Expanding the Chemical Space of Transforming Growth Factor-ß (TGFß) Receptor Type II Degraders with 3,4-Disubstituted Indole Derivatives.

The TGFß type II receptor (TßRII) is a central player in all TGFß signaling downstream events, has been linked to cancer progression, and thus, has emerged as an auspicious anti-TGFß strategy. Especially its targeted degradation presents an excellent goal for effective TGFß pathway inhibition. Here, cellular structure-activity relationship (SAR) data from the TßRII degrader chemotype 1 was successfully transformed into predictive ligand-based pharmacophore models that allowed scaffold hopping. Two distinct 3,4-disubstituted indoles were identified from virtual screening: tetrahydro-4-oxo-indole 2 and indole-3-acetate 3. Design, synthesis, and screening of focused amide libraries confirmed 2r and 3n as potent TGFß inhibitors. They were validated to fully recapitulate the ability of 1 to selectively degrade TßRII, without affecting TßRI. Consequently, 2r and 3n efficiently blocked endothelial-to-mesenchymal transition and cell migration in different cancer cell lines while not perturbing the microtubule network. Hence, 2 and 3 present novel TßRII degrader chemotypes that will (1) aid target deconvolution efforts and (2) accelerate proof-of-concept studies for small-molecule-driven TßRII degradation in vivo.

Why Humble Farmers May in Fact Grow Bigger Potatoes: A Call for Street-Smart Decision-Making in Sport.

BACKGROUND: The main task of applied sport science is to inform decision-making in sports practice, that is, enabling practitioners to compare the expectable outcomes of different options (e.g. training programs). MAIN BODY: The "evidence" provided may range from group averages to multivariable prediction models. By contrast, many decisions are still largely based on the subjective, experience-based judgement of athletes and coaches. While for the research scientist this may seem "unscientific" and even "irrational", it is important to realize the different perspectives: science values novelty, universal validity, methodological rigor, and contributions towards long-term advancement. Practitioners are judged by the performance outcomes of contemporary, specific athletes. This makes out-of-sample predictive accuracy and robustness decisive requirements for useful decision support. At this point, researchers must concede that under the framework conditions of sport (small samples, multifactorial outcomes etc.) near certainty is unattainable, even with cutting-edge methods that might theoretically enable near-perfect accuracy. Rather, the sport ecosystem favors simpler rules, learning by experience, human judgement, and integration across different sources of knowledge. In other words, the focus of practitioners on experience and human judgement, complemented-but not superseded-by scientific evidence is probably street-smart after all. A major downside of this human-driven approach is the lack of science-grade evaluation and transparency. However, methods are available to merge the assets of data- and human-driven strategies and mitigate biases. SHORT CONCLUSION: This work presents the challenges of learning, forecasting and decision-making in sport as well as specific opportunities for turning the prevailing "evidence vs. eminence" contrast into a synergy.

Impact of Molecular Orientation on Lateral and Interfacial Electron Transfer at Oxide Interfaces.

Molecular dyes, called sensitizers, with a cis-[Ru(LL)(dcb)(NCS)2] structure, where dcb is 4,4'-(CO2H)2-2,2'-bipyridine and LL is dcb or a different diimine ligand, are among the most optimal for application in dye-sensitized solar cells (DSSCs). Herein, a series of five sensitizers, three bearing two dcb ligands and two bearing one dcb ligand, were anchored to mesoporous thin films of conducting tin-doped indium oxide (ITO) or semiconducting TiO2 nanocrystallites. The number of dcb ligands impacts the surface orientation of the sensitizer; density functional theory (DFT) calculations revealed an ∼1.6 Å smaller distance between the oxide surface and the Ru metal center for sensitizers with two dcb ligands. Interfacial electron transfer kinetics from the oxide material to the oxidized sensitizer were measured as a function of the thermodynamic driving force. Analysis of the kinetic data with Marcus-Gerischer theory indicated that the electron coupling matrix element, Hab, was sensitive to distance and ranged from Hab = 0.23 to 0.70 cm-1, indicative of nonadiabatic electron transfer. The reorganization energies, λ, were also sensitive to the sensitizer location within the electric double layer and were smaller, with one exception, for sensitizers bearing two dcb ligands λ = 0.40-0.55 eV relative to those with one λ = 0.63-0.66 eV, in agreement with dielectric continuum theory. Electron transfer from the oxide to the photoexcited sensitizer was observed when the diimine ligand was more easily reduced than the dcb ligand. Lateral self-exchange "hole hopping" electron transfer between surface-anchored sensitizers was found to be absent for sensitizers with two dcb ligands, while those with only one were found to hop with rates similar to those previously reported in the literature, khh = 47-89 µs-1. Collectively, the kinetic data and analysis reveal that interfacial kinetics are highly sensitive to the surface orientation and sensitizers bearing two dcb ligands are most optimal for practical applications of DSSCs.

Multi-Electron Transfer at H-Terminated p-Si Electrolyte Interfaces: Large Photovoltages under Inversion Conditions.

Photovoltages for hydrogen-terminated p-Si(111) in an acetonitrile electrolyte were quantified with methyl viologen [1,1'-(CH3)2-4,4'-bipyridinium](PF6)2, abbreviated MV2+, and [Ru(bpy)3](PF6)2, where bpy is 2,2'-bipyridine, that respectively undergo two and three one-electron transfer reductions. The reduction potentials, E°, of the two MV2+ reductions occurred at energies within the forbidden bandgap, while the three [Ru(bpy)3]2+ reductions occurred within the continuum of conduction band states. Bandgap illumination resulted in reduction that was more positive than that measured with a degenerately doped n+-Si demonstrative of a photovoltage, Vph, that increased in the order MV2+/+ (260 mV) < MV+/0 (400 mV) < Ru2+/+ (530 mV) ∼ Ru+/0 (540 mV) ∼ Ru0/- (550 mV). Pulsed 532 nm excitation generated electron-hole pairs whose dynamics were nearly constant under depletion conditions and increased markedly as the potential was raised or lowered. A long wavelength absorption feature assigned to conduction band electrons provided additional evidence for the presence of an inversion layer. Collectively, the data reveal that the most optimal photovoltage, as well as the longest electron-hole pair lifetime and the highest surface electron concentration, occurs when E° lies energetically within the unfilled conduction band states where an inversion layer is present. The bell-shaped dependence for electron-hole pair recombination with the surface potential was predicted by the time-honored SRH model, providing a clear indication that this interface provides access to all four bias conditions, i.e., accumulation, flat band, depletion, and inversion. The implications of these findings for photocatalysis applications and solar energy conversion are discussed.

Boosting for insight and/or boosting for agency? How to maximize accurate test interpretation with natural frequencies.

BACKGROUND: Many physicians do not know how to accurately interpret test results using Bayes' rule. As a remedy, two kinds of interventions have been shown effective: boosting insight and boosting agency with natural frequencies. To boost insight, test statistics are provided in natural frequencies (rather than conditional probabilities), without instructions on how to use them. To boost agency, a training is provided on how to translate probabilities into natural frequencies and apply them in Bayes' rule. What has not been shown is whether boosting agency is sufficient or if representing test statistics in natural frequencies may additionally boost insight to maximize accurate test interpretation. METHODS: We used a pre/posttest design to assess test interpretation accuracy of 577 medical students before and after a training on two Bayesian reasoning tasks, one providing conditional probabilities, the other natural frequencies. The pretest assessed baseline abilities versus the effect of natural frequencies to boost insight. After participants received a training on how to translate conditional probabilities into natural frequencies and how to apply them in Bayes' rule, test interpretation skills were assessed using the same tasks again, comparing the effects of training-induced agency with versus without additionally boosting insight (i.e., test statistics in natural frequencies versus conditional probabilities). RESULTS: Compared to the test question formatted in conditional probabilities (34% correct answers), natural frequencies facilitated Bayesian reasoning without training (68%), that is, they increased insight. The training on how to use natural frequencies improved performance for tasks formatted in conditional probabilities (64%). Performance was maximal after training and with test statistics formatted in natural frequencies, that is, with a combination of boosting insight and agency (89%). CONCLUSIONS: Natural frequencies should be used to boost insight and agency to maximize effective use of teaching resources. Thus, mandating that test statistics are provided in natural frequencies and adopting short trainings on how to translate conditional probabilities into natural frequencies and how to apply them in Bayes' rule will help to maximize accurate test interpretation. TRIAL REGISTRATION: The study was a registered with the German Clinical Trial Registry ( DRKS00008723 ; 06/03/2015).

Isoreticular Crystallization of Highly Porous Cubic Covalent Organic Cage Compounds*.

Modular frameworks featuring well-defined pore structures in microscale domains establish tailor-made porous materials. For open molecular solids however, maintaining long-range order after desolvation is inherently challenging, since packing is usually governed by only a few supramolecular interactions. Here we report on two series of nanocubes obtained by co-condensation of two different hexahydroxy tribenzotriquinacenes (TBTQs) and benzene-1,4-diboronic acids (BDBAs) with varying linear alkyl chains in 2,5-position. n-Butyl groups at the apical position of the TBTQ vertices yielded soluble model compounds, which were analyzed by mass spectrometry and NMR spectroscopy. In contrast, methyl-substituted cages spontaneously crystallized as isostructural and highly porous solids with BET surface areas and pore volumes of up to 3426 m2 g-1 and 1.84 cm3 g-1 . Single crystal X-ray diffraction and sorption measurements revealed an intricate cubic arrangement of alternating micro- and mesopores in the range of 0.97-2.2 nm that are fine-tuned by the alkyl substituents at the BDBA linker.

Optoelectronic processes in covalent organic frameworks.

Covalent organic frameworks (COFs) are crystalline porous materials constructed from molecular building blocks using diverse linkage chemistries. Their modular construction system allows not only for tailor-made design but also for an immense variety of building blocks, opening the door to numerous different functionalities and potential applications. As a consequence, a large number of building blocks that can act as light-harvesters, semiconductors, ligands, binding sites or redox centers have recently been integrated into the scaffolds of COFs. This unique combination of reticular chemistry with the molecular control of intrinsic properties paves the way towards the design of new semiconducting materials for (opto-)electronic applications such as sensors, photocatalysts or -electrodes, supercapacitor and battery materials, solar-harvesting devices or light emitting diodes. With new developments regarding the linkage motif, highly stable but still tunable COFs have been developed for applications even under harsh conditions. Further, the molecular stacking modes and distances in the COFs have been investigated as a powerful means to control optical and electrical characteristics of these self-assembled frameworks. Advanced understanding of optoelectronic processes in COFs has enabled their implementation in optoelectronic devices with promising potential for real-world applications. This review highlights the key developments of design concepts for the synthesis of electro- and photoactive COFs as well as our understanding of optoelectronic processes in these frameworks, hence establishing a new paradigm for the rational construction of well-defined novel optoelectronic materials and devices.

How to Determine When SARS-CoV-2 Antibody Testing Is or Is Not Useful for Population Screening: A Tutorial.

Extensive testing lies at the heart of any strategy to effectively combat the SARS-COV-2 pandemic. In recent months, the use of enzyme-linked immunosorbent assay-based antibody tests has gained a lot of attention. These tests can potentially be used to assess SARS-COV-2 immunity status in individuals (e.g., essential health care personnel). They can also be used as a screening tool to identify people that had COVID-19 asymptomatically, thus getting a better estimate of the true spread of the disease, gain important insights on disease severity, and to better evaluate the effectiveness of policy measures implemented to combat the pandemic. But the usefulness of these tests depends not only on the quality of the test but also, critically, on how far disease has already spread in the population. For example, when only very few people in a population are infected, a positive test result has a high chance of being a false positive. As a consequence, the spread of the disease in a population as well as individuals' immunity status may be systematically misinterpreted. SARS-COV-2 infection rates vary greatly across both time and space. In many places, the infection rates are very low but can quickly skyrocket when the virus spreads unchecked. Here, we present two tools, natural frequency trees and positive and negative predictive value graphs, that allow one to assess the usefulness of antibody testing for a specific context at a glance. These tools should be used to support individual doctor-patient consultation for assessing individual immunity status as well as to inform policy discussions on testing initiatives.

Effects of pain, sedation and delirium monitoring on clinical and economic outcome: A retrospective study.

BACKGROUND: Significant improvements in clinical outcome can be achieved by implementing effective strategies to optimise pain management, reduce sedative exposure, and prevent and treat delirium in ICU patients. One important strategy is the monitoring of pain, agitation and delirium (PAD bundle). We hypothesised that there is no sufficient financial benefit to implement a monitoring strategy in a Diagnosis Related Group (DRG)-based reimbursement system, therefore we expected better clinical and decreased economic outcome for monitored patients. METHODS: This is a retrospective observational study using routinely collected data. We used univariate and multiple linear analysis, machine-learning analysis and a novel correlation statistic (maximal information coefficient) to explore the association between monitoring adherence and resulting clinical and economic outcome. For univariate analysis we split patients in an adherence achieved and an adherence non-achieved group. RESULTS: In total 1,323 adult patients from two campuses of a German tertiary medical centre, who spent at least one day in the ICU between admission and discharge between 1. January 2016 and 31. December 2016. Adherence to PAD monitoring was associated with shorter hospital LoS (e.g. pain monitoring 13 vs. 10 days; p<0.001), ICU LoS, duration of mechanical ventilation shown by univariate analysis. Despite the improved clinical outcome, adherence to PAD elements was associated with a decreased case mix per day and profit per day shown by univariate analysis. Multiple linear analysis did not confirm these results. PAD monitoring is important for clinical as well as economic outcome and predicted case mix better than severity of illness shown by machine learning analysis. CONCLUSION: Adherence to PAD bundles is also important for clinical as well as economic outcome. It is associated with improved clinical and worse economic outcome in comparison to non-adherence in univariate analysis but not confirmed by multiple linear analysis. TRIAL REGISTRATION: clinicaltrials.gov NCT02265263, Registered 15 October 2014.

Improving quality of care in less than 1 min: a prospective intervention study on postoperative handovers to the ICU/PACU.

PURPOSE: Standardisation of the postoperative handover process via checklists, trainings or procedural changes has shown to be effective in reducing information loss. The clinical friction of implementing these measures has received little attention. We developed and evaluated a visual aid (VA) and >1 min in situ training intervention to improve the quality of postoperative handovers to the intensive care unit (ICU) and postoperative care unit. MATERIALS AND METHODS: The VA was constructed and implemented via a brief (<1 min) training of anaesthesiologic staff during the operation. Ease of implementation was measured by amount of information transferred, handover duration and handover structure. 50 handovers were audio recorded before intervention and 50 after intervention. External validity was evaluated by blinded assessment of the recordings by experienced anaesthesiologists (n=10) on 10-point scales. RESULTS: The brief intervention resulted in increased information transfer (9.0-14.8 items, t(98)=7.44, p<0.0001, Cohen's d=1.59) and increased handover duration (81.3-192.8 s, t(98)=6.642, p=0.013, Cohen's d=1.33) with no loss in structure (1.60-1.56, t(98)=0.173, p=0.43). Blinded assessment on 10-point scales by experienced anaesthesiologists showed improved overall handover quality from 7.1 to 7.8 (t(98)=1.89, p=0.031, Cohen's d=0.21) and improved completeness of information (t(98)=2.42, p=0.009, Cohen's d=0.28) from 7.3 to 8.3. CONCLUSIONS: An intervention consisting of a simple VA and <1 min instructions significantly increased overall quality and amount of information transferred during ICU/postanaesthetic care unit handovers.

Dibenzochrysene enables tightly controlled docking and stabilizes photoexcited states in dual-pore covalent organic frameworks.

Covalent organic frameworks (COFs), consisting of covalently connected organic building units, combine attractive features such as crystallinity, open porosity and widely tunable physical properties. For optoelectronic applications, the incorporation of heteroatoms into a 2D COF has the potential to yield desired photophysical properties such as lower band gaps, but can also cause lateral offsets of adjacent layers. Here, we introduce dibenzo[g,p]chrysene (DBC) as a novel building block for the synthesis of highly crystalline and porous 2D dual-pore COFs showing interesting properties for optoelectronic applications. The newly synthesized terephthalaldehyde (TA), biphenyl (Biph), and thienothiophene (TT) DBC-COFs combine conjugation in the a,b-plane with a tight packing of adjacent layers guided through the molecular DBC node serving as specific docking site for successive layers. The resulting DBC-COFs exhibit a hexagonal dual-pore kagome geometry, which is comparable to COFs containing another molecular docking site, namely 4,4',4'',4'''-(ethylene-1,1,2,2-tetrayl)-tetraaniline (ETTA). In this context, the respective interlayer distances decrease from about 4.6 Å in ETTA-COFs to about 3.6 Å in DBC-COFs, leading to well-defined hexagonally faceted single crystals sized about 50-100 nm. The TT DBC-COF features broad light absorption covering large parts of the visible spectrum, while Biph DBC-COF shows extraordinary excited state lifetimes exceeding 10 ns. In combination with the large number of recently developed linear conjugated building blocks, the new DBC tetra-connected node is expected to enable the synthesis of a large family of highly correlated and ordered 2D COFs with promising optoelectronic properties.

Cobalt-Catalyzed Electrophilic Aminations with Anthranils: An Expedient Route to Condensed Quinolines.

The reaction of various organozinc pivalates with anthranils provides anilines derivatives, which cyclize under acidic conditions providing condensed quinolines. Using alkenylzinc pivalates, electron-rich arylzinc pivalates or heterocyclic zinc pivalates produces directly the condensed quinolines of which several structures belong to new heterocyclic scaffolds. These N-heterocycles are of particular interest for organic light emitting diodes with their high photoluminescence quantum yields and long exciton lifetimes as well as for hole-transporting materials in methylammonium lead iodide perovskites solar cells due to an optimal band alignment for holes and a large bandgap.

Enforcing Extended Porphyrin J-Aggregate Stacking in Covalent Organic Frameworks.

The potential of covalent organic frameworks (COFs) for realizing porous, crystalline networks with tailored combinations of functional building blocks has attracted considerable scientific interest in the fields of gas storage, photocatalysis, and optoelectronics. Porphyrins are widely studied in biology and chemistry and constitute promising building blocks in the field of electroactive materials, but they reveal challenges regarding crystalline packing when introduced into COF structures due to their nonplanar configuration and strong electrostatic interactions between the heterocyclic porphyrin centers. A series of porphyrin-containing imine-linked COFs with linear bridges derived from terephthalaldehyde, 2,5-dimethoxybenzene-1,4-dicarboxaldehyde, 4,4'-biphenyldicarboxaldehyde and thieno[3,2- b]thiophene-2,5-dicarboxaldehyde, were synthesized, and their structural and optical properties were examined. By combining X-ray diffraction analysis with density-functional theory (DFT) calculations on multiple length scales, we were able to elucidate the crystal structure of the newly synthesized porphyrin-based COF containing thieno[3,2- b]thiophene-2,5-dicarboxaldehyde as linear bridge. Upon COF crystallization, the porphyrin nodes lose their 4-fold rotational symmetry, leading to the formation of extended slipped J-aggregate stacks. Steady-state and time-resolved optical spectroscopy techniques confirm the realization of the first porphyrin J-aggregates on a > 50 nm length scale with strongly red-shifted Q-bands and increased absorption strength. Using the COF as a structural template, we were thus able to force the porphyrins into a covalently embedded J-aggregate arrangement. This approach could be transferred to other chromophores; hence, these COFs are promising model systems for applications in photocatalysis and solar light harvesting, as well as for potential applications in medicine and biology.

Assessing minimal medical statistical literacy using the Quick Risk Test: a prospective observational study in Germany.

OBJECTIVES: To assess minimal medical statistical literacy in medical students and senior educators using the 10-item Quick Risk Test; to assess whether deficits in statistical literacy are stable or can be reduced by training. DESIGN: Prospective observational study on the students, observational study on the university lecturers. SETTING: Charité University Medicine medical curriculum for students and a continuing medical education (CME) course at a German University for senior educators. PARTICIPANTS: 169 students taking part in compulsory final-year curricular training in medical statistical literacy (63% female, median age 25 years). Sixteen professors of medicine and other senior educators attending a CME course on medical statistical literacy (44% female, age range=30-65 years). INTERVENTIONS: Students completed a 90 min training session in medical statistical literacy. No intervention for the senior educators. OUTCOME MEASURES: Primary outcome measure was the number of correct answers out of four multiple-choice alternatives per item on the Quick Risk Test. RESULTS: Final-year students answered on average half (median=50%) of the questions correctly while senior educators answered three-quarters correctly (median=75%). For comparison, chance performance is 25%. A 90 min training session for students increased the median percentage correct from 50% to 90%. 82% of participants improved their performance. CONCLUSIONS: Medical students and educators do not master all basic concepts in medical statistics. This can be quickly assessed with the Quick Risk Test. The fact that a 90 min training session on medical statistical literacy improves students' understanding from 50% to 90% indicates that the problem is not a hard-wired inability to understand statistical concepts. This gap in physicians' education has long-lasting effects; even senior medical educators could answer only 75% of the questions correctly on average. Hence, medical students and professionals should receive enhanced training in how to interpret risk-related medical statistics.

Oligothiophene-Bridged Conjugated Covalent Organic Frameworks.

Two-dimensional covalent organic frameworks (2D-COFs) are crystalline, porous materials comprising aligned columns of π-stacked building blocks. With a view toward the application of these materials in organic electronics and optoelectronics, the construction of oligothiophene-based COFs would be highly desirable. The realization of such materials, however, has remained a challenge, in particular with respect to laterally conjugated imine-linked COFs. We have developed a new building block design employing an asymmetric modification on an otherwise symmetric backbone that allows us to construct a series of highly crystalline quaterthiophene-derived COFs with tunable electronic properties. Studying the optical response of these materials, we have observed for the first time the formation of a charge transfer state between the COF subunits across the imine bond. We believe that our new building block design provides a general strategy for the construction of well-ordered COFs from various extended building blocks, thus greatly expanding the range of applicable molecules.

The scholar role in the National Competence Based Catalogues of Learning Objectives for Undergraduate Medical Education (NKLM) compared to other international frameworks.

BACKGROUND: In Germany, a national competence based catalogue of learning objectives in medicine (NKLM) was developed by the Society for Medical Education and the Council of Medical Faculties. As many of its international counterparts the NKLM describes the qualifications of medical school graduates. The definition of such outcome frameworks indents to make medical education transparent to students, teachers and society. The NKLM aims to amend existing lists of medical topics for assessment with learnable competencies. All outcome frameworks are structured into chapters, domains or physician roles. The definition of the scholar-role poses a number of questions such as: What distinguishes necessary qualifications of a scientifically qualified physician from those of a medical scientist? METHODS: 13 outcome frameworks were identified through a systematic three-step literature review and their content compared to the scholar role in the NKLM by means of a qualitative text analysis. The three steps consist of (1) search for outcome frameworks, (2) in- and exclusion, and (3) data extraction, categorization, and validation. The results were afterwards matched with the scholar role of the NKLM. RESULTS: Extracted contents of all frameworks may be summarized into the components Common Basics, Clinical Application, Research, Teaching and Education, and Lifelong Learning. Compared to the included frameworks the NKLM emphasises competencies necessary for research and teaching while clinical application is less prominently mentioned. CONCLUSION: The scholar role of the NKLM differs from other international outcome frameworks. Discussing these results shall increase propagation and understanding of the NKLM and thus contribute to the qualification of future medical graduates in Germany.