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With the increasing digital transformation, work tasks are changing—in some cases, significantly. Our study addresses the question of whether the established criteria for work design are still sufficient or if they should get updated and additional criteria become necessary in the context of digitalization. In a multistage consensus process involving interdisciplinary groups of experts, we have identified specific criteria for the humane design of work in a world increasingly permeated by digitalized work tools. Starting with an expert workshop using a combined nominal group/focus group technique, followed by a real-time Delphi study, a content analysis and a five-stage peer comment process, we detected 13 criteria and 38 design guidelines for human-centered work in digital transformation. Mapping these with established criteria, it became apparent that some established criteria have experienced a new dynamic because of the digital transformation. For other criteria, a need for digitization-sensitive design is discernible. In addition, criteria have emerged whose necessity is rooted in the digital transformation. A diffusion and stronger interconnection of the various levels of the work system in connection with the digital transformation of work is apparent.

Zusammenfassung Ziel Etablierung von Referenzintervallen für Mangan (Mn) im Serum, Plasma und Vollblut bei adulten, gesunden Warmblutpferden mit bekannter Mn-Aufnahme und Vergleich von 2 analytischen Methoden der Mn-Bestimmung im Blut. Material und Methoden Zwischen Mai 2018 und November 2019 erfolgte auf 3 Gestüten bei 270 gesunden Pferden im Alter von 3–25 Jahren eine einmalige Blutprobenentnahme. In Vollblut, Plasma (Antikoagulans jeweils Lithium-Heparin [LH]) und Serum wurden die Mn-Konzentrationen mittels Massenspektrometrie mit induktiv gekoppeltem Plasma (ICP-MS) sowie mittels Atomabsorptionsspektrometrie (AAS) bestimmt. Die Referenzintervalle für jedes Substrat wurden nach den Empfehlungen der International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) und des Clinical and Laboratory Standards Institute (CLSI) berechnet (Bereich zwischen 2,5- und 97,5-Perzentil der analysierten Mn-Blutkonzentration). Zeitgleich mit der Blutprobenentnahme wurden repräsentative Futterproben entnommen, um den Mn-Gehalt der korrespondierenden Fütterung zu bestimmen. Ergebnisse Die Pferde zeigten im Vollblut mit einer medianen Mn-Konzentration von 12,4 µg/l (Referenzintervall: 4,99–25,1 µg/l [AAS]; 5,99–25,3 µg/l [ICP-MS]) signifikant höhere Mn-Konzentrationen (p < 0,0001) als im korrespondierenden Serum (Median: 1,65 µg/l, Referenzintervall: 0,60–3,50 µg/l [AAS]; 1,11–2,96 µg/l [ICP-MS]) oder LH-Plasma (Median: 1,35 µg/l, Referenzintervall: 0,22–2,68 µg/l [AAS]; 0,59–2,45 µg/l [ICP-MS]). Im Methodenvergleich ergaben sich für LH-Plasma und Serum zwischen der AAS und der ICP-MS statistisch signifikante Abweichungen in den Mn-Bestimmungen, wohingegen sie für das Vollblut vergleichbare Ergebnisse lieferten. Schlussfolgerung und klinische Relevanz Vollblut weist durchschnittlich 10-fach höhere Mn-Konzentrationen auf als Serum oder LH-Plasma. Bei der Bewertung von Mn-Konzentrationen im Blut muss daher berücksichtigt werden, welches Probenmaterial analysiert wurde und welche Methode zur Anwendung kam, da in Serum und Plasma zwischen AAS und ICP-MS relevante Unterschiede auftreten können.

Introduction Metabolomics studies in canine endocrine abnormalities are sparse and basic information on these abnormalities must be generated. Objectives To characterize the metabolic changes associated with elevated fructosamine, reflecting poor glycemic control, and low thyroxine, a thyroid hormone controlling metabolism. Methods Leftovers of clinical serum samples; 25 controls, 79 high fructosamine, and 47 low thyroxine, were analyzed using 1H NMR and differences were evaluated using Firth logistic regression. Results Both high fructosamine and low thyroxine were associated with changes in concentrations of multiple metabolites, including glycoprotein acetyls and lipids. Conclusion These findings suggest promising makers for further research and clinical validation.

During pregnancy and parturition, female dogs have to cope with various challenges such as providing nutrients for the growth of the fetuses, hormonal changes, whelping, nursing, milk production, and uterine involution. Metabolomic research has been used to characterize the influence of several factors on metabolism such as inter- and intra-individual factors, feeding, aging, inter-breed differences, drug action, behavior, exercise, genetic factors, neuter status, and pathologic processes. Aim of this study was to identify metabolites showing specific changes in blood serum at the different phases of pregnancy and lactation. In total, 27 privately owned female dogs of 21 different breeds were sampled at six time points: during heat, in early, mid and late pregnancy, at the suspected peak of lactation and after weaning. A validated and highly automated canine-specific NMR metabolomics technology was utilized to quantitate 123 measurands. It was evaluated which metabolite concentrations showed significant changes between the different time points. Metabolites were then grouped into five clusters based on concentration patterns and biochemical relationships between the metabolites: high in mid-pregnancy, low in mid-pregnancy, high in late pregnancy, high in lactation, and low in lactation. Several metabolites such as albumin, glycoprotein acetyls, fatty acids, lipoproteins, glucose, and some amino acids show similar patterns during pregnancy and lactation as shown in humans. The patterns of some other parameters such as branched-chain amino acids, alanine and histidine seem to differ between these species. For most metabolites, it is yet unstudied whether the observed changes arise from modified resorption from the intestines, modified production, or metabolism in the maternal or fetal tissues. Hence, further species-specific metabolomic research may support a broader understanding of the physiological changes caused by pregnancy that are likely to be key for the normal fetal growth and development. Our findings provide a baseline of normal metabolic changes during healthy canine pregnancy and parturition. Combined with future metabolomics findings, they may help monitor vital functions of pre-, intra-, and post-partum bitches and may allow early detection of illness.

Ondansetron is an effective antiemetic that is being widely used as a second-line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ondansetron during pregnancy has—following publication of controversial and seemingly contradictory results—been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester. The ensuing Summary of Product Characteristics (SmPC) was updated in November 2019 with important changes to section on “Fertility, pregnancy and lactation.” The SmPC now states that ondansetron should not be used in the first trimester of pregnancy. ENTIS, The European Network of Teratology Information Services, believes that the implementation of this regulatory step—which has important clinical consequences—is insufficiently substantiated and is not serving the interest of pregnant women with severe nausea and vomiting. Herein, we discuss the underlying evidence and argue the case against the EMA decision.

Background Diagnosis of pancreatic diseases in dogs is still challenging because of variable clinical signs, which do not always correspond with clinical pathology and histopathological findings. Objectives To characterize inflammatory and neoplastic pancreatic diseases of dogs and to correlate these findings with clinical findings and canine pancreatic lipase immunoreactivity (cPLI) results. Animals Tissue specimens and corresponding blood samples from 72 dogs submitted for routine diagnostic testing. Methods Four groups were defined histologically: (1) normal pancreas (n = 40), (2) mild pancreatitis (n = 8), (3) moderate or severe pancreatitis (acute, n = 11; chronic, n = 1), and (4) pancreatic neoplasms (n = 12). An in‐house cPLI ELISA (310 μg/L, pancreatitis) was performed. Results In dogs with normal pancreas, 92.5% of serum cPLI results were within the reference range and significantly lower than in dogs with mild acute pancreatitis, moderate or severe acute pancreatitis and pancreatic tumors. In dogs with moderate or severe acute pancreatitis, cPLI sensitivity was 90.9% (95% confidence interval [CI], 58.7%‐99.8%). Most dogs (9/12) with pancreatic tumors (group 4) had additional pancreatic inflammation and cPLI results were increased in 10 dogs. Conclusions and Clinical Importance High cPLI indicates serious acute pancreatitis but underlying pancreatic neoplasms should also be taken into consideration. This study confirms the relevance of histopathology in the diagnostic evaluation of pancreatic diseases.

Objectives Our aim was to evaluate the effects of beta-blockers during the second and third trimester on fetal growth, length of gestation and postnatal symptoms in exposed infants. Methods The current prospective observational cohort study compares 294 neonates of hypertensive mothers on metoprolol or bisoprolol during the second and/or third trimester with 225 methyldopa-exposed infants and 588 infants of nonhypertensive mothers. The risks for reduced birth weight, prematurity, neonatal bradycardia, hypoglycaemia and respiratory disorders were analysed. Results The rate of small-for-gestational-age children was significantly higher in long-term beta-blocker exposed infants (24.1%) compared with the methyldopa cohort [10.2%, odds ratio (OR)adj 2.5, 95% confidence interval (CI) 1.2-5.2] and the nonhypertensive cohort (9.9%, ORadj 4.3, 95% CI 2.6-7.1). The risk for preterm birth was significantly increased compared with nonhypertensive pregnancies (ORadj 2.2, 95% CI 1.3-3.8) but not compared with the methyldopa cohort. Neonatal adverse outcomes occurred more frequently in the study cohort (11.5%) compared with the nonhypertensive comparison group (6.5%) and the methyldopa cohort (8.4%), but without statistical significance (ORadj 1.5, 95% CI 0.7-3.0 and ORadj 1.5, 95% CI 0.7-3.3, respectively). Conclusion Long-term intrauterine exposure to metoprolol or bisoprolol may increase the risk of being born small-for-gestational-age. It is still a matter of debate to which extent maternal hypertension contributes to the lower birth weight. Serious neonatal symptoms are rare. Altogether, metoprolol and bisoprolol are well tolerated treatment options, but a case-by-case decision on close neonatal monitoring is recommended.

During the first months of the coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cases of human-to-cat transmission were reported. Seroconversion was shown in cats infected under experimental and natural conditions. This large-scale survey of 1,005 serum samples was conducted to investigate anti-SARS-CoV-2 antibody prevalence in domestic cats during the first 7 months of the pandemic in Germany and other European countries. In addition, we compared the sensitivity and specificity of two multispecies SARS-CoV-2 antibody enzyme-linked immunosorbent assays (ELISA). Results were confirmed by using an indirect immunofluorescence test (iIFT) and a surrogate virus neutralization test (sVNT). Sera that were highly positive for feline coronavirus (FCoV) antibodies (n = 103) were included to correct for cross-reactivity of the tests used. Our results showed an overall SARS-CoV-2 seropositivity of 1.9% (n = 19) in a receptor-binding domain (RBD)-based ELISA, additional 0.8% (n = 8) were giving inconclusive results. In contrast, a nucleocapsid-based ELISA revealed 0.5% (n = 5) positive and 0.2% (n = 2) inconclusive results. While the iIFT and sVNT confirmed 100% of positive and 50%–57.1% of the doubtful results as determined in the RBD ELISA, the nucleocapsid-based assay showed a high discrepancy and only one of the five positive results could be confirmed. The results indicate significant deficits of the nucleocapsid-based ELISA with respect to sensitivity and specificity. Due to a significantly higher rate (5.8%) of positive results in the group of highly FCoV antibody-positive samples, cross-reactivity of the FCoV-ELISA with SARS-CoV-2 antibodies cannot be excluded. Furthermore, we investigated the impact of direct contact of domestic cats (n = 23) to SARS-CoV-2 positive owners. Considering one inconclusive result, which got confirmed by iIFT, this exposure did not lead to a significantly higher prevalence (4.4%; p = .358) among tested subjects. Overall, we conclude that cats are a negligible entity with respect to virus transmission in Europe.

This study aimed to examine the effects of an oral supplementation on manganese (Mn) concentrations in the blood of lactating warm-blood broodmares. Furthermore, the potential relationship between Mn supply of the lactating mare and its suckling foal was investigated.During the 90-day trial, lactating mares were divided into 3 groups and daily received a daily dose of either a placebo (n = 11) or a Mn supplement of 560 mg Mn as Mn sulfate (n = 11) or Mn chelate (n = 11) in addition to the Mn intake from the basal ration (hay ad libitum, total mixed ration: Mn intake ~ 100 mg/kg dry matter). Blood samples were taken from the mares and their foals in 14-day intervals. The Mn determination in serum and whole blood as well as in the mare's milk was carried out by means of mass spectrometry with inductively coupled plasma. The Mn analysis in representative feed samples was performed by means of atomic absorption spectrometry. Data were assessed using the software IBM SPSS Statistics 27 (IBM Deutschland GmbH, Ehningen).During the trial period, the mares showed Mn concentrations 10-fold higher in whole blood (median: 15.6 µg/l; 25-75 percentile: 12.8-18.5 µg/l) than in serum (median: 1.54 µg/l; 25-75 percentile: 1.20-1.90 µg/l). The foals had Mn whole-blood concentrations 16.4-fold higher (median: 21.3 µg/l; 25-75 percentile: 16.7-28.1 µg/l) compared to their serum (median: 1.50 µg/l; 25-75 percentile: 1.30-1.70 µg/l). The Mn whole-blood levels of the foals corresponded to 1.6-fold the Mn concentration of their dams. The milk contained a median Mn concentration of 0.012 mg/kg fresh matter. Mn supplementation had no effect on the Mn blood levels of mares and their foals.Blood Mn concentrations were not affected by the Mn supplementation. However, the Mn levels differed significantly between serum and whole blood. In addition, the Mn concentrations in whole blood of suckling foals were higher compared to their dams, although the Mn concentrations in the mare's milk were low regardless of Mn supplementation. Due to the low Mn content in milk, early Mn supply, preferably by forages, is necessary to ensure that the foals are supplied with Mn according to their requirement.ZIEL: Überprüfung von Effekten einer oralen Ergänzung von Mangan (Mn) auf die Mn-Konzentration im Blut laktierender Warmblutstuten und die Untersuchung der Beziehung zwischen der Mn-Versorgung der Mutterstuten und ihrer Saugfohlen.Für die 90-tägige Fütterungssphase wurden laktierende Stuten in 3 Gruppen eingeteilt und erhielten täglich ein Placebo (n = 11) oder eine Mn-Zulage von 560 mg Mn als Mn-Sulfat (n = 11) oder Mn-Chelat (n = 11) zusätzlich zur Mn-Aufnahme aus der Grundration (Heu ad libitum, Totale Mischration: Mn-Aufnahme ~100 mg/kg Trockenmasse). In 14-tägigen Abständen wurden Blutproben von den Stuten und Fohlen entnommen. Die Mn-Bestimmung im Serum und Vollblut sowie in der Stutenmilch erfolgte mittels Massenspektrometrie mit induktiv gekoppeltem Plasma, die Mn-Analyse in repräsentativen Futterproben mittels Atomabsorptionsspektrometrie. Zur Datenauswertung diente die Software IBM SPSS Statistics 27 (IBM Deutschland GmbH, Ehningen).Während der Supplementierung zeigten die Stuten im Vollblut (Median: 15,6 µg/l; 25.–75. Perzentil: 12,8–18,5 µg/l) 10-fach höhere Mn-Konzentrationen als im Serum (Median: 1,54 µg/l; 25.–75. Perzentil: 1,20–1,90 µg/l). Die Fohlen wiesen 16,4-fach höhere Mn-Konzentrationen im Vollblut (Median: 21,3 µg/l; 25.–75. Perzentil: 16,7–28,1 µg/l) im Vergleich zum Serum (Median: 1,50 µg/l; 25.–75. Perzentil: 1,30–1,70 µg/l) auf. Die Mn-Vollblutspiegel der Fohlen entsprachen der 1,6-fachen Mn-Konzentration ihrer Mutterstuten. Die Milch enthielt eine mediane Mn-Konzentration von 0,012 mg/kg Frischmasse. Die Mn-Supplementierung hatte keinen Effekt auf die Mn-Spiegel im Blut von Stuten und ihren Fohlen.Die Mn-Supplementierung beeinflusste die Mn-Konzentrationen im Blut nicht, es unterschieden sich aber die Mn-Gehalte zwischen Serum und Vollblut. Ferner lagen die Mn-Spiegel im Vollblut der Fohlen höher als die der Stuten, obwohl die Mn-Konzentrationen – unabhängig von der Supplementierung – in der Stutenmilch niedrig waren. Aufgrund des geringen Mn-Gehalts der Milch ist eine Mn-Zufuhr, vorzugsweise über das Raufutter, notwendig, um die Mn-Versorgung der Fohlen sicherzustellen.

Pregnancy and lactation are amongst the most challenging times of a bitch’s life. Most studies focusing on the endocrinological aspect of pregnancy consider only a small number of animals. The aim of this study was to evaluate progesterone (P4) concentrations in a large number of bitches during early, mid and late pregnancy. In total, 126 bitches of various breeds were recruited following a thorough clinical and gynecological examination during estrus. Blood samples were collected three times (T1–T3) during pregnancy or from non-pregnant dogs in diestrus, and P4 was measured via chemiluminescence. At T1 (11–19 days post-ovulation (dpo)), serum P4 concentrations were 30.23 ± 6.65 ng/mL and 28.45 ± 6.26 ng/mL, at T2 (23–32 dpo) they were 22.73 ± 6.27 ng/mL and 22.59 ± 5.77 ng/mL and at T3 (52–60 dpo) they were 6.68 ± 2.18 ng/mL and 3.17 ± 2.26 ng/mL, in pregnant (n = 98) and non-pregnant (n = 23) dogs respectively. The P4 concentrations differed significantly between pregnant and non-pregnant animals at the last examination (p ≤ 0.001). In the context of hypoluteoidism, the gathered data yielded interesting results. Overall, 28 out of 98 pregnant bitches showed a greater decline (>15 ng/mL) in P4 concentrations from early to mid-pregnancy, and 56 bitches showed P4 concentrations lower than deemed adequate (>20 ng/mL at T1 and T2, >5 ng/mL at T3) according to existing recommendations. Despite not being supplemented with P4, none of those animals suffered from abortion or preterm delivery. Considering that supplementation of P4 can entail considerable risks for the bitch and the puppies, more research on P4 concentration patterns, diagnosis of hypoluteoidism and treatment indications and options is indicated.

Background A 2019 ACVIM consensus statement on diagnostics for immune-mediated hemolytic anemia (IMHA) in dogs made testing recommendations. As data on the performance of immunohematological tests was lacking, we undertook a comparative analysis. Material and methods Anticoagulated blood samples from 126 dogs suspected of having IMHA submitted to a diagnostic veterinary laboratory for a routine direct antiglobulin test (DAT) and from 28 healthy control dogs were evaluated for spherocytosis and autoagglutination before and after three saline washes. Samples were also subjected to different DATs: a gel minitube and an immunochromatographic strip kit used in clinics; neutral gel column cards, microtiter plates (at 4°, 22°, and 37°C), capillary tubes, and flow cytometry used in laboratories. Results Samples from healthy dogs yielded negative results with all immunodiagnostic tests. Among the 126 samples submitted for DAT 67 were positive by a DAT utilizing microtiter plates with goat anti-dog antiglobulin DAT at 22°C. Notably, DAT results were comparable and consistent across all evaluated methods regardless of antiglobulin and temperature used. DAT+ dogs were more severely anemic and more likely to have erythroid regeneration compared to DAT- dogs. Macroscopic agglutination in tubes or on slides was observed in 48 samples after 1:1 and 1:4 blood to saline dilution, but only persisted in four samples after washing. Among the DAT+ samples, 57% had agglutination, 87% had spherocytosis, and 45% had both. There was good correlation between spherocytosis and DAT results from the six DAT techniques, but the correlation with autoagglutination was only fair. Clinical follow-up was available for 42 dogs. Of the sample from 12 DAT+ dogs collected during treatment, 10 remained DAT+ when tested 1–24 weeks after initial assessment. Conclusions Based upon this comparative prospective survey, all in-clinic and laboratory DAT techniques produced similar results when performed by trained personnel and can therefore be recommended for detection of antibody-coated erythrocytes and immunohematological diagnosis. In addition, use of these tests for monitoring response of IMHA dogs to treatment might be valuable.

This study aimed to establish reference intervals for Mn in whole blood, plasma and serum of healthy, adult warmblood horses with known dietary Mn intake and to compare 2 methods of analysis.Between May 2018 and November 2019 a single blood sample was taken from a total of 270 clinically healthy horses (age: 3-25 years) in 3 stud farms. In lithium-heparin (LH) whole blood, LH plasma and serum Mn concentrations were analyzed by means of atomic absorption spectrometry (AAS) and inductively coupled plasma mass spectrometry (ICP-MS). The reference intervals were calculated according to the recommendations of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and the Clinical and Laboratory Standards Institute (CLSI) comprising the range between 2.5 and 97.5 percentile of the analyzed Mn concentrations. Concurrent to blood sampling feed samples were taken and analyzed in order to determine the Mn content of the corresponding feeding ration.The horses' whole-blood Mn levels were significantly (p0.0001) higher with a median Mn concentration of 12.4 μg/l (reference interval: 4.99-25.1 μg/l [AAS]; 5.99-25.3 μg/l [ICP-MS]) than in the corresponding serum (median: 1.65 μg/l, reference interval: 0.60-3.50 μg/l [AAS]; 1.11-2.96 μg/l [ICP-MS]) or LH plasma (median: 1.35 μg/l, reference interval: 0.22-2.68 μg/l [AAS]; 0.59-2.45 μg/l [ICP-MS]). In the comparison of methods, there were statistically significant differences in the Mn determinations for LH plasma and serum between AAS and ICP-MS, whereas they yielded comparable results for whole blood.Whole blood shows an average of 10-fold higher Mn concentrations than serum or LH plasma. When evaluating blood Mn concentrations, consideration must be granted to the sample material under analysis as well as to which method is employed since relevant differences were found between AAS and ICP-MS in serum and LH plasma.ZIEL: Etablierung von Referenzintervallen für Mangan (Mn) im Serum, Plasma und Vollblut bei adulten, gesunden Warmblutpferden mit bekannter Mn-Aufnahme und Vergleich von 2 analytischen Methoden der Mn-Bestimmung im Blut.Zwischen Mai 2018 und November 2019 erfolgte auf 3 Gestüten bei 270 gesunden Pferden im Alter von 3–25 Jahren eine einmalige Blutprobenentnahme. In Vollblut, Plasma (Antikoagulans jeweils Lithium-Heparin [LH]) und Serum wurden die Mn-Konzentrationen mittels Massenspektrometrie mit induktiv gekoppeltem Plasma (ICP-MS) sowie mittels Atomabsorptionsspektrometrie (AAS) bestimmt. Die Referenzintervalle für jedes Substrat wurden nach den Empfehlungen der International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) und des Clinical and Laboratory Standards Institute (CLSI) berechnet (Bereich zwischen 2,5- und 97,5-Perzentil der analysierten Mn-Blutkonzentration). Zeitgleich mit der Blutprobenentnahme wurden repräsentative Futterproben entnommen, um den Mn-Gehalt der korrespondierenden Fütterung zu bestimmen.Die Pferde zeigten im Vollblut mit einer medianen Mn-Konzentration von 12,4 µg/l (Referenzintervall: 4,99–25,1 µg/l [AAS]; 5,99–25,3 µg/l [ICP-MS]) signifikant höhere Mn-Konzentrationen (p0,0001) als im korrespondierenden Serum (Median: 1,65 µg/l, Referenzintervall: 0,60–3,50 µg/l [AAS]; 1,11–2,96 µg/l [ICP-MS]) oder LH-Plasma (Median: 1,35 µg/l, Referenzintervall: 0,22–2,68 µg/l [AAS]; 0,59–2,45 µg/l [ICP-MS]). Im Methodenvergleich ergaben sich für LH-Plasma und Serum zwischen der AAS und der ICP-MS statistisch signifikante Abweichungen in den Mn-Bestimmungen, wohingegen sie für das Vollblut vergleichbare Ergebnisse lieferten.Vollblut weist durchschnittlich 10-fach höhere Mn-Konzentrationen auf als Serum oder LH-Plasma. Bei der Bewertung von Mn-Konzentrationen im Blut muss daher berücksichtigt werden, welches Probenmaterial analysiert wurde und welche Methode zur Anwendung kam, da in Serum und Plasma zwischen AAS und ICP-MS relevante Unterschiede auftreten können.

Die Innovationen in der Therapie rheumatischer Erkrankungen haben die Lebensqualitat vieler PatientInnen deutlich verbessert, sodass mehr Frauen ihren Kinderwunsch planen und realisieren konnen. In diesem Artikel werden die Erfahrungen zu Antirheumatika in der Schwangerschaft zusammenfassend dargestellt und Empfehlungen fur den klinischen Alltag gegeben. Die Beratung zum Arzneimittelrisiko muss 2 verschiedenen Situationen Rechnung tragen: der Einschatzung einer Arzneitherapie bei ungeplanter Schwangerschaft und der geplanten Arzneistoffauswahl bei Kinderwunsch bzw. in der Schwangerschaft. Fur eine individuelle Risiko-Nutzen-Einschatzung sind, neben der Vorgeschichte der Patientin, Kenntnisse zum moglichen Risiko und Erfahrungsumfang der Arzneistoffe erforderlich sowie zu Besonderheiten und Verlauf der jeweiligen rheumatischen Erkrankung in der Schwangerschaft. Das Pharmakovigilanz- und Beratungszentrum fur Embryonaltoxikologie (PVZ Embryotox) bietet Beratungen zu Arzneimitteln in Schwangerschaft und Stillzeit an und unterstutzt die behandelnden ArztInnen bei der Therapieauswahl und Risikoeinschatzung. The innovations in the therapy of rheumatic diseases have significantly improved the quality of life of many patients. Therefore, more women can plan to have children or get pregnant. This article summarizes the experiences with antirheumatic drugs during pregnancy and provides recommendations for everyday clinical use. The counselling has to deal with 2 different situations: the risk assessment of a drug therapy in an unplanned pregnancy and the planned selection of a drug before or during pregnancy. In addition to the medical history of the patient, an individual risk-benefit assessment requires knowledge of the possible risk and scope of experience of the drugs as well as of the special features and course of the respective rheumatic disease during pregnancy. The “Pharmakovigilanz- und Beratungszentrum fur Embryonaltoxikologie” (PVZ Embryotox) offers advice on drugs in pregnancy and lactation and supports the treating physicians in the selection of therapies and risk assessment.

Introduction Phenobarbital is a commonly used anticonvulsant for the treatment of canine epileptic seizures. In addition to its central nervous system (CNS) depressing effects, long-term phenobarbital administration affects liver function. However, broader metabolic consequences of phenobarbital treatment are poorly characterized. Objectives To identify metabolic changes in the sera of phenobarbital-treated dogs and to investigate the relationship between serum phenobarbital concentration and metabolite levels. Methods Leftovers of clinical samples were used: 58 cases with phenobarbital concentrations ranging from 7.8 µg/mL to 50.8 µg/mL, and 25 controls. The study design was cross-sectional. The samples were analyzed by a canine-specific 1H NMR metabolomics platform. Differences between the case and control groups were evaluated by logistic regression. The linear relationship between metabolite and phenobarbital concentrations was evaluated using linear regression. Results Increasing concentrations of glycoprotein acetyls, LDL particle size, palmitic acid, and saturated fatty acids, and decreasing concentrations of albumin, glutamine, histidine, LDL particle concentration, multiple HDL measures, and polyunsaturated fatty acids increased the odds of the sample belonging to the phenobarbital-treated group, having a p-value .7. Albumin and glycoprotein acetyls had the best discriminative ability between the groups (AUC: .94). No linear associations between phenobarbital and metabolite concentrations were observed. Conclusion The identified metabolites are known to associate with, for example, liver and CNS function, inflammatory processes and drug binding. The lack of a linear association to phenobarbital concentration suggests that other factors than the blood phenobarbital concentration contribute to the magnitude of metabolic changes.

In November 2019, section 4.6 of the ondansetron Summary of Product Characteristics (SmPC) was revised by the European Medicines Agency (EMA). It explicitly states, “ondansetron should not be used during the first trimester of pregnancy” (Ondansetron, SmPC[cited 2020 July 08]. Available from: https://www.medicines.org.uk/emc/). Ondansetron is an effective antiemetic drug commonly prescribed as a second-line treatment for severe Nausea and Vomiting of Pregnancy (NVP) (Fiaschi L et al,BJOG 2019;126:1201–11; Oliviera L et al. Obstet Gynecol2014;124:735-42). We do not believe that the underlying evidence supports a strong regulatory discouragement.Tightening of the SmPC on the use during pregnancy follows EMA assessment of two large pharmacoepidemiological studies, each comprising more than 80,000 first trimester pregnancy exposed liveborn children.In a methodologically meticulous pharmacoepidemiological study, Huybrechts et al. studied malformation outcomes among 88,000 liveborn children exposed to ondansetron in the first trimester. Comparing to 1,727,000 unexposed liveborn, they used comprehensive propensity score adjustments for their inferential analysis. Adjusted relative risks were 1.01 (95% CI 0.98-1.05) for any malformation, 0.99 (95% CI 0.93-1.06) for cardiac malformations and 1.24 (95% CI 1.03-1.48) for oral clefts (Huybrechts et al. JAMA 2018;320:2429–37).Subject to substantial academic controversy, Zambelli-Weiner et al. reported data on 82,000 liveborn children exposed to ondansetron in the first trimester (Zambelli-Weiner et al. Reprod Toxicol2019;83:14–20). Overall, they reported a small excess risk of cardiac malformations with an adjusted odds-ratio (aOR) of 1.04 (95% CI 1.00-1.08) and a weak association with orofacial clefts, aOR 1.12 (95% CI: 0.95-1.33). When restricting exposure to about 5,500 women who were administered ondansetron in a hospital setting, the vast majority of which comprised a single intravenous dose, aOR was 1.43 (95% CI 1.28-1.61) for cardiac malformations and 1.30 (95% CI: 0.75-2.25) for orofacial clefts. This study is substantially flawed and we argue it should not be considered when weighing the totality of evidence on the safety of ondansetron in pregnancy due to: 1) strong selection bias 2) poor external validity (the cardiac malformation rate of 3.7% was extraordinarily high among 780,000 unexposed controls) 3) inadequate adjustment for confounders and covariates and, importantly, 4) serious conflict of interest (Schachtman Law. Re: Zambelli-Weiner [cited 2020 July 8]. Available from: http://schachtmanlaw.com/litigation-science-in-re-zambelli-weiner/ )In summary, robust clinical data suggest 1) no overall increased risk of major malformations 2) no increased risk of cardiac malformations 3) a small excess risk of oral clefts corresponding to three additional cases of oral cleft for every 10,000 liveborn children exposed to ondansetron in the first trimester of pregnancy (figure 1).NVP causes significant physical and psychological morbidity to the degree that some women contemplate termination of pregnancy. Denying such patients effective and low-risk treatment is inappropriate. We are confident that women suffering from severe NVP can comprehend the small excess risk of oral clefts in making an informed decision. The statement “ondansetron should never be used in pregnancy” is: 1) misconceived 2) insufficiently substantiated by evidence and 3) not in the best interest of pregnant women.

More than twelve blood group systems have been described in dogs, but little is known about their distribution frequencies within breed populations. Here, we report on an extensive typing survey carried out using available reagents and either established or new clinical kits in purebred dogs from Germany. Leftover anticoagulated blood samples were examined using an immunochromatographic strip method for DEA 1, a gel column technique for Dal and Kai 1/2, and new card agglutination tests for DEA 4 and DEA 5 (which were partially compared with the gel column technique). Monoclonal antibodies were used for DEA 1 and Kai 1/2 typing, and polyclonal antibodies were used for all other types. Among the 206 dogs, 59.2% were DEA 1+, 100% DEA 4+, 9% (Card)/11% (Gel) DEA 5+, 89.3% Dal+, 96.6% Kai 1+, and 2.9% Kai 2+. None of the dogs were Kai 1+/2+, and only one was Kai 1-/2-. Dal- dogs were found in several breeds. Erythrocytes from most DEA 1+ dogs bound strongly on the strips. The agglutination reactions for DEA 5 on the new card tests were generally less than those on the gel column. The blood group pattern DEA 4+, DEA 5-, Dal+, Kai 1+/2- and either DEA 1+ or DEA 1- was found among 80% of the dogs. In this first extensive blood typing survey of purebred dogs from Europe, the proportions of positive and negative blood types were similar to those found in the United States and, for DEA 1, were also similar to those from other European countries, with considerable breed variation in blood types. The newer typing techniques seem to work well and will likely be useful for detecting and preventing specific blood type incompatibilities in the clinic.

Pituitary pars intermedia dysfunction is the most prevalent endocrine disease in horses. Although donkeys and mules may also be affected, only a few data have been published. Reference values for diagnostic parameters, such as adrenocorticotropic hormone (ACTH), are especially scarce or even lacking. Therefore, in the present study, available data from the literature have been verified and completed to facilitate a reliable diagnosis. Clinical inspections and haematological and biochemical examinations were carried out four times in a three-month interval (February to November) in 44 donkeys and 31 mules. Data from clinically healthy animals were used as an orientation. Plasma ACTH concentrations showed seasonal changes in both animal groups. However, it was generally higher in donkeys than mules. Although blood glucose (EDTA plasma) showed no difference between groups, serum insulin concentrations were consistently higher in donkeys. Serum fructosamine levels were slightly higher in mules, whereas, in some cases, serum triglyceride levels were considerably higher in donkeys. Serum gamma-glutamyltransferase showed a striking peak in mules in August, whereas the remaining gamma-glutamyltransferase values were lower compared to donkeys. By comparing donkeys and mules, the present work reveals differences in various blood parameters which should be considered for diagnoses and future studies.

The aim of this study was to evaluate the risk of major birth defects and spontaneous abortion after metformin use during the first trimester of pregnancy. We conducted an observational cohort study comparing pregnancies with metformin treatment during the first trimester with non-exposed women matched for BMI and year of enrolment. Pregnancies were prospectively ascertained in the German Embryotox pharmacovigilance database between 2004 and 2014. The study sample included 336 pregnancies with metformin exposure for PCOS and fertility disorders (56.8%), diabetes (25.9%) and insulin resistance (14.9%) and 1011 matched controls. Independent of the treatment indication, neither the rate of major birth defects (OR adjusted 0.58, 95% CI 0.3-1.3) nor of spontaneous abortions (HR adjusted 0.95, 95% CI 0.6-1.5) was significantly increased among metformin exposed. Our study supports the evidence that metformin does not carry a developmental risk for the fetus when used during the first trimester.

The European Network of Teratology Information Services (ENTIS) is in a privileged position to perform independent post-marketing surveillance of drugs in pregnancy. The aim of this survey was to describe the legal requirements and procedures involved in obtaining ethical approval for collaborative cohort studies. We sent a survey questionnaire to all 28 Teratology Information Services (TIS), of which 25 (89%) in 18 countries completed our questionnaire. For 15 TIS, specific research ethical approval was mandatory. The review process was estimated to last from 2 up to 16 weeks. Procedures for patients' information and consent were oral (12), written (5) or both (3). Five TIS had no requirement to inform patients and seek consent. Since data on drug exposure during pregnancy are scarce, ENTIS research efforts should be further encouraged, and procedures optimized so that legitimate ethical and legal requirements do not translate into deterrent administrative constraints and costs.

Objectives To analyze the risk of spontaneous abortions and major birth defects in pregnancies of women treated with angiotensin converting enzyme inhibitors (ACEIs) during the first trimester. Study design Observational cohort study of prospectively ascertained pregnancies from the German Embryotox pharmacovigilance institute. Pregnancy outcomes after maternal exposure to ACEIs during the first trimester were compared with pregnancies without antihypertensive treatment. In a sensitivity analysis, ACEI exposed hypertensive women were compared with hypertensive women on methyldopa. Results The risk of spontaneous abortion among 329 ACEI exposed women was not increased compared to 654 women without antihypertensive treatment (adjusted hazard ratio 1.20, 95% confidence interval (CI) 0.74–1.92), whereas the risk for major birth defects (14/255; 5.5% vs. 19/567; 3.4%) was significantly increased (adjusted odds ratio 2.41, 95% CI 1.07–5.43). In contrast, birth defect rates were not significantly different between hypertensive women on ACEIs and hypertensive women on methyldopa. In addition, we did not observe a distinct pattern of birth defects among retrospectively ascertained pregnancies after ACEI exposure during the first trimester. Conclusions Women with hypertension treated with ACEIs in early pregnancy are at higher risk for major birth defects, which may be explained by other factors associated with maternal hypertension. Women (inadvertently) exposed during early pregnancy may be reassured and treatment switched to antihypertensive drugs recommended for pregnancy.

In adult cattle Fasciola hepatica infection usually follows a chronic subclinical course, and reduces both the milk yield and milk quality, resulting in considerable financial losses. Effective control of the disease is based on reliable identification of asymptomatically infected individuals, which now requires special parasitological or serological diagnostic tests. It is also known that F. hepatica infection induces alterations in some serum biochemical parameters. Therefore, the study was conducted to develop a model based on serum biochemical parameters allowing to identify cows at higher risk of chronic fascioliasis. Six hundred sixty eight adult dairy cows from 97 herds located in central and northeastern Poland were clinically examined, and blood and fecal samples from them were collected for a routine monitoring of fascioliasis and metabolic profile. Using the combination of fecal sedimentation test and indirect ELISA based on excretory/secretory products 203 cows, apparently healthy in clinical examination, were definitively classed as affected by (47 cows, 23.2%) or free from (156 cows, 76.8%) chronic fascioliasis. Their serum was screened for the activity of 4 enzymes (γ-glutamyl transpeptidase, glutamate dehydrogenase, aspartate aminotransferase, creatine kinase) and concentration of 18 other components (total bilirubin, total protein, albumin, globulin, urea, glucose, non-esterified fatty acids, β-hydroxybutyrate, sodium, potassium, chloride, calcium, magnesium, copper, zinc, iron, selenium, and haptoglobin). Logistic regression analysis was used to build 4 multivariable models allowing for identification of cows at risk of chronic fascioliasis. Then, the accuracy was compared between the models using the area under the receiver operating characteristic curve (AUROC), and an optimal cut-off value was determined for the most accurate model using Youden J index. The most accurate proved to be the model based on glutamate dehydrogenase activity and globulin, urea (all three positively linked with risk of chronic fascioliasis), and selenium concentration (negatively linked) adjusted by the access to pasture and cow's age. At the optimal cut-off of 0.37 this model had sensitivity of 85.1% (CI 95%:72.3%, 92.6%), specificity of 90.4% (CI 95%:84.7%, 94.1%), positive likelihood ratio of 8.8 (CI 95%:5.4, 14.5), and negative likelihood ratio of 0.16 (CI 95%:0.08, 0.33). This model performed significantly better than model including only γ-glutamyl transpeptidase or model including both γ-glutamyl transpeptidase and aspartate aminotransferase (both also adjusted by the access to pasture and cow's age), and was the only model which performed significantly better than the basic model based solely on the access to pasture and cow's age.

The purpose of this study was to assess a change in different blood parameters before and after a 160 km endurance race and to evaluate differences in cardiac biomarkers between horses that completed the race and horses that did not. The study population consisted of 52 healthy endurance horses. Horses participating in the study were assigned to three groups: horses that successfully completed the race (“finishers”), horses that failed to qualify at the veterinary check for primarily metabolic reasons (“metabolic”) and horses that failed to qualify at the veterinary check for primarily gait related reasons (“gait related”). The latter two groups were combined to form a final group of “non-finishers” that were excluded for either “gait related” or “metabolic” disorders. Venous blood samples were taken before and after the endurance race. Serum and EDTA-plasma were analyzed for cardiac troponin I (cTNI), heart fatty acid binding protein (HFABP), alpha-hydroxybutyrate dehydrogenase (α-HBDH), atrial natriuretic peptide (ANP), lactate dehydrogenase (LDH), symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). Lactate dehydrogenase (P = .001), SDMA (P= .001) and ADMA (P= .002) increased significantly after the endurance race in the finisher group. A significant increase in cTNI and α-HBDH concentration after the endurance race compared to the values before the endurance race was detected in the finisher (P= .001, P= .001) and gait related group (P= .002, P= .007). The longer the distance completed, the more these five blood parameters increased. No differences between the groups could be found and none of the measured blood parameters showed significant differences among groups before or after racing.

Introduction In cases of drunk-driving, allegations that alcohol has been consumed after the incident, are proved by analyzing congener alcohols in the blood sample. 1-Propanol, one of the main congener compounds, was tested, whether it is also endogenously formed when a person has consumed alcoholic beverages. Methods Eleven male and 13 female volunteers consumed congener-free vodka (37.5 vol% ethanol, individual doses: 0.15–0.32 l) within one hour. Blood samples were taken up to 10 h and analyzed for ethanol and congener alcohols by headspace gas chromatography-mass spectrometry. Results Ethanol concentrations reached in blood a maximum of 0.65–1.23 g/l and decreased by 0.18 g/l/h (median values). Of the congener alcohols analyzed, only methanol and 1-propanol were detected in the plasma samples of all subjects. The endogenous methanol concentration increased from 0.66 mg/l by 0.22 mg/l/h to 2.19 mg/l (medians). 1-Propanol was not detected prior to alcohol consumption. Maximum concentrations of 0.10–0.32 mg/L were measured after 1.0–4.5 h. A plateau of the 1-propanol concentration was observed in the plasma samples of the 18 subjects lasting for 0.5–4.0 h and this alcohol was completely eliminated at ethanol concentrations of 0.17 g/l (median, range 0.03–0.55 g/l). Conclusion The results of the study confirm the formation of 1-propanol after consumption of 1-propanol-free beverages, which should be taken into account when evaluating its concentration.