Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis: Extended Results of a Placebo-Controlled Phase 2 Trial.

BACKGROUND AND OBJECTIVES: Vidofludimus calcium suppressed MRI disease activity compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS) in the first cohort of the phase 2 EMPhASIS study. Because 30 mg and 45 mg showed comparable activity on multiple end points, the study enrolled an additional low-dose cohort to further investigate a dose-response relationship. METHODS: In a randomized, placebo-controlled, phase 2 trial, patients with RRMS, aged 18-55 years, and with ≥2 relapses in the last 2 years or ≥1 relapse in the last year, and ≥1 gadolinium-enhancing brain lesion in the last 6 months. Patients were randomly assigned (1:1:1) vidofludimus calcium (30 or 45 mg) or placebo in cohort 1 and vidofludimus calcium (10 mg) or placebo (4:1) in cohort 2 for 24 weeks. The primary end point was the cumulative number of combined unique active (CUA) lesions at week 24. Secondary end points were clinical outcomes and safety. RESULTS: Across cohorts 1 and 2, 268 patients were randomized to placebo (n = 81), 10 mg (n = 47) vidofludimus calcium, 30 mg (n = 71) vidofludimus calcium, or 45 mg (n = 69) vidofludimus calcium. The mean cumulative CUA lesions over 24 weeks was 5.8 (95% CI 4.1-8.2) for placebo, 5.9 (95% CI 3.9-9.0) for 10 mg treatment group, 1.4 (95% CI 0.9-2.1) for 30 mg treatment group, and 1.7 (95% CI 1.1-2.5) for 45 mg treatment group. Serum neurofilament light chain decreased in a dose-dependent manner. The number of patients with confirmed disability worsening after 24 weeks was 3 (3.7%) patients receiving placebo and 3 (1.6%) patients receiving any dose of vidofludimus calcium. Treatment-emergent adverse events occurred in 35 (43%) placebo patients compared with 11 (23%) and 71 (37%) patients in the 10 mg or any dose of vidofludimus calcium groups, respectively. The incidence of liver enzyme elevations and infections were similar between placebo and any dose of vidofludimus calcium. No new safety signals were observed. DISCUSSION: Compared with placebo, vidofludimus calcium suppressed the development of new brain lesions with daily doses of 30 mg and 45 mg, but not 10 mg, establishing the lowest efficacious dose is 30 mg. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among adults with active RRMS and ≥1 Gd+ brain lesion in the past 6 months, the cumulative number of active lesions decreased with vidofludimus calcium. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT03846219) and EudraCT (2018-001896-19).

Organocatalytic Asymmetric Conjugate Addition of Fluorooxindoles to Quinone Methides.

Fluorooxindoles undergo asymmetric Michael addition to para-quinone methides under phase-transfer conditions with 10 mol% of a readily available cinchona alkaloid ammonium catalyst. This reaction affords sterically encumbered, multifunctional fluorinated organic compounds displaying two adjacent chirality centers with high yields, ee's and dr's.

Organometallic Chirality Sensing via "Click"-like η6-Arene Coordination with an Achiral Cp*Ru(II) Piano Stool Complex.

Piano stool complexes have been studied over many years and found widespread applications in organic synthesis, catalysis, materials and drug development. We now report the first examples of quantitative chiroptical molecular recognition of chiral compounds through click-like η6-arene coordination with readily available half sandwich complexes. This conceptually new approach to chirality sensing is based on irreversible acetonitrile displacement of [Cp*Ru(CH3CN)3]PF6 by an aromatic target molecule, a process that is fast and complete within a few minutes at room temperature. The metal coordination coincides with characteristic circular dichroism inductions that can be easily correlated to the absolute configuration and enantiomeric ratio of the bound molecule. A relay assay that decouples the determination of the enantiomeric composition and of the total sample amount by a practical CD/UV measurement protocol was developed and successfully tested. The introduction of piano stool complexes to the chiroptical sensing realm is mechanistically unique and extends the scope of currently known methods with small-molecule probes that require the presence of amino, alcohol, carboxylate or other privileged functional groups for binding of the target compound. A broad application range including pharmaceutically relevant multifunctional molecules and the use in chromatography-free asymmetric reaction analysis are also demonstrated.

Patient-Reported Outcomes following Tibial Plateau Fractures: Mid- to Short-Term Implications for Knee Function and Activity Level.

Background: Patients with complex proximal tibial plateau fractures (TPFs) tend to overestimate the prognosis of their injury, potentially due to factors such as a limited understanding, optimism, and the influence of the pain intensity. Understanding the reasons behind this misperception is crucial for healthcare providers to effectively communicate with patients and establish realistic expectations for treatment outcomes. The purpose of this study was to analyze the outcomes of TPFs, with a particular focus on patient-reported outcome measures concerning functional recovery, pain levels, and overall satisfaction with treatment. The authors aim to provide valuable insights into the realistic expectations and potential limitations that patients may encounter during their recovery journey. Methods: In this retrospective single-center study, all surgically treated TPFs between January 2014 and December 2019 with a minimum follow-up of 12 months were included. Several patient-reported outcome measures were obtained, including the International Knee documentation Committee Score (IKDC), Lyholm score, Tegner score, and visual analog scale (VAS) for pain. Fractures were classified according to Schatzker, and then subgrouped into simple (Schatzker I-III) and complex (Schatzker IV-VI) fractures. Results: A total of 54 patients (mean age 51.1 ± 11.9 years, 59.3% female) with a mean follow-up time of 3.9 years were included. Schatzker II fractures were present in 48% (n = 26) of the cases, with Schatzker III in 6% (n = 3), Schatzker IV fractures in 6% (n = 3), and Schatker VI fractures in 41% (n = 22) of the cases. All outcome scores showed a significant improvement between the first year after surgery and the last follow-up (mean: 3.9 years). Simple fractures showed significantly lower patient-reported outcomes when compared to the preinjury state; however, good to excellent results were observed. Patient-reported outcomes of complex fractures showed no significant changes in the study period with good to excellent results. When it comes to the Lysholm score, there were no significant differences in the outcome between simple and complex fractures. Furthermore, there was a return-to-sports rate of 100%, with high rates of changing sporting activity in 25% (simple fractures) and 45% in complex fractures. Conclusions: The data from this study showed that both simple and complex tibial plateau fractures show favorable outcomes at the midterm follow-up, and that injury severity does not correlate with worse results. While patients may tend to overestimate the recovery speed, this research highlights the importance of long-term follow-up, demonstrating a substantial improvement between one year post-surgery and the final evaluation. Return-to-sports rates were high, with adjustments needed for certain activities. However, patients should recognize the need to shift to lower-impact sports and the lengthy recovery process.

Lethal metabolism of Candida albicans respiratory mutants.

The destructive impact of fungi in agriculture and animal and human health, coincident with increases in antifungal resistance, underscores the need for new and alternative drug targets to counteract these trends. Cellular metabolism relies on many intermediates with intrinsic toxicity and promiscuous enzymatic activity generates others. Fuller knowledge of these toxic entities and their generation may offer opportunities of antifungal development. From this perspective our observation of media-conditional lethal metabolism in respiratory mutants of the opportunistic fungal pathogen Candida albicans was of interest. C. albicans mutants defective in NADH:ubiquinone oxidoreductase (Complex I of the electron transport chain) exhibit normal growth in synthetic complete medium. In YPD medium, however, the mutants grow normally until early stationary phase whereupon a dramatic loss of viability occurs. Upwards of 90% of cells die over the subsequent four to six hours with a loss of membrane integrity. The extent of cell death was proportional to the amount of BactoPeptone, and to a lesser extent, the amount of yeast extract. YPD medium conditioned by growth of the mutant was toxic to wild-type cells indicating mutant metabolism established a toxic milieu in the media. Conditioned media contained a volatile component that contributed to toxicity, but only in the presence of a component of BactoPeptone. Fractionation experiments revealed purine nucleosides or bases as the synergistic component. GC-mass spectrometry analysis revealed acetal (1,1-diethoxyethane) as the active volatile. This previously unreported and lethal synergistic interaction of acetal and purines suggests a hitherto unrecognized toxic metabolism potentially exploitable in the search for antifungal targets.

Circular Dichroism Sensing: Strategies and Applications.

The analysis of the absolute configuration, enantiomeric composition, and concentration of chiral compounds are frequently encountered tasks across the chemical and health sciences. Chiroptical sensing methods can streamline this work and allow high-throughput screening with remarkable reduction of operational time and cost. During the last few years, significant methodological advances with innovative chirality sensing systems, the use of computer-generated calibration curves, machine learning assistance, and chemometric data processing, to name a few, have emerged and are now matched with commercially available multi-well plate CD readers. These developments have reframed the chirality sensing space and provide new opportunities that are of interest to a large group of chemists. This review will discuss chirality sensing strategies and applications with representative small-molecule CD sensors. Emphasis will be given to important milestones and recent advances that accelerate chiral compound analysis by outperforming traditional methods, conquer new directions, and pioneering efforts that lie at the forefront of chiroptical high-throughput screening developments. The goal is to provide the reader with a thorough understanding of the current state and a perspective of future directions of this rapidly emerging field.

General alkyl fluoride functionalization via short-lived carbocation-organozincate ion pairs.

Fluorinated organic compounds are frequently used across the chemical and life sciences. Although a large, structurally diverse pool of alkyl fluorides is nowadays available, synthetic applications trail behind the widely accepted utility of other halides. We envisioned that C(sp2)-C(sp3) cross-coupling reactions of alkyl fluorides with fluorophilic organozinc compounds should be possible through a heterolytic mechanism that involves short-lived ion pairs and uses the stability of the Zn-F bond as the thermodynamic driving force. This would be mechanistically different from previously reported radical reactions and overcome long-standing limitations of organometallic cross-coupling methodology, including competing ß-hydride elimination, homodimerization and hydrodefluorination. Here, we show a practical Csp3-F bond functionalization method that expands the currently restricted synthetic space of unactivated primary, secondary and tertiary C(sp3)-F bonds but also uses benzylic, propargylic and acyl fluorides. Many functional groups and sterically demanding substrates are tolerated, which allows practical carbon-carbon bond formation and late-stage functionalization.

The (Un)ideal Physicist: How Humans Rely on Object Interaction for Friction Estimates.

To estimate object properties such as mass or friction, our brain relies on visual information to efficiently compute approximations. The role of sensorimotor feedback, however, is not well understood. Here we tested healthy adults (N = 79) in an inclined-plane problem, that is, how much a plane can be tilted before an object starts to slide, and contrasted the interaction group with observation groups who accessed involved forces by watching objects being manipulated. We created objects of different masses and levels of friction and asked participants to estimate the critical tilt angle after pushing an object, lifting it, or both. Estimates correlated with applied forces and were biased toward object mass, with higher estimates for heavier objects. Our findings highlight that inferences about physical object properties are tightly linked to the human sensorimotor system and that humans integrate sensorimotor information even at the risk of nonveridical perceptual estimates.

Chemometric sensing of stereoisomeric compound mixtures with a redox-responsive optical probe.

The analysis of mixtures of chiral compounds is a common task in academic and industrial laboratories typically achieved by laborious and time-consuming physical separation of the individual stereoisomers to allow interference-free quantification, for example using chiral chromatography coupled with UV detection. Current practice thus impedes high-throughput and slows down progress in countless chiral compound development projects. Here we describe a chemometric solution to this problem using a redox-responsive naphthoquinone that enables chromatography-free click chemistry sensing of challenging mixtures. The achiral probe covalently binds amino alcohols within a few minutes at room temperature and generates characteristic UVA and CDA spectra that are intentionally altered via sodium borohydride reduction to provide a second, strikingly different chiroptical data set (UVB and CDB). Chemometric partial least squares processing of the chiroptical outputs then enables spectral deconvolution and accurate determination of individual analyte concentrations. The success of this approach is demonstrated with 35 samples covering considerably varied total analyte amounts and stereoisomeric ratios. All chemicals and machine learning algorithms are readily available and can be immediately adapted by any laboratory.

Infection with swim bladder nematode Anguillicola crassus in relation to European eel growth, age, and habitat along the German Baltic coast.

One possible reason for the European eel (Anguilla anguilla) population decline is the neozoan eel swim bladder nematode Anguillicola crassus. To investigate whether the prevalence of A. crassus and the associated swim bladder pathology is related to eel habitat, growth rate, and age, 728 yellow eels from 6 habitats differing in salinity and located along the German Baltic coast were examined between 2005 and 2009. The prevalence of A. crassus varied between habitats, ranging from 9 to 57%. Infection prevalence and the percentage of eels with a damaged swim bladder were significantly higher in inner coastal waters compared to more saline open coastal water. In infected eels, 1 to 32 adult and preadult individuals of A. crassus were observed. The mean infection intensity varied between habitats from 2 to 7 nematodes per eel but did not significantly differ between inner and open coastal waters. Infection prevalence and intensity decreased significantly with age when all open coastal waters and all habitats were combined. Both the lower prevalence of A. crassus and the swim bladder damage of older eels and of eels originating from open coastal water habitats suggest that these eels have a higher fitness for spawning migrations than eels from inner coastal waters. The present study underlines the importance of eel screening on a sufficiently small geographical scale for the accurate estimation of eel recruitment and the identification of priority areas that are likely to produce healthy silver eels.

Global responses to the COVID-19 pandemic by recreational anglers: considerations for developing more resilient and sustainable fisheries.

The global COVID-19 pandemic resulted in many jurisdictions implementing orders restricting the movements of people to inhibit virus transmission, with recreational angling often either not permitted or access to fisheries and/or related infrastructure being prevented. Following the lifting of restrictions, initial angler surveys and licence sales suggested increased participation and effort, and altered angler demographics, but with evidence remaining limited. Here, we overcome this evidence gap by identifying temporal changes in angling interest, licence sales, and angling effort in world regions by comparing data in the 'pre-pandemic' (up to and including 2019); 'acute pandemic' (2020) and 'COVID-acclimated' (2021) periods. We then identified how changes can inform the development of more resilient and sustainable recreational fisheries. Interest in angling (measured here as angling-related internet search term volumes) increased substantially in all regions during 2020. Patterns in licence sales revealed marked increases in some countries during 2020 but not in others. Where licence sales increased, this was rarely sustained in 2021; where there were declines, these related to fewer tourist anglers due to movement restrictions. Data from most countries indicated a younger demographic of people who participated in angling in 2020, including in urban areas, but this was not sustained in 2021. These short-lived changes in recreational angling indicate efforts to retain younger anglers could increase overall participation levels, where efforts can target education in appropriate angling practices and create more urban angling opportunities. These efforts would then provide recreational fisheries with greater resilience to cope with future global crises, including facilitating the ability of people to access angling opportunities during periods of high societal stress. Supplementary Information: The online version contains supplementary material available at 10.1007/s11160-023-09784-5.

Enantioseparation and racemization of 3-fluorooxindoles.

Fluorinated oxindoles are frequently used building blocks in asymmetric synthesis and represent an important scaffold found in a variety of biologically relevant compounds. While it is understood that incorporation of fluorine atoms into organic molecules can improve their pharmacological properties, the impact on the configurational stability of chiral organofluorines is still underexplored. In this study, semipreparative HPLC enantioseparations of five oxindoles were carried out, and the resulting enantiomerically enriched solutions were used to investigate base promoted racemization kinetics at room temperature. It was found that incorporation of fluorine at the chiral center increases the configurational stability, while substitutions on the aromatic ring and at the lactam moiety also have significant effects on the rate of racemization, which generally follows reversible first-order reaction kinetics.

Design, synthesis and biological evaluation of Nucleosidic CD99 inhibitors that selectively reduce Ewing sarcoma viability.

Ewing Sarcoma (ES) is a cancer of bone and soft tissues affecting mostly children and young adults. Aggressive progression and poor prognosis of this malignancy call for novel and targeted treatments. CD99 is a transmembrane protein that is abundantly expressed on ES cells and is a diagnostic marker for the disease. ES cells are selectively sensitive to CD99 inhibition compared to most normal cells and other tumors. Therefore, CD99 is a good molecular target for ES treatment. Clofarabine and cladribine are two FDA approved drugs that are administered for their inhibitory acts on DNA synthesis to treat relapsed or refractory acute lymphoblastic and myeloid leukemia. They have also been shown to directly bind to CD99 and inhibit ES growth through a distinct mechanism. In the current study, we designed, synthesized and tested new ES specific derivatives of both drugs that would continue to target CD99 but with expected reduction in cellular membrane permeability and rendered unsuitable for inhibiting DNA synthesis. By using commercially available clofarabine and cladribine purine nucleoside analogs, we modified the primary alcohol moiety at the deoxyribose C-5' terminal site to suppress phosphorylation and thus inhibition of subsequent DNA synthesis pathways. In addition, we incorporated a variety of polar groups in the ribose and purine rings to reduce membrane permeability and investigated the effects of configurational changes in the sugar moiety. Among 26 new derivatives, we identified two compounds, BK50164 and BK60106, that cause cell death specifically in ES primarily due to inhibition of CD99 but not via inhibition of DNA synthesis. These findings provide a road map for the future development selective CD99 inhibitors for targeted treatment of ES.

Motivation by reward jointly improves speed and accuracy, whereas task-relevance and meaningful images do not.

Visual selection is characterized by a trade-off between speed and accuracy. Speed or accuracy of the selection process can be affected by higher level factors-for example, expecting a reward, obtaining task-relevant information, or seeing an intrinsically relevant target. Recently, motivation by reward has been shown to simultaneously increase speed and accuracy, thus going beyond the speed-accuracy-trade-off. Here, we compared the motivating abilities of monetary reward, task-relevance, and image content to simultaneously increase speed and accuracy. We used a saccadic distraction task that required suppressing a distractor and selecting a target. Across different blocks successful target selection was followed either by (i) a monetary reward, (ii) obtaining task-relevant information, or (iii) seeing the face of a famous person. Each block additionally contained the same number of irrelevant trials lacking these consequences, and participants were informed about the upcoming trial type. We found that postsaccadic vision of a face affected neither speed nor accuracy, suggesting that image content does not affect visual selection via motivational mechanisms. Task relevance increased speed but decreased selection accuracy, an observation compatible with a classical speed-accuracy trade-off. Motivation by reward, however, simultaneously increased response speed and accuracy. Saccades in all conditions deviated away from the distractor, suggesting that the distractor was suppressed, and this deviation was strongest in the reward block. Drift-diffusion modelling revealed that task-relevance affected behavior by affecting decision thresholds, whereas motivation by reward additionally increased the rate of information uptake. The present findings thus show that the three consequences differ in their motivational abilities.

[Influence of the COVID-19 pandemic on fracture epidemiology exemplified by tibial plateau fractures]. / Einfluss der COVID-19-Pandemie auf die Frakturepidemiologie am Beispiel der Tibiaplateaufraktur.

BACKGROUND: During the COVID-19 pandemic interventions, such as contact restrictions, lockdowns and postponement of elective surgeries were taken to ease the burden on the healthcare system. Among the population, these interventions led to changes in recreational behavior as well as personal transportation. OBJECTIVE: This paper examines the epidemiological data of tibial plateau fractures (TPF) before and during the pandemic and to what extent pandemic control measures had an impact. MATERIAL AND METHODS: In this retrospective monocentric study of a German level 1 trauma center, the intra-articular tibial plateau fractures of the years 2019 and 2020 were compared regarding incidence, demographics, cause of the accident, and treatment strategy. Fracture classification was according to Schatzker, AO/OTA, and Moore. RESULTS: Incidence showed a decrease of -8.5% as well as a shift in the age incidence curves. There was a decrease in incidence during lockdown periods but also an increase in late summer 2020 compared to 2019. Tripping accidents (+12.4%) and bicycle accidents (+6.6%) increased in the pandemic year, whereas motorized traffic accidents (-7%) and skiing accidents (-10%) decreased. In terms of fracture morphology, 2020 showed an increase in impression fractures and a decrease in complex fractures. The number of surgically treated patients decreased by 7.3%. CONCLUSION: The 12 months of pandemic resulted in only a slight incidence decrease of intra-articular tibial plateau fractures. The pandemic control measures showed effects within the calendar year and led directly and indirectly to a change in incidence, cause of the accident, fracture entities and care strategy.

Changing patterns in the epidemiology of tibial plateau fractures: a 10-year review at a level-I trauma center.

PURPOSE: Mobility patterns of western societies have been changing due to ongoing demographic change. Therefore, continuously updated epidemiological data on fracture morphology and treatment strategies are needed. METHODS: This retrospective single-center study included all tibial plateau fractures (TPF) between January 2011 and December 2020 in a level-I trauma center in Central Europe. Epidemiology, trauma mechanism and fracture morphology were analyzed. Age- and sex-specific differences regarding fracture classification (Schatzker, AO/OTA, Moore) and changes during the study period are highlighted. RESULTS: A total of 607 patients (55.2% women, 44.8% men, mean age 52.9 years (± 17.9)) were included in the study, 462 (76.1%) thereof having undergone surgical treatment. Over the decade, an increase in mean age (+ 7.4 years; p = 0.10), incidence (+ 68%; p < 0.05) and low-energy trauma was observed, with the highest peak in elderly women. Within classifications, AO/OTA 41-B3 (24.9%), Schatzker II (26.8%) and Moore V (46.6%) fractures were the most common. CONCLUSION: Incidence (+ 68%), mean age and fractures with signs of knee dislocation of tibial plateau fracture increased over the last decade and low-energy trauma mechanism are more frequent. As the increase in incidence is mainly seen in older women, the comorbidities and need for immediate postoperative full weight-bearing have to be considered in treatment strategies.

Selective Csp3-F Bond Functionalization with Lithium Iodide.

A highly efficient method for C-F bond functionalization of a broad variety of activated and unactivated aliphatic substrates with inexpensive lithium iodide is presented. Primary, secondary, tertiary, benzylic, propargylic and α-functionalized alkyl fluorides react in chlorinated or aromatic solvents at room temperature or upon heating to the corresponding iodides which are isolated in 91-99% yield. The reaction is selective for aliphatic monofluorides and can be coupled with in situ nucleophilic iodide replacements to install carbon-carbon, carbon-nitrogen and carbon-sulfur bonds with high yields. Alkyl difluorides, trifluorides, even in activated benzylic positions, are inert under the same conditions and aryl fluoride bonds are also tolerated.

Organocuprate Cross-Coupling Reactions with Alkyl Fluorides.

Cross-coupling of alkyl fluorides and organocuprates is accomplished via aluminum halide mediated C-F bond activation and subsequent Csp2-Csp3 and Csp3-Csp3 bond formation. Relatively mild conditions allow for smooth activation of notoriously challenging primary and secondary alkyl fluorides while competing alkyl chain rearrangement, HF elimination, and homocoupling reactions are effectively controlled. The utility and functional group tolerance are demonstrated with 23 examples and a variety of coupling products obtained in up to 88% yield.

Data-Driven Prediction of Circular Dichroism-Based Calibration Curves for the Rapid Screening of Chiral Primary Amine Enantiomeric Excess Values.

Here, we describe the prediction of the circular dichroism (CD) response of a three-component chiroptical sensor for enantiomeric excess (ee) determination of chiral amines using a multivariate fit to electronic and steric parameters. These computationally derived parameters can be computed for nearly any amine and correlate well with the CD response of the 12 amines comprising the training set. The resulting model was used to accurately predict the CD response of a test set of chiral amines. Theoretical calibration curves were then created and used to determine the ee of solutions of unknown ee. Using this method, the error in ee determination differed by less than 10% compared to experimentally generated calibration curves.

Current foveal inspection and previous peripheral preview influence subsequent eye movement decisions.

Humans visually inspect the world with their fovea and select new parts of the scene using saccadic eye movements. Foveal inspection and the decision of where and when to look next proceed simultaneously, but there is mixed evidence concerning their independence. Here, we tested their interdependence using drift-diffusion modeling. Participants first made a saccade to a predetermined inspection target and subsequently decided between two selection targets. We found that the inspected target's meaningfulness and the opportunity to preview it peripherally affects fixation durations and the upcoming saccadic selection. Drift-diffusion modeling showed that meaningfulness and the absence of peripheral preview can both delay the subsequent saccadic decision process and affect the rate at which peripheral information is accumulated. Our results thus show that foveal inspection and peripheral selection are dependent on each other and that peripheral information can be maintained across the saccade to influence subsequent eye movement decisions.