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The Northern California Current is a highly productive marine upwelling ecosystem that is economically and ecologically important. It is home to both commercially harvested species and those that are federally listed under the U.S. Endangered Species Act. Recently, there has been a global shift from single-species fisheries management to ecosystem-based fisheries management, which acknowledges that more complex dynamics can reverberate through a food web. Here, we have integrated new research into an end-to-end ecosystem model (i.e., physics to fisheries) using data from long-term ocean surveys, phytoplankton satellite imagery paired with a vertically generalized production model, a recently assembled diet database, fishery catch information, species distribution models, and existing literature. This spatially-explicit model includes 90 living and detrital functional groups ranging from phytoplankton, krill, and forage fish to salmon, seabirds, and marine mammals, and nine fisheries that occur off the coast of Washington, Oregon, and Northern California. This model was updated from previous regional models to account for more recent changes in the Northern California Current (e.g., increases in market squid and some gelatinous zooplankton such as pyrosomes and salps), to expand the previous domain to increase the spatial resolution, to include data from previously unincorporated surveys, and to add improved characterization of endangered species, such as Chinook salmon (Oncorhynchus tshawytscha) and southern resident killer whales (Orcinus orca). Our model is mass-balanced, ecologically plausible, without extinctions, and stable over 150-year simulations. Ammonium and nitrate availability, total primary production rates, and model-derived phytoplankton time series are within realistic ranges. As we move towards holistic ecosystem-based fisheries management, we must continue to openly and collaboratively integrate our disparate datasets and collective knowledge to solve the intricate problems we face. As a tool for future research, we provide the data and code to use our ecosystem model.

Cystinuria is one of various disorders that cause biomineralization in the urinary system, including bladder stone formation in humans. It is most prevalent in children and adolescents and more aggressive in males. There is no cure, and only limited disease management techniques help to solubilize the stones. Recurrence, even after treatment, occurs frequently. Other than a buildup of cystine, little is known about factors involved in the formation, expansion, and recurrence of these stones. This study sought to define the growth of bladder stones, guided by micro-computed tomography imaging, and to profile dynamic stone proteome changes in a cystinuria mouse model. After bladder stones developed in vivo, they were harvested and separated into four developmental stages (sand, small, medium and large stone), based on their size. Data-dependent and data-independent acquisitions allowed deep profiling of stone proteomics. The proteomic signatures and pathways illustrated major changes as the stones grew. Stones initiate from a small nidus, grow outward, and show major enrichment in ribosomal proteins and factors related to coagulation and platelet degranulation, suggesting a major dysregulation in specific pathways that can be targeted for new therapeutic options.

Chronic non-cancer pain is a highly prevalent health issue with personal and societal consequences. Patients suffering from chronic non-cancer pain are mainly cared for by primary care physicians, but research shows that the latter perceive treating chronic pain as difficult. This qualitative descriptive study aimed to explore how primary care physicians in Switzerland manage patients with chronic non-cancer pain and what factors influence patient management. Data were collected through semi-structured interviews amongst primary care physicians in the German speaking part of Switzerland. A thematic analysis of the interviews allowed to identify four main themes: Investigation of chronic pain; patient-provider relationship; patient characteristics, and medical recommendations. These themes were closely interconnected and influenced each other. Physicians not only enquired about the origin of pain but also about the patients' beliefs and expectations towards it. They stressed the role of communication in fostering a good patient-physician relationship and to help patients cope with their pain. In addition to purely medical considerations, the psychological, social and economic situation of their patients and their possible impacts on the management of chronic non-cancer pain played a crucial role when recommending a treatment. This study highlighted the complexity of chronic pain management, which entails that primary care physicians need to figure out a unique strategy for each patient. By integrating patients' values and beliefs, as well as socioeconomic aspects, primary care physicians are in a position to take the lead in chronic non-cancer pain management. However, considering the burden of this disease, more continuous medical education on chronic pain is needed for primary care physicians, especially to better take into account the social determinants of pain.

The Northern California Current is a highly productive marine upwelling ecosystem that is economically and ecologically important. It is home to both commercially harvested species and those that are federally listed under the U.S. Endangered Species Act. Recently, there has been a global shift from single-species fisheries management to ecosystem-based fisheries management, which acknowledges that more complex dynamics can reverberate through a food web. Here, we have integrated new research into an end-to-end ecosystem model (i.e., physics to fisheries) using data from long-term ocean surveys, phytoplankton satellite imagery paired with a vertically generalized production model, a recently assembled diet database, fishery catch information, species distribution models, and existing literature. This spatially-explicit model includes 90 living and detrital functional groups ranging from phytoplankton, krill, and forage fish to salmon, seabirds, and marine mammals, and nine fisheries that occur off the coast of Washington, Oregon, and Northern California. This model was updated from previous regional models to account for more recent changes in the Northern California Current (e.g., increases in market squid and some gelatinous zooplankton such as pyrosomes and salps), to expand the previous domain to increase the spatial resolution, to include data from previously unincorporated surveys, and to add improved characterization of endangered species, such as Chinook salmon (Oncorhynchus tshawytscha) and southern resident killer whales (Orcinus orca). Our model is mass-balanced, ecologically plausible, without extinctions, and stable over 150-year simulations. Ammonium and nitrate availability, total primary production rates, and model-derived phytoplankton time series are within realistic ranges. As we move towards holistic ecosystem-based fisheries management, we must continue to openly and collaboratively integrate our disparate datasets and collective knowledge to solve the intricate problems we face. As a tool for future research, we provide the data and code to use our ecosystem model.

Neurodegeneration is a major age-related pathology. Cognitive decline is characteristic of patients with Alzheimer's and related dementias and cancer patients after chemo- or radio-therapies. A recently emerged driver of these and other age-related pathologies is cellular senescence, a cell fate that entails a permanent cell cycle arrest and pro-inflammatory senescence-associated secretory phenotype (SASP). Although there is a link between inflammation and neurodegenerative diseases, there are many open questions regarding how cellular senescence affects neurodegenerative pathologies. Among the various cell types in the brain, astrocytes are the most abundant. Astrocytes have proliferative capacity and are essential for neuron survival. Here, we investigated the phenotype of primary human astrocytes made senescent by X-irradiation, and identified genes encoding glutamate and potassium transporters as specifically downregulated upon senescence. This down regulation led to neuronal cell death in co-culture assays. Unbiased RNA sequencing of transcripts expressed by non-senescent and senescent astrocytes confirmed that glutamate homeostasis pathway declines upon senescence. Our results suggest a key role for cellular senescence, particularly in astrocytes, in excitotoxicity, which may lead to neurodegeneration including Alzheimer's disease and related dementias.

The standard way to study Large Language Models (LLMs) through benchmarks or psychology questionnaires is to provide many different queries from similar minimal contexts (e.g. multiple choice questions). However, due to LLM's highly context-dependent nature, conclusions from such minimal-context evaluations may be little informative about the model's behavior in deployment (where it will be exposed to many new contexts). We argue that context-dependence should be studied as another dimension of LLM comparison alongside others such as cognitive abilities, knowledge, or model size. In this paper, we present a case-study about the stability of value expression over different contexts (simulated conversations on different topics), and as measured using a standard psychology questionnaire (PVQ) and behavioral downstream tasks. We consider 21 LLMs from six families. Reusing methods from psychology, we study Rank-order stability on the population (interpersonal) level, and Ipsative stability on the individual (intrapersonal) level. We explore two settings: with and without instructing LLMs to simulate particular personalities. We observe similar trends in the stability of models and model families—Mixtral, Mistral, GPT-3.5 and Qwen families being more stable than LLaMa-2 and Phi—over those two settings, two different simulated populations, and even on three downstream behavioral tasks. When instructed to simulate particular personas, LLMs exhibit low Rank-Order stability, and this stability further diminishes with conversation length. This highlights the need for future research directions on LLMs that can coherently simulate a diversity of personas, as well as how context-dependence can be studied in more thorough and efficient ways. This paper provides a foundational step in that direction, and, to our knowledge, it is the first study of value stability in LLMs. The project website with code is available at https://sites.google.com/view/llmvaluestability. [ABSTRACT FROM AUTHOR]

Chronic non-cancer pain is a highly prevalent health issue with personal and societal consequences. Patients suffering from chronic non-cancer pain are mainly cared for by primary care physicians, but research shows that the latter perceive treating chronic pain as difficult. This qualitative descriptive study aimed to explore how primary care physicians in Switzerland manage patients with chronic non-cancer pain and what factors influence patient management. Data were collected through semi-structured interviews amongst primary care physicians in the German speaking part of Switzerland. A thematic analysis of the interviews allowed to identify four main themes: Investigation of chronic pain; patient-provider relationship; patient characteristics, and medical recommendations. These themes were closely interconnected and influenced each other. Physicians not only enquired about the origin of pain but also about the patients' beliefs and expectations towards it. They stressed the role of communication in fostering a good patient-physician relationship and to help patients cope with their pain. In addition to purely medical considerations, the psychological, social and economic situation of their patients and their possible impacts on the management of chronic non-cancer pain played a crucial role when recommending a treatment. This study highlighted the complexity of chronic pain management, which entails that primary care physicians need to figure out a unique strategy for each patient. By integrating patients' values and beliefs, as well as socioeconomic aspects, primary care physicians are in a position to take the lead in chronic non-cancer pain management. However, considering the burden of this disease, more continuous medical education on chronic pain is needed for primary care physicians, especially to better take into account the social determinants of pain. [ABSTRACT FROM AUTHOR]

The identity of artists and localisation of workshops are rarely known with certainty before the mid-15th century. We investigated the material used by one of the most prolific and enigmatic medieval sculptors, the Master of the Rimini Altarpiece or Master of Rimini, active around 1420–40. The isotope fingerprints (Sr, S and O) of a representative corpus of masterpieces but also minor artworks, attributed to the Master of Rimini and his workshop, are virtually identical, demonstrating the unity of the corpus and a material evidence behind the stylistic and iconographic ascriptions. The material used is exclusively Franconian (N-Bavarian) alabaster, 600 km distant from the supposed zone of activity of the Master of Rimini workshop according to recent literature. The same material was later used by the prominent Late Medieval German carver Tilman Riemenschneider, active in Würzburg after 1483, whose small corpus of alabaster sculptures we have been able to characterize almost entirely. Based on these findings, we propose here an alternative to the prevailing hypothesis of a Flemish or N-French workshop being founded on similarities of the Rimini sculpture with motives in Flemish and French painting. Our scenario, returning to the initial proposal of a German localisation of the Master of Rimini workshop, assumes the migration of an artist, perhaps trained in the Low Countries or strongly inspired by the Flemish art, to Southern Germany where he founded a highly productive export workshop, well situated on the crossroads of medieval trade, with a pan-European radiance. This study sheds a spotlight on the on the trade networks of luxury goods, the raw material used for their production, and the high-end art market in Europe as well as on international migration of artists and styles, at the eve of the Renaissance.

AimsGlomerular damage indicated by proteinuria is a main symptom in diabetic nephropathy. Mineralocorticoid receptor (MR) antagonists (MRAs) are beneficial irrespective of aldosterone availability. Thus, we hypothesized an alternatively activated MR to promote glomerular damage in proteinuric diabetic nephropathy. Specifically, we aimed first to demonstrate the presence of steroid hormones serving as alternative MR targets in type II diabetic patients with proteinuric kidney disease, second whether MR selectivity was modified, third to characterize MR and glucocorticoid receptor (GR) expression and activity in glomerular cell types exposed to eu- and hyperglycemic conditions, fourth to characterize the pro-fibrotic potential of primary human renal mesangial cells (HRMC) upon stimulation with aldosterone and cortisol, and fifth to specify the involvement of the MR and/or GR in pro-fibrotic signaling.Materials and methodsUrinary steroid hormone profiles of patients with diabetic kidney disease were analyzed by gas chromatography-mass spectrometry and compared to an age and gender matched healthy control group taken out of a population study. In both cohorts, the activity of the MR pre-receptor enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2), which inactivates cortisol to prevent it from binding to the MR, was assessed to define a change in MR selectivity. Expression of HSD11B2, MR and GR was quantified in HRMC and primary human renal glomerular endothelial cells (HRGEC). Activity of MR and GR was explored in HRMC by measuring the MR/GR down-stream signal SGK1 and the pro-fibrotic genes TGFB1, FN1 and COL1A1 in normal and high glucose conditions with the MR/GR agonists aldosterone/cortisol and the MR/GR antagonists spironolactone/RU486.ResultsPatients with diabetic kidney disease excreted more tetrahydroaldosterone than the control group reaching significance in men. The excretion of MR-agonistic steroid hormones was only increased for 18-hydroxytetrahydrocorticosterone in diabetic women. The excretion of most glucocorticoids was higher in the diabetic cohort. Higher apparent systemic HSD11B2 activity suggested less activation of the MR by cortisol in diabetic patients. Both cell types, HRMC and HRGEC, lacked expression of HSD11B2. Hyperglycemic conditions did not change MR and GR expression and activity. Stimulation with both aldosterone and cortisol promoted upregulation of pro-fibrotic genes in HRMC. This effect of MR and/or GR activation was more pronounced in high glucose conditions and partially inhibited by MRAs and GR antagonists.ConclusionsIn patients with diabetic kidney disease alternative MR activation is conceivable as cortisol and cortisone metabolites are increased. Systemic availability of active metabolites is counteracted via an increased HSD11B2 activity. As this cortisol deactivation is absent in HRMC and HRGEC, cortisol binding to the MR is enabled. Both, cortisol and aldosterone stimulation led to an increased expression of pro-fibrotic genes in HRMC. This mechanism was related to the MR as well as the GR and more marked in high glucose conditions linking the benefit of MRAs in diabetic kidney disease to these findings.

ObjectivesTo determine the prevalence of use of complementary medicine (CM) in Switzerland in 2017, its development since the 2012 Swiss Health Survey, and to examine specific and non-specific sociodemographic, lifestyle and health-related determinants of CM use as compared to determinants of conventional health care use.Materials and methodsWe used data of 18,832 participants from the cross-sectional Swiss Health Survey conducted by the Swiss Federal Statistical Office in 2017 and compared these data with those from 2012. We defined four CM categories: (1) traditional Chinese medicine, including acupuncture; (2) homeopathy; (3) herbal medicine; (4) other CM therapies (shiatsu, reflexology, osteopathy, Ayurveda, naturopathy, kinesiology, Feldenkrais, autogenic training, neural therapy, bioresonance therapy, anthroposophic medicine). Independent determinants of CM use and of conventional health care use were assessed using multivariate weighted logistic regression models.ResultsPrevalence of CM use significantly increased between 2012 and 2017 from 24.7% (95% CI: 23.9-25.4%) to 28.9% (95% CI: 28.1-29.7%), respectively, pConclusionPrevalence of CM use significantly increased in Switzerland from 2012 to 2017. Gender, nationality, age, lifestyle and BMI were independent specific determinants of CM use as compared to conventional health care use. Healthier lifestyle was associated with CM use, which may have potentially significant implications for public health and preventive medicine initiatives. The nationality of CM users underlines the role of culture in driving the choice to use CM but also raises the question of whether all populations have equal access to CM within a same country.

The COVID-19 outbreak has generated significant uncertainty about the future, especially for young adults. Health and economic threats, as well as more diffuse concerns about the consequences of COVID-19, can trigger feelings of anxiety, leading individuals to adopt uncertainty-reducing behaviours. We tested whether anxiety was associated with an increase in willingness to be exposed to the risk of COVID-19 infection (WiRE) using an online survey administered to 3,110 French individuals aged between 18 and 35 years old during the first pandemic wave and lockdown period (April 2020). Overall, 56.5% of the sample declared a positive WiRE. A one standard deviation increase in psychological state anxiety raised the WiRE by +3.9 pp (95% CI [+1.6, 6.2]). Unemployment was associated with a higher WiRE (+8.2 percentage points (pp); 95% CI [+0.9, 15.4]). One standard deviation increases in perceived hospitalisation risk and in income (+1160€) were associated with a -4.1 pp (95% CI [-6.2, 2.1]) decrease in the WiRE and +2.7 pp increase (95% CI [+1.1, 4.4]), respectively. Overall, our results suggest that both psychological anxiety and the prospect of economic losses can undermine young adults’ adherence to physical distancing recommendations. Public policies targeting young adults must consider both their economic situation and their mental health, and they must use uncertainty-reducing communication strategies.

Cystinuria is one of various disorders that cause biomineralization in the urinary system, including bladder stone formation in humans. It is most prevalent in children and adolescents and more aggressive in males. There is no cure, and only limited disease management techniques help to solubilize the stones. Recurrence, even after treatment, occurs frequently. Other than a buildup of cystine, little is known about factors involved in the formation, expansion, and recurrence of these stones. This study sought to define the growth of bladder stones, guided by micro-computed tomography imaging, and to profile dynamic stone proteome changes in a cystinuria mouse model. After bladder stones developed in vivo, they were harvested and separated into four developmental stages (sand, small, medium and large stone), based on their size. Data-dependent and data-independent acquisitions allowed deep profiling of stone proteomics. The proteomic signatures and pathways illustrated major changes as the stones grew. Stones initiate from a small nidus, grow outward, and show major enrichment in ribosomal proteins and factors related to coagulation and platelet degranulation, suggesting a major dysregulation in specific pathways that can be targeted for new therapeutic options.

BackgroundData on microcirculatory pattern of COVID-19 critically ill patients are scarce. The objective was to compare sublingual microcirculation parameters of critically ill patients according to the severity of the disease.MethodsThe study is a single-center prospective study with critically ill COVID-19 patients admitted in ICU. Sublingual microcirculation was assessed by IDF microscopy within 48 hours of ICU admission. Microcirculatory flow index (MFI), proportion of perfused vessel (PPV), total vessel density (TVD), De Backer score (DBS), perfused vessel density (PVD) and heterogeneity index (HI) were assessed. Patients were divided in 2 groups (severe and critical) according to the World health organization definition.FindingsFrom 19th of March to 7th of April 2020, 43 patients were included. Fourteen patients (33%) were in the severe group and twenty-nine patients (67%) in the critical group. Patients in the critical group were all mechanically ventilated. The critical group had significantly higher values of MFI, DBS and PVD in comparison to severe group (respectively, PaCO2: 49 [44-45] vs 36 [33-37] mmHg; pConclusionCritical COVID-19 patients under mechanical ventilation seem to have higher red blood cell velocity than severe non-ventilated patients.

[This corrects the article DOI: 10.1371/journal.pone.0214549.].

In France, social distancing measures have been adopted to contain the spread of COVID-19, culminating in national Lockdowns. The use of hand washing, hydro-alcoholic rubs and mask-wearing also increased over time. As these measures are likely to impact the transmission of many communicable diseases, we studied the changes in common infectious diseases incidence in France during the first year of COVID-19 circulation. We examined the weekly incidence of acute gastroenteritis, chickenpox, acute respiratory infections and bronchiolitis reported in general practitioner networks since January 2016. We obtained search engine query volume for French terms related to these diseases and sales data for relevant drugs over the same period. A periodic regression model was fit to disease incidence, drug sales and search query volume before the COVID-19 period and extrapolated afterwards. We compared the expected values with observations made in 2020. During the first lockdown period, incidence dropped by 67% for gastroenteritis, by 79% for bronchiolitis, by 49% for acute respiratory infection and 90% for chickenpox compared to the past years. Reductions with respect to the expected incidence reflected the strength of implemented measures. Incidence in children was impacted the most. Reduction in primary care consultations dropped during a short period at the beginning of the first lockdown period but remained more than 95% of the expected value afterwards. In primary care, the large decrease in reported gastroenteritis, chickenpox or bronchiolitis observed during the period where many barrier measures were implemented imply that the circulation of common viruses was reduced and informs on the overall effect of these measures.

ObjectiveDiagnostic ratios calculated from urinary steroid hormone metabolites are used as a measure for the relative activity of steroidogenic enzymes or pathways in the clinical investigation of steroid metabolism disorders. However, population-based sex- and age-specific reference intervals and day-night differences in adults are lacking.MethodsSixty-five diagnostic ratios were calculated from steroid metabolites measured by GC-MS in day- and night-time and in 24-hour urine from 1128 adults recruited within the Swiss Kidney Project on Genes in Hypertension (SKIPOGH), a population-based, multicenter cohort study. Differences related to sex, age and day- and night-time were evaluated and reference curves in function of age and sex were modelled by multivariable linear mixed regression for diagnostic ratios and were compared to values from the literature.ResultsMost ratios had sex- and age-specific relationships. For each ratio, percentiles were plotted in function of age and sex in order to create reference curves and sex- and age-specific reference intervals derived from 2.5th and 97.5th percentiles were obtained. Most ratios reflected a higher enzyme activity during the day compared to the night.ConclusionsSex- and age-specific references for 24 hours, day and night urine steroid metabolite ratios may help distinguishing between health and disease when investigating human disorders affecting steroid synthesis and metabolism. The day-night differences observed for most of the diagnostic ratios suggest a circadian rhythm for enzymes involved in human steroid hormones metabolism.

Spheroids encapsulated within alginate capsules are emerging as suitable in vitro tools to investigate the impact of mechanical forces on tumor growth since the internal tumor pressure can be retrieved from the deformation of the capsule. Here we focus on the particular case of Cellular Capsule Technology (CCT). We show in this contribution that a modeling approach accounting for the triphasic nature of the spheroid (extracellular matrix, tumor cells and interstitial fluid) offers a new perspective of analysis revealing that the pressure retrieved experimentally cannot be interpreted as a direct picture of the pressure sustained by the tumor cells and, as such, cannot therefore be used to quantify the critical pressure which induces stress-induced phenotype switch in tumor cells. The proposed multiphase reactive poro-mechanical model was cross-validated. Parameter sensitivity analyses on the digital twin revealed that the main parameters determining the encapsulated growth configuration are different from those driving growth in free condition, confirming that radically different phenomena are at play. Results reported in this contribution support the idea that multiphase reactive poro-mechanics is an exceptional theoretical framework to attain an in-depth understanding of CCT experiments, to confirm their hypotheses and to further improve their design.

BACKGROUND:The transmembrane receptor tyrosine kinase HER2 is overexpressed in approximately 15% of breast tumors and correlates with poor clinical prognosis. Several treatments that target HER2 are approved for treatment of HER2-positive metastatic breast cancer. The serum biomarkers most widely used to monitor anti-HER2 therapies in patients with HER2-positive metastatic breast cancer currently are CA15.3 and CEA. Nevertheless, their clinical utility in patients with breast cancer remains a subject of discussion and controversy; thus, additional markers may prove useful in monitoring the therapeutic responses of these patients. The extracellular domain of HER2 can be shed by proteolytic cleavage into the circulation and this shed form, sHER2, is reported to be augmented during metastasis of HER2-positive breast tumors. Here, we studied the clinical usefulness of sHER2, CA15.3, and CEA for monitoring treatment for breast cancer. METHODS:We measured prospectively pretreatment and post-treatment serum levels (day 1, 30, 60 and 90) of these three biomarkers in 47 HER2-positive, metastatic breast cancer patients treated with trastuzumab in combination with paclitaxel. Evaluation of the disease was performed according to the Response Evaluation Criteria in Solid Tumor (RECIST) at day 90. RESULTS:Patients with progressive disease at day 90 had smaller relative changes between day 1 and day 30 than those with complete, partial or stable responses at day 90: -9% versus -38% for sHER2 (P = 0.02), +23% versus -17% for CA15.3 (P = 0.005) and +29% versus -26% for CEA (P = 0.02). Patients with progressive disease at day 90 were less likely than the other patients to have a relative decrease of > 20% in their biomarker levels at day 30: 6% vs 33% for sHER2 (P = 0.03), 0% vs 27% for CA15.3 (P = 0.03), 4% vs 29% for CEA (P = 0.04). No patient with progressive disease at day 90 had > 20% reduction of the average combined biomarker levels at day 30 whereas 63% of the other patients had (P = 0.003). Moreover, when we analyzed a > 10% reduction of the average biomarker levels no patient with progressive disease at day 90 had a decrease > 10% at day 30 whereas 78% of other patients had (P 10% appears to be the best parameter to distinguish patients who go on to have progressive disease from those who will have a complete, partial or stable response.

BACKGROUND:Osteopathy is commonly used for spinal pain, but knowledge about back pain management by osteopaths is scarce. OBJECTIVE:The aim of this study was to survey osteopaths across the French-speaking part of Switzerland about the scope of their practice and their management of patients with back pain. DESIGN:This cross-sectional observational study was based on an online survey conducted from March to June 2017. Setting and participants: All registered osteopaths of the French-speaking part of Switzerland were asked to complete the survey. Outcome measures: In addition to descriptive statistics (practice characteristics, patients' profiles, scope of treatment modalities, health promotion, research, and osteopathic practice), we explored variables associated with osteopaths' practice, such as age and gender. RESULTS:A total of 241 osteopaths completed the questionnaire (response rate: 28.8%). Almost two thirds of osteopaths were female. Ages ranged from 25 to 72 years with an overall mean of 42.0 (SD 10.7) years. Male osteopaths reported more weekly working hours than female osteopaths did (38.2 [SD 11.0] vs 31.6 [SD 8.9], respectively, p

Monitoring of cyanobacteria in freshwater ecosystems is a complex task, which is time consuming and expensive due to the chaotic population dynamics and highly heterogeneous distribution of cyanobacteria populations in water bodies. The financial cost constitutes a strong limitation for the implementation of long-term monitoring programs in developing countries, particularly in Africa. The work presented here was performed in the framework of an international project addressing the sustainable monitoring and management of surface water resources used for the production of drinking water in three African countries. We tested the potential of a citizen approach for monitoring cyanobacterial blooms, which are a growing threat to the drinking water supply. This pilot study was designed, implemented and evaluated in close interaction with the Pasteur Institute of the Ivory Coast and with the populations of three villages located on the shoreline of a freshwater lagoon located near Abidjan city. Based on the use of a smartphone application, the citizens of the three villages were invited to report water color changes, as these changes could reflect cyanobacteria proliferations. A two-year experimentation period has shown that it is possible to mobilize the local populations to monitor cyanobacterial blooms. The data collected by citizens were consistent with the data obtained by a classical monitoring of cyanobacteria performed over seven months, but it appeared that new approaches were needed to validate the citizen data. This participatory approach also provided great improvements to the understanding and awareness of local populations regarding water quality and cyanobacterial bloom issues. Finally, we discuss some of the difficulties and limitations of our participatory monitoring approach that should be considered by further implementations. Despite these difficulties, our work suggests that citizen monitoring is a promising approach that may complement the classical approach to sustainable monitoring of cyanobacteria in developing countries.

BackgroundChronic subclinical hemolysis is frequent in patients implanted with Left Ventricular Assist Device (LVAD) and is associated with adverse outcomes. Consequences of LVADs-induced subclinical hemolysis on kidney structure and function is currently unknown.MethodsThirty-three patients implanted with a Heartmate II LVAD (Abbott, Inc, Chicago IL) were retrospectively studied. Hemolysis, Acute Kidney Injury (AKI) and the evolution of estimated Glomerular Filtration Rate were analyzed. Proximal Tubulopathy (PT) groups were defined according to proteinuria, normoglycemic glycosuria, and electrolytic disorders. The Receiver Operating Characteristic (ROC) curve was used to analyze threshold of LDH values associated with PT.ResultsMedian LDH between PT groups were statistically different, 688 IU/L [642-703] and 356 IU/L [320-494] in the "PT" and "no PT" groups, respectively p = 0.006. To determine PT group, LDH threshold > 600 IU/L was associated with a sensitivity of 85.7% (95% CI, 42.1-99.6) and a specificity of 84.6% (95% CI, 65.1-95.6). The ROC's Area Under Curve was 0.83 (95% CI, 0.68-0.98). In the "PT" group, patients had 4.2 [2.5-5.0] AKI episodes per year of exposure, versus 1.6 [0.4-3.7] in the "no PT" group, p = 0.03. A higher occurrence of AKI was associated with subsequent development of Chronic Kidney Disease (CKD) (p = 0.02) and death (p = 0.05).ConclusionsLVADs-induced subclinical hemolysis is associated with proximal tubular functional alterations, which in turn contribute to the occurrence of AKI and subsequent CKD. Owing to renal toxicity of hemolysis, measures to reduce subclinical hemolysis intensity as canula position or pump parameters should be systematically considered, as well as specific nephroprotective therapies.

Neurodegeneration is a major age-related pathology. Cognitive decline is characteristic of patients with Alzheimer's and related dementias and cancer patients after chemo- or radio-therapies. A recently emerged driver of these and other age-related pathologies is cellular senescence, a cell fate that entails a permanent cell cycle arrest and pro-inflammatory senescence-associated secretory phenotype (SASP). Although there is a link between inflammation and neurodegenerative diseases, there are many open questions regarding how cellular senescence affects neurodegenerative pathologies. Among the various cell types in the brain, astrocytes are the most abundant. Astrocytes have proliferative capacity and are essential for neuron survival. Here, we investigated the phenotype of primary human astrocytes made senescent by X-irradiation, and identified genes encoding glutamate and potassium transporters as specifically downregulated upon senescence. This down regulation led to neuronal cell death in co-culture assays. Unbiased RNA sequencing of transcripts expressed by non-senescent and senescent astrocytes confirmed that glutamate homeostasis pathway declines upon senescence. Our results suggest a key role for cellular senescence, particularly in astrocytes, in excitotoxicity, which may lead to neurodegeneration including Alzheimer's disease and related dementias.

ObjectivesIn a previous analysis of a post-myocardial infarction (MI) cohort, abnormally high systemic vascular resistances (SVR) were shown to be frequently revealed by MRI during the healing period, independently of MI severity, giving evidence of vascular dysfunction and limiting further recovery of cardiac function. The present ancillary and exploratory analysis of the same cohort was aimed at characterizing those patients suffering from high SVR remotely from MI with a large a panel of cardiovascular MRI parameters and blood biomarkers.MethodsMRI and blood sampling were performed 2-4 days after a reperfused MI and 6 months thereafter in 121 patients. SVR were monitored with a phase-contrast MRI sequence and patients with abnormally high SVR at 6-months were characterized through MRI parameters and blood biomarkers, including Galectin-3, an indicator of cardiovascular inflammation and fibrosis after MI. SVR were normal at 6-months in 90 patients (SVR-) and abnormally high in 31 among whom 21 already had high SVR at the acute phase (SVR++) while 10 did not (SVR+).ResultsWhen compared with SVR-, both SVR+ and SVR++ exhibited lower recovery in cardiac function from baseline to 6-months, while baseline levels of Galectin-3 were significantly different in both SVR+ (median: 14.4 (interquartile range: 12.3-16.7) ng.mL-1) and SVR++ (13.0 (11.7-19.4) ng.mL-1) compared to SVR- (11.7 (9.8-13.5) ng.mL-1, both p < 0.05). Plasma Galectin-3 was an independent baseline predictor of high SVR at 6-months (p = 0.002), together with the baseline levels of SVR and left ventricular end-diastolic volume, whereas indices of MI severity and left ventricular function were not. In conclusion, plasma Galectin-3 predicts a deleterious vascular dysfunction affecting post-MI patients, an observation that could lead to consider new therapeutic targets if confirmed through dedicated prospective studies.

AIM:Characterizing tumor heterogeneity with textural indices extracted from 18F-fluorodeoxyglucose positron emission tomography (FDG PET/CT) is of growing interest in oncology. Several series showed promising results to predict survival in patients with head and neck squamous cell carcinoma (HNSCC), analyzing various tumor segmentation methods and textural indices. This preliminary study aimed at assessing the inter-observer and inter-segmentation method variability of textural indices in HNSCC pre-therapeutic FDG PET/CT. MATERIALS AND METHODS:Consecutive patients with HNSCC referred in our department for a pre-therapeutic FDG PET/CT from January to March 2016 were retrospectively included. Two nuclear medicine physicians separately segmented all tumors using 3 different segmentation methods: a relative standardized uptake value (SUV) threshold (40%SUVmax), a signal-to-noise adaptive SUV threshold (DAISNE) and an image gradient-based method (PET-EDGE). SUV and metabolic tumor volume were recorded. Thirty-one textural indices were calculated using LIFEx software (www.lifexsoft.org). After correlation analysis, selected indices' inter-segmentation method and inter-observer variability were calculated. RESULTS:Forty-three patients (mean age 63.8±9.3y) were analyzed. Due to a too small segmented tumor volume of interest, textural analysis could not be performed in 6, 11 and 15 cases with respectively DAISNE, 40%SUVmax and PET-EDGE segmentation methods. Five independent textural indices were selected (Homogeneity, Correlation, Entropy, Busyness and LZLGE). There was a high inter-contouring method variability for Homogeneity, Correlation, Entropy and LZLGE (p

Side effects are frequent in pharmacological pain management, potentially preceding analgesia and limiting drug tolerability. Discussing side effects is part of informed consent, yet can favor nocebo effects. This study aimed to test whether a positive suggestion regarding side effects, which could act as reminders of the medication having been absorbed, might favor analgesia in a clinical interaction model. Sixty-six healthy males participated in a study "to validate pupillometry as an objective measure of analgesia". Participants were unknowingly randomized double-blind to positive vs control information about side effects embedded in a video regarding the study drugs. Sequences of moderately painful heat stimuli applied before and after treatment with diclofenac and atropine served to evaluate analgesia. Atropine was deceptively presented as a co-analgesic, but used to induce side effects. Adverse events (AE) were collected with the General Assessment of Side Effects (GASE) questionnaire prior to the second induced pain sequence. Debriefing fully informed participants regarding the purpose of the study and showed them the two videos.The combination of medication led to significant analgesia, without a between-group difference. Positive information about side effects increased the attribution of AE to the treatment compared to the control information. The total GASE score was correlated with analgesia, i.e., the more AEs reported, the stronger the analgesia. Interestingly, there was a significant between-groups difference on this correlation: the GASE score and analgesia correlated only in the positive information group. This provides evidence for a selective link between AEs and pain relief in the group who received the suggestion that AEs could be taken as a sign "that help was on the way". During debriefing, 65% of participants said they would prefer to receive the positive message in a clinical context. Although the present results cannot be translated immediately to clinical pain conditions, they do indicate the importance of testing this type of modulation in a clinical context.

The purpose of this study was to quantitatively assess gait characteristics and weight-bearing forces during ambulation in goats free of lameness using a pressure-sensing walkway as a biometric tool for stride, gait, and force analysis. Forty-six non-lame adult goats ranging in age from 5 to 6 years, mixed-breeds, and with a mean body weight of 52 ± 7.1 kgs were used. Goats were trained to walk over a pressure-sensing walkway. Data for analysis was collected on 2 different days, 3 days apart. On each day, 2 to 5 walking passes, in the same direction, were captured for each goat. Data from 2 valid passes meeting the criteria for consistent walking gait on each day were averaged then used for analysis. Analysis was performed, including the day-effect, for stride, gait, and force characteristics. Of the 46 goats enrolled in the study, complete data sets were achieved in 33 (72%) goats. Gait biometrics were similar among the assessment days; therefore, all data was pooled for the purpose of characterizing data for individual limb and biometric parameter comparisons at the individual goat level. Statistical analysis revealed that no difference within the paired limbs, and that there were significant differences between the front limbs and hind limbs. Maximum force and maximum peak pressure were significantly greater for the front limbs as compared with the hind limbs (p < 0.001). Based on the results, gait and force characteristics can be consistently measured in goats using a pressure-sensing walkway during a consistent walking gait. Goats apply greater force to the forelimbs during the weight-bearing phase of stride as compared with the hind limbs. The use of objective assessment tools is expected to improve the ability of researchers and clinicians to monitor changes in weight bearing and gait and will contribute to improved animal welfare.

OBJECTIVE:More than 27,000 complementary medicine (CM) therapists are registered in Switzerland, but limited data are available on their occupational profile and role in the healthcare system. Herein we aimed to gain a better understanding of the professional profile of non-physician licensed therapists, focusing on acupuncture, osteopathy, and European naturopathy. DESIGN:This cross-sectional study was based on an online anonymous survey conducted from March to June 2017. SETTING AND PARTICIPANTS:All 1549 non-physician registered osteopaths, acupuncturists, and naturopaths in the French-speaking part of Switzerland were asked to complete the survey. MAIN OUTCOME MEASURES:We measured the therapists' demographics, training and practice characteristics, and workload. RESULTS:A total of 426 therapists returned the questionnaire (response rate: 27.5%). The mean age of the respondents was 46.0 years (SD 11.6) and most were women (67.8%). CM represented the main professional activity for a majority of therapists (82.8%), most of whom were independent (86.3%). The length and number of consultations per month varied across professions. Multivariate analysis showed that acupuncturists and naturopaths performed significantly fewer consults per month than osteopaths did. However, consultation length was significantly longer for acupuncturists and naturopaths than for osteopaths. Acupuncturists (71.6%) and naturopaths (64.4%) were significantly more favorable than osteopaths (27.7%) to have consultation costs covered by basic health insurance. Professional profiles differed between osteopaths, on the one hand, and naturopaths and acupuncturists, on the other, mainly regarding workload, treatment duration, and main reasons to consult. CONCLUSIONS:This first study to investigate a variety of therapist profiles in Switzerland provides useful information about their activities and role within the Swiss healthcare system. Although all three professions are encompassed under the same umbrella term (CM), our study showed that they have specific work cultures and areas of intervention in the healthcare system.

BACKGROUND:Few studies have examined the consumption trajectories of inmates after entry to prison. The aim of this study was to assess the changes in the consumption of psychoactive substance between the period before detention and during incarceration and to characterize the profiles of prisoners with similar consumption trajectories during incarceration. METHODS AND FINDINGS:A multicenter, cross-sectional study was performed in all of the prisons from one region of France. All prisoners incarcerated during their 3rd months, over 18 years old, and with a sufficient level of French fluency to participate in the study were recruited over a period of 12 months. A total of 800 prisoners were recruited. All prisoners were interviewed face-to-face by a trained interviewer. A majority of prisoners had used at least one psychoactive substance in the weeks prior to incarceration. During incarceration, a substantial reduction in alcohol and illicit drug consumption was observed. The initiation of consumption and an increase in consumption were primarily related to medications. Five different profiles of consumption before incarceration were identified. These profiles all had a high probability of migrating to a similar profile during detention, characterized by less severe consumption of psychoactive substances. CONCLUSIONS:Based on their consumption profile prior to incarceration, most prisoners would benefit from a specific medical evaluation as soon as possible following entry into detention. Prison could be an opportunity for reduced consumption and/or the initiation of treatment for the majority of prisoners, despite the pejorative development observed for a minority of prisoners during incarceration.

BACKGROUND:To investigate the ongoing controversy on the effect of BMI (body mass index) on EOP (early onset preeclampsia) vs LOP (late onset), especially focusing on diabetes and maternal booking/pre-pregnancy BMI as possible independent variables. METHODS:18 year-observational cohort study (2001-2018). The study population consisted of all consecutive births delivered at the Centre Hospitalier Universitaire Hospitalier Sud Reunion's maternity (ap. 4,300 birth per year, only level 3 maternity in the south of Reunion Island, sole allowed to follow and deliver all preeclampsia cases of the area). History of pregnancies, deliveries and neonatal outcomes have been collected in standardized fashion into an epidemiological perinatal data base. RESULTS:Chronic hypertension and, history of preeclampsia in multigravidas, were the strongest risk factors for EOP. Primiparity, age over 35 years and BMI ≥ 35 kg/m² were rather associated with LOP. In a multivariate analysis with EOP or LOP as outcome variables compared with controls (normotensive), maternal age and pre-pregnancy BMI were independent risk factors for both EOP and LOP (p < 0.001). However, analyzing by increment of 5 (years of age, kg/m² for BMI) rising maternal ages and incidence of preeclampsia were strictly parallel for EOP and LOP, while increment of BMI was only associated with LOP. Controlling for maternal ages and booking/pre-pregnancy BMI, diabetes was not an independent risk factor neither for EOP or LOP. CONCLUSIONS:Metabolic factors, other than diabetes, associated with pre-pregnancy maternal corpulence are specifically associated with LOP. This may be a direction for future researches on the maternal preeclamptic syndrome. This may explain the discrepancy we are facing nowadays where high-income countries report 90% of their preeclampsia being LOP, while it is only 60-70% in medium-low income countries.

IntroductionTo evaluate the consequences of bronchopulmonary dysplasia (BPD) on academic outcomes and healthcare use in adolescents born very preterm.MethodsThis cohort study included 15-year-old adolescents born very preterm (< 32 weeks) between 2011 and 2013, with and without BPD, and controls born full term. Data regarding academic performance, current medical follow-up, and family characteristics were collected. Multivariate logistic regression was used to quantify relationships between academic outcomes and BPD.ResultsFrom the 1341 children included in the initial cohort, 985 adolescents were eligible and 351 included (55 preterms with a history of BPD, 249 without, and 47 controls). Among adolescents born very preterm, a history of BPD was associated with a higher risk to attend a school for children with special needs (p < 0.05) and to have repeated a grade (p = 0.01). It was also associated with an increased number of medical and paramedical consultations. A history of BPD was not associated with the parents' employment status, family structure, or the presence of younger siblings.ConclusionThis study highlights that a history of BPD is associated with poorer academic outcomes and high healthcare use in adolescence.

ObjectivesTo assess premedication practices before tracheal intubation of premature newborns in the delivery room (DR).Study designFrom the national population-based prospective EPIPAGE 2 cohort in 2011, we extracted all live born preterms intubated in the DR in level-3 centers, without subsequent circulatory resuscitation. Studied outcomes included the rate and type of premedication, infants' and maternities' characteristics and survival and major neonatal morbidities at discharge from hospital. Univariate and multivariate analysis were performed and a generalized estimating equation was used to identify factors associated with premedication use.ResultsOut of 1494 included neonates born in 65 maternities, 76 (5.1%) received a premedication. Midazolam was the most used drug accounting for 49% of the nine drugs regimens observed. Premedicated, as compared to non premedicated neonates, had a higher median [IQR] gestational age (30 [28-31] vs 28 [27-30] weeks, pConclusionPremedication rate before tracheal intubation was only 5.1% in the DR of level-3 maternities for premature neonates below 34 weeks of gestation in France in 2011 and seemed to be mainly associated with centers' local policies.

ObjectiveTo determine whether there is an association between severe intraventricular hemorrhage and early extubation in preterm infants born before 29 weeks of gestational age and intubated at birth.MethodsThis study included 1587 preterm infants from a nationwide French population cohort (EPIPAGE-2). Secondary data on intubated preterm infants were analyzed. After gestational age and propensity score matching (1:1) we built two comparable groups: an early extubation group and a delayed extubation group. Each neonate in one group was paired with a neonate in the other group having the same propensity score and gestational age. Early extubation was defined as extubation within 48 hours of life. Severe intraventricular hemorrhages were defined as grade III or IV hemorrhages according to the Papile classification.ResultsAfter matching, there were 398 neonates in each group. Using a generalized estimating equation model, we found that intraventricular hemorrhage was not associated with early extubation (adjusted OR 0.9, 95%CI 0.6-1.4). This result was supported by sensitivity analyses.ConclusionThe practice of early extubation was not associated with an increased proportion of intraventricular hemorrhages. To complete these results, the long-term neurologic outcomes of these infants need to be assessed.

ObjectiveUrinary steroid metabolomics by GC-MS is an established method in both clinical and research settings to describe steroidogenic disorders. However, population-based reference intervals for adults do not exist.MethodsWe measured daytime and night time urinary excretion of 40 steroid metabolites by GC-MS in 1128 adult participants of European ancestry, aged 18 to 90 years, within a large population-based, multicentric, cross-sectional study. Age and sex-related patterns in adjacent daytime and night time urine collections over 24 hours were modelled for each steroid metabolite by multivariable linear mixed regression. We compared our results with those obtained through a systematic literature review on reference intervals of urinary steroid excretion.ResultsFlexible models were created for all urinary steroid metabolites thereby estimating sex- and age-related changes of the urinary steroid metabolome. Most urinary steroid metabolites showed an age-dependence with the exception of 6β-OH-cortisol, 18-OH-cortisol, and β-cortol. Reference intervals for all metabolites excreted during 24 hours were derived from the 2.5th and 97.5th percentile of modelled reference curves. The excretion rate per period of metabolites predominantly derived from the adrenals was mainly higher during the day than at night and the correlation between day and night time metabolite excretion was highly positive for most androgens and moderately positive for glucocorticoids.ConclusionsThis study gives unprecedented new insights into sex- and age-specificity of the human adult steroid metabolome and provides further information on the day/night variation of urinary steroid hormone excretion. The population-based reference ranges for 40 GC-MS-measured metabolites will facilitate the interpretation of steroid profiles in clinical practice.

Small series have suggested that Fluorodesoxyglucose Positron-Emission-Tomography with Computed-Tomography (FDG-PET/CT) is feasible to screen for cancer in patients with unprovoked venous thromboembolism (VTE), but without validation in a large population. The aim was to assess diagnostic accuracy indices of FDG-PET/CT for occult cancer diagnosis in patients with unprovoked VTE.We analysed patients from the FDG-PET/CT group of a randomized trial that compared a screening strategy based on FDG-PET/CT with a limited screening strategy for occult malignancy detection in patients with unprovoked VTE. FDG-PET/CT was interpreted as positive for cancer, as negative or as equivocal. Patients were considered as having cancer on the basis of screening results, or of any test performed during a two-years follow-up period. We ran two sets of analysis, considering patients with equivocal FDG-PET/CT as positive, then as negative for malignancy.Between March 2009, and August 2012, 172 patients were included. FDG-PET/CT was interpreted as positive for malignancy in 10 patients (5.8%), as equivocal in 23 patients (13.4%) and as negative in 139 patients (80.8%). Malignancy was diagnosed in 7/10 (70.0%), 2/23 (8.7%) and 1/139 (0.7%) patients, respectively. Grouping positive and equivocal results, sensitivity and specificity were 90% (95%CI 60% to 98%) and 85% (95%CI 79% to 90%), respectively. Grouping negative and equivocal results, sensitivity and specificity were 70% (95%CI 40% to 89%) and 98% (95%CI 95% to 99%), respectively.FDG-PET/CT showed good accuracy for occult cancer screening in patients with unprovoked VTE. Remaining challenges include the need to define specific interpretation criteria in this dedicated population.

OBJECTIVE:Recent guidelines for chronic or recurrent low back pain recommend non-pharmacologic treatments as first-line options. The objective of this study was thus to explore the perceived usefulness of several conventional and complementary medicine treatments for chronic or recurrent low back pain by primary care physicians and their reported prescribing behavior. DESIGN:An exploratory cross-sectional study. SETTING AND PARTICIPANTS:Primary care physicians of the French-speaking part of Switzerland. MAIN OUTCOME MEASURES:Primary care physicians' perceived usefulness of each conventional and complementary medicine treatment and their reported recommendation behavior were considered dependent variables in multivariate logistic regression models. All correlations were computed between binary variables, and phi coefficients were calculated to estimate correlation strengths. RESULTS:533 primary care physicians answered the questionnaire (response rate: 25.6%). The top 3 conventional treatments most often considered useful by primary care physicians for chronic or recurrent low back pain were physiotherapy (94.8%), nonsteroidal anti-inflammatory drugs (87.9%), and manual therapy (82.5%), whereas the most prescribed conventional treatments were physiotherapy (99.2%), nonsteroidal anti-inflammatory drugs (97.4%), and acetaminophen (94.4%). Osteopathic treatment (78.4%), yoga (69.3%), and therapeutic massage (63.9%) were the complementary medicine treatments most often considered useful by primary care physicians in managing chronic or recurrent low back pain. Being a female physician, younger than 56 years, trained in complementary medicine, or using complementary medicine were all associated with higher perceived usefulness of complementary medicine treatments in general. The most recommended complementary medicine treatments by primary care physicians were osteopathic treatment (87.3%), acupuncture (69.3%), and therapeutic massage (58.7%). Being a female physician, younger than 56, and using complementary medicine were all associated with more complementary medicine recommendation in general. CONCLUSION:Our results highlight the importance of better understanding the prescribing patterns of primary care physicians for chronic or recurrent low back pain. Considering the frequency and burden of chronic or recurrent low back pain, programs focusing on the most (cost-) effective treatments should be implemented.

BACKGROUND AND OBJECTIVES:The kidney stone's structure might provide clinical information in addition to the stone composition. The Raman chemical imaging is a technology used for the production of two-dimension maps of the constituents' distribution in samples. We aimed at determining the use of Raman chemical imaging in urinary stone analysis. MATERIAL AND METHODS:Fourteen calculi were analyzed by Raman chemical imaging using a confocal Raman microspectrophotometer. They were selected according to their heterogeneous composition and morphology. Raman chemical imaging was performed on the whole section of stones. Once acquired, the data were baseline corrected and analyzed by MCR-ALS. Results were then compared to the spectra obtained by Fourier Transform Infrared spectroscopy. RESULTS:Raman chemical imaging succeeded in identifying almost all the chemical components of each sample, including monohydrate and dihydrate calcium oxalate, anhydrous and dihydrate uric acid, apatite, struvite, brushite, and rare chemicals like whitlockite, ammonium urate and drugs. However, proteins couldn't be detected because of the huge autofluorescence background and the small concentration of these poor Raman scatterers. Carbapatite and calcium oxalate were correctly detected even when they represented less than 5 percent of the whole stones. Moreover, Raman chemical imaging provided the distribution of components within the stones: nuclei were accurately identified, as well as thin layers of other components. Conversion of dihydrate to monohydrate calcium oxalate was correctly observed in the centre of one sample. The calcium oxalate monohydrate had different Raman spectra according to its localization. CONCLUSION:Raman chemical imaging showed a good accuracy in comparison with infrared spectroscopy in identifying components of kidney stones. This analysis was also useful in determining the organization of components within stones, which help locating constituents in low quantity, such as nuclei. However, this analysis is time-consuming, making it more suitable for research studies rather than routine analysis.

Modelling cultural ecosystem services is an enduring challenge, raising issues about the integration and spatialization of immaterial values and benefits, and their contingency on local preferences. Building on the Recreation Opportunity Spectrum framework, we present a novel methodology for assessing the recreation service using GPS tracks downloaded from crowd-sourced websites: the Grelou model (Georeferencing REcreation in Local OUtdoors), here applied to the Grenoble living area (French Alps). GPS tracks revealed the complete spatial extent of visitor presence and enabled modelling visitation networks for ten recreation activities with great spatial accuracy, thus providing a spatial estimate of recreational multifunctionality-expressed as the sum of networks. After coupling track networks with landscape preference and proximity factors, Grelou assessed the recreation service as a combination of opportunity and preferences, and identified recreation hotspots of different profiles such as aroundoor leisure or outdoor sport. We performed an online survey among local sports associations using an interactive map to select districts visited by respondents (~1000 people). The declared visitor presence for recreation purposes was highly spatially congruent with Grelou outputs (R2 = 0.89). Detailed analysis of responses on selection criteria for recreationists validates our choice of critical factors underlying both the recreation opportunity potential and the expected visitation frequency over the whole study area. We also analyzed outputs of the InVESt recreation model against the same visitation explanatory factors. Differences between the two models allowed us to pinpoint biases and weaknesses in the InVESt recreation modelling framework based on crowd-sourced photographs. By making use of an increasingly available data source (GPS tracks), Grelou offers a standardized and flexible way to assess the recreation service associated with multiple recreation practices. Its high spatial accuracy supports the analysis of spatial relationships with other ecoystems services and the integration of recreation into environmental assessments, land management and planning.

Spinal muscular atrophy (SMA) is a monogenic disorder caused by loss of function mutations in the survival motor neuron 1 gene, which results in a broad range of disease severity, from neonatal to adult onset. There is currently a concerted effort to define the natural history of the disease and develop outcome measures that accurately capture its complexity. As several therapeutic strategies are currently under investigation and both the FDA and EMA have recently approved the first medical treatment for SMA, there is a critical need to identify the right association of responsive outcome measures and biomarkers for individual patient follow-up. As an approved treatment becomes available, untreated patients will soon become rare, further intensifying the need for a rapid, prospective and longitudinal study of the natural history of SMA Type 2 and 3. Here we present the baseline assessments of 81 patients aged 2 to 30 years of which 19 are non-sitter SMA Type 2, 34 are sitter SMA Type 2, 9 non-ambulant SMA Type 3 and 19 ambulant SMA Type 3. Collecting these data at nine sites in France, Germany and Belgium established the feasibility of gathering consistent data from numerous and demanding assessments in a multicenter SMA study. Most assessments discriminated between the four groups well. This included the Motor Function Measure (MFM), pulmonary function testing, strength, electroneuromyography, muscle imaging and workspace volume. Additionally, all of the assessments showed good correlation with the MFM score. As the untreated patient population decreases, having reliable and valid multi-site data will be imperative for recruitment in clinical trials. The pending two-year study results will evaluate the sensitivity of the studied outcomes and biomarkers to disease progression. TRIAL REGISTRATION:ClinicalTrials.gov (NCT02391831).

A novel paradigm of diastolic left ventricular (LV) dysfunction proposes involvement of the cardiac microvasculature. Vitamin K dependent matrix Gla protein (MGP) plays a role in preserving microcirculatory integrity. We hypothesized that LV filling pressure-a measure of diastolic LV dysfunction-increases with higher plasma level of inactive desphospho-uncarboxylated MGP (dp-ucMGP). We also studied the distribution of active and inactive MGP in human myocardium.We measured echocardiographic diastolic LV function and plasma dp-ucMGP (ELISA) in 668 Flemish and for replication in 386 Swiss.Among Flemish and Swiss, E/e' (6.78 vs. 6.73) and dp-ucMGP (3.94 μg/L vs. 4.20 μg/L) were similarly distributed. In multivariable-adjusted models, for each doubling of dp-ucMGP, E/e' increased by 0.26, 0.33 and 0.31 in Flemish, Swiss and both cohorts combined (P≤0.026); the odds ratios for having E/e' ≥ 8.5 were 1.99, 3.29 and 2.36, respectively (P≤0.017). Cardiac biopsies from patients with ischemic or dilated cardiomyopathy and healthy hearts (n = 4 for each) were stained with conformation-specific MGP antibodies. In diseased compared with normal hearts, uncarboxylated inactive MGP was more prevalent (P≤0.004) in the perivascular matrix and interstitium (204.4 vs. 8.6 μm2 per field) and phosphorylated active MGP in and around capillaries and interstitial cells (31.3 vs. 6.6 number of positive capillaries and cells per field).Our study supports a role of activated MGP in maintaining myocardial integrity and diastolic LV performance and can potentially be translated into new strategies for managing diastolic LV dysfunction and preventing its progression to heart failure.

Different pulmonary hypertension (PH) mechanisms are associated with hereditary haemorrhagic telangiectasia (HHT).We conducted a retrospective study of all suspected cases of PH (echocardiographically estimated systolic pulmonary artery pressure [sPAP] ≥ 40 mmHg) in patients with definite HHT recorded in the French National Reference Centre for HHT database. When right heart catheterization (RHC) was performed, PH cases were confirmed and classified among the PH groups according to the European guidelines. Among 2,598 patients in the database, 110 (4.2%) had suspected PH. Forty-seven of these 110 patients had RHC: 38/47 (81%) had a confirmed diagnosis of PH. The majority of these had isolated post-capillary PH (n = 20). We identified for the first time other haemodynamic profiles: pre-capillary pulmonary arterial hypertension (PAH) cases (n = 3) with slightly raised pulmonary vascular resistances (PVR), and combined post- and pre-capillary PH cases (n = 4). Compared to controls, survival probability was lower in patients with PAH.This study revealed the diversity of PH mechanisms in HHT. The description of combined post- and pre-capillary PH with/or without high cardiac output (CO) suggests either a continuum between the pre- and post-capillary haemodynamic profiles or a different course in response to high CO.

Complementary medicine (CM) is utilized in a growing number of academic centers despite the debate concerning its value, risks and benefits. Healthcare professionals often feel uncomfortable discussing CM with patients, and little is known about their sources of knowledge in the field of CM.To assess healthcare professionals' sources of knowledge and attitude toward CM in an academic hospital.The cross-sectional web-based survey took place from October to December 2013. A total of 4,925 healthcare professionals working at Lausanne University Hospital, Switzerland, were invited to answer the questionnaire.Factors influencing healthcare professionals' opinion toward CM, knowledge and communication about CM.The questionnaire was answered by 1,247 healthcare professionals. The three key factors influencing professionals' opinion toward CM were personal experience, clinical experience and evidence demonstrating the physiological mechanism of CM. Personal experience was more associated with nurses' and midwives' opinion compared to physicians' (80.8% vs 57.1%, OR = 3.08, [95% CI: 2.35-4.05], P

The principal aim was to investigate the feasibility of assessing mother-infant interactions at discharge and at 6 months infant corrected age in singletons born before 32 weeks of gestation. The secondary aims were to describe these interactions and their disorders, explore the association between maternal emotional state and the interactions, and assess the relationship between disordered interactions and infant social withdrawal behaviour.OLIMPE is an ancillary study of the population-based study EPIPAGE 2, which recruited preterm neonates in France in 2011. 163 dyads participated at discharge and 148 at 6 months. Interactions were observed with the Attachment During Stress (ADS) scale, which includes two behavioural subscales, for the mother (m-ADS) and her infant (i-ADS). Two professionals independently completed the ADS scales for one third of the observations. Maternal emotional state was assessed using self-administered questionnaires of depression, anxiety, and stress. Infant's social withdrawal behaviour at 6 months was measured by the Alarm Distress Baby scale.At discharge, 15.3% of the m-ADS scales and 43.3% of the i-ADS scales had at least one unobserved component. At 6 months, all items on both scales were noticeable in >90% of the dyads. Reliability, estimated by the kappa coefficient, ranged between 0.39 and 0.76 at discharge, and between 0.21 and 0.69 at 6 months. Disordered interactions were indicated on 48.6% of the m-ADS scales and 36.5% of the i-ADS scales at discharge. At 6 months, these rates were 32.6% and 26.0%. Disordered interactions at 6 months were associated with identified disorder at discharge. Insecure infant attachment was not influenced by maternal mental health but was strongly associated with infant social withdrawal behaviour.The ADS scale can be used to screen for early interaction disorders after premature birth and may help to target dyads that would most benefit from early intervention.

It is currently recognized that an optimized nutritional approach, consisting of an early and substantial supply of protein and energy by parenteral route, may be beneficial for very low birth weight infants and recent guidelines endorse this strategy. However, the impact of the enhanced parenteral nutrition (PN) on acid-basic balance has never been investigated. The aim of the present study is to assess the effect of nutrient intake on acid-base homeostasis in a large population of preterm infants on PN.This observational study described the acid-base profile of very preterm infants (≤29 week's gestation) receiving PN during the first week of life. For this purpose three different cohorts of infants who received increasing (group 1 to group 3) nutritional intakes were considered. Nutrition data were recorded daily and correlated to acid-base data (pH, base excess, and lactate). The outcome measure to assess metabolic acidosis was the base excess (BE).161 infants were included. 1127 daily nutritional records and 795 blood gas data were analyzed. The three groups were different with regard to nutritional intravenous intakes. Group 3 in particular had a higher mean intake of both amino acids (3.3 ± 0.8 g/kg/d) and lipids (2.8 ± 1.4 g/kg/d) during the first week of life. Metabolic acidosis was more severe in the group with the highest parenteral intake of amino acids and lipids: mean BE = -8.7 ± 3.4 (group 3); -6.4 ± 3.4 (group 2); -5.1 ± 3.0 (group 1)]. At the multivariate analysis the significant risk factors for metabolic acidosis were: gestational age, initial base excess, amino acid and lipid intravenous intakes.Acid-base homeostasis was influenced by the nutritional intake. Earlier and higher intravenous amino acid and lipid intakes particularly increased the risk of metabolic acidosis. The nutritional tolerance was different depending on gestational age, and the smaller infants (24-26 week's gestation) displayed greater acidotic disequilibrium and a higher need of bicarbonate.

OBJECTIVES:Several automated algorithms for epidemiological surveillance in hospitals have been proposed. However, the usefulness of these methods to detect nosocomial outbreaks remains unclear. The goal of this review was to describe outbreak detection algorithms that have been tested within hospitals, consider how they were evaluated, and synthesize their results. METHODS:We developed a search query using keywords associated with hospital outbreak detection and searched the MEDLINE database. To ensure the highest sensitivity, no limitations were initially imposed on publication languages and dates, although we subsequently excluded studies published before 2000. Every study that described a method to detect outbreaks within hospitals was included, without any exclusion based on study design. Additional studies were identified through citations in retrieved studies. RESULTS:Twenty-nine studies were included. The detection algorithms were grouped into 5 categories: simple thresholds (n = 6), statistical process control (n = 12), scan statistics (n = 6), traditional statistical models (n = 6), and data mining methods (n = 4). The evaluation of the algorithms was often solely descriptive (n = 15), but more complex epidemiological criteria were also investigated (n = 10). The performance measures varied widely between studies: e.g., the sensitivity of an algorithm in a real world setting could vary between 17 and 100%. CONCLUSION:Even if outbreak detection algorithms are useful complementary tools for traditional surveillance, the heterogeneity in results among published studies does not support quantitative synthesis of their performance. A standardized framework should be followed when evaluating outbreak detection methods to allow comparison of algorithms across studies and synthesis of results.

Systemic sclerosis-related interstitial lung disease (SSc-ILD) is the leading cause of death in SSc. In this study, we aimed to describe the baseline severity and evolution of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) in patients with SSc-ILD and to assess the baseline clinical, biological and high-resolution CT scan (HRCT) predictors of this evolution. Baseline and serial FVC and DLCO were collected in 75 SSc-ILD patients followed during 6.4±4.2 years (n = 557 individual data). FVC and DLCO evolution was modelled using a linear mixed model with random effect. During follow-up, FVC was stable while DLCO significantly decreased (-1.5±0.3%/year (p

Epichloë grass endophytes comprise a group of filamentous fungi of both sexual and asexual species. Known for the beneficial characteristics they endow upon their grass hosts, the identification of these endophyte species has been of great interest agronomically and scientifically. The use of simple sequence repeat loci and the variation in repeat elements has been used to rapidly identify endophyte species and strains, however, little is known of how the structure of repeat elements changes between species and strains, and where these repeat elements are located in the fungal genome. We report on an in-depth analysis of the structure and genomic location of the simple sequence repeat locus B10, commonly used for Epichloë endophyte species identification. The B10 repeat was found to be located within an exon of a putative bZIP transcription factor, suggesting possible impacts on polypeptide sequence and thus protein function. Analysis of this repeat in the asexual endophyte hybrid Epichloë uncinata revealed that the structure of B10 alleles reflects the ancestral species that hybridized to give rise to this species. Understanding the structure and sequence of these simple sequence repeats provides a useful set of tools for readily distinguishing strains and for gaining insights into the ancestral species that have undergone hybridization events.