Structure of permethyltantalocenephenylmethanecarbothialdehyde hydride, (η^5-C_5Me_5)_2Ta(η^2-SCHCH_2C_6H_5)H

Hydridobis( 7] 5-pentamethylcyclopentadienyl) (phenylmethanecarbothialdehyde-kC,kS)tantalum C_(28)H_(39)STa, Mr= 588.63, monoclinic, P2_1 c, ɑ = 15.729 (5), b = 10.203 (2), c = 17.599 (5) Å, β = 116.18 (2)º , v = 2535 (1) Å^3, z = 4, D_x = 1.54 g cm^(-3), λ(Mo Kɑ) = 0.71073 A, μ = 46.6 cm^(-1), F(000) = 1184, room temperature (297 K), R = 0.068 for 2333 reflections with F_o^2 > 0, R = 0.054 for 2179 with F_o^2 > 3σ(F_o^2). The structure is disordered, with two enantiomeric molecules occupying the same crystallographic site. For the major component, the thioaldehyde ligand has an S-C bond length of 1.86 (2) Å. The ligand is bonded to the Ta center with a Ta-S bond distance of 2.418 (9) Å and a Ta-C bond distance of 2.28 (2) Å

Effects of flanking sequences and cellular context on subcellular behavior and pathology of mutant HTT

Huntington’s disease (HD) is caused by an expansion of a poly glutamine (polyQ) stretch in the huntingtin protein (HTT) that is necessary to cause pathology and formation of HTT aggregates. Here we ask whether expanded polyQ is sufficient to cause pathology and aggregate formation. By addressing the sufficiency question, one can identify cellular processes and structural parameters that influence HD pathology and HTT subcellular behavior (i.e. aggregation state and subcellular location). Using Drosophila, we compare the effects of expressing mutant full-length human HTT (fl-mHTT) to the effects of mutant human HTTexon1 and to two commonly used synthetic fragments, HTT171 and shortstop (HTT118). Expanded polyQ alone is not sufficient to cause inclusion formation since full-length HTT and HTTex1 with expanded polyQ are both toxic although full-length HTT remains diffuse while HTTex1 forms inclusions. Further, inclusions are not sufficient to cause pathology since HTT171-120Q forms inclusions but is benign and co-expression of HTT171-120Q with non-aggregating pathogenic fl-mHTT recruits fl-mHTT to aggregates and rescues its pathogenicity. Additionally, the influence of sequences outside the expanded polyQ domain is revealed by finding that small modifications to the HTT118 or HTT171 fragments can dramatically alter their subcellular behavior and pathogenicity. Finally, mutant HTT subcellular behavior is strongly modified by different cell and tissue environments (e.g. fl-mHTT appears as diffuse nuclear in one tissue and diffuse cytoplasmic in another but toxic in both). These observations underscore the importance of cellular and structural context for the interpretation and comparison of experiments using different fragments and tissues to report the effects of expanded polyQ

Effects of flanking sequences and cellular context on subcellular behavior and pathology of mutant HTT

Huntington’s disease (HD) is caused by an expansion of a poly glutamine (polyQ) stretch in the huntingtin protein (HTT) that is necessary to cause pathology and formation of HTT aggregates. Here we ask whether expanded polyQ is sufficient to cause pathology and aggregate formation. By addressing the sufficiency question, one can identify cellular processes and structural parameters that influence HD pathology and HTT subcellular behavior (i.e. aggregation state and subcellular location). Using Drosophila, we compare the effects of expressing mutant full-length human HTT (fl-mHTT) to the effects of mutant human HTTexon1 and to two commonly used synthetic fragments, HTT171 and shortstop (HTT118). Expanded polyQ alone is not sufficient to cause inclusion formation since full-length HTT and HTTex1 with expanded polyQ are both toxic although full-length HTT remains diffuse while HTTex1 forms inclusions. Further, inclusions are not sufficient to cause pathology since HTT171-120Q forms inclusions but is benign and co-expression of HTT171-120Q with non-aggregating pathogenic fl-mHTT recruits fl-mHTT to aggregates and rescues its pathogenicity. Additionally, the influence of sequences outside the expanded polyQ domain is revealed by finding that small modifications to the HTT118 or HTT171 fragments can dramatically alter their subcellular behavior and pathogenicity. Finally, mutant HTT subcellular behavior is strongly modified by different cell and tissue environments (e.g. fl-mHTT appears as diffuse nuclear in one tissue and diffuse cytoplasmic in another but toxic in both). These observations underscore the importance of cellular and structural context for the interpretation and comparison of experiments using different fragments and tissues to report the effects of expanded polyQ

Acceptance and commitment therapy delivered via a mobile phone messaging robot to decrease postoperative opioid use in patients with orthopedic trauma: Randomized controlled trial

BACKGROUND: Acceptance and commitment therapy (ACT) is a pragmatic approach to help individuals decrease avoidable pain. OBJECTIVE: This study aims to evaluate the effects of ACT delivered via an automated mobile messaging robot on postoperative opioid use and patient-reported outcomes (PROs) in patients with orthopedic trauma who underwent operative intervention for their injuries. METHODS: Adult patients presenting to a level 1 trauma center who underwent operative fixation of a traumatic upper or lower extremity fracture and who used mobile phone text messaging were eligible for the study. Patients were randomized in a 1:1 ratio to either the intervention group, who received twice-daily mobile phone messages communicating an ACT-based intervention for the first 2 weeks after surgery, or the control group, who received no messages. Baseline PROs were completed. Two weeks after the operative intervention, follow-up was performed in the form of an opioid medication pill count and postoperative administration of PROs. The mean number of opioid tablets used by patients was calculated and compared between groups. The mean PRO scores were also compared between the groups. RESULTS: A total of 82 subjects were enrolled in the study. Of the 82 participants, 76 (38 ACT and 38 controls) completed the study. No differences between groups in demographic factors were identified. The intervention group used an average of 26.1 (SD 21.4) opioid tablets, whereas the control group used 41.1 (SD 22.0) tablets, resulting in 36.5% ([41.1-26.1]/41.1) less tablets used by subjects receiving the mobile phone-based ACT intervention (P=.004). The intervention group subjects reported a lower postoperative Patient-Reported Outcome Measure Information System Pain Intensity score (mean 45.9, SD 7.2) than control group subjects (mean 49.7, SD 8.8; P=.04). CONCLUSIONS: In this study, the delivery of an ACT-based intervention via an automated mobile messaging robot in the acute postoperative period decreased opioid use in selected patients with orthopedic trauma. Participants receiving the ACT-based intervention also reported lower pain intensity after 2 weeks, although this may not represent a clinically important difference. TRIAL REGISTRATION: ClinicalTrials.gov NCT03991546; https://clinicaltrials.gov/ct2/show/NCT03991546

Use of the Behavior Assessment Tool in 18 Pilot Residency Programs

Background: The purpose of this study was to determine the feasibility and evaluate the effectiveness of the American Board of Orthopaedic Surgery Behavior Tool (ABOSBT) for measuring professionalism. Methods: Through collaboration between the American Board of Orthopaedic Surgery and American Orthopaedic Association\u27s Council of Residency Directors, 18 residency programs piloted the use of the ABOSBT. Residents requested assessments from faculty at the end of their clinical rotations, and a 360° request was performed near the end of the academic year. Program Directors (PDs) rated individual resident professionalism (based on historical observation) at the outset of the study, for comparison to the ABOSBT results. Results: Nine thousand eight hundred ninety-two evaluations were completed using the ABOSBT for 449 different residents by 1,012 evaluators. 97.6% of all evaluations were scored level 4 or 5 (high levels of professional behavior) across all of the 5 domains. In total, 2.4% of all evaluations scored level 3 or below reflecting poorer performance. Of 431 residents, the ABOSBT identified 26 of 32 residents who were low performers (2 or more \u3c level 3 scores in a domain) and who also scored below expectations by the PD at the start of the pilot project (81% sensitivity and 57% specificity), including 13 of these residents scoring poorly in all 5 domains. Evaluators found the ABOSBT was easy to use (96%) and that it was an effective tool to assess resident professional behavior (81%). Conclusions: The ABOSBT was able to identify 2.4% low score evaluations ( Level of Evidence: Level II

SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation

SUMMARY A key feature in Huntington disease (HD) is the accumulation of mutant Huntingtin (HTT) protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression

Plasmodium vivax and Mixed Infections Are Associated with Severe Malaria in Children: A Prospective Cohort Study from Papua New Guinea

In a study carried out in Papua New Guinea, Blaise Genton and colleagues show thatPlasmodium vivax is associated with severe malaria

The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design

Abstract: Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised. This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process. The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text. The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits. In order to encourage its wide dissemination this article is freely accessible on the BMJ and Trials journal websites.“To maximise the benefit to society, you need to not just do research but do it well” Douglas G Altma