Do German university medical centres promote robust and transparent research? A cross-sectional study of institutional policies.

BACKGROUND: In light of replication and translational failures, biomedical research practices have recently come under scrutiny. Experts have pointed out that the current incentive structures at research institutions do not sufficiently incentivise researchers to invest in robustness and transparency and instead incentivise them to optimize their fitness in the struggle for publications and grants. This cross-sectional study aimed to describe whether and how relevant policies of university medical centres in Germany support the robust and transparent conduct of research and how prevalent traditional metrics are. METHODS: For 38 German university medical centres, we searched for institutional policies for academic degrees and academic appointments as well as websites for their core facilities and research in general between December 2020 and February 2021. We screened the documents for mentions of indicators of robust and transparent research (study registration; reporting of results; sharing of research data, code and protocols; open access; and measures to increase robustness) and for mentions of more traditional metrics of career progression (number of publications; number and value of awarded grants; impact factors; and authorship order). RESULTS: While open access was mentioned in 16% of PhD regulations, other indicators of robust and transparent research were mentioned in less than 10% of institutional policies for academic degrees and academic appointments. These indicators were more frequently mentioned on the core facility and general research websites. Institutional policies for academic degrees and academic appointments had frequent mentions of traditional metrics. CONCLUSIONS: References to robust and transparent research practices are, with a few exceptions, generally uncommon in institutional policies at German university medical centres, while traditional criteria for academic promotion and tenure still prevail.

Sources of Information and Health Care Experiences Related to COVID-19 among Women Involved in Criminal Legal System in Three U.S. Cities.

Women in the United States criminal legal (CL) system are at the nexus of several drivers of the COVID-19 pandemic, including incarceration, poverty, chronic illness and racism. There are 1.25 million women incarcerated or on community supervision (probation or parole) in the U.S. We present findings regarding the impact of COVID-19 on women in the CL system (N=344) during the early days of the pandemic. Participants were drawn from community settings in an ongoing study of cervical cancer risk in three U.S. cities: Birmingham, Alabama, Oakland, California and Kansas City, which straddles the states of Kansas and Missouri. Regional differences were found in COVID-19 testing and perceived susceptibility to the virus, but not in COVID-related disruptions to health care. We found differences by race/ethnicity in trusted sources of information about COVID. Black women had higher odds of choosing TV as their most trusted source of information, while White women were more likely to cite government or social service agencies as their most trusted source. Notably, 15% of women said they did not trust any source of information regarding COVID-19. COVID-19 disproportionately impacts populations with high levels of mistrust towards medical and government institutions, a result of the twin legacies of medical mistreatment and structural racism. Our findings underscore the need for innovative strategies to reach these groups with accurate and timely information.

Optical imaging probes and their potential contribution to radiotracer development.

Optical imaging has long been considered a method for histological or microscopic investigations. Over the last 15 years, however, this method was applied for preclinical molecular imaging and, just recently, was also able to show its principal potential for clinical applications (e .g. fluorescence-guided surgery). Reviewing the development and preclinical evaluation of new fluorescent dyes and target-specific dye conjugates, these often show characteristic patterns of their routes of excretion and biodistribution, which could also be interesting for the development and optimization of radiopharmaceuticals. Especially ionic charges show a great influence on biodistribution and net-charge and charge-distribution on a conjugate often determines unspecific binding or background signals in liver, kidney or intestine, and other organs. Learning from fluorescent probe behaviour in vivo and translating this knowledge to radiopharmaceuticals might be useful to further optimize emerging and existing radiopharmaceuticals with respect to their biodistribution and thereby availability for binding to their targets.

Development and evaluation of a non-peptidic ligand for the molecular imaging of inflammatory processes using S100A9 (MRP14) as a novel target.

The establishment of novel molecular imaging tools to monitor the local activity of inflammation remains an interdisciplinary challenge. Our target, the alarmin S100A9, one subunit of the heterodimer S100A8/S100A9 (calprotectin), is locally secreted in high concentrations from immigrated and activated phagocytes at local sites of inflammation. Calprotectin is already a well established serum biomarker for many inflammatory disorders. Here we show the development and first evaluation of the novel S100A9 specific molecular imaging probe for optical imaging of local inflammatory activity in vivo.

Specific biomarkers of receptors, pathways of inhibition and targeted therapies: pre-clinical developments.

A deeper understanding of the role of specific genes, proteins, pathways and networks in health and disease, coupled with the development of technologies to assay these molecules and pathways in patients, promises to revolutionise the practice of clinical medicine. Especially the discovery and development of novel drugs targeted to disease-specific alterations could benefit significantly from non-invasive imaging techniques assessing the dynamics of specific disease-related parameters. Here we review the application of imaging biomarkers in the management of patients with brain tumours, especially malignant glioma. In our other review we focused on imaging biomarkers of general biochemical and physiological processes related with tumour growth such as energy, protein, DNA and membrane metabolism, vascular function, hypoxia and cell death. In this part of the review, we will discuss the use of imaging biomarkers of specific disease-related molecular genetic alterations such as apoptosis, angiogenesis, cell membrane receptors and signalling pathways and their application in targeted therapies.

Non-invasive approaches to visualize the endothelin axis in vivo using state-of-the-art molecular imaging modalities.

The endothelin axis plays a major role in cardiovascular diseases and a number of human cancers. This review summarizes the work that has been published in the past ten years using labeled endothelin receptor ligands for the visualization of endothelin receptor expression in vivo.

E2f3a and E2f3b make overlapping but different contributions to total E2f3 activity.

The E2f transcription factors are key downstream targets of the retinoblastoma protein tumor suppressor that control cell proliferation. E2F3 has garnered particular attention because it is amplified in various human tumors. E2f3 mutant mice typically die around birth and E2f3-deficient cells have a proliferation defect that correlates with impaired E2f target gene activation and also induction of p19(Arf) and p53. The E2f3 locus encodes two isoforms, E2f3a and E2f3b, which differ in their N-termini. However, it is unclear how E2f3a versus E2f3b contributes to E2f3's requirement in either proliferation or development. To address this, we use E2f3a- and E2f3b-specific knockouts. We show that inactivation of E2f3a results in a low penetrance proliferation defect in vitro whereas loss of E2f3b has no effect. This proliferation defect appears insufficient to disrupt normal development as E2f3a and E2f3b mutant mice are both fully viable and have no detectable defects. However, when combined with E2f1 mutation, inactivation of E2f3a, but not E2f3b, causes significant proliferation defects in vitro, neonatal lethality and also a striking cartilage defect. Thus, we conclude that E2f3a and E2f3b have largely overlapping functions in vivo and that E2f3a can fully substitute for E2f1 and E2f3 in most murine tissues.

UVA radiation causes DNA strand breaks, chromosomal aberrations and tumorigenic transformation in HaCaT skin keratinocytes.

The role of UVA-radiation-the major fraction in sunlight-in human skin carcinogenesis is still elusive. We here report that different UVA exposure regime (4 x 5 J/cm(2) per week or 1 x 20 J/cm(2) per week) caused tumorigenic conversion (tumors in nude mice) of the HaCaT skin keratinocytes. While tumorigenicity was not associated with general telomere shortening, we found new chromosomal changes characteristic for each recultivated tumor. Since this suggested a nontelomere-dependent relationship between UVA irradiation and chromosomal aberrations, we investigated for alternate mechanisms of UVA-dependent genomic instability. Using the alkaline and neutral comet assay as well as gamma-H2AX foci formation on irradiated HaCaT cells (20-60 J/cm(2)), we show a dose-dependent and long lasting induction of DNA single and double (ds) strand breaks. Extending this to normal human skin keratinocytes, we demonstrate a comparable damage response and, additionally, a significant induction and maintenance of micronuclei (MN) with more acentric fragments (indicative of ds breaks) than entire chromosomes particularly 5 days post irradiation. Thus, physiologically relevant UVA doses cause long-lasting DNA strand breaks, a prerequisite for chromosomal aberration that most likely contribute to tumorigenic conversion of the HaCaT cells. Since normal keratinocytes responded similarly, UVA may likewise contribute to the complex karyotype characteristic for human skin carcinomas.

3D MR flow analysis in realistic rapid-prototyping model systems of the thoracic aorta: comparison with in vivo data and computational fluid dynamics in identical vessel geometries.

The knowledge of local vascular anatomy and function in the human body is of high interest for the diagnosis and treatment of cardiovascular disease. A comprehensive analysis of the hemodynamics in the thoracic aorta is presented based on the integration of flow-sensitive 4D MRI with state-of-the-art rapid prototyping technology and computational fluid dynamics (CFD). Rapid prototyping was used to transform aortic geometries as measured by contrast-enhanced MR angiography into realistic vascular models with large anatomical coverage. Integration into a flow circuit with patient-specific pulsatile in-flow conditions and application of flow-sensitive 4D MRI permitted detailed analysis of local and global 3D flow dynamics in a realistic vascular geometry. Visualization of characteristic 3D flow patterns and quantitative comparisons of the in vitro experiments with in vivo data and CFD simulations in identical vascular geometries were performed to evaluate the accuracy of vascular model systems. The results indicate the potential of such patient-specific model systems for detailed experimental simulation of realistic vascular hemodynamics. Further studies are warranted to examine the influence of refined boundary conditions of the human circulatory system such as fluid-wall interaction and their effect on normal and pathological blood flow characteristics associated with vascular geometry.

Efficacy of lyophilised C-strain vaccine after oral immunisation of domestic pigs and wild boar against classical swine fever: first results.

The aim of this study was to evaluate the efficacy of lyophilised C-strain vaccine in domestic pigs and wild boar after oral application. A new spherical bait form (diameter 3 cm) containing lyophilised vaccine virus and the recent vaccine baits were used for animal experiments. Four vaccination groups were established in experiment 1 (group 1: recent liquid bait vaccine; group 2: spherical baits containing one dose of the lyophilised vaccine; groups 3 (domestic pigs) and 4 (wild boar): spherical baits containing two doses of the lyophilised vaccine) and two groups in experiment 2 (group 1: recent liquid bait vaccine; group 2: spherical baits with two doses of the lyophilised vaccine). Challenge was carried out with the highly virulent virus strain "Alfort 187" (using 100 TCID50 in the first and 1.000 TCID50 in the second experiment). Our results showed that the animals vaccinated with lyophilised C-strain vaccine developed high neutralising antibody titres comparable to those obtained after vaccination with the recent bait vaccine. All pigs which picked up the baits remained healthy after challenge. Neither clinical symptoms nor viremia or virus shedding were observed after infection except in one pig (group 2, experiment 2) which had not consumed the vaccine bait. The surviving domestic pigs and wild boar were tested negative for CSFV and viral RNA at the end of the study. This result demonstrates that lyophilised vaccine may become an effective vaccine formulation for oral immunisation of wild boar against CSF in the near future.

The nonpeptidyl caspase binding radioligand (S)-1-(4-(2-[18F]Fluoroethoxy)-benzyl)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin ([18F]CbR) as potential positron emission tomography-compatible apoptosis imaging agent.

AIM: Radiolabeled Annexin V-derivatives are well characterized phosphatidylserine-targeting biomarkers and considered as state-of-the-art tracers for non-invasive molecular imaging of apoptosis. In contrast to Annexin V-derived imaging agents being surrogate markers of apoptosis, activated cysteinyl aspartate-specific proteases (caspases) represent the common final path of apoptosis being a suitable in vivo target for the exclusive imaging of apoptotic tissues in vivo. METHODS: We suggest 5-pyrrolidinylsulfonyl isatins as a potential nonpeptidyl class of caspase inhibitors for the design of caspase binding radioligands (CbRs), that could be used for in vivo visualization of activated effector caspases. The caspase inhibitor (S)-(+)-5-[1-(2-Methoxy-methylpyrrolidinyl)sulfonyl]isatin 1 (K(i, caspase)-3 (1)=60 nM) was chosen as lead structure for the development of nonpeptidyl CbRs. Its structural expansion at the N-1-position the yields moderate lipophilic p-(2-fluoroethoxy)benzyl variant 2 (log D=2.2), without loss of caspase binding potency (IC(50, caspase)-3 (2)=36.4 nM). RESULTS: Subsequent automated radiosynthesis of the corresponding (18)F-labeled target CbR [(18)F]2 was performed by direct (18)F-labeling of tosylate precursor 4. CONCLUSIONS: As shown by biodistribution studies and small animal positron emission tomography a nonpeptidyl 5-pyrrolidinylsulfonyl isatin-type caspase inhibitor (S)-1-(4-(2-[(18)F]Fluoroetho-xy)benzyl)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin [(18)F]2 with rapid blood clearance characteristics could potentially detect apoptosis in vivo.

Molecular imaging of matrix metalloproteinases in vivo using small molecule inhibitors for SPECT and PET.

Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent secreted or membrane anchored endopeptidases. MMPs are involved in many physiological processes but also take part in the pathophysiological mechanisms responsible for a wide range of diseases. Pathological expression and activation of MMPs are associated with cancer, atherosclerosis, stroke, arthritis, periodontal disease, multiple sclerosis and liver fibrosis. Thus, noninvasive visualisation and quantification of MMP activity in vivo are of great interest in basic research and clinical application. This can be achieved by scintigraphic molecular imaging techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) provided suitable radiolabelled tracers exist, e.g. radioactive inhibitors of matrix metalloproteinases (MMPIs). The approach to monitor MMP activity in vivo using radiolabelled small molecule inhibitors suitable for SPECT and PET is summarised in this review. Briefly, latest advances in scintigraphic imaging are introduced and followed by a report about the enzyme class of MMPs. The involvement of MMPs in cancer and atherosclerosis is exemplified and small molecule MMPIs are classified. Subsequently, the development of radiolabelled small molecule MMPIs, their synthesis and in vitro and in vivo evaluation is reviewed. Finally, an outlook on the clinical potential of labelled MMPIs in diagnostic algorithms is given.

Three-dimensional dynamic hip contact area and pressure distribution during activities of daily living.

Estimation of the hip joint contact area and pressure distribution during activities of daily living is important in predicting joint degeneration mechanism, prosthetic implant wear, providing biomechanical rationales for preoperative planning and postoperative rehabilitation. These biomechanical data were estimated utilizing a generic hip model, the Discrete Element Analysis technique, and the in vivo hip joint contact force data. The three-dimensional joint potential contact area was obtained from the anteroposterior radiograph of a subject and the actual joint contact area and pressure distribution in eight activities of daily living were calculated. During fast, normal, and slow walking, the peak pressure of moderate magnitude was located at the lateral roof of the acetabulum during mid-stance. In standing up and sitting down, and during knee bending, the peak pressures were located at the edge of the posterior horn and the magnitude of the peak pressure during sitting down was 2.8 times that of normal walking. The peak pressure was found at the lateral roof in climbing up stairs which was higher than that in going down stairs. These results can be used to rationalize rehabilitation protocols, functional restrictions after complex acetabular reconstructions, and prosthetic component wear and fatigue test set up. The same model and analysis can provide further insight to soft tissue loading and pathology such as labral injury. When the pressure distribution on the acetabulum is inverted onto the femoral head, prediction of subchondral bone collapse associated with avascular necrosis can be achieved with improved accuracy.

Partial sensory and motor deficit of ipsilateral lower limb after continuous interscalene brachial plexus block.

We describe a partial sensory and motor block of the ipsilateral lower limb after interscalene infusion. After and injection of 20 mL of ropivacaine through the needle, the catheter was advanced 5 cm, and an infusion of ropivacaine 0.2% 5 mL/h commenced. Six hours later, the patient reported a left sensory and motor hemisyndrome, which resolved after the infusion was discontinued. Cervical computed tomography showed the tip of the catheter close to the intervertebral foramen at the C7-T1 level and several intravertebral paramedullar air bubbles. We conclude that the neurological symptoms were caused by an injection of local anesthetic via an interscalene catheter placed in proximity to the epidural space. To avoid this complication, we recommend advancing the catheter no more than 2-3 cm and performing frequent neurological evaluation of patients.

Interlayer stacking disorder in zeolite beta family: a Raman spectroscopic study.

Raman spectroscopy has been applied to series of BEA- and BEC-type samples differing from each other in size, Si/Al ratio and polymorph percentage in order to analyse the effect of interlayer stacking arrangements on the vibrational modes of zeolite beta. The Raman peaks observed in the spectral range 250-550 cm-1 were assigned to the rings building the basic (001)-layer and to those linking the adjacent layers in zeolite beta. It is shown that the intensity ratio rho between the Raman signals at 314 and 343 cm-1 is most sensitive to the degree of periodicity faults along the c direction. A larger value of rho indicates a larger size of polymorph stacking sequence, i.e. improvement of the stacking faultlessness. The interlayer stacking disorder and the degree of connectivity point defects are higher in nanosized zeolite beta than in micron-sized crystals. The Al content influences the concentration of defected SiOH groups, but is less important for the interlayer stacking sequences in colloidal zeolite beta.

Non-invasive molecular imaging of beta-adrenoceptors in vivo: perspectives for PET-radioligands.

Recently, the spectrum of molecular imaging devices such as positron emission tomography (PET) was further expanded by the now clinically available combined imaging modalities such as PET-CT and the preclinically used small animal PET scanners. These are powerful tools that can bridge the gap between preclinical and clinical evaluation studies of new radiotracers for molecular imaging of healthy and diseased states in vivo. The beta-adrenoceptor (beta-AR) radioligands discussed in this review represent a class of molecular probes for the non-invasive in vivo assessment of beta-AR density eg. in the heart with PET. The beta-AR radioligands (S)-[11C]CGP 12177 (1) or (S)-[11C]CGP 12388 (2) are currently investigated in clinical studies with PET. Additionally, subtype-selective beta1-AR radioligands are used in preclinical research which show potential for the diagnostics of the "beta1-AR organ" as such the heart can be defined. Non-invasive quantification of beta-ARs could facilitate the accurate choice and control of therapeutic interventions. Here we summarize the state-of-the-art of the radiochemistry of radioactive beta-AR radioligands.

Advanced crown and bridge design.

The present article describes the CAD construction procedure of copings, reduced crowns, anatomical crowns, hybrid bridges, and other construction software features contained in the Digident dental CAD/CAM system (Girrbach Dental, Pforzheim, Germany). The individual design of a crown or a bridge framework will, of course, influence the stability and the longevity of the final dental restoration. Especially an anatomically reduced crown framework possesses--in comparison to a simple coping design--several advantages, while for some materials, a full crown design is esthetically not suitable. An anatomically reduced crown design results in a mechanical support of the occlusal cusps, as the high strength framework is mechanically more favorable than the veneering ceramics or composites. Moreover, the reduced construction of the anatomical shape allows the creation of ceramic layers of approximately homogeneous thickness. This has the effect that the residual stresses in the veneering ceramic after the thermal treatment, i.e., several firing and cooling cycles, are minimized. A prerequisite for the computer-aided anatomical construction of crowns is the inclusion of adjacent teeth and the articulation of the opposing jaw. In these terms, the opposing jaw or a bite impression have to be scanned, digitized, and positioned virtually in bite relation. While taking patient-specific articulator parameters into account, a software-integrated "virtual articulator" allows simulation of dynamic occlusion and therefore a computer-aided reduction of interfering contact points.

Human peritoneal macrophages in culture: a model for studying inflammatory disorders in vitro.

In this study we characterized a model of human peritoneal macrophages maintained in culture for up to 48 h that can be used to study different functions of this cell population in vitro. The cells remained viable and functionally active over time, with well-preserved phagocytic properties. They expressed a macrophage marker, CD14. Once in culture, human peritoneal macrophages secreted C1q and nitric oxide in a pattern described in murine, guinea pig, and rat peritoneal macrophages. The described model can be used to study physiology and pathophysiology of peritoneal macrophages in vitro, offering all the advantages of the use of a human cell population.