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.

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.

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.

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.

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.

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.

Detection of antibodies specific for HLA-A,B,C,DR,DQ and DP by the erythrocyte antibody rosette inhibition (EAI) and immune phagocytosis inhibition (IPI) tests.

Two methods for the detection of murine monoclonal antibodies against determinants of the human major histocompatibility complex (MHC) were evaluated. These methods are based upon the function of Fc receptors; the erythrocyte antibody rosette inhibition test (EAI test) using B-lymphocytes and the immune phagocytosis inhibition test (IPI test) using monocytes. Compared to the EAI test the IPI test was technically easier and gave better discrimination between positive and negative results. The inhibition by antibodies of monomorphic class II MHC or polymorphic HLA-DR antigens was stronger in the IPI than in the EAI test. Antibodies against HLA-DQ and DP antigens evoked inhibition only using the EAI test. Using IgG derived from placenta in different dilutions the detection of its anti-HLA antibodies was more readily achieved in the IPI test than in the EAI test.

Primary nonfunction of islet grafts in autoimmune diabetic nonobese diabetic mice is prevented by treatment with interleukin-4 and interleukin-10.

In isologous islet transplantation in spontaneously diabetic nonobese (NOD) mice, destruction of the islet graft is caused by recurrence of T helper (Th)1-driven insulitis[fnc,1. We established a model of transplantation in which female NOD recipients were rendered diabetic by a single injection of cyclophosphamide (250 mg/kg). Under these conditions, 500 freshly isolated islets from young NOD mice transplanted under the kidney capsule did not lead to normoglycemia within 3 day after transplantation, but underwent immediate impairment of function. This primary nonfunction was seen in > 80% of the recipients. Treatment of the recipients with the Th2-associated cytokine interleukin (IL)-4 alone did not prevent primary nonfunction, whereas treatment of the recipients with a combination of IL-4 and IL-10 restored immediate function of the grafts. Cytokine treatment did not prevent later rejection of grafts. Histological analysis of the grafts revealed less severely infiltrated islets, with well preserved islet architecture, in only normoglycemic animals treated with IL-4 or with IL-4 and IL-10. Staining for lymphocytes, macrophages, and tumor necrosis factor (TNF)-alpha did not show differences between the groups, but IFN-gamma was markedly less expressed in IL-4- and IL-10-treated grafts. Concomitantly, analysis of animals treated for 8 days after injection of cyclophosphamide, with IL-4 and IL-10, revealed a reduction of IL-12 mRNA in the pancreas. We conclude from these data that primary nonfunction of islet grafts is prevented by treatment of the recipients with a combination of IL-4 and IL-10, via downregulation of Th1 cytokines.

Quality team approach in evaluating three automated hematology analyzers with five-part differential capability.

Three modern hematology analyzers (Abbott Cell-Dyn 3000, Coulter STKS, and Sysmex NE-8000) with high throughput and 5-part differential capability were evaluated using a protocol designed by a quality team. Effective use of the team process to evaluate instrumentation empowers laboratory personnel to share in decision-making activities, improves job satisfaction, and produces the best purchasing decision. Instruments were compared using a combination of statistical analysis and written evaluations provided by team members. Tools and concepts from this study provide a comprehensive model for an effective multi-instrument evaluation.

Size and position of a single condyle allograft influence knee kinematics.

An optimal match for size and shape between the donor femur and the host knee is considered a critical factor influencing the outcome of a knee allograft implantation. An in vitro allograft model was developed to determine the influence of the size and position of a lateral distal femoral condylar allograft on knee kinematics. Functional knee motion was simulated in a cadaver host knee in the intact state after removing and reimplanting the native lateral condyle of the distal femur and after serially replacing the native condyle with eight donor allografts. Each allograft was first tested in an optimal position and subsequently shifted 3 mm proximal and 3 mm distal to the joint line to quantify changes in joint kinematics due to the position of the allograft. The intact knee and the knee with the ideally implanted native allograft followed similar kinematic trends. Decreasing the width of the allograft increased the valgus knee orientation at full flexion, translated the tibia posteriorly at full extension, and externally rotated the tibia throughout knee flexion. The proximal shift in allograft position increased the valgus orientation at full extension, translated the tibia posteriorly at mid-flexion, and externally rotated the tibia throughout flexion. The distal shift in position had the opposite effect on the kinematics of the proximal shift. These results indicate that improving techniques for preoperative size-matching and intraoperative allograft placement may help to reduce biomechanical complications following implantation of the allograft.

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.

Concentrations and profiles of PCDDs and PCDFs in human mammary carcinoma tissue.

PCDD/PCDF concentrations in eight mammary carcinoma tissue samples obtained after surgical excision were similar to those found in two healthy breast glandular tissue samples from autopsy material. These levels agree well with mean concentrations in human adipose tissue from German adults. An analogous consistency was found for the congener profiles of the normalized concentrations, also in comparison with mothers' milk from Germany. In spite of similar congener profiles the concentrations in four axillary adipose tissue samples corresponding to the carcinoma samples were about 40% lower. This discrepancy was not found in one tissue pair from a healthy breast.

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.

Virtual reality (VR) techniques in orthopaedic research and practice.

Modeling the musculoskeletal joint system using biomechanical analysis and computer graphics techniques allows us to visualize normal, diseased and reconstructed joint function. This model can be used to study the loading of bones and joints under theoretical and simulated activities. In this study, intact cadavers were imaged using MRI, CT scanning and cryo-sectioning techniques. Using sequential pixel information of bone and soft tissue boundaries collected from digital camera images, MRI and CT scans, the volumetric models of the musculoskeletal joint system are reconstructed. "Descriptive geometry" techniques which treat bones as rigid bodies and cartilage, ligament and muscles as deformable bodies were used to construct the model. Joint resultant forces and moments were determined using an inverse dynamics formulation, while ligament tension, joint contact pressure, and bone stresses are solved through a simplified Rigid Body Spring Modeling technique and the Finite Element Method. The results under static and dynamic loading activities can be visualized using interactive computer graphics. The advantages of such a model are the elimination of the need for large numbers of intact cadaveric specimens, and the unprecedented capability to study joint loading responses under normal, abnormal and surgically reconstructed states. Such a model and its analytical capability are ideal for pre-operative planning and computer-assisted orthopaedic surgery. This Visual, Interactive, Computational, and Anatomic Model(VICAM) and its associated analysis capability represent the next generation of technology which will have an enormous impact in orthopaedic research, education and patient care.

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.