Identification, validation and biological characterisation of novel glioblastoma tumour microenvironment subtypes: implications for precision immunotherapy.

BACKGROUND: New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts to subtype patients based on molecular profiles have failed to direct treatment strategies. We hypothesised that interrogation of the GBM tumour microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision immunotherapy treatment strategies. MATERIALS AND METHODS: A refined and validated microenvironment cell population (MCP) counter method was applied to >800 GBM patient tumours (GBM-MCP-counter). Specifically, partition around medoids (PAM) clustering of GBM-MCP-counter scores in the GLIOTRAIN discovery cohort identified three novel patient clusters, uniquely characterised by TME composition, functional orientation markers and immune checkpoint proteins. Validation was carried out in three independent GBM-RNA-seq datasets. Neoantigen, mutational and gene ontology analysis identified mutations and uniquely altered pathways across subtypes. The longitudinal Glioma Longitudinal AnalySiS (GLASS) cohort and three immunotherapy clinical trial cohorts [treatment with neoadjuvant/adjuvant anti-programmed cell death protein 1 (PD-1) or PSVRIPO] were further interrogated to assess subtype alterations between primary and recurrent tumours and to assess the utility of TME classifiers as immunotherapy biomarkers. RESULTS: TMEHigh tumours (30%) displayed elevated lymphocyte, myeloid cell immune checkpoint, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 transcripts. TMEHigh/mesenchymal+ patients featured tertiary lymphoid structures. TMEMed (46%) tumours were enriched for endothelial cell gene expression profiles and displayed heterogeneous immune populations. TMELow (24%) tumours were manifest as an 'immune-desert' group. TME subtype transitions upon recurrence were identified in the longitudinal GLASS cohort. Assessment of GBM immunotherapy trial datasets revealed that TMEHigh patients receiving neoadjuvant anti-PD-1 had significantly increased overall survival (P = 0.04). Moreover, TMEHigh patients treated with adjuvant anti-PD-1 or oncolytic virus (PVSRIPO) showed a trend towards improved survival. CONCLUSIONS: We have established a novel TME-based classification system for application in intracranial malignancies. TME subtypes represent canonical 'termini a quo' (starting points) to support an improved precision immunotherapy treatment approach.

Marginal ice zone dynamics: future research perspectives and pathways.

Perspectives are discussed on future directions for the field of marginal ice zone (MIZ) dynamics, based on the extraordinary progress made over the past decade in its theory, modelling and observations. Research themes are proposed that would shift the field's focus towards the broader implications of MIZ dynamics in the climate system. In particular, pathways are recommended for research that highlights the impacts of trends in the MIZ on the responses of Arctic and Antarctic sea ice to climate change. This article is part of the theme issue 'Theory, modelling and observations of marginal ice zone dynamics: multidisciplinary perspectives and outlooks'.

Wind waves in sea ice of the western Arctic and a global coupled wave-ice model.

The retreat of Arctic sea ice is enabling increased ocean wave activity at the sea ice edge, yet the interactions between surface waves and sea ice are not fully understood. Here, we examine in situ observations of wave spectra spanning 2012-2021 in the western Arctic marginal ice zone (MIZ). Swells exceeding 30 cm are rarely observed beyond 100 km inside the MIZ. However, local wind waves are observed in patches of open water amid partial ice cover during the summer. These local waves remain fetch-limited between ice floes with heights less than 1 m. To investigate these waves at climate scales, we conduct experiments varying wave attenuation and generation in ice with a global model including coupled interactions between waves and sea ice. A weak high-frequency attenuation rate is required to simulate the local waves in observations. The choices of attenuation scheme and wind input in ice have a remarkable impact on the extent of wave activity across ice-covered oceans, particularly in the Antarctic. As well as demonstrating the need for stronger constraints on wave attenuation, our results suggest that further attention should be directed towards locally generated wind waves and their role in sea ice evolution. This article is part of the theme issue 'Theory, modelling and observations of marginal ice zone dynamics: multidisciplinary perspectives and outlooks'.

Storm-induced sea-ice breakup and the implications for ice extent.

The propagation of large, storm-generated waves through sea ice has so far not been measured, limiting our understanding of how ocean waves break sea ice. Without improved knowledge of ice breakup, we are unable to understand recent changes, or predict future changes, in Arctic and Antarctic sea ice. Here we show that storm-generated ocean waves propagating through Antarctic sea ice are able to transport enough energy to break sea ice hundreds of kilometres from the ice edge. Our results, which are based on concurrent observations at multiple locations, establish that large waves break sea ice much farther from the ice edge than would be predicted by the commonly assumed exponential decay. We observed the wave height decay to be almost linear for large waves--those with a significant wave height greater than three metres--and to be exponential only for small waves. This implies a more prominent role for large ocean waves in sea-ice breakup and retreat than previously thought. We examine the wider relevance of this by comparing observed Antarctic sea-ice edge positions with changes in modelled significant wave heights for the Southern Ocean between 1997 and 2009, and find that the retreat and expansion of the sea-ice edge correlate with mean significant wave height increases and decreases, respectively. This includes capturing the spatial variability in sea-ice trends found in the Ross and Amundsen-Bellingshausen seas. Climate models fail to capture recent changes in sea ice in both polar regions. Our results suggest that the incorporation of explicit or parameterized interactions between ocean waves and sea ice may resolve this problem.

Three-dimensional time-domain scattering of waves in the marginal ice zone.

Three-dimensional scattering of ocean surface waves in the marginal ice zone (MIZ) is determined in the time domain. The solution is found using spectral analysis of the linear operator for the Boltzmann equation. The method to calculate the scattering kernel that arises in the Boltzmann model from the single-floe solution is also presented along with new identities for the far-field scattering, which can be used to validate the single-floe solution. The spectrum of the operator is computed, and it is shown to have a universal structure under a special non-dimensionalization. This universal structure implies that under a scaling wave scattering in the MIZ has similar properties for a large range of ice types and wave periods. A scattering theory solution using fast Fourier transforms is given to find the solution for directional incident wave packets. A numerical solution method is also given using the split-step method and this is used to validate the spectral solution. Numerical calculations of the evolution of a typical wave field are presented.This article is part of the theme issue 'Modelling of sea-ice phenomena'.

[Bovine dilated cardiomyopathy: Almost forgotten but still present]. / Bovine dilatative Kardiomyopathie: Altbekannt und dennoch gegenwärtig.

INTRODUCTION: Numerous cases of bovine dilatative cardiomyopathy (BDCMP) were registered in the nineteen-eighties, but the prevalence decreased steadily thanks to classical selection measures, i.e. excluding putative carrier animals from breeding. The cases described here show that the recessively inherited disease is still present in the Swiss cattle population. By use of a direct gene test developed a few years ago, a clinical tentative diagnosis can be confirmed. Since the end of the year 2016, carriers are officially labelled as such in Switzerland. Currently, about 2% of the insemination sires of the Holstein, Red Holstein and Swiss Fleckvieh breeds carry the causative mutation in the OPA3 gene. A combination of increased awareness of the disease and use of the gene test should allow for complete elimination of the disease from the Swiss cattle population.

INTRODUCTION: De nombreux cas de cardiomyopathie dilatative bovine (CMPDB) ont été rapportés dans les années 1980. Leur prévalence a ensuite fortement diminué grâce à des mesures classiques de sélection, à savoir l'exclusion de l'élevage des porteurs potentiels. Les cas décrits ici montrent que cette maladie héréditaire récessive, quoique rare, est toujours bien présente dans la population bovine suisse. Un test génétique direct développé il y a quelques années permet de confirmer définitivement un diagnostic de suspicion clinique. Depuis fin 2016, les porteurs de la mutation sont signalés officiellement en Suisse: environ 2% des taureaux d'insémination des races Holstein, Red Holstein et tachetée rouge sont porteurs de la mutation causative du gène OPA3. Une attention augmentée et un usage accru du test génétique rendent possible pour la première fois une éradication complète de la maladie du cheptel bovin suisse.

[The significance of cryptosporidiosis for the health of calves in Switzerland]. / Die Bedeutung der Cryptosporidiose für die Kälbergesundheit in der Schweiz.

INTRODUCTION: Diarrhea in calves is one of the most important cattle diseases in Switzerland. The diagnosis and treatment of calf diarrhea represent a major challenge. Single-celled Cryptosporidium parasites are the most prevalent causative agents of calf diarrhea besides rotavirus in the first weeks of life, and are responsible for about 50% of diarrheal cases. Cryptosporidium parvum has been described as a cause of diarrhea in one to three weeks old calves since the 1970s. Oral ingestion of persistent environmental oocysts results in severe diarrhea lasting four to six days and shedding of large numbers of infectious oocysts. A tiny amount of 10 oocysts is already sufficient to cause disease. Detailed knowledge about the epidemiology and virulence of the different C. parvum strains is still lacking. In addition, current diagnostic tests cannot reliably distinguish between non-pathogenic (e.g. C. bovis) and pathogenic Cryptosporidium species. Until now, no effective therapeutic drug or vaccine against calf cryptosporidiosis has been found. Water-borne epidemics and the zoonotic potential of Cryptosporidium in immunodeficient patients are of great medical importance. The increasing number of cryptosporidiosis cases associated with high infant mortality in less industrialized and impoverished regions (including South-East Asia and sub-Saharan Africa) has intensified the research in recent years. The recent discoveries of new therapeutics against C. parvum may benefit calf medicine in the near future. This review article reports on these new developments, highlights calf cryptosporidiosis in Switzerland and draws attention to a new research project.

INTRODUCTION: La diarrhée chez les veaux est l'une des maladies du bétail les plus courantes en Suisse. Le diagnostic de la cause et le traitement de la diarrhée des veaux représentent un défi majeur. En Suisse, les cryptosporidies sont, avec les rotavirus, l'agent causal le plus fréquent de diarrhée du veau dans les premières semaines et elles sont responsables d'environ 50% des cas. Le parasite unicellulaire Cryptosporidium parvum a été décrit depuis les années 1970 comme un agent de diarrhée chez les veaux d'une à trois semaines. Après ingestion orale d'oocystes persistants dans l'environnement, il se produit après quelques jours une diarrhée sévère de quatre à six jours avec excrétion massive d'oocystes déjà infectieux. Même quelques oocystes persistants dans l'environnement peuvent être pathogènes. Du point de vue épidémiologique, il existe encore de grandes lacunes dans la connaissance de la variabilité suspectée dans la virulence de diverses souches de C. parvum. En outre, des espèces non pathogènes (entre autres Cryptosporidium bovis) peuvent être présentes chez les veaux, qui ne se distinguent pas de C. parvum avec les tests diagnostiques actuels. Jusqu'à présent, aucun médicament efficace sur le plan thérapeutique et aucun vaccin contre la cryptosporidiose du veau n'ont été trouvés. En médecine humaine, les épidémies transmises par l'eau (en particulier aux États-Unis) et l'importance zoonotique des cryptosporidies comme pathogènes opportunistes chez les personnes immunodéficientes jouent un rôle de premier plan. La forte morbidité de la cryptosporidiose associée à une forte mortalité infantile dans les régions les moins industrialisées et les plus pauvres (entre autres en Asie du Sud-Est et en Afrique subsaharienne) ont relancé la recherche sur ces parasites au cours des dernières années. En particulier, la découverte de nouveaux médicaments contre C. parvum est susceptible de bénéficier à la médecine du veau dans un proche avenir. Cet article de synthèse fait le point sur ces nouveaux développements mais surtout sur la cryptosporidiose du veau en Suisse et attire l'attention sur un nouveau projet de recherche.

[Fanconi-Bickel-Syndrom: a novel genetic disease in Original Braunvieh]. / Fanconi-Bickel-Syndrom: eine bislang unerkannte Erbkrankheit beim Braunvieh.

INTRODUCTION: This case report describes a new genetic disease of the Braunvieh breed in Switzerland. The bovine disorder also occurs in German Fleckvieh, and corresponds to human Fanconi-Bickel syndrome which is an inherited glycogen storage disease caused by mutations of the SLC2A2 gene encoding the glucose transporter GLUT2. This case report describes a single affected Original Braunvieh calf genotyped as homozygous for the FH2-associated SLC2A2 frame shift mutation. The clinical examination showed stunted growth, polyuria and polydipsia, as well as poor claw horn and coat quality. Necropsy revealed a pale cortex of the kidneys and a unilateral renal hypoplasia. Histology showed tubulonephrosis of the proximal tubules with protein- and glucose-rich contents. Glycogen accumulation was not evident in any organ. This finding is different from the reported lesions in two previously described GLUT2-deficient Fleckvieh heifers. In the presented case, growth retardation mainly seems to be associated with renal dysfunction. A direct gene test is available to eliminate the mutant allele from the population.

[AntibioticScout.ch: Decision support for the prudent use of antimicrobials: Application in cattle]. / AntibioticScout.ch: Entscheidungshilfe für den umsichtigen Einsatz von antimikrobiellen Wirkstoffen: Anwendung beim Rind.

INTRODUCTION: The administration of antibiotics in livestock has been criticized for many years, in particular because of an inappropriate use and the appearance of antibiotic residues in the environment, which can promote the emergence and spread of resistant bacteria. However, antibiotics are essential for the successful and sustainable control of bacterial pathogens. With the aim of optimizing the use of antibiotics in food animals and minimizing the prevalence of resistant bacteria, AntibioticScout. ch provides a decision aid for the prudent use of antimicrobial drugs. This approach emphasizes the importance of supportive therapy and the hallmarks of preventive concepts. Procedures to improve animal health and animal welfare in accordance with the principles of good veterinary practice are primary and effective tools to reduce the use of antimicrobial drugs. The necessary reduction in the use of antibiotics must, therefore, be accompanied by appropriate management strategies in animal husbandry. In particular, hygiene, animal welfare and biosecurity measures are crucial to ensure an optimal health status in farm animals.

INTRODUCTION: On discute depuis des années de l'usage des antibiotiques dans l'élevage des animaux de rente, en particulier en ce qui concerne leur utilisation incorrecte et la charge environnementale liée à des résidus d'antibiotiques susceptibles de favoriser l'apparition et la propagation de résistances. Toutefois les antibiotiques sont essentiels pour assurer une lutte efficace et durable contre les maladies d'origine bactérienne. Dans le but d'optimiser l'usage des antibiotiques dans l'élevage des animaux de rente et, par conséquence, de réduire le développement de résistances, AntibioticScout.ch propose une aide à la décision pour un usage prudent de ces substances ("prudent use"). Parallèlement, on attire l'attention sur les traitements adjuvants et sur les mesures de prévention. Des mesures visant à améliorer la santé et le bien-être des animaux en tenant compte des fondements d'une bonne pratique vétérinaire sont des instruments efficaces pour réduire l'usage des antibiotiques. Cette réduction indispensable doit donc être combinée avec des mesures de gestion adéquates dans les élevages. Ce sont en particulier l'hygiène et les conditions d'élevage correctes ainsi que la mise en place de mesures de biosécurité qui sont décisives pour l'optimisation de la santé des troupeaux.

A transposable element insertion in APOB causes cholesterol deficiency in Holstein cattle.

Cholesterol deficiency, a new autosomal recessive inherited genetic defect in Holstein cattle, has been recently reported to have an influence on the rearing success of calves. The affected animals show unresponsive diarrhea accompanied by hypocholesterolemia and usually die within the first weeks or months of life. Here, we show that whole genome sequencing combined with the knowledge about the pedigree and inbreeding status of a livestock population facilitates the identification of the causative mutation. We resequenced the entire genomes of an affected calf and a healthy partially inbred male carrying one copy of the critical 2.24-Mb chromosome 11 segment in its ancestral state and one copy of the same segment with the cholesterol deficiency mutation. We detected a single structural variant, homozygous in the affected case and heterozygous in the non-affected carrier male. The genetic makeup of this key animal provides extremely strong support for the causality of this mutation. The mutation represents a 1.3kb insertion of a transposable LTR element (ERV2-1) in the coding sequence of the APOB gene, which leads to truncated transcripts and aberrant splicing. This finding was further supported by RNA sequencing of the liver transcriptome of an affected calf. The encoded apolipoprotein B is an essential apolipoprotein on chylomicrons and low-density lipoproteins, and therefore, the mutation represents a loss of function mutation similar to autosomal recessive inherited familial hypobetalipoproteinemia-1 (FHBL1) in humans. Our findings provide a direct gene test to improve selection against this deleterious mutation in Holstein cattle.

[Calf health and antimicrobial use in Swiss dairy herds: Management, prevalence and treatment of calf diseases]. / Gesundheit und Antibiotikaverbrauch bei Aufzuchtkälbern in Milchviehbetrieben: Managementfaktoren, Prävalenz und Behandlung von Kälberkrankheiten.

INTRODUCTION: Fifty-two dairy herds in the canton Fribourg were included during one winter in a study on calf management, prevalence and treatments of calf diseases. Colostrum management was optimal in 46.2% of the herds only, and 51.3% of the calves had been sick at least once during the observation period. The most commonly observed diseases included respiratory disease (57.5%), diarrhea (32.8%) and umbilical disease (5.7%). Cases of pneumonia were treated with antimicrobials first by the farmers in 65.4% of the herds. Calf diarrhea was treated with antimicrobial drugs by 57.7% of the farmers. Fluorochinolones were used in 47% of all parenteral treatments and oral antimicrobial drugs included macrolides in 11% of the cases. These results provide information on calf management, calf health and treatment strategies in an area where dairying is the most important sector of the farming industry. They show clearly that the farmers are not sufficiently informed about the use of critically important antimicrobial drugs and about the etiology of calf diarrhea. Improvements in colostrum management and treatment strategies are urgently needed.

INTRODUCTION: Dans le but de recueillir des données actuelles sur le management des veaux d'élevage ainsi que sur la prévalence et le traitement des maladies des veaux, 52 exploitations laitières du canton de Fribourg ont été suivies durant une saison d'hiver. Le management du colostrum n'était optimal que dans 46.2% des exploitations et 51.3% des animaux sont tombés au moins une fois malades durant la période d'observation. Ce sont le plus souvent des pneumonies (57.5%), des diarrhées (32.8%) et des affections de l'ombilic (5.7%) qui ont été diagnostiquées. Dans 65.4% des exploitations, les pneumonies ont été traitées par les agriculteurs avec des antibiotiques. Chez 57.7% des éleveurs, les diarrhées étaient traitées avec des antibiotiques. Les traitements par voie parentérale ont été effectués dans 47% des cas avec des fluoroquinolones et, pour les traitements par voie orale, des médicaments contenant des macrolides ont été utilisés dans 11% des cas. Ces résultats livrent des informations sur le management des veaux ainsi que sur leur santé et sur les traitements pratiqués dans une région où l'élevage laitier a une grande importance. Il apparait que les agriculteurs sont insuffisamment informés quant à l'usage des antibiotiques de réserve et quant à l'origine des diarrhées des veaux. Il faut clairement tendre à des améliorations en matière de management du colostrum, de stratégies de traitement et d'usage des antibiotiques.

[Bacterial resistance in bacteria isolated from the nasal cavity of Swiss dairy calves]. / Resistenzen bei Bakterienisolaten aus der Nase von Aufzuchtkälbern in Milchviehbetrieben.

INTRODUCTION: Fifty-six E. coli, 37 P. multocida und 8 M. haemolytica were isolated from 157 nasal swabs taken from calves in 52 dairy herds. The antibiotic susceptibility of the organisms was determined by measurement of the minimal inhibitory concentrations. Of the 56 E. coli isolates, 55.3% exhibited resistance to tetracyclines, 55.3% to sulfonamides, 39.3% to beta-lactams, 30.3% to aminoglycosides, 8.9% to fluorochinolones and 3.5% to 3rd generation cephalosporins. The 3rd generation cephalosporin- resistant isolates contained the extended spectrum-beta-lactamase gene blaCTX-M-14 and came from 2 farms where the milk of cows under antimicrobial treatment was fed to the calves and mastitis was treated with cefquinome as first line therapy. Of the 37 P. multocida isolates, 48.6% exhibited resistance to tetracyclines, 16.2% to beta-lactams, and 5.4% each to macrolides, aminoglycosides and sulfonamides. The 8 M. haemolytica isolates showed no resistances against the tested antibiotics.

INTRODUCTION: Dans 52 exploitations laitières, 157 écouvillons ont été prélevés des fosses nasales de veaux d'élevage, desquels ont été isolés 56 Escherichia coli, 37 Pasteurella multocida et 8 Mannheimia haemolytica. Les profils de résistance de ces germes ont été déterminés par la mesure de la concentration minimale inhibitrice. Pour les E. coli, 55.3% des souches isolées montraient une résistance aux tétracyclines, 55.3% aux sulfamidés, 39.3% aux béta-lactamines, 30.3% aux aminoglycosides, 8.9% aux fluoroquinolones et 3.5% aux céphalosporines de 3ème génération. Les souches résistantes aux céphalosporines de 3ème génération présentaient un gène de béta-lactamase à spectre étendu blaCTX-M-14 et provenaient de deux exploitations dans lesquelles le lait de vaches sous traitement antibiotique était distribué aux veaux et où le cefquinome était utilisé comme antibiotique de premier recours pour le traitement des mammites. Pour P. multocida, 48.6% des couches étaient résistantes aux tétracyclines, 16.2% aux béta-lactamines et 5.4% chacun aux macrolides, aux aminoglycosides et aux sulfamidés. Les 8 isolats de M. haemolytica étaient sensibles à tous les antibiotiques testés.

[Ceco-cecal intussusception in a Simmental heifer]. / Caeco-caecale Invagination bei einem Simmentaler Rind.

This report describes the clinical, laboratory and ultrasonographic findings in a Simmental heifer with a ceco-cecal intussusception. The general condition of the heifer was moderately reduced and it showed mild colic signs. Physical examination revealed a firm longish mass visible and palpable in the right flank. Findings upon rectal examination, fecal output und defecation were normal. Ultrasound examination of the mass revealed features typical for an intussusception. Based on the slow development of symptoms, normal fecal output and ultrasonography findings, a ceco-cecal intussusception was diagnosed. Right flank laparatomy was performed under general anaesthesia, and an end-to-side anastomosis between the jejunum and the spiral colon was made after resection of the intussuscepted intestines. Recovery was uneventful.

Gammaglobulin and selenium status in healthy neonatal dairy calves in Switzerland.

Serum samples from 142 calves and their dams were analyzed for gammaglobulins (gammaG, calves) and selenium concentrations (Se, calves and dams). A questionnaire provided information about birth and colostrum management. The calves and their dams were distributed into two groups according the calves' gammaG concentration (< 10 and >= 10 g/L), Se concentrations were compared between groups. The correlation between gammaG and Se concentrations in the calves and their dams was analyzed. Risk factors for failure of passive transfer and Se deficiency were assessed based on the questionnaire. The gammaG concentration of 42.9 % of the calves was < 10 g/L (median: 10.9). Calves showed significantly higher gammaG values after optimized colostrum administration than calves with suboptimal colostrum administration (p < 0.004). The median Se concentration was 26.8 and 36.5 µg/L for the calves and dams, respectively. A high correlation was observed between the Se concentration of the dam and her calf (r = 0.72, p < 0.001). The calves' Se and gammaG concentrations were not significantly correlated. These results demonstrate that further efforts toward better information of farmers regarding colostrum management and Se supply are warranted.

[Evaluation of associations between barn characteristics, results of barn climate parameter measurements and health indicators in Swiss veal calf herds]. / Evaluation der Zusammenhänge zwischen Stallmerkmalen, gemessenen Stallklimaparametern und Indikatoren für Tiergesundheit in Schweizer Kälbermastbetrieben.

INTRODUCTION: Easy-to-use digital devices to measure climate parameters that can also be used in calf barns have become available commercially in recent years. Data collected in a prospective cohort study in 43 Swiss veal calf operations were evaluated with regard to validity of measured climate parameters, potential associations of those with barn features, and relationships between values of climate parameters and barn characteristics, respectively, with indicators of calf health. Barn parameters, such as ventilation system, access to an outdoor pen and barn size, were recorded, and temperature, air humidity, ammonia and carbone dioxide concentrations were measured at five different locations in each barn during an average of six farm visits over a year. Furthermore, continuous measurements of temperature and humidity (over a period of 72 hours each) were performed once in summer and once in winter in each farm. Whether barn parameters and measured barn climate values are associated as significant risk factors with indicators of calf health (antimicrobial use, mortality and daily weight gain) was explored with statistical methods. Values outside the optimal range were observed for all parameters measured punctually during farm visits and in all seasons. Values of temperature and humidity outside the optimal range were observed more often by continuous than by punctual measurements. Relevant correlations were observed neither among the barn climate values measured punctually nor among measured barn climate values and number of calves, barn surface, bedded surface and barn volume. High maximal group size and presence of mechanic ventilation were positively associated with high antimicrobial use, and high maximal group size and high number of fattening groups were associated with mortality >3%. Farms in lowland regions and high air volume per calf were positively associated with daily weight gain. None of the measured barn climate parameters was associated with the calf health indicators antimicrobial use, mortality and daily weight gain. Therefore, climate parameter measurements appear inadequate to predict calf health in veal fattening operations. The present results show that these (easily) measured parameters are difficult to interpret and should be considered critically.

INTRODUCTION: Des instruments de mesure digitaux faciles à l'emploi pour les paramètres climatiques, qui peuvent aussi être utilisés dans les étables, sont disponibles depuis quelque temps.Afin d'évaluer la validité des valeurs de paramètres du climat mesurées, d'éventuelles associations de ces mesures avec certaines caractéristiques des étables, et les relations des mesures de paramètres associés au climat, respectivement des spécificités des étables, avec des indicateurs de santé animale, des données récoltées dans le cadre d'une étude prospective dans 43 exploitations d'engraissement de veaux en Suisse ont été analysées. D'une part, différents paramètres des étables (tels que le système d'aération, l'accès à un enclos externe, la surface de l'étable) ont été répertoriés. D'autre part, des mesures ponctuelles de la température, de l'humidité de l'air et des concentrations d'ammoniac et de dioxide de carbone ont été effectuées à cinq endroits de chaque étable lors de visites d'exploitation (en moyenne six par ferme sur une durée d'une année). De plus, des mesures continues de la température et de l'humidité ont été conduites sur 72 heures, une fois en été et une fois en hiver, dans chaque exploitation. À l'aide de méthodes statistiques, on a évalué si les caractéristiques des étables et les valeurs de climat mesurées sont associées en tant que facteurs de risque significatifs avec les indicateurs de santé animale (usage d'antibiotiques, mortalité et gain de poids journalier). Lors des mesures ponctuelles, des valeurs en dehors des domaines optimaux ont été observées pour tous les paramètres mesurés et à chaque saison. Des valeurs en dehors des domaines optimaux pour la température et l'humidité ont été constatées plus souvent par les mesures continues que par les mesures ponctuelles. Aucune corrélation significatrice n'a été observée entre les valeurs des paramètres de climat mesurées ponctuellement ou entre les valeurs des paramètres du climat mesurées et le nombre de veaux présents dans l'étable, la surface totale de l'étable, la surface paillée ou le volume de l'étable. Les groupes comptant beaucoup de veaux et la présence d'une ventilation mécanique étaient associés positivement à un usage élevé d'antibiotiques. Les groupes comprenant beaucoup de veaux et la présence d'un grand nombre de groupes étaient associés avec un taux de mortalité supérieur à 3%. Les exploitations en zone de plaine et le volume d'air par veau étaient associés positivement avec le gain de poids journalier. Aucun des paramètres de climat mesurés ne montrait d'association avec les indicateurs de santé animale (usage des antibiotiques, mortalité et gain de poids journalier). Ils semblent donc être inadéquats pour évaluer la santé des veaux dans des exploitations d'engraissement. Nos résultats montrent que les mesures de paramètres du climat sont difficiles à interpréter et doivent être considérés de manière critique.

Potential of a rumen bolus containing 1,25-dihydroxyvitamin D3 glycosides for the prevention of hypocalcaemia in primiparous and multiparous dairy cows.

Periparturient hypocalcaemia is a widespread metabolic disorder in dairy cows. Clinical and subclinical cases occur primarily in multiparous (Multi) cows, but subclinical cases have also been reported in primiparous (Primi) cows. A preventive strategy was investigated by administering the physiologically active vitamin D3 metabolite, 1,25-dihydroxyvitamin D3 (1,25-dihydroxycholecalciferol, 1,25(OH)2D3) as a rumen bolus. The bolus contained tablets of 1,25(OH)2D3 glycoside extract from Solanum glaucophyllum (SGE), releasing SGE over several days. The aim was to study the effect of a bolus containing 0 (C) or 500 µg (SGE) of 1,25(OH)2D3 on 1,25(OH)2D3 and mineral status in periparturient cows up to three weeks into lactation and on colostrum, milk and calves' blood mineral contents. The bolus was administered three to four days prior to expected calving to Primi and Multi cows fed a herbage-based diet (dietary cation-anion difference of +522 mEq/kg DM). One C or SGE bolus was applied to 12 Primi and 12 Multi cows. Blood was regularly sampled (and selected a posteriori for antepartum samples) in regard to the actual calving day (d0), immediately prior to bolus application and at day -2, 0.5, 1, 1.5, 2, 4, 8, 11, 15, 18 and 22. Additional samples included urine (at bolus application, d0.5 and d2), colostrum, milk samples (weekly) and calves' blood (d2). Blood serum 1,25(OH)2D3 increased between d0.5 and d2 in Primi-SGE, but remained unchanged in Primi-C, as did parathyroid hormone (PTH) and Ca in all Primi. Urinary Ca of Primi-SGE was increased on d2, indicating regulation of Ca excess. Three Multi-C cows with confirmed clinical hypocalcaemia needed treatment and thus were excluded from the dataset and replaced. Blood serum 1,25(OH)2D3 and PTH increased while Ca dropped by 40% between d0.5 and d2 in Multi-C, whereas 1,25(OH)2D3, Ca and PTH remained unchanged in Multi-SGE. Blood serum carboxyterminal telopeptide of type I collagen was higher in Primi than in Multi and increased with time, except in Primi-C. Mineral contents in colostrum, milk and blood serum of calves were not influenced to a relevant degree. In conclusion, Primi-C did not, in contrast to Multi-C, develop subclinical hypocalcaemia (<2.0 mmol Ca/l). Prevention of hypocalcaemia with one SGE bolus applied three to four days prior to expected calving was successful in maintaining blood Ca within normal range in Multi over the critical first two days and up to the first three weeks of lactation, without any observed detrimental effects on cows or calves.

Antimicrobial susceptibility in E. coli and Pasteurellaceae at the beginning and at the end of the fattening process in veal calves: Comparing 'outdoor veal calf' and conventional operations.

Animal husbandry requires practical measures to limit antimicrobial resistance (AMR). Therefore, a novel management and housing concept for veal calf fattening was implemented on 19 intervention farms (IF) and evaluated regarding its effects on AMR in Escherichia (E.) coli, Pasteurella (P.) multocida and Mannheimia (M.) haemolytica in comparison with 19 conventional control farms (CF). Treatment intensity (-80%) and mortality (-50%) were significantly lower in IF than in CF, however, production parameters did not differ significantly between groups. Rectal and nasopharyngeal swabs were taken at the beginning and the end of the fattening period. Susceptibility testing by determination of the minimum inhibitory concentration was performed on 5420 isolates. The presence of AMR was described as prevalence of resistant isolates (%), by calculating the Antimicrobial Resistance Index (ARI: number of resistance of one isolate to single drugs/total number of drugs tested), by the occurrence of pansusceptible isolates (susceptible to all tested drugs, ARI=0), and by calculating the prevalence of multidrug (≥3) resistant isolates (MDR). Before slaughter, odds for carrying pansusceptible E. coli were higher in IF than in CF (+65%, p=0.022), whereas ARI was lower (-16%, p=0.003), and MDR isolates were less prevalent (-65%, p=0.001). For P. multocida, odds for carrying pansusceptible isolates were higher in IF before slaughter compared to CF (+990%, p=0.009). No differences between IF and CF were seen regarding the prevalence of pansuceptible M. haemolytica. These findings indicate that easy-to-implement measures to improve calf management can lead to a limitation of AMR in Swiss veal fattening farms.

Intestinal atresia and ectopia in a bovine fetus.

A 2-year-old Red Holstein cow was presented with uterine torsion at 235 days of pregnancy. The fetus extracted by cesarean section had weak vital signs and marked abdominal distention. An edematous pouch that contained tubular structures with peristaltic activity was associated with the umbilical cord. Because of poor prognosis, both dam and fetus were euthanized. At necropsy, the fetus had severe distention of the forestomachs, abomasum, and proximal small intestine; absence of distal small intestine, cecum, and proximal colon; atresia of the 2 blind ends of the intestine; and atrophy of distal colon and rectum. The tubular structures associated with the umbilical cord were identified as the segments of intestine that were absent in the fetus. Intestinal atresia combined with ectopia may be caused by local ischemia during temporary herniation and rotation of the fetal gut into the extraembryonic coelom. The close connection between ectopic intestine and amniotic sheath of the umbilical cord in this case may have facilitated vascularization and allowed development and viability of the ectopic intestine.

[Tremorgenic syndrome in a cattle herd after feeding silage contaminated with A. clavatus]. / Tremorgenes Syndrom in einem Rinderbestand nach Verfütterung einer mit A. clavatus befallenen Silage.

The clinical signs, pathological and laboratory findings of cattle suffering from a tremorgenic syndrome are described. Animals on a farm with a total of 22 cows, 18 heifers and 9 calves were fed mouldy grass and spent malt-grain silage. Five heifers were affected with muscular tremor, hyperexcitability and hypersensitivity. They were ataxic or in sternal recumbency, while their appetite remained normal. Haematology and blood chemistry in two heifers as well as cerebrospinal fluid from one sick animal were unremarkable. The pathological examination of one animal brought no macroscopic changes to light. Histological examination, however, revealed the degeneration of motor neurones in the midbrain, brain stem and spinal cord. Analysis of a silage sample provided evidence of the presence of Aspergillus clavatus, a mould capable of producing neurotoxic tremorgenic mycotoxins. Epidemiology, clinical findings, pathology and microbiological examination suggest that the five cattle were suffering from neuromycotoxicosis.

[Meta-analysis to estimate the economic losses caused by reduced milk yield and reproductive performance associated with bovine paratuberculosis in Switzerland]. / Eine Meta-Analyse zur Schätzung der wirtschaftlichen Einbussen durch Milch- und Reproduktionsverluste infolge boviner Paratuberkulose in der Schweiz.

INTRODUCTION: Especially in regions with intensive cattle farming, paratuberculosis in ruminants can cause considerable economic losses for example through loss of sick animals, reduced milk yield and decreased reproduction performance. Although quantifying the actual economic losses is complex, this study attempts to quantify the losses caused by paratuberculosis in infected dairy farms in Switzerland by means of meta-analyses. For this purpose, in an elaborate selection process, data from 12 studies on milk yield and from three studies on the calving to conception interval were finally selected for further calculations. In addition, data from eight studies each on milk fat concentration and milk protein concentration were evaluated. For the meta-analyses, only studies in which «sick¼ (seropositive) and «healthy¼ (seronegative) animals based on the results of serum ELISA tests were compared at the individual animal level were considered. With a paratuberculosis prevalence of 5,99 % in cattle in Switzerland, a total loss of CHF 12 034 329,96 (95 % CI [CHF 8 625 406,02; CHF 16 409 276,30]; 11 095 652,20 € [7 952 624,35 €; 15 129 352,70 €]) per year was calculated for a population of 559 900 dairy cows. The main part of the losses is caused by an extended calving to conception interval: Seropositive animals need an average of 14,93 days longer (95 % CI [1,73; 28,13]) from calving to successful insemination as seronegative animals. This results in total costs for the extended calving to conception interval due to paratuberculosis of CHF 7 365 591,21 per year (95 % CI [CHF 900 394,95; CHF 14 838 087,61]; 6 791 075,10 € [830 164,14 €; 13 680 716,80 €]). Milk yield reduction based on a lactation period of 305 days results in an economic loss of CHF 4 668 738,75 per year (95 % CI [CHF 1 571 188,69; CHF 7 725 011,07]; 4 304 577,13 € [1 448 635,97 €; 7 122 460,21 €]). Milk fat and milk protein content were not found to be significantly changed. Despite a large number of studies in the screening phase, it was not possible to calculate all types of losses attributable to paratuberculosis due to lack of comparability between the studies, which is essential for meta-analyses. Nevertheless, it was possible to carry out four different meta-analyses, the results of which give a first impression of the economic importance of paratuberculosis in dairy cows in Switzerland.

INTRODUCTION: La paratuberculose des ruminants cause, particulièrement dans les régions ayant une industrie laitière intensive, des pertes économiques considérables, par exemple par la perte d'animaux malades, la réduction de la production laitière et une reproduction diminuée. Malgré la complexité de la quantification des pertes économiques effectives, on a essayé dans l'étude présentée ici de calculer les pertes causées par la paratuberculose dans les exploitations laitières en Suisse au moyen de méta-analyses. Dans ce but, des données extraites par un processus de sélection compliqué de 12 études sur la production laitière et de trois études sur la période de tarissement ont été utilisées pour calculer les pertes dues à la paratuberculose. De plus, huit études chacune sur la concentration de graisse et des protéines du lait ont été prises en compte. Seules des études où les animaux étaient classifiés comme «sains¼ (séronégatifs) et «malades¼ (séropositifs) sur la base d'un test ELISA sérique ont été prises en considération pour les méta-analyses. Pour une prévalence de la paratuberculose de 5,99 % chez les bovins en Suisse, on a pu calculer pour une population de 559 900 vaches laitières une perte totale de 12 034 329,96 CHF (IC 95 % [8 625 406,02 CHF; 16 409 276,30 CHF]; 11 095 652,20 € [7 952 624,35 €; 15 129 352,70 €]) par année. La plus grande partie de ces pertes sont dues à une période de tarissement prolongée: les vaches séropositifs ont besoin en moyenne de 14,93 jours de plus (IC 95 % [1,73; 28,13]) du vêlage à une insémination menant à une gestation que les animaux séronégatifs. Il en résulte des coûts dus à la paratuberculose en raison d'une période de tarissement prolongée de 7 365 591,21 CHF par année (IC 95 % [900 394,95 CHF; 14 838 087,61 CHF]; 6 791 075,10 € [830 164,14 €; 13 680 716,80 €]). La diminution de la production laitière cause pour une durée de lactation de 305 jours une perte économique de 4 668 738,75 CHF par année (IC 95 % [1 571 188,69 CHF; 7 725 011,07 CHF]; 4 304 577,13 € [1 448 635,97 €; 7 122 460,21 €]). Les pertes en valeurs de graisse et de protéines du lait n'étaient pas significatives. Malgré le nombre élevé d'études prises en compte dans la phase de recherche de publications pertinentes, il n'a pas été possible de calculer tous les types de pertes, car les études n'étaient pas suffisamment comparables entre elles, ce qui est une condition essentielle pour une méta-analyse. Il a cependant été possible de procéder à quatre méta-analyses différentes, dont les résultats donnent une idée de l'importance économique des pertes liées à la paratuberculose chez les vaches laitières en Suisse.