julilili42/papers huggingface dataset:
The STArgardt Remofuscin Treatment Trial (STARTT): design and baseline characteristics of enrolled Stargardt patients
2022-07-22

<ns3:p><ns3:bold>Background: </ns3:bold>This report describes the study design and baseline characteristics of patients with Stargardt disease (STGD1) enrolled in the STArgardt Remofuscin Treatment Trial (STARTT).</ns3:p><ns3:p> <ns3:bold>Methods: </ns3:bold>In total, 87 patients with genetically confirmed STGD1 were randomized in a double-masked, placebo-controlled proof of concept trial to evaluate the safety and efficacy of 20 milligram oral remofuscin for 24 months. The primary outcome measure is change in mean quantitative autofluorescence value of an 8-segment ring centred on the fovea (qAF<ns3:sub>8</ns3:sub>). Secondary efficacy variables are best corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), mesopic microperimetry (mMP), spectral domain optical coherence tomography (SD-OCT), reading speed on Radner reading charts, and patient-reported visual function as assessed by the National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ-25) and Functional Reading Independence (FRI) Index.</ns3:p><ns3:p> <ns3:bold>Results: </ns3:bold>Mean age of participants was 35±11 years with 49 (56%) female. Median qAF<ns3:sub>8</ns3:sub> value was 438 Units (range 210-729). Median BCVA and LLVA in decimal units were 0.50 (range 0.13-0.80) and 0.20 (range 0.06-0.63), respectively. The median of the mean retinal sensitivity with mMP was 20.4 dB (range 0.0-28.8). SD-OCT showed median central subfield retinal thickness of 142 μm (range 72-265) and median macular volume of 1.65 mm<ns3:sup>3</ns3:sup> (range 1.13-2.19). Compared to persons without vision impairment,<ns3:sup> </ns3:sup>both reading performance and patient-reported visual function were significantly lower (p&lt;0.001, one sample t-test). Mean reading speed was 108±39 words/minute with logRAD-score of 0.45±0.28. Mean VFQ-25 composite score was 72±13. Mean FRI Index score 2.8±0.6.</ns3:p><ns3:p> <ns3:bold>Conclusions: </ns3:bold>This trial design may serve as reference for future clinical trials as it explores the utility of qAF<ns3:sub>8</ns3:sub> as primary outcome measure. The baseline data represent the largest, multi-national, STGD1 cohort to date that underwent standardized qAF imaging, reading speed assessment and vision-related quality of life measures which all contribute to the characterization of STGD1.</ns3:p><ns3:p> <ns3:bold>EudraCT registration:</ns3:bold> 2018-001496-20 (09/05/2019)</ns3:p>
Pharmacology and Drug Targets – The Basis of Therapeutics
2022-07-22

This chapter covers (i) basics of pharmacology such as dosage forms, routes of administration, delivery to the target site, (ii) pharmacodynamics (PD), and (iii) pharmacokinetics (PK) and provides (iv) examples of its use in drug discovery and development. In particular, basic principles of drug–target receptor interactions, agonistic and antagonistic mechanisms of action (MoA), liberation/absorption/distribution/metabolism/elimination (LADME) phases of PK, dosage forms, PK/PD modelling, drug–drug interactions (DDIs), drug transporters, aspects of clinical pharmacology, therapeutic window/index calculations, and illustrative examples of how these tools are utilized in drug discovery and development are provided.
Translational Medicine – The Bridging Discipline. Role and Tools in the Drug Development Process
2022-07-22

Translational medicine (TM) is the 'bridging' discipline between discovery/research and full/late development. The purpose of TM is to test innovative preclinical ideas in the clinical setting to assess if they hold promise for a full clinical development and if larger and longer investments are warranted to move beyond the prototype stage and to fully develop the programme. TM belongs to the field of early clinical development where the focus is on learning about key projects features (as opposed to late development where the focus is on confirming). The classical path to achieve this has traditionally been the forward or 'bench-to-beside' translation, where ideas from the preclinical world are tested in the clinical setting. In recent years, the value and importance of the backward or 'beside-to-bench' translation have been implemented/advanced. It allows to capitalize on data and learning from seemingly failed trails and leverage the creative strength of clinical observations and thinking. This chapter explains why TM is needed, introduces the main/core concepts, and provides examples and illustrations of different approaches in TM.
High-Resolution Atomic Force Microscopy Study of Protein Surface Conformations
2022-07-22

Journal Article High-Resolution Atomic Force Microscopy Study of Protein Surface Conformations Get access EV Dubrovin, EV Dubrovin Lomonosov Moscow State University, Faculty of Physics, Moscow, Russian FederationFederal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russian Federation Corresponding author: dubrovin@polly.phys.msu.ru Search for other works by this author on: Oxford Academic Google Scholar NA Barinov, NA Barinov Lomonosov Moscow State University, Faculty of Physics, Moscow, Russian FederationFederal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russian Federation Search for other works by this author on: Oxford Academic Google Scholar TE Schäffer, TE Schäffer University of Tübingen, Institute of Applied Physics, Tübingen, Germany Search for other works by this author on: Oxford Academic Google Scholar DV Klinov DV Klinov Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russian FederationPeoples’ Friendship University of Russia, Moscow, Russian Federation Search for other works by this author on: Oxford Academic Google Scholar Microscopy and Microanalysis, Volume 28, Issue S1, 1 August 2022, Pages 1024–1025, https://doi.org/10.1017/S1431927622004408 Published: 01 August 2022
Biopharmaceutical Innovation at a Glance
2022-07-22

Biopharmaceutical Research & Development (R&D) aims at finding new modalities to diagnose, prevent, and treat human diseases. Prototypes of innovative approaches are tested in biological systems of increasing size, complexity, and relevance. The early phase spans from individual receptors over cell, organ systems to first therapeutic exploration in small and well-defined patient populations. This exploratory phase ends once clinical proof of concept (PoC) is established. Subsequently, large clinical programs are undertaken to confirm the efficacy and (if applicable) superiority of the new approach by means of long clinical programs. Health authorities around the world play a key role in this process. During the clinical test phase, together with the biopharmaceutical companies, they surveil and ensure the scientifically sound and safe conduct of clinical trials. In a second step, health authorities review the entire data set that has been generated during both the exploratory and the confirmatory phases. If, based on these data, they come to conclude that the benefits conferred to the patients outweigh the risks, authorization to market the drug in the respective country is conferred. In order to get reimbursed, approved new drugs need to undergo an economic review process. There the decision is made if the new drug confers enough clinical benefits to justify its price. The drug approval process and the economic evaluation/reimbursement process are two distinct processes carried out by different institutions. Although R&D leverages a number of academic disciplines like epidemiology, genetics, biology, chemistry, bioinformatics, pharmacology, toxicology, pharmacy, and medicine, it is not primarily an academic discipline and cannot be studied in one program at a university. It is difficult to find coherent overarching information on concepts generally applicable to the industry beyond individual company processes. Thus, this book attempts to bridge this gap and provide an overview and concepts and reliable details which apply across the industry and are valuable for everyone working in or with the biopharmaceutical industry.
Biomarkers: Definitions and Utility for Drug Development
2022-07-22

Biomarkers (biological markers) are objective measures of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarkers can be subdivided by the context of use or classified into physiological, biological, imaging and digital biomarker modalities. In the era of precision medicine, biomarkers are key for tailoring treatments by identifying responder populations and co-developing diagnostics. This chapter introduces biomarker definitions, biomarker modalities and clinical applications with the ultimate goal to illustrate the emerging impact of biomarkers on drug development and healthcare.
Mouthpart Ecomorphology and Predatory Behaviour in Selected Rove Beetles of the “Staphylinine Group” (Coleoptera: Staphylinidae: Staphylininae, Paederinae)
2022-07-23

The representatives of the megadiverse rove beetle subfamilies Paederinae and Staphylininae (Coleoptera: Staphylinidae) are considered generalist predators, although their exact prey-capture behaviour and performance and possible links to mouthpart morphology have rarely been described. Here, we examine these relationships for selected species by SEM analyses of mouthparts and front legs and highspeed videography of prey-capture behaviour. We describe the observed behaviours and structural properties and quantify relationships between prey type, mouthpart morphology, and predatory performance based on morphometric measurements of both the shape and lever properties of the mandible. We show that the Staphylininae considered have morphological and behavioural properties generally associated with generalist predation and that the Paederinae considered display characteristics that are highly specialized on elusive prey such as Collembola. We found correlations between mandible shape and leverage, and body size and prey type. We report distinct prey-capture behaviours: the beetles use front legs and/or mandibles to attack prey, drag prey, or cage it between their legs. These strategies differ among species and situations. Overall, this exploratory study provides insights into the morphology and types of prey capture that must have played a major role in the evolution of these beetles.
Iron‐Catalyzed Cross‐Coupling of Thioesters and Organomanganese Reagents**
2022-07-23

Abstract We report a Fukuyama‐type coupling of thioesters with aliphatic organomanganese reagents utilizing a cheap and easily available iron(III) precatalyst. The reactions exhibit a wide tolerance of solvents and functional groups, allowing for the conversion of thioesters derived from natural products and pharmaceutical compounds. A strong steric impact from each reaction component (carboxylic moiety, thiol substituent and manganese reagent) was displayed, which enabled regioselective transformation of dithioesters. Mechanistic investigations showed that the released thiolate does not act as a mere spectator ligand, but rather positively influences the stability of intermediate alkyl(II)ferrates.
Quantifying knapping actions: a method for measuring the angle of blow on flakes
2022-07-23

Abstract Stone artifacts are critical for investigating the evolution of hominin behavior—they are among our only proxies for hominin behavior in deep time. Hominin cognition and skill are often inferred by reconstructing the technical decisions hominins made throughout the knapping process. However, despite many advancements in understanding how hominins knapped, some of the key factors involved in past flake production cannot be easily/readily derived from stone artifacts. In particular, the angle at which the knapper strikes the hammer against the core to remove the flake, or the angle of blow, is a key component of the knapping process that has up to now remained unmeasurable on archeological assemblages. In this study, we introduce a new method for estimating the angle of blow from the ventral surface of flakes. This method was derived from a controlled experiment that explicitly connects fracture mechanics to flake variability. We find that a feature of the flake’s bulb of percussion, what we call the bulb angle, is a measurable indicator of the angle of blow. Our experimental finding is further validated in two additional datasets from controlled and replicative knapping experiments. These results demonstrate the utility of continuing to link flake variation with technical decision-making to fracture mechanics. In addition, they also provide a useful and relatively simple means to capture a currently invisible aspect of hominin stone tool production behavior.
Assessing the Accuracy of an Artificial Intelligence-Based Segmentation Algorithm for the Thoracic Aorta in Computed Tomography Applications
2022-07-23

The aim was to evaluate the accuracy of a prototypical artificial intelligence-based algorithm for automated segmentation and diameter measurement of the thoracic aorta (TA) using CT. One hundred twenty-two patients who underwent dual-source CT were retrospectively included. Ninety-three of these patients had been administered intravenous iodinated contrast. Images were evaluated using the prototypical algorithm, which segments the TA and determines the corresponding diameters at predefined anatomical locations based on the American Heart Association guidelines. The reference standard was established by two radiologists individually in a blinded, randomized fashion. Equivalency was tested and inter-reader agreement was assessed using intra-class correlation (ICC). In total, 99.2% of the parameters measured by the prototype were assessable. In nine patients, the prototype failed to determine one diameter along the vessel. Measurements along the TA did not differ between the algorithm and readers (p &gt; 0.05), establishing equivalence. Inter-reader agreement between the algorithm and readers (ICC ≥ 0.961; 95% CI: 0.940–0.974), and between the readers was excellent (ICC ≥ 0.879; 95% CI: 0.818–0.92). The evaluated prototypical AI-based algorithm accurately measured TA diameters at each region of interest independent of the use of either contrast utilization or pathology. This indicates that the prototypical algorithm has substantial potential as a valuable tool in the rapid clinical evaluation of aortic pathology.
Downstream Processing of Amorphous and Co-Amorphous Olanzapine Powder Blends
2022-07-23

The work evaluates the stability of amorphous and co-amorphous olanzapine (OLZ) in tablets manufactured by direct compression. The flowability and the compressibility of amorphous and co-amorphous OLZ with saccharin (SAC) and the properties of the tablets obtained were measured and compared to those of tablets made with crystalline OLZ. The flowability of the amorphous and mostly of the co-amorphous OLZ powders decreased in comparison with the crystalline OLZ due to the higher cohesiveness of the former materials. The stability of the amorphous and co-amorphous OLZ prior to and after tableting was monitored by XRPD, FTIR, and NIR spectroscopies. Tablets presented long-lasting amorphous OLZ with enhanced water solubility, but the release rate of the drug decreased in comparison with tablets containing crystalline OLZ. In physical mixtures made of crystalline OLZ and SAC, an extent of amorphization of approximately 20% was accomplished through the application of compaction pressures and dwell times of 155 MPa and 5 min, respectively. The work highlighted the stability of amorphous and co-amorphous OLZ during tableting and the positive effect of compaction pressure on the formation of co-amorphous OLZ, providing an expedited amorphization technique, given that the process development-associated hurdles were overcome.
Multiparametric Classification of Non-Muscle Invasive Papillary Urothelial Neoplasms: Combining Morphological, Phenotypical, and Molecular Features for Improved Risk Stratification
2022-07-23

Diagnosis and grading of non-invasive papillary urothelial tumors according to the current WHO classification poses some challenges for pathologists. The diagnostic reproducibility of separating low-grade and high-grade lesions is low, which impacts their clinical management. Whereas papillary urothelial neoplasms with low malignant potential (PUN-LMP) and low-grade papillary non-invasive carcinoma (LG-PUC) are comparable and show frequent local recurrence but rarely metastasize, high-grade papillary non-invasive carcinoma (HG-PUC) has a poor prognosis. The main objective of this work is to develop a multiparametric classification to unambiguously distinguish low-grade and high-grade tumors, considering immunohistochemical stains for p53, FGFR3, CK20, MIB-1, p16, p21 and p-HH3, and pathogenic mutations in TP53, FGFR3, TP53, ERCC2, PIK3CA, PTEN and STAG2. We reviewed and analyzed the clinical and histological data of 45 patients with a consensus diagnosis of PUN-LMP (n = 8), non-invasive LG-PUC (n = 23), and HG-PUC (n = 14). The proliferation index and mitotic count assessed with MIB-1 and P-HH3 staining, respectively correlated with grading and clinical behavior. Targeted sequencing confirmed frequent FGFR3 mutations in non-invasive papillary tumors and identified mutations in TP53 as high-risk. Cluster analysis of the different immunohistochemical and molecular parameters allowed a clear separation in two different clusters: cluster 1 corresponding to PUN-LMP and LG-PUC (low MIB-1 and mitotic count/FGFR3 and STAG2 mutations) and cluster 2, HG-PUC (high MIB-1 and mitosis count/CK20 +++ expression, FGFR3 WT and TP53 mutation). Further analysis is required to validate and analyze the reproducibility of these clusters and their biological and clinical implication.
Advanced placement course credit and undergraduate student success in gateway science courses
2022-07-23

Abstract Approximately 2 million students take Advanced Placement (AP) examinations annually. However, departmental policies that allow students to replace introductory courses with AP credit greatly vary within and across universities, even across relatively similar universities. This study examines the impact of AP credit policies on second‐course success in introductory Biology, Chemistry, and Physics course sequences at six large public research universities ( N = 48,230 students). Applying logistic regression analyses, we found that general performance indicators and measures of systemic inequities during high school were predictive of students earning skip‐eligible scores. Interestingly, we descriptively discovered wide variation across institutions and disciplines in the percentage of students who chose to skip when meeting their local policies. However, logistic regression analysis did not find general trends of inequalities for skipping courses for students with skip‐eligible scores. We then applied inverse‐probability weights with regression adjustment to examine the effects of course skipping. We found that students who skipped their first course with AP credit actually performed similarly well or better in subsequent courses than did students who did not skip, even in contexts where lower AP scores were accepted. Therefore, our study suggests administrators to increase coherence in AP credit policies across departments and disciplines. In particular, we encourage modifying AP credit policies and academic advising to encourage students to skip when they have eligible AP scores. Benefits may include reductions in unnecessary coursework that is burdensome for both students and universities, potentially freeing up resources to better support students who were not privileged to enroll in AP courses during their high school education.
The Diagnostic Value of the Added MR Imaging of the Scrotum in the Preoperative Workup of Sonographically Indeterminate Testicular Lesions—A Retrospective Multicenter Analysis
2022-07-23

Background: The purpose of this study was to retrospectively analyze the diagnostic accuracy of magnetic resonance imaging (MRI) examinations of the scrotum in comparison with standard ultrasound (US) and histopathology. Methods: A retrospective multi-center analysis of MRI examinations of the scrotum performed between 06/2008 and 04/2021 was conducted. Results: A total of n = 113 patients were included. A total of 53 histopathologies were available, with 52.8% malignant and 50.9% benign findings. Related to histopathology, imaging was true negative, false negative, false positive, and true positive in 4.1%, 2.1%, 25.0% and 37.5% for standard ultrasound (US) and 9.1%, 1.8%, 25.5% and 43.6% for MRI. Sensitivity, specificity, positive predictive value and negative predictive value were 94.7%, 20.0%, 36.0% and 88.9% for US and 85.7%, 72.8%, 52.1% and 93.7% for MRI, respectively. Benign lesions were significantly smaller than malignant ones in standard US (p = 0.001), histopathology (p = 0.001) and MRI (p = 0.004). The size of malignant tumors did not differ significantly between histopathology and standard US (0.72) and between histopathology and MRI (p = 0.88). Conclusions: MRI shows good sensitivity and specificity for the estimation of testicular tumors in this collective. Benign lesions are significantly smaller than malignant ones. Both MRI and US can estimate the size of malignant tumors adequately.
A Meta-Analysis of the Relative Contribution of Leadership Styles to Followers’ Mental Health
2022-07-24

It is well-established that different leadership styles are associated with followers’ mental health. However, little is known about the relative strength of the relationship of different leadership styles with followers’ mental health. So far, there is no meta-analysis comparing the incremental contribution of different leadership styles to mental health and studying potentially problematic construct proliferation. We included studies that compared at least two leadership styles in view of their relationships with followers’ mental health and directly estimated the relative contribution of seven leadership styles (i.e., transformational, transactional, laissez-faire, task-oriented, relationship-oriented, and destructive leadership, as well as leader-member exchange) to followers’ mental health. Using meta-analytical regression models, we compared the strength of the relationships between these leadership styles and followers’ overall mental health as well as positive (well-being and psychological functioning) and negative aspects of their mental health (affective symptoms, stress, and health complaints). Fifty-three studies with 217 effect sizes comprising 93,470 participants met the inclusion criteria. Transformational and destructive leadership were the strongest predictors of overall and negative aspects of mental health among followers. In contrast, the strongest predictors of positive mental health outcomes among followers were relations-oriented and task-oriented leadership, followed by transformational leadership. In sum, our results suggest that various leadership styles make unique contributions to explaining followers’ mental health and thus construct proliferation mostly does not pose a major problem when predicting relevant outcomes in this domain of leadership research. Our results are relevant for leadership development programs and for future organizational leadership models.