Genetic Testing in Acute and Chronic Pancreatitis

Purpose of review Premature intracellular activation of pancreatic zymogens leads to the initiation of pancreatitis, which in up to 25% leads to chronic tissue destruction, exocrine and endocrine organ failure, and a moderate increased risk of pancreatic cancer development. Whereas in many cases, the trigger of organ damage is identified, diagnostic workup in a significant number of patients does not reveal the underlying etiology of pancreatic inflammation. In these cases, alterations in different pancreatic susceptibility genes have been described to be directly or indirectly involved in disease development. In this review, we want to give an update on the most important pancreatitis risk genes and their impact on clinical diagnostics and risk stratification as well as possible treatment options. Recent findings Genetic testing is not routinely implemented in the diagnostic workup of acute or chronic pancreatitis, as most genetic variations are not considered causative for pancreatitis development but confer increased susceptibility and genetic testing rarely changes disease management. However, in patients with recurrent pancreatitis episodes of unknown etiology after intensive diagnostic work-up, in patients with a family history of pancreatitis, relatives of patients with hereditary pancreatitis, and patients with disease onset at young age, genetic testing and counseling is recommended. Besides well-established susceptibility genes such as PRSS1, SPINK1, CPA1, and CFTR, additional genes such as TRPV6 and rare genetic alterations in established risk genes have been recently identified which significantly contribute to the risk of pancreatitis, involving different molecular mechanisms. Summary When genetic testing is considered, we propose screening at least for PRSS1, SPINK1, CPA1, and CFTR gene variants. The emergence of next-generation sequencing methods could also render larger gene panels possible and clinically meaningful to detect rare variants with high-risk phenotypes. Here we summarize, evaluate, and convey in the form of practical recommendations the current level of knowledge with respect to definition, etiology, and genetic diagnostics of all forms of inherited pancreatitis

Two valid and reliable tests for monitoring age-related memory performance and neophobia differences in dogs

The prolonged lifespan of companion dogs has resulted in increased behavioural and physical challenges linked to old age. The development of behavioural tests to identify and monitor age-related differences has begun. However, standardised testing requires validation. The present study aimed to assess external validity, interobserver reliability, and test–retest reliability of an indoor test battery for the rapid assessment of age-related behavioural differences in dogs. Two experimenters tested young dogs (N = 20, mean age ± SD = 2.7 ± 0.4 years) and old dogs (N = 18, mean age ± SD = 11.8 ± 1.3 years) in the test battery once and then again after two weeks. Our results found external validity for two subtests out of six. On both test occasions, old dogs committed more errors than young dogs in a memory subtest and showed more object avoidance when encountering a novel object. Interobserver reliability and test–retest reliability was high. We conclude that the Memory and Novel object subtests are valid and reliable for monitoring age-related memory performance and object neophobic differences in dogs

CCL1 is a major regulatory T cell attracting factor in human breast cancer

BACKGROUND Regulatory T cells (Treg) suppress cytotoxic T cell anti-tumoral immune responses and thereby promote tumor progression. Prevention of intratumoral Treg accumulation by inhibition of their migration to the tumor microenvironment is a promising therapeutic strategy. The aim of this study was to identify the role of the two major Treg-attracting chemokines CCL1 and CCL22 in human breast cancer. METHODS One hundred ninety-nine tissue samples of patients with invasive breast cancer were stained for CCL1 and CCL22 by immunohistochemistry. Chemokine expression and tumor infiltration by regulatory T cells, determined by expression of the transcription factor FoxP3, were quantified and their correlation to clinical features was statistically analyzed. RESULTS Both CCL1 and CCL22 were expressed in most breast cancer tissues. CCL1 was significantly over-expressed in invasive breast cancer as compared to normal breast tissue. CCL1, but surprisingly not CCL22, showed a significant correlation with the number of tumor-infiltrating FoxP3+ Treg (p< 0.001). High numbers of intratumoral CCL1 expressing cells were related to high grade tumors (G4) and a positive estrogen receptor (ER) status whereas high CCL22 expression was generally seen in lower grade tumors. The median survival of 88 patients with high intratumoral CCL1 expression was 37 months compared to 50 months for the 87 patients with low CCL1 levels, this trend was however not statistically significant. CONCLUSIONS We found a high expression of CCL1 in human breast cancer. CCL1 significantly correlated with the infiltration of immunosuppressive FoxP3+ Treg, that are known to negatively affect survival. Thus, CCL1 may serve as prognostic marker and novel therapeutic target in breast cancer

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Synthèse des connaissances et modélisation des relations entre la diversité végétale, l'environnement et la gestion dans les prairies

Grasslands and pastures are herbaceous production systems that cover about 40% of the earth's surface (52.5 million km2). Herbaceous production in these systems is the main source of food for many extensively or semi-extensively farmed herbivore species. Given their complexity, grasslands and pastures are unique ecosystems for studying vegetation fluctuations and provide a conceptual framework for understanding the evolution of these plant communities in terms of feedbacks between natural (environmental) and human (management) components in the soil-vegetation-atmosphere continuum. In chapter 3 we developed a comprehensive understanding of species richness modification due to management (mowing) and climate (warming) variation worldwide. The results show that both mowing and warming modify species richness, which on average increased by c. 32% with once-a-year mowing (against no mowing) and declined by c. 13% with warming (against ambient temperature). Where available, we accounted for harvested biomass as a concomitant variable and we found that overall it decreased by c. 21% (mowing) and increased by c. 11% (warming). In Chapters 4 and 5 we addressed the modelling of fluctuations in the relative abundance of plant species (or species types) on two case studies: a long-term observation site in the French Massif Central and an experiment conducted during the thesis in the island of Sardinia in Italy. In the first case, the ModVege crop model was coupled with CoSMo to simulate the relative abundance of functional types and species.Three modelling solutions - the ModVege model for biomass estimation and its version coupled to CoSMo (ModVege-CoSMo) for functional types and individual species - were evaluated for biomass production and relative abundance of species types and individual species using multi-year data collected from 2006 to 2018 of both mowed and undisturbed multi-species grasslands. For biomass production, the performance of the CoSMo-based solutions was similar to that of ModVege, with an average difference of 30%. The accuracy in simulating the relative abundance of plant species was also generally satisfactory. In Chapter 5, annual grass species were simulated using the CropSyst crop growth model and its CoSMo-based version. In particular, we dynamically simulated relative species abundance in four pure (two grasses, i.e. spring oat and annual ryegrass, and two legumes, i.e. balansa and subterranean clovers) and three mixed2 (50:50, 25:75 and 75:25 of grasses and legumes) stands of annual self-reseeding grassland species with two mowing regimes (two or three cuts). The simulation of biomass production was satisfactory, with minimal differences between CropSyst and CoSMo-CropSyst. The accuracy of CropSyst-CoSMo in simulating the relative abundances of the four species in the mixtures was overall satisfactory for high mowing frequency management. By integrating synthesis research (i.e. meta-analysis) and process-based modelling (supported by long-term observations and field experiments), this thesis explored and learned how generic simulation models can be extended to ensure consistency between the growth dynamics of the plant species represented in a community and the biophysical processes in the same community.Les prairies et les pâturages sont des systèmes de production herbacée qui couvrent environ 40 % de la surface de la terre (52,5 millions de km2). La production herbacée dans ces systèmes est la principale source de nourriture pour de nombreuses espèces d'herbivores élevées de manière extensive ou semi-extensive. Compte tenu de leur complexité, les prairies et les pâturages sont des écosystèmes uniques pour l'étude des fluctuations de la végétation et fournissent un cadre conceptuel pour comprendre l'évolution de ces communautés végétales en termes de rétroactions entre les composantes naturelles (environnementales) et humaines (gestion) dans le continuum sol-végétation-atmosphère. Dans le chapitre 3, nous avons développé une compréhension globale de la modification de la richesse en espèces due à la gestion (fauchage) et aux variations climatiques (réchauffement) dans le monde entier. Les résultats montrent que le fauchage et le réchauffement modifient la richesse en espèces, qui augmente en moyenne d'environ 32 % avec le fauchage annuel (par rapport à l'absence de fauchage) et diminue d'environ 13 % avec le réchauffement (par rapport à la température ambiante). Lorsque cela était possible, nous avons pris en compte la biomasse récoltée en tant que variable concomitante et nous avons constaté que, dans l'ensemble, elle diminuait d'environ 21 % (fauchage) et augmentait d'environ 11 % (réchauffement). Dans les chapitres 4 et 5, nous avons abordé la modélisation des fluctuations de l'abondance relative des espèces végétales (ou des types d'espèces) sur deux études de cas : un site d'observation à long terme dans le Massif central français et une expérience menée pendant la thèse sur l'île de Sardaigne en Italie. Dans le premier cas, le modèle de culture ModVege a été couplé à CoSMo pour simuler l'abondance relative des types fonctionnels et des espèces.Trois solutions de modélisation - le modèle ModVege pour l'estimation de la biomasse et sa version couplée à CoSMo (ModVege-CoSMo) pour les types fonctionnels et les espèces individuelles - ont été évaluées pour la production de biomasse et l'abondance relative des types d'espèces et des espèces individuelles à l'aide de données pluriannuelles collectées de 2006 à 2018 dans des prairies multi-espèces fauchées et non perturbées. Pour la production de biomasse, la performance des solutions basées sur CoSMo était similaire à celle de ModVege, avec une différence moyenne de <1,2 t ha-1 entre les simulations et les observations. ModVege-CoSMo a simulé avec suffisamment de précision les fluctuations des types fonctionnels dans tous les traitements, avec des erreurs quadratiques moyennes relatives (RRMSE) rarement supérieures à 30 %. La précision de la simulation de l'abondance relative des espèces végétales était également généralement satisfaisante. Dans le chapitre 5, les espèces de graminées annuelles ont été simulées à l'aide du modèle de croissance des cultures CropSyst et de sa version basée sur CoSMo. En particulier, nous avons simulé de manière dynamique l'abondance relative des espèces dans quatre peuplements purs (deux graminées, à savoir l'avoine de printemps et le ray-grass annuel, et deux légumineuses, à savoir le balansa et le trèfle souterrain) et trois peuplements mixtes2 (50:50, 25:75 et 75:25 de graminées et de légumineuses) d'espèces de graminées annuelles auto-ensemencées avec deux régimes de fauche (deux ou trois coupes). La simulation de la production de biomasse a été satisfaisante, avec des différences minimes entre CropSyst et CoSMo-CropSyst. La précision de CropSyst-CoSMo dans la simulation des abondances relatives des quatre espèces dans les mélanges était globalement satisfaisante pour une gestion à fréquence de fauche élevée. En intégrant la recherche de synthèse (c'est-à-dire la méta-analyse) et la modélisation basée sur les processus (soutenue par des observations à long terme et des expériences sur le terrain), cette thèse a exploré et appris comment les modèles de simulation génériques peuvent être étendus pour assurer la cohérence entre la dynamique de croissance des espèces végétales représentées dans une communauté et les processus biophysiques dans la même communauté