for a first ACS.

Assessing an Adolescent's Capacity for Autonomous Decision-Making in Clinical Care.

The purpose of this article is to provide policy guidance on how to assess the capacity of minor adolescents for autonomous decision-making without a third party authorization, in the field of clinical care. In June 2014, a two-day meeting gathered 20 professionals from all continents, working in the field of adolescent medicine, neurosciences, developmental and clinical psychology, sociology, ethics, and law. Formal presentations and discussions were based on a literature search and the participants' experience. The assessment of adolescent decision-making capacity includes the following: (1) a review of the legal context consistent with the principles of the Convention on the Rights of the Child; (2) an empathetic relationship between the adolescent and the health care professional/team; (3) the respect of the adolescent's developmental stage and capacities; (4) the inclusion, if relevant, of relatives, peers, teachers, or social and mental health providers with the adolescent's consent; (5) the control of coercion and other social forces that influence decision-making; and (6) a deliberative stepwise appraisal of the adolescent's decision-making process. This stepwise approach, already used among adults with psychiatric disorders, includes understanding the different facets of the given situation, reasoning on the involved issues, appreciating the outcomes linked with the decision(s), and expressing a choice. Contextual and psychosocial factors play pivotal roles in the assessment of adolescents' decision-making capacity. The evaluation must be guided by a well-established procedure, and health professionals should be trained accordingly. These proposals are the first to have been developed by a multicultural, multidisciplinary expert panel.

Estudo clínico e videofluoroscópico da disfagia na fase subaguda do acidente vascular encefálico

OBJETIVO: Correlacionar, em pacientes portadores de acidente vascular encefálico (AVE) na fase subaguda, as alterações clínicas da deglutição com as observadas na videofluoroscopia. MATERIAIS E MÉTODOS: De 37 portadores de AVE subagudo confirmado por exame de imagem, 26 pacientes de ambos os sexos, com idade média de 59,69 anos, foram avaliados clínica e videofluoroscopicamente. Consideramos como variáveis para pareamento estatístico os parâmetros clínicos indicativos de penetração/aspiração e sua confirmação na videofluoroscopia. RESULTADOS: Identificamos disfagia em 19 (73%) dos 26 pacientes que fizeram videofluoroscopia; dez (38,46%) apresentaram penetração/aspiração de líquidos. Os dados resultantes mostraram não existir correlação (p < 0,05) entre a presença de disfagia e/ou disartria e a presença de penetração/aspiração de líquidos na videofluoroscopia. Houve correlação entre a presença de penetração/aspiração de líquidos observados na videofluoroscopia com os seguintes parâmetros clínicos: estado dos dentes (p = 0,047), mobilidade (p = 0,019) e sensibilidade da face (p = 0,039) e mobilidade da língua (p = 0,012). CONCLUSÃO: Não foi possível definir a presença de penetração/aspiração de líquidos nas vias aéreas por dados epidemiológicos do AVE. A existência de mau estado de preservação dos dentes, alterações na mobilidade da face e da língua e na sensibilidade da face mostrou risco aumentado de penetração/aspiração para líquidos. Permanece importante a indicação da videofluoroscopia para melhor avaliação dos quadros de disfagia após AVE.

Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized (13)C magnetic resonance.

BACKGROUND: The heart relies on continuous energy production and imbalances herein impair cardiac function directly. The tricarboxylic acid (TCA) cycle is the primary means of energy generation in the healthy myocardium, but direct noninvasive quantification of metabolic fluxes is challenging due to the low concentration of most metabolites. Hyperpolarized (13)C magnetic resonance spectroscopy (MRS) provides the opportunity to measure cellular metabolism in real time in vivo. The aim of this work was to noninvasively measure myocardial TCA cycle flux (VTCA) in vivo within a single minute. METHODS AND RESULTS: Hyperpolarized [1-(13)C]acetate was administered at different concentrations in healthy rats. (13)C incorporation into [1-(13)C]acetylcarnitine and the TCA cycle intermediate [5-(13)C]citrate was dynamically detected in vivo with a time resolution of 3s. Different kinetic models were established and evaluated to determine the metabolic fluxes by simultaneously fitting the evolution of the (13)C labeling in acetate, acetylcarnitine, and citrate. VTCA was estimated to be 6.7±1.7μmol·g(-1)·min(-1) (dry weight), and was best estimated with a model using only the labeling in citrate and acetylcarnitine, independent of the precursor. The TCA cycle rate was not linear with the citrate-to-acetate metabolite ratio, and could thus not be quantified using a ratiometric approach. The (13)C signal evolution of citrate, i.e. citrate formation was independent of the amount of injected acetate, while the (13)C signal evolution of acetylcarnitine revealed a dose dependency with the injected acetate. The (13)C labeling of citrate did not correlate to that of acetylcarnitine, leading to the hypothesis that acetylcarnitine formation is not an indication of mitochondrial TCA cycle activity in the heart. CONCLUSIONS: Hyperpolarized [1-(13)C]acetate is a metabolic probe independent of pyruvate dehydrogenase (PDH) activity. It allows the direct estimation of VTCA in vivo, which was shown to be neither dependent on the administered acetate dose nor on the (13)C labeling of acetylcarnitine. Dynamic (13)C MRS coupled to the injection of hyperpolarized [1-(13)C]acetate can enable the measurement of metabolic changes during impaired heart function.

Risk factors, aetiology and outcome of ischaemic stroke in young adults: the Swiss Young Stroke Study (SYSS).

Ischaemic stroke (IS) in young adults has been increasingly recognized as a serious health condition. Stroke aetiology is different in young adults than in the older population. This study aimed to investigate aetiology and risk factors, and to search for predictors of outcome and recurrence in young IS patients. We conducted a prospective multicentre study of consecutive IS patients aged 16-55 years. Baseline demographic data, risk factors, stroke aetiology including systematic genetic screening for Fabry disease and severity were assessed and related to functional neurological outcome (modified Rankin Scale, mRS), case fatality, employment status, place of residence, and recurrent cerebrovascular events at 3 months. In 624 IS patients (60 % men), median age was 46 (IQR 39-51) years and median NIHSS on admission 3 (IQR 1-8). Modifiable vascular risk factors were found in 73 %. Stroke aetiology was mostly cardioembolism (32 %) and of other defined origin (24 %), including cervicocerebral artery dissection (17 %). Fabry disease was diagnosed in 2 patients (0.3 %). Aetiology remained unknown in 20 %. Outcome at 3 months was favourable (mRS 0-1) in 61 % and fatal in 2.9 %. Stroke severity (p < 0.001) and diabetes mellitus (p = 0.023) predicted unfavourable outcome. Stroke recurrence rate at 3 months was 2.7 %. Previous stroke or TIA predicted recurrent cerebrovascular events (p = 0.012). In conclusion, most young adults with IS had modifiable vascular risk factors, emphasizing the importance of prevention strategies. Outcome was unfavourable in more than a third of patients and was associated with initial stroke severity and diabetes mellitus. Previous cerebrovascular events predicted recurrent ones.

A novel set of DIP-STR markers for improved analysis of challenging DNA mixtures.

Currently available molecular biology tools allow forensic scientists to characterize DNA evidence found at crime scenes for a large variety of samples, including those of limited quantity and quality, and achieve high levels of individualization. Yet, standard forensic markers provide limited or no results when applied to mixed DNA samples where the contributors are present in very different proportions (unbalanced DNA mixtures). This becomes an issue mostly for the analysis of trace samples collected on the victim or from touched objects. To this end, we recently proposed an innovative type of genetic marker, named DIP-STR that relies on pairing deletion/insertion polymorphisms (DIP) with standard short tandem repeats (STR). This novel compound marker allows detection of the minor DNA contributor in a DNA mixture of any gender and cellular origin with unprecedented resolution (beyond a DNA ratio of 1:1000). To provide a novel analytical tool useful in practice to common forensic laboratories, this article describes the first set of 10 DIP-STR markers selected according to forensic technical standards. The novel DIP-STR regions are short (between 146 and 271 bp), include only highly polymorphic tri-, tetra- and pentanucleotide tandem repeats and are located on different chromosomes or chromosomal arms to provide statistically independent results. This novel set of DIP-STR can target the amplification of 0.03-0.1 ng of DNA when mixed with a 1000-fold excess of major DNA. DIP-STR relative allele frequencies are estimated based on a survey of 103 Swiss individuals. Finally, this study provides an estimate of the occurrence of informative alleles and a calculation of the corresponding random match probability of the detected minor DIP-STR genotype assessed across 10,506 pairwise conceptual mixtures.

Erratum of initial paper: Postmortem computed tomography angiography vs. conventional autopsy: advantages and inconveniences of each method.

PURPOSE: Postmortem computed tomography angiography (PMCTA) was introduced into forensic investigations a few years ago. It provides reliable images that can be consulted at any time. Conventional autopsy remains the reference standard for defining the cause of death, but provides only limited possibility of a second examination. This study compares these two procedures and discusses findings that can be detected exclusively using each method. MATERIALS AND METHODS: This retrospective study compared radiological reports from PMCTA to reports from conventional autopsy for 50 forensic autopsy cases. Reported findings from autopsy and PMCTA were extracted and compared to each other. PMCTA was performed using a modified heart-lung machine and the oily contrast agent Angiofil® (Fumedica AG, Muri, Switzerland). RESULTS: PMCTA and conventional autopsy would have drawn similar conclusions regarding causes of death. Nearly 60 % of all findings were visualized with both techniques. PMCTA demonstrates a higher sensitivity for identifying skeletal and vascular lesions. However, vascular occlusions due to postmortem blood clots could be falsely assumed to be vascular lesions. In contrast, conventional autopsy does not detect all bone fractures or the exact source of bleeding. Conventional autopsy provides important information about organ morphology and remains the only way to diagnose a vital vascular occlusion with certitude. CONCLUSION: Overall, PMCTA and conventional autopsy provide comparable findings. However, each technique presents advantages and disadvantages for detecting specific findings. To correctly interpret findings and clearly define the indications for PMCTA, these differences must be understood.

Spatial pattern of landslides in Swiss Rhone valley

The present study analyses the spatial pattern of quaternary gravitational slope deformations (GSD) and historical/present-day instabilities (HPI) inventoried in the Swiss Rhone Valley. The main objective is to test if these events are clustered (spatial attraction) or randomly distributed (spatial independency). Moreover, analogies with the cluster behaviour of earthquakes inventoried in the same area were examined. The Ripley's K-function was applied to measure and test for randomness. This indicator allows describing the spatial pattern of a point process at increasing distance values. To account for the non-constant intensity of the geological phenomena, a modification of the K-function for inhomogeneous point processes was adopted. The specific goal is to explore the spatial attraction (i.e. cluster behaviour) among landslide events and between gravitational slope deformations and earthquakes. To discover if the two classes of instabilities (GSD and HPI) are spatially independently distributed, the cross K-function was computed. The results show that all the geological events under study are spatially clustered at a well-defined distance range. GSD and HPI show a similar pattern distribution with clusters in the range 0.75?9 km. The cross K-function reveals an attraction between the two classes of instabilities in the range 0?4 km confirming that HPI are more prone to occur within large-scale slope deformations. The K-function computed for GSD and earthquakes indicates that both present a cluster tendency in the range 0?10 km, suggesting that earthquakes could represent a potential predisposing factor which could influence the GSD distribution.

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation.

Intestinal helminths are potent regulators of their host's immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions.

Diagnostic methods and treatment options for focal cortical dysplasia.

Our inability to adequately treat many patients with refractory epilepsy caused by focal cortical dysplasia (FCD), surgical inaccessibility and failures are significant clinical drawbacks. The targeting of physiologic features of epileptogenesis in FCD and colocalizing functionality has enhanced completeness of surgical resection, the main determinant of outcome. Electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) and magnetoencephalography are helpful in guiding electrode implantation and surgical treatment, and high-frequency oscillations help defining the extent of the epileptogenic dysplasia. Ultra high-field MRI has a role in understanding the laminar organization of the cortex, and fluorodeoxyglucose-positron emission tomography (FDG-PET) is highly sensitive for detecting FCD in MRI-negative cases. Multimodal imaging is clinically valuable, either by improving the rate of postoperative seizure freedom or by reducing postoperative deficits. However, there is no level 1 evidence that it improves outcomes. Proof for a specific effect of antiepileptic drugs (AEDs) in FCD is lacking. Pathogenic mutations recently described in mammalian target of rapamycin (mTOR) genes in FCD have yielded important insights into novel treatment options with mTOR inhibitors, which might represent an example of personalized treatment of epilepsy based on the known mechanisms of disease. The ketogenic diet (KD) has been demonstrated to be particularly effective in children with epilepsy caused by structural abnormalities, especially FCD. It attenuates epigenetic chromatin modifications, a master regulator for gene expression and functional adaptation of the cell, thereby modifying disease progression. This could imply lasting benefit of dietary manipulation. Neurostimulation techniques have produced variable clinical outcomes in FCD. In widespread dysplasias, vagus nerve stimulation (VNS) has achieved responder rates >50%; however, the efficacy of noninvasive cranial nerve stimulation modalities such as transcutaneous VNS (tVNS) and noninvasive (nVNS) requires further study. Although review of current strategies underscores the serious shortcomings of treatment-resistant cases, initial evidence from novel approaches suggests that future success is possible.