Search

Introduction: Titanium isotopes are a novel tool to study the evolution of the Solar System and planetary differentiation. Mass-independent, nucleosynthetic, Ti isotope variations are used to establish genetic relationships between different planetary bodies sampled by meteorites. In contrast, mass-dependent Ti isotope data are an emerging tool for tracing magmatic processes. In this study, we apply Ti isotope systematics to the ureilite parent body (UPB). Ureilites are carbon-rich achondrites derived from a single and now-disrupted parent body e.g. [1]. Most ureilites are ultramafic and considered to represent partial melting residues of primordial material after the extraction of ironsulphide and silicate melts e.g., [2]. They experienced variable degrees of partial melting. Moreover, it is suggested that partial melting was not rigorous enough to erase all primordial compositions e.g., [3]. For example, O and Cr isotope evidence suggest that the UPB formed from two distinct precursor reservoirs [4]. Moreover, ureilites display the largest depletions in the abundance of the neutron-rich isotopes (e.g., 50Ti, 54Cr) among bulk meteorites [5]. Hence, their nucleosynthetic isotope composition is key for modelling mixing processes within the protoplanetary disk. Since high-precision Ti isotope data of ureilites are scarce, we address this gap in this study. Regarding mass-dependent Ti isotope data, considerable variations in δ49Ti (the per mil deviation of the 49Ti/47Ti ratio relative to the Origins Laboratory (OL)-Ti standard [6]) of ~3.8 ‰ were reported for terrestrial rocks, produced by crystal-liquid fractionation during magmatic differentiation e.g., [7], and kinetic, disequilibrium isotope effects [8]. In addition, significant equilibrium Ti isotope fractionation may occur at low oxygen fugacities similar to those inferred for the UPB [9,10]. Hence, determining the Ti isotope composition of ureilites provides additional constraints on the origin and igneous processing of the UPB. Samples and Methods: Ten monomict ureilites from Antarctica were selected for both mass-independent and mass-dependent Ti isotope analyses. The selected olivine-bearing meteorites have Fo contents 75 to 95, covering nearly the full range known for ureilites [1]. Sample analysis followed the protocol of [8,10]. After Parr bomb digestion, two aliquots were taken for mass-independent and mass-dependent Ti isotope analyses and processed in different laboratories. A 47Ti-49Ti double-spike was added to the aliquots for the mass-dependent analyses. Titanium was purified using a three-step ion-exchange procedure [8,10]. Isotope measurements were performed on two different Thermo Scientific Neptune Plus MC-ICP-MS at ETH Zurich Results and Discussion: All investigated ureilites display ε50Ti deficits relative to Earth. Their nucleosynthetic Ti isotope compositions overlap with each other within analytical uncertainty and define an average of -1.95 ± 0.03 (2SE) for ε50Ti. The anomalous ureilite EET 87517, is not included in this average because it exhibits a distinctly different ε50Ti of -1.27 ±0.08. This sample is also anomalous in its Os and Mo isotope composition [3,11]. This nucleosynthetic heterogeneity may indicate that the UPB formed by mixing of two distinct reservoirs in the protoplanetary disk [4,12]. However, it is also possible that these variations reflect the effect of partial melting, which led to the separation of isotopically distinct presolar phases [3]. New mass-dependent δ49Ti values vary from -0.129 ± 0.034 to 0.089 ± 0.034 ‰ (2SD). Low δ49Ti values are associated with both depleted and cumulate ureilites and likely trace Ti isotope fractionation during partial melting and fractional crystallisation on the UPB. Two depleted ureilites (EET 83225, EET 87517) display distinctly higher δ49Ti of 0.062 ± 0.028 and 0.089 ± 0.034, possibly resulting from the reaction with a melt phase enriched in heavy Ti isotopes, which formed during partial melting. [ABSTRACT FROM AUTHOR]

Introduction: Nucleosynthetic isotope variations, which reflect the heterogeneous distribution of presolar dust in the protoplanetary disk, can be used to constrain the genetic relationships between planetary materials in the solar system. Previous studies identified distinct nucleosynthetic 50Ti and 54Cr compositions in different solar system materials [1-3]. Early solar system processes and asteroid belt dynamics can be investigated using these isotope variations. The disruption of asteroid 2008 TC3 in the atmosphere delivered fragments of chondritic origin, enstatite achondrites and ureilites of varying lithologies collectively described as the Almahata Sitta samples [4,5]. Sample fragments also include four ureilite-related trachyandesites [5], which are thought to originate from the ureilite parent body (UPB) [6]. The nucleosynthetic Ti and Cr isotope composition of these fragments can provide powerful insights into their origin and genetic relationship to other planetary bodies. The diversity of meteorite fragments indicates that the parent body of the Almahata Sitta samples, asteroid 2008 TC3, may be the product of second-generation asteroid accretion [4,5]. This study presents high-precision Ti and Cr isotope compositions for nine Almahata Sitta meteorite fragments, which are representative of non-carbonaceous chondrites (NC) and carbonaceous chondrites (CC). They are linked through the formation of asteroid 2008 TC3. The Ti and Cr isotope data of these samples contributes to the Almahata Sitta meteorite research, evaluating the various meteorite types existing within the parent body (asteroid 2008 TC3), as well as further constraining the composition of the ureilite-related trachyandesites. Methods: The samples were dissolved following the Ti-Cr procedure of [7]. A three-stage ion-exchange chromatographic procedure described in [8] was performed for Ti separation and purification. Chromium was collected in the matrix elution step of the first ion exchange column for Ti separation and then further purified using the Cr separation protocol modified after [7]. Isotopic analyses were performed on a Neptune Plus multi-collector ICP-MS at ETH Zürich. The Ti isotope data was corrected for instrumental mass bias using internal normalisation to a 49Ti/47Ti ratio of 0.749766 [9]. The terrestrial basalt BHVO-2 was analysed to evaluate data precision and accuracy and yielded an external reproducibility (2SD) of ~20 ppm for 46Ti/47Ti, ~10 ppm for 48Ti/47Ti, and ~20 ppm for 50Ti/47Ti. The Cr isotope data were internally normalised to a 50Cr/52Cr ratio of 0.051859 [10]. Repeat analyses of the terrestrial rock standards DTS2-b and JP-1 yielded an external reproducibility (2SD) of ~10 ppm for 54Cr/52Cr and 53Cr/52Cr. Results and Discussion: We analysed Almahata Sitta samples previously classified by [5,11]. They included four ureilites, two enstatite chondrites, one CB and one R-like chondrite. Our nucleosynthetic Ti and Cr isotope data of the analysed samples overlap with those of the respective meteorite groups. Thus, the combined Ti and Cr isotope analysis confirms the petrological determination of the Almahata Sitta sample fragments. For example, the sample fragments proposed to be CB-, R- and enstatite chondrite-like through petrological classification have a Ti and Cr isotope composition identical to the CB-, R- and enstatite chondrites, respectively. Our data also indicates that our ureilitic samples do not contain significant CC clasts because the data is consistent with the average ureilitic composition of [12,13]. The ureilite-related trachyandesite sample MS-MU-011, also called ALM-A, yields 54Cr isotope data that are identical within analytical uncertainties with ALM-A from [13]. Both the Cr and Ti isotope data of ALM-A fall within the ureilite composition field. This confirms that the trachyandesites likely originated from the UPB. Furthermore, our 50Ti and 54Cr isotope data shows that the Almahata Sitta parent body also contains CB-, R- and enstatite chondrites like fragments, which originated from the CC and NC reservoir. This supports the previous conclusion that planetary materials with two distinct isotope compositions (NC and CC) exist within asteroid 2008 TC3 [4,11]. [ABSTRACT FROM AUTHOR]

Background: As only a few studies have examined the impact of the COVID-19 pandemic on the mental health outpatient system so far, the aim of the COVID Ψ Outpatient Survey was to gain insight from outpatient providers in Germany regarding changes in utilization; associated problems and challenges; telemedicine services; interactions with inpatient and nursing home services; and experiences with post-COVID syndromes., Methods: Between July and September 2021, we invited 351 randomly selected outpatient mental health specialists to take part in the online survey via e-mail. Additionally, we extended an invitation to professional associations to encourage their members to participate. N = 105 physicians of most regions of Germany took part in the survey., Results: Survey participants reported changes in utilization during the high incidence phases (HIP) of the pandemic using pre-formulated categories: For the first HIP in spring 2020, 31% of the survey participants reported a decrease > 20% and 5% an increase > 20% of patient contacts. For the third HIP in spring 2021, 4% reported a decrease > 20% of contacts, while 30% an increase > 20%. Participants chose "patient's fears of infection" and "providers protection measures" as reasons for decreases, and "pandemic related anxieties", "economic stressors", and "capacity reductions of the inpatient system" as reasons for increases of patient contact. Many providers introduced telemedicine services. A majority reported consultations for post-COVID syndromes already in spring 2021., Conclusions: The survey hinted at changes in utilization, multiple problems but as well good-practice-solutions in the mental health outpatient system during the COVID-19 pandemic., Competing Interests: Declarations. Conflict of interest: All authors have no conflict of interest to declare. Consent for publication: Not applicable as no individual data was published. Ethical approval and consent to participate: The Data Protection Officer at University Medical Center Mainz confirmed that no data protection vote was required because no personal data were processed. The ethics commission of the Ludwig Maximilians University Munich had already approved the first study [17], i.e., the anonymous survey of mental healthcare institutions, as no personal or individual patient data were collected. Therefore, no additional vote was gathered for this second survey. Informed consent was obtained from all participants included in the survey., (© 2024. The Author(s).)

Diseases of the musculature can be caused, for example, by alimentary or traumatic issues. In three bald eagles with painful lameness and/or a reduced range of the hip joint, a muscular disease was diagnosed via radiographic examination. The eagles were kept in a falconry and trained as demonstration birds, which were displayed on a gloved hand and flown in falconry education programs. The imaging revealed varying degrees of calcification of the adductors along the course of the puboischiofemoral muscle of the left hind limb in all cases. A histological examination of the affected musculature of one eagle confirmed the presence of a myopathy with muscle fiber atrophy, fibrosis, and metaplastic bone formation. Increased mechanical stress and injuries to the affected muscle groups are discussed as the cause of these alterations. The adductor muscles of the left leg of bald eagles in falconry husbandry appear to be particularly prone to muscular injuries and the development of heterotopic ossification. The healing process of such an injury with the stiffened musculature can lead to restrictions in the movement of the hip joint. Thus, the conscious and professional handling of the eagles is essential for maintaining the health of these birds.

Vector-borne diseases (VBDs) are considered as (re-)emerging, but information on the transmission cycles and wildlife reservoirs is often incomplete, particularly with regard to urban areas. The present study investigated blood samples from European hedgehogs ( Erinaceus europaeus ) presented at wildlife rehabilitation centres in the region of Hanover. Past exposure to B. burgdorferi sensu lato (s.l.) and tick-borne encephalitis virus (TBEV) was assessed by serological detection of antibodies, while current infections with Borrelia spp., Anaplasma phagocytophilum , Rickettsia spp., Neoehrlichia mikurensis , Bartonella spp., Babesia spp. and Spiroplasma ixodetis were investigated by (q)PCR. Of 539 hedgehogs tested for anti- Borrelia antibodies, 84.8% (457/539) were seropositive, with a higher seropositivity rate in adult than subadult animals, while anti-TBEV antibodies were detected in one animal only (0.2%; 1/526). By qPCR, 31.2% (168/539) of hedgehog blood samples were positive for Borrelia spp., 49.7% (261/525) for A. phagocytophilum , 13.0% (68/525) for Bartonella spp., 8.2% for S. ixodetis (43/525), 8.0% (42/525) for Rickettsia spp. and 1.3% (7/525) for Babesia spp., while N. mikurensis was not detected. While further differentiation of Borrelia spp. infections was not successful, 63.2% of the A. phagocytophilum infections were assigned to the zoonotic ecotype I and among Rickettsia spp. infections, 50.0% to R. helvetica by ecotype- or species-specific qPCR, respectively. Sequencing revealed the presence of a Rickettsia sp. closely related to Rickettsia felis in addition to a Bartonella sp. previously described from hedgehogs, as well as Babesia microti and Babesia venatorum . These findings show that hedgehogs from rehabilitation centres are valuable sources to identify One Health pathogens in urban areas. The hedgehogs are not only exposed to pathogens from fleas and ticks in urban areas, but they also act as potent amplifiers for these vectors and their pathogens, relevant for citizens and their pets., Competing Interests: The authors declare that they have no conflicts of interest., (© 2024 The Authors.)

Birds of prey and owls are susceptible to diseases of and traumatic injuries to their feet, which regularly require surgical intervention. A precise knowledge of the blood vessel topography is essential for a targeted therapy. Therefore, the metatarsal and digital vasculature was examined in eight species of birds of prey and owls. The study included contrast micro-computed tomography scans and anatomical dissections after intravascular injection of colored latex. In all examined species, the dorsal metatarsal arteries provided the main supply to the foot and their branching pattern and number differed between species. They continued distally as digital arteries. All examined species showed a basic pattern of four collaterally located digital blood vessels per toe: a prominent artery and small vein on one side and a small artery and prominent vein on the other side. Digital veins united to form common digital veins, most of which joined into a superficial, medially located metatarsal vein. This vein provided the main drainage of the foot. The detailed visualization of the topography of pedal blood vessels will help veterinary surgeons during surgical procedures. In addition, differences in the plantar arterial arch between hawks and falcons were discussed regarding their possible influence on the prevalence of pododermatitis (bumblefoot).

Background: The European hedgehog (Erinaceus europaeus) is known for high levels of ectoparasitism that not only represents a health risk for the animals themselves, but also for pet animals and humans as hedgehogs are frequently taken into human care. In the present study, patterns of ectoparasite infestation were assessed in hedgehogs taken into care at northern German animal rehabilitation centres., Methods: Ectoparasites (ticks, fleas and mites) of 498 hedgehogs were collected over a period of 3 years from July 2018 to May 2021. Species were identified based on morphological characteristics and also via amplification and sequencing of the partial cytochrome c oxidase subunit 2 (COX-2) gene for fleas of the family Ceratophyllidae. Seasonal changes in infestation patterns as well as correlations with animal age, body weight and health status were assessed using generalised linear models., Results: Infestation with ticks, fleas and mites occurred throughout the year. Overall, 86.5% (431/498) of the examined hedgehogs were infested with ticks, 91.4% (455/498) with fleas and 17.7% (88/498) with mites. Ixodes ricinus and Ixodes hexagonus/Ixodes canisuga were the most common tick species detected, with the additional occurrence of one Ixodes frontalis. Significant seasonal changes were observed for I. ricinus, but not for I. hexagonus/I. canisuga. Additionally, I. ricinus nymph prevalence declined significantly as of 2020, probably as a consequence of the climate change-related drought as of 2018. In hedgehogs with flea infestations, Archaeopsylla erinacei, Ceratophyllus sciurorum, Nosopsyllus fasciatus and Ctenocephalides felis were identified. In all cases of mite infestation, Caparinia tripilis was detected, in addition to specimens of the family Macronyssidae and free-living mites of the family Acaridae. Statistical analyses showed correlations regarding the factors month, year, body weight and age, but no correlation was evident regarding the health status of the animals., Conclusions: With a detected infestation rate of 98.6%, almost all of the examined hedgehogs were infested with at least one ectoparasite species. The seasonal activity patterns of the different ectoparasite species together with the complex annual cycle of hedgehogs lead to different seasonal patterns in ectoparasite prevalence and infestation intensities. Due to the risk of transmission of zoonotic pathogens as well as the possible negative impact on the host itself, hedgehogs should be treated against ectoparasites when taken into care facilities., (© 2023. The Author(s).)

The pregnane X receptor (PXR) is a ligand-activated regulator of cytochrome P450 (CYP)3A enzymes. Among the ligands of human PXR is hyperforin, a constituent of St John's wort (SJW) extracts and potent inducer of human CYP3A4. It was the aim of this study to compare the effect of hyperforin and SJW formulations controlled for its content on CYP3A23-3A1 in rats. Hyperiplant was used as it contains a high hyperforin content and Rebalance because it is controlled for a low hyperforin content. In silico analysis revealed a weak hyperforin-rPXR binding affinity, which was further supported in cell-based reporter gene assays showing no hyperforin-mediated reporter activation in presence of rPXR. However, cellular exposure to Hyperiplant and Rebalance transactivated the CYP3A reporter 3.8-fold and 2.8-fold, respectively, and they induced Cyp3a23-3a1 mRNA expression in rat hepatoma cells compared with control 48-fold and 18-fold, respectively. In Wistar rats treated for 10 days with 400 mg/kg of Hyperiplant, we observed 1.8 times the Cyp3a23-3a1 mRNA expression, a 2.6-fold higher CYP3A23-3A1 protein amount, and a 1.6-fold increase in activity compared with controls. For Rebalance we only observed a 1.8-fold hepatic increase of CYP3A23-3A1 protein compared with control animals. Even though there are differing effects on r Cyp3a23-3a1 /CYP3A23-3A1 in rat liver reflecting the hyperforin content of the SJW extracts, the modulation is most likely not linked to an interaction of hyperforin with rPXR. SIGNIFICANCE STATEMENT: Treatment with St John's wort (SJW) has been reported to affect CYP3A expression and activity in rats. Our comparative study further supports this finding but shows that the pregnane X receptor-ligand hyperforin is not the driving force for changes in rat CYP3A23-3A1 expression and function in vivo and in vitro. Importantly, CYP3A induction mimics findings in humans, but our results suggest that another so far unknown constituent of SJW is responsible for the expression- and function-modifying effects in rat liver., (Copyright © 2023 by The Author(s).)

Background: The Bruton's tyrosine kinase inhibitor ibrutinib and the proteasome inhibitor bortezomib have single-agent activity, non-overlapping toxicities, and regulatory approval in mantle cell lymphoma (MCL). In vitro, their combination provides synergistic cytotoxicity. In this investigator-initiated phase 1/2 trial, we established the recommended phase 2 dose of ibrutinib in combination with bortezomib, and assessed its efficacy in patients with relapsed or refractory MCL., Methods: In this phase 1/2 study open in 15 sites in Switzerland, Germany and Italy, patients with relapsed or refractory MCL after ≤2 lines of chemotherapy and both ibrutinib-naïve and bortezomib-naïve received six cycles of ibrutinibb and bortezomib, followed by ibrutinib maintenance. For the phase 1 study, a standard 3 + 3 dose escalation design was used to determine the recommended phase 2 dose of ibrutinib in combination with bortezomib. The primary endpoint in phase 1 was the dose limiting toxicities in cycle 1. The phase 2 study was an open-label, single-arm trial with a Simon's two-stage min-max design, with a primary endpoint of overall response rate (ORR) assessed by CT/MRI. This study was registered with ClinicalTrials.gov, NCT02356458., Findings: Between August 2015 and September 2016, nine patients were treated in the phase 1 study, and 49 patients were treated between November 2016 and March 2020 in the phase 2 of the trial. The ORR was 81.8% (90% CI 71.1, 89.8%, CR(u) 21.8%) which increased with continued ibrutinib (median 10.6 months) to 87.3%, (CR(u) 41.8%). 75.6% of patients had at least one high-risk feature (Ki-67 > 30%, blastoid or pleomorphic variant, p53 overexpression, TP53 mutations and/or deletions). In these patients, ibrutinib and bortezomib were also effective with an ORR of 74%, increasing to 82% during maintenance. With a median follow-up of 25.4 months, the median duration of response was 22.7, and the median PFS was 18.6 months. PFS reached 30.8 and 32.9 months for patients with a CR or Cru, respectively., Interpretation: The combination of ibrutinib and bortezomib shows durable efficacy in patients with relapsed or refractory MCL, also in the presence of high-risk features., Funding: SAKK (Hubacher Fund), Swiss State Secretariat for Education, Research and Innovation, Swiss Cancer Research Foundation, and Janssen., Competing Interests: U.N. reports consulting fees and advisory board participation to/through the institution from and with Janssen-Cilag, Celgene (BMS), Takeda, AstraZeneca, Roche, Novartis, Incyte, Beigene, Kyowa Kirin, Gilead, Pierre Fabre and Miltenyi, payment of honoraria to the institution form Celgene (BMS), Novartis, Takeda, and Gilead, and meeting and/or travel support to the institution from Janssen, Roche, Gilead and Takeda. M.D. reports grants or contracts for research from Abbvie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, and Roche to the institution, payment of honoraria from AstraZeneca, Beigene, Gilead/Kite, Janssen, Lilly, Novartis and Roche, meeting and/or travel support from Janssen and Roche, and Data Safety Monitoring Board or Advisory Boards with Abbvie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, and Roche. C.S. reports consulting fees from BMS and Janssen, payments of honoraria from BMS and AstraZeneca, and meeting and/or travel support from Kite Gilead. E.D. reports and research funding from ADC Therapeutics and Takeda, consulting fees from Roche, Beigene, Abbvie, AstraZeneca, and Takeda, payments or honoraria from Abbvie, Roche, Incyte and Beigene, support for meetings and/or travel from Abbvie and Beigene, a Data Safety Monitoring Board or Advisory Board role with Abbvie, Beigene, Takeda, and Roche, and the receipt of equipment, materials, drugs, medical writing, gifts or other services from ADC Therapeutics. T.Z. reports consulting fees from Beigene Switzerland GmbH. G.H. reports grants or contracts for research from Gilead/Kite, Incyte, Janssen, Morphosys, Pfizer, Roche, and Abbvie, consulting fees from Abbvie, ADC Therapeutics, AstraZeneca, BMS, Genmab, Gilead/Kite, Incyte, Janssen, Miltenyi, Novartis, Roche, and Lilly, payments or honoraria from Abbvie, AstraZeneca, Beigene, BMS, Genmab, Gilead, Incyte, Janssen, Lilly, and Roche, meeting and/or travel support from Janssen and Gilead/Kite, and Data Safety Monitoring Board or Advisory Boards with Miltenyi. U.M. reports meeting and/or travel support from Janssen-Cilag, an advisory board role with Janssen-Cilag, and participation in the committee of the German-Swiss-Austrian guidelines for mantle cell lymphoma. S.F. reports grants or contracts for research, consulting fees, honoraria, meeting and/or travel support, and advisory board activities from and with Janssen. S.B. reports grants or contracts for research from Janssen-Cilag Neuss and Miltenyi Bergisch Gladbach to the institution, honoraria from Roche, Abbvie, Janssen, AstraZeneca, and Sanofi, and a travel support from Janssen. E.Z. reports grants or contracts for research from AstraZeneca, Beigene, Celgene, Incyte, Janssen, and Roche, for research to the institution from Incyte, AstraZeneca, Beigene, Celgene/BMS, Merck/MSD, and Roche, honoraria for an educational event from Abbvie, an advisory board role with Abbvie, AstraZeneca, Beigene, Celgene/BMS, Celltrion Healthcare, Curis, Eli Lilly, Gilead/Kite, Incyte, Ipsen, Janssen, MeiPharma, Miltenyi Biomedicine, Merck/MSD, and Roche, Data Safety Monitoring Board activities with Merck/MSD, and meeting and/or travel support from Abbvie, Gilead/Kite, Janssen, and Roche, and an expert statement for Bristol Myers Squib. C.R. reports consulting fees to the institution from Abbvie, Celgene/BMS, and Roche, honoraria to the institution from Amgen, Janssen, Abbvie, Celgene/BMS, and Takeda, payment for expert testimonies to the institution from Gilead and Janssen, and meeting and/or travel support from Sanofi and Amgen. All other authors declare no competing interests., (© 2023 The Authors.)

Background: Severe mental illnesses are risk factors for SARS-CoV-2-related morbidity and mortality. Vaccination is an effective protection; therefore, high vaccination rates should be a major priority for people with mental illnesses., Objectives: (1) Identification of at-risk groups for non-vaccination and structures and interventions needed for widespread vaccination among people with mental illnesses from the perspective of outpatient psychiatrists and neurologists, (2) discussion of the results in the context of the international literature and (3) recommendations derived from them., Material and Methods: Qualitative content analysis of COVID-19 vaccination-related questions from the COVID Ψ online survey of n = 85 psychiatrists and neurologists in Germany., Results: In the survey, people with schizophrenia, severe lack of drive, low socioeconomic status and homelessness were seen as risk groups for non-vaccination. Increased and targeted information, education, addressing and motivation and easily accessible vaccination offers by general practitioners, psychiatrists, and neurologists as well as complementary institutions were considered as important interventions., Discussion: COVID-19 vaccinations as well as information, motivation and access support should be systematically offered by as many institutions of the psychiatric, psychotherapeutic and complementary care systems in Germany as possible., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here we describe the impact of performance status (14% ECOG performance status 2), comorbidity (40% HCT-comorbidity index ≥ 2), and physical functioning (41% short physical performance battery < 9 and 17% ADL index < 6) on overall survival (OS) in 115 older patients (age ≥ 66 years) treated on a clinical trial with a 10-day decitabine schedule. None of the patient-related variables showed a significant association with OS. Multivariable analysis revealed that age > 76 years was significantly associated with reduced OS (HR 1.58; p = 0.043) and female sex was associated with superior OS (HR 0.62; p = 0.06). We further compared the genetic profiles of these subgroups. This revealed comparable mutational profiles in patients younger and older than 76 years, but, interestingly, revealed significantly more prevalent mutated ASXL1, STAG2, and U2AF1 in male compared to female patients. In this cohort of older patients treated with decitabine age and sex, but not comorbidities, physical functioning or cytogenetic risk were associated with overall survival., (© 2023. The Author(s).)

A 4-year-old female bearded dragon ( Pogona vitticeps ) was referred to the Clinic for Small Mammals, Reptiles and Birds of the University of Veterinary Medicine, Hannover, Germany for diagnostics and treatment of a growing mass in the right cervical region. The owner reported that the mass had grown over the past 4 weeks with only little alteration in the lizard´s behavior when the animal started rubbing its neck against the cage equipment. Physical examination as well as ultrasonographic and computed tomographic diagnostics revealed a highly vascularized mass, which allowed for the hypothesis of an aneurysm or a neoplasia. Complete surgical resection of the mass could be performed uneventfully. The bearded dragon recovered well from anesthesia and the surgical procedure. The microbiological sample of the excised mass revealed Group F-67 Salmonella. Histopathological examination of the excised mass revealed a histiocytic cell proliferation with centrally located blood filled cavities, hemorrhages and granulation tissue resembling features of a pseudoaneurysm. This report describes the diagnosis of an atypical growing mass in a bearded dragon and its successful removal., Competing Interests: The authors confirm that they do not have any conflict of interest., (Thieme. All rights reserved.)

Background: Limb fractures represent the most common orthopaedic disease in pet rabbits. However, only a few studies have evaluated therapeutic details of limb fractures. There are no data available for long-term outcomes of limb fracture treatment., Methods: The medical records of six institutions were reviewed retrospectively to identify cases of traumatic limb bone fractures in pet rabbits between 1999 and 2020. The medical records (n = 387) were analysed for details of fracture prevalence, aetiology, therapy protocols, treatment complications, outcome and long-term effects. In addition to the retrospective data evaluation, 13 rabbits were re-evaluated in person in recent clinical analyses, including orthopaedic examination, radiography and computed-tomographic imaging. Details of long-term effects of fracture treatment were requested over the telephone for a further 232 animals using a standardised questionnaire., Results: Long bone fractures accounted for the majority of all fractures (296/387; 76.5%). Hindlimb fractures (301/387; 77.7%) were more common than forelimb fractures (86/387; 22.2%), and tibial fractures and combined fractures of the tibia and fibula (119/387; 30.8%) were observed most frequently. Most fracture treatments were based on osteosynthesis procedures (243/328; 74.1%). Treatment complications occurred in 130 out of 328 (39.6%) cases. A high bodyweight (p = 0.047) and an older age (p = 0.01) were found to be significant risk factors for the emergence of therapy complications. Overall, 75.4% of animals (175/232) had a satisfactory long-term outcome. Limb posture anomalies were evaluated in 61 cases (26.3%)., Limitations: The multi-centre approach led to the inclusion of various institutions, veterinarians, treatment protocols and rabbit populations that might have influenced the results. The medical records were reviewed retrospectively, so there were some data that were lacking or could not be collected in a standardised manner. Furthermore, rabbit owners' evaluation of long-term outcomes might be prone to error, despite the use of a standardised interview questionnaire., Conclusion: Limb fractures are a common orthopaedic issue in pet rabbits. The patient's bodyweight and age are significant risk factors for the emergence of complications during the fracture treatment process. Long-term orthopaedic effects, such as abnormal limb posture and permanent lameness of the affected limb, were observed regularly., (© 2022 The Authors. Veterinary Record published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)

Introduction: Standard-dose eribulin mesylate (1.4 mg/m 2 d1 + 8) achieves clinical benefit rates of 26%-52% in patients with metastatic breast cancer (mBC). <10% of patients in the registration trial were ≥ 70 years old; dose reductions were common in these older patients., Materials and Methods: This single-arm phase II trial explored the efficacy of reduced starting dosing of first-line eribulin at 1 mg/m 2 d1 + 8 q3 weeks in patients with mBC aged ≥70 years. The primary endpoint was a disease control rate (DCR) ≥55%. The secondary endpoints were objective response (OR), progression-free survival (PFS), overall survival (OS), and patient-reported neurotoxicity., Results: Overall, 77 patients were accrued; their median age was 76 years and Eastern Cooperative Oncology Group performance status was 0-1 in 90%. The DCR was 40% (90% confidence interval [CI]: 31-50); therefore, the primary endpoint was not reached. The overall response rate was 22% (95%CI: 13-33), median PFS 5.4 months (95%CI: 4.5-7.7), and median OS 16.1 months (95%CI: 13.5-26.9). Dose modifications were necessary in 35% of patients. In nine patients, more than fifteen cycles were given; 48 patients (62%) experienced at least one grade 3 toxicity. Median patient-reported neurotoxicity scores remained stable for at least fifteen cycles. The main reason for treatment discontinuation was disease progression (57%)., Discussion: We report the first prospective data on first-line eribulin in older patients. The reduced starting dose of 1.1 mg/m 2 was safe, with prolonged treatment and DC achieved in a considerable proportion of patients (but less than the 55% assumed), without cumulative neurotoxicity. The reduced dose was apparently within the range of the minimal effective dose, as shown by the efficacy lack in patients requiring further dose reductions. Thus, our results do not support the approach of a reduced starting dose for older patients., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose This is an official guideline, published and coordinated by the Germany Society for Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, DGGG). Because of their rarity and heterogeneous histopathology, uterine sarcomas are challenging in terms of their clinical management and therefore require a multidisciplinary approach. To our knowledge, there are currently no binding evidence-based recommendations for the appropriate management of this heterogeneous group of tumors. Methods This S2k guideline was first published in 2015. The update published here is once again the result of the consensus of a representative interdisciplinary committee of experts who were commissioned by the Guidelines Committee of the DGGG to carry out a systematic search of the literature on uterine sarcomas. Members of the participating professional societies achieved a formal consensus after a structured consensus process. Recommendations 1.1 Epidemiology, classification, staging of uterine sarcomas. 1.2 Symptoms, general diagnostic workup, general pathology or genetic predisposition to uterine sarcomas. 2. Management of leiomyosarcomas. 3. Management of low-grade endometrial stromal sarcomas. 4. Management of high-grade endometrial stromal sarcoma and undifferentiated uterine sarcomas. 5. Management of adenosarcomas. 6. Rhabdomyosarcomas of the uterus in children and adolescents. 7. Follow-up of uterine sarcomas. 8. Management of morcellated uterine sarcomas. 9. Information provided to patients., Competing Interests: Conflict of Interest/Interessenkonflikt The conflicts of interest of all of the authors are listed in the long version of the guideline./Die Interessenkonflikte der Autoren sind in der Langfassung der Leitlinie aufgelistet., (Thieme. All rights reserved.)

Objective:  The aim of this study was to measure surface pressures and force distribution on radius and ulna in healthy and dysplastic elbow joints in different positions using the finite element analysis (FEA)., Study Design:  FEA was performed on computed tomographic data of healthy and fragmented coronoid process diseased elbow joints of Labrador Retrievers. It considered the articular cartilage, collateral ligaments, triceps and biceps muscle. The analysis of each joint was performed in four positions (standing position: 145 degrees and three positions of the stance phase of gait: beginning: 115 degrees, middle: 110 degrees, end: 145 degrees joint angle) in consideration of different ground reaction forces (standing: 88.3 N; stance phase of gait: 182.5 N)., Results:  Mean values of total force of 317.5 N (standing), 590.7 N (beginning), 330.9 N (middle) and 730.9 N (end) were measured. The percentual force distribution resulted in a total of 49.56 ± 26.58% on the ulna with a very inhomogeneous distribution. A significant difference was detected between the positions 'standing' and 'end' ( p  = 0.0497) regardless of the joint condition. In some FEA results, visual assessment of the surface pressures indicated an increase in pressure in the region of the medial compartment without a uniform pattern. An increase in pressure resulted in an area increase in the pressure marks on the joint surface and measurable pressure was increased at a larger joint angle., Clinical Significance:  FEA can provide information about the transmission of force in the joint. Prior to the use of FEA in scientific clinical research for the simulation of force, further model improvements are necessary., Competing Interests: None declared., (Thieme. All rights reserved.)

Differences in drug tolerability among vertebrate groups and species can create substantial challenges for wildlife and ex situ conservation programmes. Knowledge of tolerance in the use of new drugs is, therefore, important to avoid severe toxicity in species, which are both commonly admitted in veterinary clinics and are of conservation concern. Antimalarial drugs have been developed for use in human medicine, but treatment with different agents has also long been used in avian medicine, as haemosporidian infections play a major role in many avian species. This study investigates the effects of the application of atovaquone-proguanil (Malarone ® , GlaxoSmithKline) in common buzzards ( Buteo buteo ). The potential effects of treatment on body condition, growth rate, and chemical blood parameters of nestlings were assessed. All individuals survived the treatment, and no effects on body condition, growth rate, and chemical blood parameters were observed. Our results suggest the tolerability of Malarone ® in common buzzards at a single dose of on average 11 mg/kg body weight. For its safe use, we recommend further studies to determine pharmacokinetics in different avian species as well as to assess the effects of repeated treatment.

Objective:  To illustrate the arterial vascularity of the proximal tibia three-dimensionally and to evaluate the impact of fragment rotation on the cranial tibial artery by tibia plateau levelling osteotomy (TPLO)., Methods:  Radiographic angiography and computed tomography (CT) were performed on 12 pelvic limbs from six large-breed canine cadavers before and after TPLO. Three-dimensional (3D) models of the stifle, including osseous and vascular structures, were obtained, and the integrity of the cranial tibial artery was assessed. Post-TPLO CT images were used to analyze compression of the cranial tibial artery by the rotated fragment., Results:  The uncompressed cranial tibial artery caliber, measured proximally and distally to the osteotomy, was 9.52 mm 2 (6.07-18.90 mm 2 ). In all adequately rotated fragments, the mean caliber of the artery on the level of the osteotomy was 1.57 mm 2 (0.89-2.93 mm 2 ) after TPLO. This represented a significant decrease of approximately 81%. Only slight cross-sectional area decrease (8.8%) was seen in one limb, which was revealed to have insufficient fragment rotation (2.83 mm). Another limb only showed signs of stretching of the artery (31.51%), which was under-rotated and medially displaced. Pre-TPLO 3D reconstructions were mainly consistent with previous anatomic studies except for the distance between tibial cortex and cranial tibial artery, which appeared closer., Conclusion:  Sufficient fragment rotation leads to compression of the cranial tibial artery. Intraoperative hemorrhage can be caused by laceration of the main cranial tibial artery or by multiple small branches reaching craniolaterally., Competing Interests: The programs to perform model construction were financially supported by ZIM (Zentrales Innovationsprogramm Mittelstand) and Frank Goblet, Steinbeis-Innovationszentrum Systemlösungen in Mess- und Automatisierungstechnik Mannheim declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This script is part of a dissertation., (Thieme. All rights reserved.)

Psychiatric inpatient treatment, an important pillar of mental health care, is often of longer duration in Germany than in other countries. The COVID-19 pandemic called for infection prevention and control measures and thereby led to shifts in demand and inpatient capacities. The Germany-wide COVID Ψ Psychiatry Survey surveyed department heads of German psychiatric inpatient institutions. It assessed changes in utilization during the first two high incidence phases of the pandemic (spring 2020 and winter 2020/21) and also consequences for care, telemedicine experiences, hygiene measures, treatment of patients with mental illness and co-occuring SARS-CoV-2, and coercive measures in such patients. A total of n = 71 psychiatric departments (of 346 contacted) participated in the survey. The results showed a median decrease of inpatient treatment to 80% of 2019 levels and of day hospital treatment to 50% (first phase) and 70% (second phase). Reductions were mainly due to decreases in elective admissions, and emergency admissions remained unchanged or increased in 87% of departments. Utilization was reduced for affective, anxiety, personality, and addiction disorders but appeared roughly unaffected for psychotic disorders. A lack of integration of patients into their living environment, disease exacerbations, loss of contact, and suicide attempts were reported as problems resulting from reduced capacities and insufficient outpatient treatment alternatives. Almost all departments (96%) treated patients with severe mental illness and co-occurring SARS-CoV-2 infection. The majority established special wards and separate areas for (potentially) infectious patients. Telephone and video consultations were found to provide benefits in affective and anxiety disorders. Involuntary admissions of persons without mental illness because of infection protection law violations were reported by 6% of the hospitals. The survey showed high adaptability of psychiatric departments, which managed large capacity shifts and introduced new services for infectious patients, which include telemedicine services. However, the pandemic exacerbated some of the shortcomings of the German mental health system: Avoidable complications resulted from the lack of cooperation and integrated care sequences between in- and outpatient sectors and limited options for psychiatric hospitals to provide outpatient services. Preventive approaches to handle comparable pandemic situations in the future should focus on addressing these shortcomings., Competing Interests: PF received research support/honoraria for lectures or advisory activities from: Abbott, Boehringer-Ingelheim, Janssen, Essex, Lundbeck, Otsuka, Recordati, Richter, Servier, and Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wiegand, Bröcker, Fehr, Lohmann, Maicher, Röthke, Rueb, Wessels, de Greck, Pfennig, Unterecker, Tüscher, Walter, Falkai, Lieb, Hölzel and Adorjan.)

Objective: The use of the iodine-containing contrast agent diatrizoate was investigated in healthy rabbits and in rabbits with gastric dilatation and intestinal obstruction. For this purpose, transit times through the gastrointestinal tract and clinical use were investigated during a one year period. In addition, a possible influence on thyroid hormone levels was evaluated., Material and Methods: Transit times of contrast agent through the different intestinal sections were examined radiographically in 14 healthy rabbits. For this purpose, 7 ml/kg of a 300 mg iodine/ml and 600 mg diatrizoate/ml containing solution were administered. Radiographs were obtained at different time intervals. Three different doses (D1 2 ml/kg, D2 7 ml/kg, D3 10 ml/kg) were administered, and blood samples were collected at two time points (60 min, 24 h) to analyze thyroid hormone levels (TT4, fT4, TSH). In addition, 70 rabbits that had received the contrast agent diatrizoate because of gastric dilatation and suspected intestinal obstruction were retrospectively evaluated during a period of one year. Focus was placed on arrival of the contrast agent in the cecum, laboratory changes, and mortalities., Results: In all healthy rabbits, contrast medium was detectable in the cecum after a mean of 45-60 min. In the animals suffering from gastrointestinal obstruction, this was delayed to a mean of 121.2 min. These animals showed hypothermia in 92.4 % and hyperglycemia in 45.9 %. 56.1 % exhibited an increase in urea and 33.9 % an increase in creatinine. In 71.4 % of cases, medical treatment was possible, however 12 % of these individuals succumbed to the disease. 28.6 % of the cases were managed surgically which was associated with a mortality of 50 %. TT4, fT4, and TSH levels displayed significant alterations among the three contrast agent doses (p < 0.05). These changes were found to be transient when follow-up was performed two weeks later., Conclusion and Clinical Relevance: When ileus is suspected in rabbits, diatrizoate may be helpful in evaluating the progression of the disease in addition to the use of native radiographs. Sufficient hydration and monitoring of renal function are advisable. Transient changes in thyroid hormones were evident but lacked clinical relevance., Competing Interests: Die Autoren bestätigen, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Objective: Tissue Doppler imaging (TDI) is a new technique to measure the myocardial velocities of the avian heart. Using this technique, the present study investigated the influence of isoflurane anesthesia on the systolic and diastolic longitudinal myocardial velocities in racing pigeons., Material and Methods: Racing pigeons (n = 40) were anesthetized with isoflurane with a semi-open anesthesia system with an anesthetic mask and spontaneous breath. The echocardiographic examination was performed during the stage of surgical anesthesia with the failure of the toe pinch and wing twitch reflexes and with deep regular breaths. Echocardiographic measurements were taken in conscious and anesthetized pigeons in the right parasternal longitudinal horizontal heart view., Results: The results demonstrated a significant decrease in heart rate, systolic and diastolic A' wave myocardial velocities. The diastolic E' wave velocities were less influenced by anesthesia and significantly decreased only for some heart wall segments. The systolic myocardial velocities were significantly negatively correlated with the heart rate. Using the TDI curve, the isovolumic contraction (IVC) and relaxation time (IVR) and the time of atrioventricular delay during anesthesia could be determined. There is a significant increase in IVR and atrioventricular delay during anesthesia CONCLUSION AND CLINICAL RELEVANCEN: A higher heart rate in anesthesia should be interpreted as a compensation for reduced heart performance. The results of the present study indicate the necessity for establishing normal heart values in conscious and anesthetized pigeons., Competing Interests: The authors declare no conflict of interest., (Thieme. All rights reserved.)

Objective: CR1447, a novel transdermal formulation of 4-hydroxytestosterone, has aromatase-inhibiting and androgen receptor (AR)-modulating properties (IC 50 4.4 nM) with antitumor effects against AR-positive tumor cells in vitro. This trial investigated the efficacy and safety of CR1447 for patients with metastatic estrogen receptor-positive (A) and AR-positive triple-negative breast cancers (B)., Design and Methods: (A) included patients with at most one prior endocrine therapy line without progression ≥6 months, whereas (B) included patients with ≤2 prior chemotherapy lines, all displaying advanced signs of disease. The primary endpoint was disease control at week 24 (DC24). The null hypothesis was DC24 ≤30% (A) and ≤15% (B). Thirty-seven patients were recruited (29 in (A) and 8 in (B)); accrual was stopped following an interim analysis demonstrating futility in (A) and slow accrual in (B)., Results: DC24 was attained in 5/21 (95% CI: 8.2-47.2) patients in (A) and none in (B). The median progression-free survival was 5.1 months (95% CI: 2.5-5.6) in (A) and 2.5 months (95% CI: 0.7-2.6) in (B). The median overall survival was 24.6 months (95% CI: 22.9-not applicable) in (A) and 10.8 months (95% CI: 3.3-10.9) in (B). CR1447 had a favorable safety profile without treatment-related grade 3-5 toxicities in (A). Especially no side effects linked to androgenic effects were observed., Conclusions: Despite this trial being negative, the 24% DC24 rate in a second-line setting, and the prolonged partial response experienced by a patient, indicate activity. Further evaluation of CR1447 in endocrine-sensitive patients or combination trials appears warranted., Competing Interests: W S is a scientific advisor for CURADIS. The other authors have nothing to disclose., (© The authors.)

Introduction: Recent data suggest that margins ≥2 mm after breast-conserving surgery may improve local control in invasive breast cancer (BC). By allowing large resection volumes, oncoplastic breast-conserving surgery (OBCII; Clough level II/Tübingen 5-6) may achieve better local control than conventional breast conserving surgery (BCS; Tübingen 1-2) or oncoplastic breast conservation with low resection volumes (OBCI; Clough level I/Tübingen 3-4)., Methods: Data from consecutive high-risk BC patients treated in 15 centers from the Oncoplastic Breast Consortium (OPBC) network, between January 2010 and December 2013, were retrospectively reviewed., Results: A total of 3,177 women were included, 30% of whom were treated with OBC (OBCI n = 663; OBCII n = 297). The BCS/OBCI group had significantly smaller tumors and smaller resection margins compared with OBCII (pT1: 50% vs. 37%, p = 0.002; proportion with margin <1 mm: 17% vs. 6%, p < 0.001). There were significantly more re-excisions due to R1 ("ink on tumor") in the BCS/OBCI compared with the OBCII group (11% vs. 7%, p = 0.049). Univariate and multivariable regression analysis adjusted for tumor biology, tumor size, radiotherapy, and systemic treatment demonstrated no differences in local, regional, or distant recurrence-free or overall survival between the two groups., Conclusions: Large resection volumes in oncoplastic surgery increases the distance from cancer cells to the margin of the specimen and reduces reexcision rates significantly. With OBCII larger tumors are resected with similar local, regional and distant recurrence-free as well as overall survival rates as BCS/OBCI., (© 2021. The Author(s).)

The B-type natriuretic peptide (BNP), a member of the natriuretic peptide family and a cardiac hormone, is produced mainly in the ventricular myocytes and released into the circulation due to mechanical stimuli during an increasing cardiac wall stretch. BNP has a significant role in the regulation of the cardiovascular system and body fluid. The concentration of this hormone and of the biologically inactive amino-terminal-prohormone in the blood plasma is a helpful diagnostic tool for detecting cardiovascular diseases in human medicine and can be used as a prognostic marker for the risk of mortality, whilst such a tool does not exist for avian medicine. To date, the amino acid sequence of BNP is not known for many of the species commonly presented in avian consultation. In this study, the amino acid sequence of BNP and the prepropeptide was described for 12 parrot species as well as 3 raptor and 3 owl species by polymerase chain reaction (PCR) after RNA isolation from the heart. The results showed a high similarity between the amino acid sequences in the mature peptide region of the BNP. The prepropeptide showed several differences between the examined species, some of them shared by closely related species.

Background: Previous studies have raised serious concerns on cardiovascular safety of widely prescribed nonsteroidal anti-inflammatory drugs (NSAIDs). Therefore, the aim of this study was to characterize the electrophysiological effects of certain NSAIDs in an established whole heart model of proarrhythmia., Methods and Results: Thirty-eight hearts of New Zealand White rabbits were harvested and retrogradely perfused employing a Langendorff setup, and electrophysiology studies were performed to investigate action potential duration at 90% of repolarization (APD 90 ), QT intervals, and effective refractory period (ERP). After generating baseline data, hearts were perfused with ibuprofen (Group 1, n = 12; 10 and 30 μM), indomethacin (Group 2, n = 13; 10 and 20 μM) and diclofenac (Group 3, n = 13; 10 and 20 μM), respectively, and the pacing protocols were repeated for each concentration. In all groups, perfusion with the NSAIDs resulted in a significant and reproducible shortening of APD 90 and QT interval. In all groups, the arrhythmia susceptibility was significantly raised as occurrence of monomorphic ventricular tachycardia under programmed ventricular stimulation was significantly increased under perfusion with ibuprofen, indomethacin and diclofenac in all concentrations., Conclusion: The perfusion with ibuprofen, indomethacin and diclofenac in commonly used doses raised the arrhythmia susceptibility in an established rabbit whole-heart model while APD shortening and shortened ERP seem to be crucial for arrhythmogenesis., (© 2021 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)