Case Report: Clinical Use of a Patient-Individual Magnetic Resonance Imaging-Based Stereotactic Navigation Device for Brain Biopsies in Three Dogs

Three-dimensional (3D) printing techniques for patient-individual medicine has found its way into veterinary neurosurgery. Because of the high accuracy of 3D printed specific neurosurgical navigation devices, it seems to be a safe and reliable option to use patient- individual constructions for sampling brain tissue. Due to the complexity and vulnerability of the brain a particularly precise and safe procedure is required. In a recent cadaver study a better accuracy for the 3D printed MRI-based patient individual stereotactic brain biopsy device for dogs is determined compared to the accuracies of other biopsy systems which are currently used in veterinary medicine. This case report describes the clinical use of this 3D printed MRI-based patient individual brain biopsy device for brain sampling in three dogs. The system was characterized by a simple handling. Furthermore, it was an effective and reliable tool to gain diagnostic brain biopsy samples in dogs with no significant side effects

A quantitative synthesis study on body mass index and associated factors among adult men and women in Switzerland.

Excess weight is caused by multiple factors and has increased sharply in Switzerland since the 1990s. Its consequences represent a major challenge for Switzerland, both in terms of health and the economy. Until now, there has been no cross-dataset overview study on excess weight in adults in Switzerland. Therefore, our aim was to conduct the first synthesis on excess weight in Switzerland. We included all existing nationwide Swiss studies (eight total), which included information on body mass index (BMI). Mixed multinomial logistic regression analyses were performed to assess the associations between different socio-demographic, lifestyle cofactors and the World Health Organization (WHO) categories for BMI. Along with lifestyle factors, socio-demographic factors were among the strongest determinants of BMI. In addition, self-rated health status was significantly lower for underweight, pre-obese and obese men and women than for normal weight persons. The present study is the first to synthesise all nationwide evidence on the importance of several socio-demographic and lifestyle factors as risk factors for excess weight. In particular, the highlighted importance of lifestyle factors for excess weight opens up the opportunity for further public health interventions

A quantitative synthesis study on body mass index and associated factors among adult men and women in Switzerland

Excess weight is caused by multiple factors and has increased sharply in Switzerland since the 1990s. Its consequences represent a major challenge for Switzerland, both in terms of health and the economy. Until now, there has been no cross-dataset overview study on excess weight in adults in Switzerland. Therefore, our aim was to conduct the first synthesis on excess weight in Switzerland. We included all existing nationwide Swiss studies (eight total), which included information on body mass index (BMI). Mixed multinomial logistic regression analyses were performed to assess the associations between different socio-demographic, lifestyle cofactors and the World Health Organization (WHO) categories for BMI. Along with lifestyle factors, socio-demographic factors were among the strongest determinants of BMI. In addition, self-rated health status was significantly lower for underweight, pre-obese and obese men and women than for normal weight persons. The present study is the first to synthesise all nationwide evidence on the importance of several socio-demographic and lifestyle factors as risk factors for excess weight. In particular, the highlighted importance of lifestyle factors for excess weight opens up the opportunity for further public health interventions

Principal Stratum Strategy: Potential Role in Drug Development

A randomized trial allows estimation of the causal effect of an intervention compared to a control in the overall population and in subpopulations defined by baseline characteristics. Often, however, clinical questions also arise regarding the treatment effect in subpopulations of patients, which would experience clinical or disease related events post-randomization. Events that occur after treatment initiation and potentially affect the interpretation or the existence of the measurements are called {\it intercurrent events} in the ICH E9(R1) guideline. If the intercurrent event is a consequence of treatment, randomization alone is no longer sufficient to meaningfully estimate the treatment effect. Analyses comparing the subgroups of patients without the intercurrent events for intervention and control will not estimate a causal effect. This is well known, but post-hoc analyses of this kind are commonly performed in drug development. An alternative approach is the principal stratum strategy, which classifies subjects according to their potential occurrence of an intercurrent event on both study arms. We illustrate with examples that questions formulated through principal strata occur naturally in drug development and argue that approaching these questions with the ICH E9(R1) estimand framework has the potential to lead to more transparent assumptions as well as more adequate analyses and conclusions. In addition, we provide an overview of assumptions required for estimation of effects in principal strata. Most of these assumptions are unverifiable and should hence be based on solid scientific understanding. Sensitivity analyses are needed to assess robustness of conclusions

The Discovery of Nonpeptide Endothelin Receptor Antagonists. Progression towards Bosentan

Since its discovery, endothelin-1 has attracted considerable scientific interest for its extremely potent and long-lasting vasoconstrictor effect and its binding to G-protein-coupled receptors. The endothelins appear to be part of a functional regulatory system in the circulation and strong evidence has accumulated for their involvement in clinical disorders associated with vasoconstriction (e.g. renal failure, congestive heart failure).In a program aimed at identifying nonpeptide ET receptor antagonists, a distinct class of substituted arylsulfonamido pyrimidines was discovered from a chemical substance library. Lead optimization led to orally active antagonists of ETA and ETB receptors possessing mixed or receptor-subtype-selective profiles in the low nanomolar range. From these compounds, the mixed antagonist bosentan was selected for development; it shows efficacy in several pathophysiological models of local and systemic vasoconstriction and promising clinical results in patients suffering from congestive heart failure.Chemical modifications in this structural class in combination with X-ray crystal data analysis for key compounds led to more in-depth understanding of antagonist-receptor interaction. Structural determinants of bosentan binding to the ETA receptor were defined on the molecular level by site-directed mutagenesis experiments. This led to a 3D model of the antagonist binding domain which proved valuable to rationalize structure-activity relationships

Sociodemographic and regional differences in neonatal and infant mortality in Switzerland: The Swiss National Cohort

SummaryBackgroundDespite a well-funded healthcare system with universal insurance coverage, Switzerland has one of the highest neonatal and infant mortality rates among high-income countries. Identifying avoidable risk factors targeted by evidence-based policies is a public health priority. We describe neonatal and infant mortality in Switzerland from 2011–2018 and explore associations with neonatal and pregnancy-related variables, parental sociodemographic information, regional factors, and socioeconomic position (SEP) using data from a long-term nation-wide cohort study.MethodsWe included 680,077 live births—representing 99.3% of all infants born in Switzerland between January 2011 and December 2018. We deterministically linked the national live birth register with the mortality register and with census and survey data to create a longitudinal dataset of neonatal and pregnancy-related variables; parental sociodemographic information, such as civil status, age, religion, education, nationality; regional factors, such as urbanity, language region; and the Swiss neighbourhood index of SEP (Swiss-SEP index). Information on maternal education was available for a random subset of 242,949 infants. We investigated associations with neonatal and infant mortality by fitting multivariable Poisson regression models with robust standard errors. Several sensitivity analyses assessed the robustness of our findings.ResultsOverall, neonatal mortality rates between 2011 and 2018 were 3.0 per 1000 live births, varying regionally from 3.2 in German-speaking to 2.4 in French-speaking and 2.1 in Italian-speaking Switzerland. For infant mortality, respective rates were 3.7 per 1000 live births overall, varying from 3.9 to 3.3 and 2.9. Adjusting for sex, maternal age, multiple birth and birth rank, neonatal mortality remained significantly associated with language region [rate ratio (RR) 0.72, 95% confidence interval (CI): 0.64–0.80 for French-speaking and RR 0.66, 95% CI: 0.51–0.87 for Italian-speaking region], with marital status (RR 1.55, 95% CI: 1.40–1.71 for unmarried), nationality (RR 1.40, 95% CI: 1.21–1.62 for non-European Economic Area vs. Swiss), and the Swiss-SEP index (RR 1.17, 95% CI: 1.00–1.36 for lowest vs. highest SEP quintile). In the subset, we showed a possible association of neonatal mortality with maternal education (RR 1.24, 95% CI: 0.95–1.61 for compulsory vs tertiary education).ConclusionWe provide detailed evidence about the social patterning of neonatal and infant mortality in Switzerland and reveal important regional differences with about 30% lower risks in French-and Italian-speaking compared with German-speaking regions. Underlying causes for such regional differences, such as cultural, lifestyle, or healthcare-related factors, warrant further exploration to inform and provide an evidence base for public health policies

Cluster analysis of resistance combinations in Escherichia coli from different human and animal populations in Germany 2014-2017

Recent findings on Antibiotic Resistance (AR) have brought renewed attention to the comparison of data on AR from human and animal sectors. This is however a major challenge since the data is not harmonized. This study performs a comparative analysis of data on resistance combinations in Escherichia coli (E. coli) from different routine surveillance and monitoring systems for human and different animal populations in Germany. Data on E. coli isolates were collected between 2014 and 2017 from human clinical isolates, non-clinical animal isolates from food-producing animals and food, and clinical animal isolates from food-producing and companion animals from national routine surveillance and monitoring for AR in Germany. Sixteen possible resistance combinations to four antibiotics—ampicillin, cefotaxime, ciprofloxacin and gentamicin–for these populations were used for hierarchical clustering (Euclidian and average distance). All analyses were performed with the software R 3.5.1 (Rstudio 1.1.442). Data of 333,496 E. coli isolates and forty-one different human and animal populations were included in the cluster analysis. Three main clusters were detected. Within these three clusters, all human populations (intensive care unit (ICU), general ward and outpatient care) showed similar relative frequencies of the resistance combinations and clustered together. They demonstrated similarities with clinical isolates from different animal populations and most isolates from pigs from both non-clinical and clinical isolates. Isolates from healthy poultry demonstrated similarities in relative frequencies of resistance combinations and clustered together. However, they clustered separately from the human isolates. All isolates from different animal populations with low relative frequencies of resistance combinations clustered together. They also clustered separately from the human populations. Cluster analysis has been able to demonstrate the linkage among human isolates and isolates from various animal populations based on the resistance combinations. Further analyses based on these findings might support a better one-health approach for AR in Germany.Peer Reviewe

Hierarchical contribution of individual lifestyle factors and their interactions on adenomatous and serrated polyp risk.

BACKGROUND Individual colorectal polyp risk factors are well characterized; however, insights into their pathway-specific interactions are scarce. We aimed to identify the impact of individual risk factors and their joint effects on adenomatous (AP) and serrated polyp (SP) risk. METHODS We collected information on 363 lifestyle and metabolic parameters from 1597 colonoscopy participants, resulting in over 521,000 data points. We used multivariate statistics and machine-learning approaches to assess associations of single variables and their interactions with AP and SP risk. RESULTS Individual factors and their interactions showed common and polyp subtype-specific effects. Abdominal obesity, high body mass index (BMI), metabolic syndrome, and red meat consumption globally increased polyp risk. Age, gender, and western diet associated with AP risk, while smoking was associated with SP risk. CRC family history was associated with advanced adenomas and diabetes with sessile serrated lesions. Regarding lifestyle factor interactions, no lifestyle or dietary adjustments mitigated the adverse smoking effect on SP risk, whereas its negative effect was exacerbated by alcohol in the conventional pathway. The adverse effect of red meat on SP risk was not ameliorated by any factor, but was further exacerbated by western diet along the conventional pathway. No modification of any factor reduced the negative impact of metabolic syndrome on AP risk, whereas increased fatless fish or meat substitutes' intake mitigated its effect on SP risk. CONCLUSIONS Individual risk factors and their interactions for polyp formation along the adenomatous and serrated pathways are strongly heterogeneous. Our findings may facilitate tailored lifestyle recommendations and contribute to a better understanding of how risk factor combinations impact colorectal carcinogenesis

Das Gewicht der Schweiz: Eine quantitative Synthesestudie zum Body Mass Index und Bauchumfang sowie den damit verbundenen Kofaktoren bei erwachsenen Männern und Frauen in der Schweiz

Übergewicht wird multifaktoriell verursacht und hat in der Schweiz seit den 1990er Jahren stark zugenommen. Eine breit abgestützte Untersuchung der involvierten Kofaktoren würde es ermöglichen, Risikofaktoren und damit auch Interventionsprogramme präziser als bisher zu definieren. Für die erwachsene Bevölkerung in der Schweiz wurden bisher die bestehenden gesamtschweizerischen bevölkerungsweiten Studien zu Übergewicht noch nie zusammengefasst in einer Synthesestudie ausgewertet. Wir haben alle uns bekannten gesamtschweizerischen und bevölkerungsbezogenen Studien aus den Bereichen Gesundheit, Ernährung und Wirtschaft zusammengetragen, die auch Informationen über den Body Mass Index (BMI) sowie wenn möglich auch zu Bauchumfang/Taillenumfang (Waist Circumference, WC) und Waist-to-Height-Ratio (WHtR) enthielten. Eingeschlossen wurden die Nationale Ernährungserhebung Schweiz (menuCH, 2014/2015), die Schweizerischen Gesundheitsbefragungen 2012 und 2017, das Swiss Household Panel 2013-2017, die Schweizer Erhebung über Einkommen & Lebensbedingungen (SILC, 2017), das Swiss Food Panel (2010 und 2017) sowie der Swiss Survey on Salt Intake (2010/2011). Wir haben die mehrheitlich repräsentativen Datensätze nicht gepoolt, sondern mittels mixed multinomial logistic Regressionsanalysen übergreifende Gesamteffekte geschätzt. Zusätzlich haben wir die anthropometrischen Monitoring-Daten der Stellungspflichtigen 2019 vergleichend hinzugezogen. Grundsätzlich sind von zehn erwachsenen Menschen in der Schweiz rund drei Personen (31.7 %) von Übergewicht und rund eine Person (11.2 %) von Adipositas betroffen. Die Analyse der acht bevölkerungsbasierten Studien zeigt, dass die Kofaktoren Geschlecht, Alter, Bildung, Körperhöhe, Sprachregion und körperliche Aktivität signifikant mit dem BMI zusammenhängen. Betrachtet man auch die Kofaktoren, welche nicht in allen Studien erhoben worden sind, dann finden sich weitere signifikante Assoziationen zu Stadt/Land, Nationalität, Fleischkonsum, Konsum von Süssgetränken, Einhalt der Empfehlungen zu körperlicher Aktivität, selbsteingeschätztem Gesundheitszustand und Schlafstörungen. Die Daten der Stellungspflichtigen für die Armee decken sich in der Aussagerichtung weitgehend mit diesem Bild: Der BMI der jungen Schweizer Männer 2019 ist assoziiert mit Alter, Körperhöhe, Sprachregionen, Stadt/Land, sozioökonomischem Berufsstatus, sozioökonomischem Nachbarschaftsindex, Blutdruck und Leistung im Sporttest. Die vergleichende Analyse zwischen BMI, WC und WHtR in den beiden populationsbasierten Studien menuCH und Swiss Salt Survey sowie bei den Stellungspflichtigen zeigt einerseits eine weitgehende Kongruenz zwischen den anthropometrischen Massen auf, anderseits aber auch den Mehrwert des WHtR, welcher den WC relativiert zur Körperhöhe und zu mehr akzentuierten Koeffizienten führt. Unsere Resultate zur Bedeutung der Körperhöhe als relevanter Kofaktor bestätigen, dass es sich beider Prävention von Übergewicht gleich mehrfach lohnt, bereits im Kindesalter anzusetzen: Einerseits wird dadurch ein günstiger kindlicher Gesundheitsstatus (Balance zwischen Ernährung, Bewegung und Gesundheit) gefördert, welcher sich auch auf das Wachstum auswirkt, andererseits werden damit früh gesundheitsrelevante Verhaltensmuster erlernt (Ernährung, Schlaf, Bewegung), was ebenfalls bis ins Erwachsenenleben nachwirkt. Dieser Ansatz ist ganz im Sinne des Life Course Approach to Health, wie er beispielweise auch in der NCD-Strategie des Bundesrates eingeflossen ist. Weiter haben sich in unseren Modellen die soziodemografischen Faktoren als besonders wichtig herausgestellt. Zukünftige Studien sollten Interaktionen zwischen soziodemografischen Faktoren, Lebensstilfaktoren und Gesundheitsfaktoren, welche für einzelne Datensätze gut dokumentiert sind, ebenfalls im Sinne einer Synthese über verschiedene Datensätze hinweg untersuchen. Unsere Ergebnisse schlagen vor, dabei ein besonderes Augenmerk auf Süssgetränke, Schlafstörungen und den selbsteingeschätzten Gesundheitszustand zu legen