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Zusammenfassung Hintergrund Verletzungen des medialen Bandkomplexes gehören zu den häufigsten Knieverletzungen. Sie heilen zwar meist mit konservativer Therapie problemlos aus, persistierende Instabilitäten erhöhen aber die Belastung der Kreuzbänder und benötigen speziell bei deren Beteiligung eine adäquate Therapie. Anatomie und Biomechanik Der mediale Seitenbandkomplex besteht im Wesentlichen aus dem oberflächlichen Seitenband (sMCL), welches der primäre Stabilisator gegen Valgus ist, dem tiefen Seitenband (dMCL) mit dessen schräg verlaufendem ventralem Anteil (AML), die nur sekundäre Stabilisatoren gegen Valgus darstellen, aber primär gegen Außenrotation stabilisieren, und dem hinteren Schrägband (POL), das in vollständiger Streckung gegen Valgus sowie gegen Innenrotation stabilisiert. Therapie Chronische Instabilitäten bzw. höhergradige Verletzungen mit Dislokation der Bandstümpfe oder multiligamentäre Verletzungen bedürfen einer operativen Versorgung. Im Akutstadium zeigen Avulsionsverletzungen bei anatomischer Refixation gutes Heilungspotenzial, während bei intraligamentären Verletzungen zusätzlich zur Naht der Bandanteile eine Augmentation mit Sehnenmaterial empfohlen wird. Bei chronischen Instabilitäten ist die Differenzierung des Instabilitätsmusters ausschlaggebend für die Wahl der Rekonstruktionstechnik (reine sMCL-Rekonstruktion oder kombinierte Rekonstruktion von sMCL und AML). In beiden Fällen kommt die hier beschriebene Technik mit flachem Transplantat der Anatomie näher als bei konventionellen Verfahren. Diskussion Rekonstruktionstechniken unter Verwendung flacher Sehnentransplantate, die alle betroffenen Bandanteile adressieren, haben sich biomechanisch als sehr effektiv erwiesen, komplexe mediale Instabilitäten suffizient zu behandeln. Ob diese auch klinisch überlegen sind, werden zukünftige klinische Studien zeigen müssen.

The serotonin transporter (SERT) mRNA was previously reported to be a quantitative and pathophysiology-based biomarker of heavy drinking in 5HTTLPR:LL genotype-carriers treated with ondansetron. Here, we validated the potential use of SERT mRNA for quantitative prediction of recent alcohol consumption (in the absence of treatment) and compared it with the known biomarkers ethyl glucuronide (EtG) and ethyl sulfate (EtS).Binge drinking men and women of European ancestry aged 21 to 65 years were enrolled in a 12-day, in-patient, randomized, double-blind, crossover study, where they were administered three beverage doses (placebo, 0.5 g/kg [0.4 g/kg] ethanol, and 1 g/kg [0.9 g/kg] ethanol for men [women]) individually in three 4-day periods (experiments), separated by minimum 7-day washout period. Diet, sleep, and physical activity were controlled throughout the inpatient experiments. Twenty-nine participants were randomized to receive beverage doses counterbalancing the sequence of treatment and gender within subgroups stratified by SERT genotypes 5HTTLPR:LL+rs25531:AA (LThe association between administered beverage dose and SERT mRNA from completers of at least one 4-day experiment (N = 18) assessed by a linear mixed model was not statistically significant. Significant positive associations were found with beverage dose and plasma EtG, EtS and EtG/EtS ratio (β = 5.8, SE = 1.2, p 0.0001; β = 1.3, SE = 0.6, p = 0.023; and β = 3.0, SE = 0.7, p 0.0001, respectively; the C-statistics for discriminating outcomes were 0.97, 0.8, and 0.92, respectively). Additionally, we observed a sequence effect with a greater placebo effect on SERT mRNA when it was administered during the first experiment (p = 0.0009), but not on EtG/EtS measures.The findings do not validate the use of SERT as a biomarker of heavy drinking. Larger and more innovative studies addressing the effects of placebo, race, gender, and response to treatment with serotonergic agents are needed to fully assess the utility of SERT as a biomarker of heavy and binge drinking.

Metformin has been shown to repress transcription of the bile salt export pump (BSEP) in human primary hepatocytes. The primary objective of this study was to assess the effect of oral metformin on the human pharmacokinetics (PKs) of two BSEP probe substrates: pravastatin and chenodeoxycholic acid (CDCA; also known as chenodiol). Endogenous bile acid levels were assessed as a secondary measure of metformin impact. An open-label, randomized, single-dose, placebo-controlled, fasted, crossover PK study was conducted in 12 healthy adult volunteers. Metformin (500 mg b.i.d.) or placebo (b.i.d.) was administered orally for 6 days. On day 7, a single dose of the BSEP substrates pravastatin (80 mg) and CDCA (250 mg) were administered orally. Plasma samples were quantified for pravastatin, CDCA, and endogenous bile acids. Compared to placebo, metformin increased pravastatin plasma exposure, did not impact CDCA plasma exposure, and reduced conjugated primary bile acid levels in the blood. These results are consistent with metformin repressing BSEP expression. This differential effect reflects the degree of enterohepatic recirculation of victim substrates.

Participation in cancer research trials by minority populations is imperative in reducing disparities in clinical outcomes. Even with increased awareness of the importance of minority patient inclusion in clinical research to improve cancer care and survival, significant barriers persist in accruing and retaining minority patients into clinical trials. This study sought to identify and address barriers to minority accrual to a minimal risk clinical research study in real-time.

Clinical reasoning theories agree that knowledge and the diagnostic process are associated with diagnostic success. However, the exact contributions of these components of clinical reasoning to diagnostic success remain unclear. This is particularly the case when operationalizing the diagnostic process with diagnostic activities (i.e., teachable practices that generate knowledge). Therefore, we conducted a study investigating to what extent knowledge and diagnostic activities uniquely explain variance in diagnostic success with virtual patients among medical students. The sample consisted of N = 106 medical students in their third to fifth year of university studies in Germany (6-years curriculum). Participants completed professional knowledge tests before diagnosing virtual patients. Diagnostic success with the virtual patients was assessed with diagnostic accuracy as well as a comprehensive diagnostic score to answer the call for more extensive measurement of clinical reasoning outcomes. The three diagnostic activities hypothesis generation, evidence generation, and evidence evaluation were tracked. Professional knowledge predicted performance in terms of the comprehensive diagnostic score and displayed a small association with diagnostic accuracy. Diagnostic activities predicted comprehensive diagnostic score and diagnostic accuracy. Hierarchical regressions showed that the diagnostic activities made a unique contribution to diagnostic success, even when knowledge was taken into account. Our results support the argument that the diagnostic process is more than an embodiment of knowledge and explains variance in diagnostic success over and above knowledge. We discuss possible mechanisms explaining this finding.

Virtual Reality (VR) and photogrammetry are emerging technologies that facilitate and shape the ongoing digital transformation of education. VR offers new opportunities for creating immersive and interactive educational experiences. Photogrammetry enables new ways to create lifelike educational virtual environments and is becoming an alternative to manual 3D modeling with graphics software. The manner in which VR affects the authenticity of educational experiences has been addressed in previous educational and psychological research. Empirical papers have so far focused on the authenticity of educational VR environments created by 3D modeling. However, little is known about the authenticity of educational VR environments developed with photogrammetry. Given that VR provides rich multi-sensory experiences and interests can be stimulated by engaging contexts, educational VR environments also possess great potential to support interest development. What is still unknown regarding this topic are the beneficial characteristics of VR environments and the individual variables required to trigger and explain interest development. Consequently, we conducted an experiment following up on the mentioned authenticity and interest research questions in the context of higher education. A two-group between-subjects design was used and N = 64 educational science and psychology university students gathered information about a railroad bridge wearing a head-mounted display (HMD). The control group encountered an educational virtual environment created with 3D modeling. The intervention group was presented with the same educational virtual environment but the main object of the railroad bridge was generated by photogrammetry. Situational interest was measured in the pretest and the posttest; authenticity-related variables (i.e., presence and representation fidelity) were assessed in the posttest. Concerning authenticity, there were no significant group differences. Photogrammetry might thus not affect authenticity in educational contexts in which participants focus on gathering information. Regarding interest development, there were two main findings. First, interest in VR for learning increased from pretest to posttest, supporting that interest can be induced in VR. Second, a large share of posttest interest was explained by presence and pretest interest, highlighting the importance of these variables.

Interaction with patient-facing medical devices requires integrated performance of both physical and cognitive tasks that are highly dependent on many user characteristics. Quantifying product use variability early in the design process is useful for device designers seeking to personalize medical device features to maximize performance and improve health outcomes, but three barriers make this difficult. First, patient populations often differ from the general population and can be difficult to recruit and access for human performance evaluations. Second, users of patient-facing devices are highly heterogeneous, leading to highly varied and complicated use-cases. Finally, there are numerous unique tasks for each medical device that make it resource prohibitive to perform comprehensive device use evaluations, particularly in the early stages of design. To address these challenges, a method for modeling highly prevalent patient user sub-populations to be used in targeted device personalization is proposed. In this study, Internal Medicine domain-expert input is used to identify patient characteristics critical to the performance of generic physical and cognitive tasks required for commonly prescribed medical devices. Then, a novel approach to quantify those characteristics is proposed, utilizing variables from the US National Health and Nutrition Examination Survey (NHANES) dataset, demonstrating a means to characterize specific patient populations. The data are statistically clustered to identify meaningful, task-specific device user sub-populations. The approach is demonstrated on the diabetes population for tasks related to hand-held self-management glucometer device use. The cluster results are then discussed, including their practical application to design personalization.

Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4CRBN ubiquitin ligase are a new class of cancer therapy in active clinical development with evidence of activity against acute myeloid leukemia in early-phase trials. However, other than activation of the integrated stress response, the downstream effects of GSPT1 degradation leading to cell death are largely undefined, and no murine models are available to study these agents. We identified the domains of GSPT1 essential for cell survival and show that GSPT1 degradation leads to impaired translation termination, activation of the integrated stress response pathway, and TP53-independent cell death. CRISPR/Cas9 screens implicated decreased translation initiation as protective following GSPT1 degradation, suggesting that cells with higher levels of translation are more susceptible to the effects of GSPT1 degradation. We defined 2 Crbn amino acids that prevent Gspt1 degradation in mice, generated a knockin mouse with alteration of these residues, and demonstrated the efficacy of GSPT1-degrading drugs in vivo with relative sparing of numbers and function of long-term hematopoietic stem cells. Our results provide a mechanistic basis for the use of GSPT1 degraders for the treatment of cancer, including TP53-mutant acute myeloid leukemia.

Several reports have indicated that the thermal tolerance of Salmonella at low-water activity increases significantly, but information on the impact of diverse food matrices is still scarce. The goal of this research was to determine the kinetic parameters (decimal reduction time, D; time required for the first decimal reduction, δ) of thermal resistance of Salmonella in a previously cooked low water activity food. Commercial toasted oats cereal (TOC) was used as the food model, with or without sucrose (25%) addition. TOC samples were inoculated with 108 CFU/mL of a single strain of one of three Salmonella serovars (Agona, Tennessee, Typhimurium). TOC samples were ground and equilibrated to aw values of 0.11, 0.33 and 0.53, respectively. Ground TOC was heated at temperatures between 65 °C and 105 °C and viable counts were determined over time (depending on the temperature for up to 6 h). Death kinetic parameters were determined using linear and Weibull regression models. More than 70% of Weibull’s adjusted regression coefficients (Radj2) and only 38% of the linear model’s Radj2 had values greater than 0.8. For all serovars, both D and δ values increased consistently at a 0.11 aw compared to 0.33 and 0.53. At 0.33 aw, the δ values for Typhimurium, Tennessee and Agona were 0.55, 1.01 and 2.87, respectively, at 85 °C, but these values increased to 65, 105 and 64 min, respectively, at 0.11 aw. At 100 °C, δ values were 0.9, 5.5 and 2.3 min, respectively, at 0.11 aw. The addition of sucrose resulted in a consistent reduction of eight out of nine δ values determined at 0.11 aw at 85, 95 and 100 °C, but this trend was not consistent at 0.33 and 0.53 aw. The Z values (increase of temperature required to decrease δ-value one log) were determined with modified δ values for a fixed β (a fitting parameter that describes the shape of the curve), and ranged between 8.9 °C and 13.4 °C; they were not influenced by aw, strain or sugar content. These findings indicated that in TOC, high thermal tolerance was consistent among serovars and thermal tolerance was inversely dependent on aw.

Background The comparative utility of performance-based functional assessments in predicting adverse outcomes in CKD is unknown. To examine their relative utility, we examined three performance-based functional assessments in an observational cohort of patients with CKD. Methods We recruited 350 participants with stage II–V, predialysis CKD. Participants were administered three performance-based functional assessments: Short Physical Performance Battery (SPPB), Modified Mini-Mental Status Exam (M3SE), and Lawton Instrumental Activities of Daily Living (IADL). Scores were dichotomized on the basis of the median and combined into a summary score. Outcomes included 50% GFR reduction, ESKD, and death. We used Cox proportional hazards to assess the association of performance-based functional assessments with outcomes. Results Compared with high performers, low SPPB performers had the highest adjusted rate of death, ESKD, or 50% reduction in GFR (HR, 1.96; 95% CI, 1.28 to 2.99). Low SPPB had the strongest association with death when adjusted for multiple covariates (HR, 2.43; 95% CI, 1.36 to 4.34). M3SE performance was not associated with any adverse outcome. None of the performance-based functional assessments were associated with ESKD, but a low IADL score was associated with a lower hazard ratio for ESKD or 50% decline GFR (HR, 0.49; 95% CI, 0.24 to 1.00). Conclusions Low SPPB score was the strongest predictor of death and all adverse outcomes as a composite. Future trials should determine if outcomes for patients with CKD who have poor physical performance and low SPPB scores are improved by targeted interventions. Clinical Trial registry name and registration number: Safe Kidney Care Cohort Study, NCT01407367

Collaborations between researchers and practitioners have recently become increasingly popular in education, and educational design research (EDR) may benefit greatly from investigating such partnerships. One important domain in which EDR on collaborations between researchers and practitioners can be applied is research on simulation-based learning. However, frameworks describing both research and design processes in research programs on simulation-based learning are currently lacking. The framework proposed in this paper addresses this research gap. It is derived from theory and delineates levels, phases, activities, roles, and products of research programs to develop simulations as complex scientific artifacts for research purposes. This dual-level framework applies to research programs with a research committee and multiple subordinate research projects. The proposed framework is illustrated by examples from the actual research and design process of an interdisciplinary research program investigating the facilitation of diagnostic competences through instructional support in simulations. On a theoretical level, the framework contributes primarily to the literature of EDR by offering a unique dual-level perspective. Moreover, on a practical level, the framework may help by providing recommendations to guide the research and design process in research programs.

Background Patients with chronic kidney disease (CKD) face risks of not only end-stage kidney disease (ESKD), cardiovascular disease (CVD) and death, but also decline in kidney function, quality of life (QOL) and mental and physical well-being. This study describes the multidimensional trajectories of CKD using clinical events, kidney function and patient-reported outcome measures (PROMs). We hypothesized that more advanced CKD stages would associate with more rapid decline in each outcome. Methods Among 3939 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study, we evaluated multidimensional disease trajectories by G- and A-stages of enrollment estimated glomerular filtration rate (eGFR) and albuminuria, respectively. These trajectories included clinical events (ESKD, CVD, heart failure and death), eGFR decline and PROMs [kidney disease QOL (KDQOL) burden, effects and symptoms questionnaires, as well as the 12-item short form mental and physical component summaries]. We also evaluated a group-based multitrajectory model to group participants on the basis of longitudinal PROMs and compared group assignments by enrollment G- and A-stage. Results The mean participant age was 58 years, 45% were women, mean baseline eGFR was 44 mL/min/1.73 m2 and median urine albumin:creatinine ratio was 52 mg/g. The incidence of all clinical events was greater and eGFR decline was faster with more advanced G- and A-stages. While baseline KDQOL and physical component measures were lower with more advanced G- and A-stage of CKD, changes in PROMs were inconsistently related to the baseline CKD stage. Groups formed on PROM trajectories were fairly distinct from existing CKD staging (observed agreement 60.6%) and were associated with the risk of ESKD, CVD, heart failure and death. Conclusions More advanced baseline CKD stage was associated with a higher risk of clinical events and faster eGFR decline, and was only weakly related to changes in patient-reported metrics over time.

Molecular glue compounds induce protein–protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation. Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets. They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations between the cytotoxicity of 4,518 clinical and preclinical small molecules and the expression levels of E3 ligase components across hundreds of human cancer cell lines, we identify CR8—a cyclin-dependent kinase (CDK) inhibitor—as a compound that acts as a molecular glue degrader. The CDK-bound form of CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12–cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues.

Ziel dieser Operation ist es, das mediale patellofemorale Ligament mittels distal gestieltem Quadricepssehnenstreifen zu ersetzen. Hierzu wird mit einem minimal invasiven Instrumentarium ein Quadricepssehnenstreifen uber einen kleinen superomedialen Zugang entnommen und dann nach medial zwischen zweiter und dritter Schicht des medialen Retinakulums geshuttelt. Einer der entscheidendsten Schritte ist das bildwandergestutzte Aufsuchen des Isometriepunkts, sodass physiologische Langenveranderungen und ein zufriedenstellendes postoperatives Ergebnis resultieren. Hiernach kann das Transplantat unter dosiertem Zug und Zentralisierung der Patella femoral fixiert werden. Eine fruhfunktionelle Nachbehandlung fuhrt hierbei zu einem guten Outcome.

ZusammenfassungDie Technologie der Dermatofluoroskopie beruht auf einer selektiven Anregung der Melaninfluoreszenz durch stufenweise 2-Photonen-Absorption. Hierbei wird das Melanin in einer Spektralregion angeregt, in der keine andere Hautkomponente absorbiert. Dadurch wird die Melaninfluoreszenz erstmals messbar. Unter Verwendung dieser Technik wird die Läsion Punkt für Punkt abgetastet. Die Fluoreszenzsignale werden dann mithilfe eines auf künstlicher Intelligenz basierten Algorithmus analysiert und das Ergebnis Score-basiert dargestellt. In Studien zeigte die Dermatofluoroskopie eine hohe diagnostische Genauigkeit mit guter Sensitivität und Spezifität. Das Medizinprodukt DermaFC® der Klasse IIa ist seit 2017 CE-zertifiziert und für den Einsatz als Diagnoseunterstützung bei melanozytären melanomverdächtigen Läsionen zugelassen. Nicht geeignet ist die Dermatofluoroskopie bei schwach pigmentierten Läsionen sowie schlecht zugänglichen Lokalisationen.

Enterococcus faecium is a ubiquitous opportunistic pathogen that is exhibiting increasing levels of antimicrobial resistance (AMR). Many of the genes that confer resistance and pathogenic functions are localized on mobile genetic elements (MGEs), which facilitate their transfer between lineages. Here, features including resistance determinants, virulence factors and MGEs were profiled in a set of 1273 E. faecium genomes from two disparate geographic locations (in the UK and Canada) from a range of agricultural, clinical and associated habitats. Neither lineages of E. faecium , type A and B, nor MGEs are constrained by geographic proximity, but our results show evidence of a strong association of many profiled genes and MGEs with habitat. Many features were associated with a group of clinical and municipal wastewater genomes that are likely forming a new human-associated ecotype within type A. The evolutionary dynamics of E. faecium make it a highly versatile emerging pathogen, and its ability to acquire, transmit and lose features presents a high risk for the emergence of new pathogenic variants and novel resistance combinations. This study provides a workflow for MGE-centric surveillance of AMR in Enterococcus that can be adapted to other pathogens.