Rapid Identification of a Scalable Catalyst for the Asymmetric Hydrogenation of a Sterically Demanding Aryl Enamide

High throughput screening was used to find a cost-effective and scalable catalyst for the asymmetric hydrogenation of a sterically demanding enamide as an intermediate towards a new potent melanocortin receptor agonist useful in the treatment of obesity. Lessons drawn from the testing of a first library of 96 chiral monodentate phosphoramidites led to the design of a second focused library of 16 chiral ligands, allowing the discovery of a new efficient catalyst. This catalyst was based on rhodium and a bulky monodentate phosphite ligand. The catalyst was scaled up and used in the kilogram production of the desired bulky chiral amide

European Resuscitation Council Guidelines for Resuscitation 2015 Section 10. Education and implementation of resuscitation

M. Castren on Educ Implementation Resuscitation -työryhmän jäsen.Peer reviewe

Sham surgery controls in Parkinson's disease clinical trials: Views of participants

Background: Sham surgery controls are increasingly used in neurosurgical clinical trials in Parkinson's disease (PD) but remain controversial. We interviewed participants of such trials, specifically examining their understanding and attitudes regarding sham surgery. Methods: We conducted semistructured qualitative interviews with participants of 3 sham surgery–controlled trials for PD, focusing on their understanding of sham design, their reactions to it, its impact on decision making, and their understanding of posttrial availability of the experimental intervention and its impact on decisions to participate. Results: All subjects (n = 90) understood the 2‐arm design; most (86%) described the procedural differences between the arms accurately. Ninety‐two percent referred to scientific or regulatory reasons as rationales for the sham control, with 62% specifically referring to the placebo effect. Ninety‐one percent said posttrial availability of the experimental intervention had a strong (48%) or some (43%) influence on their decision to participate, but only 68% understood the conditions for posttrial availability. Conclusions: Most subjects in sham surgery–controlled PD trials comprehend the sham surgery design and its rationale. Although there is room for improvement, most subjects of sham surgery trials appear to be adequately informed. © 2012 Movement Disorder SocietyPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93771/1/25155_ftp.pd

Ruthenacycles and Iridacycles as Catalysts for Asymmetric Transfer Hydrogenation and Racemisation

Ruthenacycles, which are easily prepared in a single step by reaction between enantiopure aromatic amines and [Ru(arene)Cl2]2 in the presence of NaOH and KPF6, are very good asymmetric transfer hydrogenation catalysts. A range of aromatic ketones were reduced using isopropanol in good yields with ee’s up to 98%. Iridacycles, which are prepared in similar fashion from [IrCp*Cl2]2 are excellent catalysts for the racemisation of secondary alcohols and chlorohydrins at room temperature. This allowed the development of a new dynamic kinetic resolution of chlorohydrins to the enantiopure epoxides in up to 90% yield and 98% enantiomeric excess (ee) using a mutant of the enzyme Haloalcohol dehalogenase C and an iridacycle as racemisation catalyst.

Microparticles from tumors exposed to radiation promote immune evasion in part by PD-L1

Radiotherapy induces immune-related responses in cancer patients by various mechanisms. Here, we investigate the immunomodulatory role of tumor-derived microparticles (TMPs)-extracellular vesicles shed from tumor cells-following radiotherapy. We demonstrate that breast carcinoma cells exposed to radiation shed TMPs containing elevated levels of immune-modulating proteins, one of which is programmed death-ligand 1 (PD-L1). These TMPs inhibit cytotoxic T lymphocyte (CTL) activity both in vitro and in vivo, and thus promote tumor growth. Evidently, adoptive transfer of CTLs pre-cultured with TMPs from irradiated breast carcinoma cells increases tumor growth rates in mice recipients in comparison with control mice receiving CTLs pre-cultured with TMPs from untreated tumor cells. In addition, blocking the PD-1-PD-L1 axis, either genetically or pharmacologically, partially alleviates TMP-mediated inhibition of CTL activity, suggesting that the immunomodulatory effects of TMPs in response to radiotherapy is mediated, in part, by PD-L1. Overall, our findings provide mechanistic insights into the tumor immune surveillance state in response to radiotherapy and suggest a therapeutic synergy between radiotherapy and immune checkpoint inhibitors

Tissue-Specific T2* Biomarkers in Patellar Tendinopathy by Subregional Quantification Using 3D Ultrashort Echo Time MRI

Background: Quantitative MRI of patellar tendinopathy (PT) can be challenging due to spatial variation of T2* relaxation times. Purpose: 1) To compare T2* quantification using a standard approach with analysis in specific tissue compartments of the patellar tendon. 2) To evaluate test–retest reliability of different methods for fitting ultrashort echo time (UTE)-relaxometry data. Study Type: Prospective. Subjects: Sixty-five athletes with PT. Field Strength/Sequence: 3D UTE scans covering the patellar tendon were acquired using a 3.0T scanner and a 16-channel surface coil. Assessment: Voxelwise median T2* was quantified with monoexponential, fractional-order, and biexponential fitting. We applied two methods for T2* analysis: first, a standard approach by analyzing all voxels covering the proximal patellar tendon. Second, within subregions of the patellar tendon, by using thresholds on biexponential fitting parameter percentage short T2* (0–30% for mostly long T2*, 30–60% for mixed T2*, and 60–100% for mostly short T2*). Statistical Tests: Average test–retest reliability was assessed in three athletes using coefficients-of-variation (CV) and coefficients-of-repeatability (CR). Results: With standard image analysis, we found a median [interquartile range, IQR] monoexponential T2* of 6.43 msec [4.32–8.55] and fractional order T2* 4.39 msec [3.06–5.78]. The percentage of short T2* components was 52.9% [35.5–69.6]. Subregional monoexponential T2* was 13.78 msec [12.11–16.46], 7.65 msec [6.49–8.61], and 3.05 msec [2.52–3.60] and fractional order T2* 11.82 msec [10.09–14.44], 5.14 msec [4.25–5.96], and 2.19 msec [1.82–2.64] for 0–30%, 30–60%, and 60–100% short T2*, respectively. Biexponential component short T2* was 1.693 msec [1.417–2.003] for tissue with mostly short T2* and long T2* of 15.79 msec [13.47–18.61] for mostly long T2*. The average CR (CV) was 2 msec (15%), 2 msec (19%) and 10% (22%) for monoexponential, fractional order and percentage short T2*, respectively. Data Conclusion: Patellar tendinopathy is characterized by regional variability in binding states of water. Quantitative multicompartment T2* analysis in PT can be facilitated using a voxel selection method based on using biexponential fitting parameters. Level of Evidence: 1. Technical Efficacy Stage: 1

Effects of a simple cardiac rehabilitation program on improvement of self-reported physical activity in atrial fibrillation - Data from the RACE 3 study

Background and aim: Physical inactivity is associated with an increased prevalence of atrial fibrillation (AF). We aim to evaluate whether cardiac rehabilitation (CR) motivates patients to become and stay physical active, and whether CR affects sinus rhythm maintenance and quality of life (QoL) in patients with persistent AF and moderate heart failure. Methods: In the Routine versus Aggressive risk factor driven upstream rhythm Control for prevention of Early atrial fibrillation in heart failure study patients were randomized to conventional or targeted therapy. Targeted therapy contained next to optimal risk factor management a 3-month CR program, including self-reported physical activity and counseling. Successful physical activity was assessed in the targeted group, defined as activity of moderate intensity >= 150 min/week, or >= 75 min/week of vigorous intensity. AF was assessed at 1 year on 7-days Holter monitoring, QoL using general health, fatigue and AF symptom questionnaires. Results: All 119 patients within the targeted group participated in the CR program, 106 (89%) completed it. At baseline 80 (67%) patients were successfully physical active, 39 (33%) were not. NTproBNP was lower in active patients. During 1-year follow-up physical active patients stayed active: 72 (90%) at 12 weeks, 72 (90%) at 1 year. Inactive patients became active: at 12 weeks 25 (64%) patients and 30 (77%) at 1 year. No benefits were seen on sinus rhythm maintenance and QoL for successful physical active patients. Conclusion: In patients with persistent AF and moderate heart failure participation in CR contributes to improve and to maintain physical activity. (C) 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Radiographic Predictors of Conversion to Total Knee Arthroplasty After Tibial Plateau Fracture Surgery:Results in a Large Multicenter Cohort

Background: Radiographic measurements of initial displacement of tibial plateau fractures and of postoperative reduction are used to determine treatment strategy and prognosis. We assessed the association between radiographic measurements and the risk of conversion to total knee arthroplasty (TKA) at the time of follow-up.Methods: A total of 862 patients surgically treated for tibial plateau fractures between 2003 and 2018 were eligible for this multicenter cross-sectional study. Patients were approached for follow-up, and 477 (55%) responded. The initial gap and step-off were measured on the preoperative computed tomography (CT) scans of the responders. Condylar widening, residual incongruity, and coronal and sagittal alignment were measured on postoperative radiographs. Critical cutoff values for gap and step-off were determined using receiver operating characteristic curves. Postoperative reduction measurements were categorized as adequate or inadequate on the basis of cutoff values in international guidelines. Multivariable analysis was performed to assess the association between each radiographic measurement and conversion to TKA.Results: Sixty-seven (14%) of the patients had conversion to TKA after a mean follow-up of 6.5 ± 4.1 years. Assessment of the preoperative CT scans revealed that a gap of &gt;8.5 mm (hazard ratio [HR] = 2.6, p &lt; 0.001) and step-off of &gt;6.0 mm (HR = 3.0, p &lt; 0.001) were independently associated with conversion to TKA. Assessment of the postoperative radiographs demonstrated that residual incongruity of 2 to 4 mm was not associated with increased risk of TKA compared with adequate fracture reduction of &lt;2 mm (HR = 0.6, p = 0.176). Articular incongruity of &gt;4 mm resulted in increased risk of TKA. Coronal (HR = 1.6, p = 0.05) and sagittal malalignment (HR = 3.7 p &lt; 0.001) of the tibia were strongly associated with conversion to TKA.Conclusions: Substantial preoperative fracture displacement was a strong predictor of conversion to TKA. Postoperative gaps or step-offs of &gt;4 mm as well as inadequate alignment of the tibia were strongly associated with an increased risk of TKA.Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.</p