Exercise for people with a fragility fracture of the pelvis or lower limb: A systematic review of interventions evaluated in clinical trials and reporting quality

Background. To aid design of exercise trials for people with pelvic and lower limb fragility fractures a systematic review was conducted to identify what types of exercise and mobility outcomes have been assessed, investigate intervention reporting quality, and evaluate risk of bias in published trials. Methods. Systematic searches of electronic databases (CENTRAL, MEDLINE, EMBASE, PEDro) 1996-2019 were conducted to identify randomised controlled trials of exercise for pelvic or lower limb fragility fractures. Two reviewers independently screened titles and abstracts. One reviewer extracted data, a second verified. Two reviewers independently assessed risk of bias. Intervention reporting quality was based on TIDieR, assessed by one reviewer and verified by a second. Narrative synthesis was undertaken. Registration. PROSPERO CRD42017060905. Results. Searches identified 37 trials including 3564 participants, median sample size 81(IQR 48-124), participants aged 81 years (IQR 79-82) and 76%(2536/3356) female. All trials focussed on people with hip fracture except one on ankle fracture. Exercise types focussed on resistance exercise in 14 trials, weight bearing exercise in 5 trials, 13 varied dose of sessions with health professionals, and 2 trials each focussed on treadmill gait training, timing of weight bearing or aerobic exercise. 30/37(81%) of trials reported adequate sequence generation, 25/37(68%) sufficient allocation concealment. 10/37(27%) trials lacked outcome assessor blinding. Of 65 exercise interventions, reporting was clear for 33(51%) in terms of when started, 61(94%) for where delivered, 49(75%) for who delivered, 47(72%) for group or individual, 29(45%) for duration, 46(71%) for session frequency, 8(12%) for full prescription details to enable the exercises to be reproduced, 32(49%) clearly reported tailoring or modification, and 23(35%) reported exercise adherence. Subjectively assessed mobility was assessed in 22/37(59%) studies and 29/37(78%) used an objective measure. Conclusions. All trials focussed on hip fracture, apart from one ankle fracture trial. Research into pelvic and other lower limb fragility fractures is indicated. A range of exercise types were investigated but to date deficiencies in intervention reporting hamper reproducibility. Adoption of TIDieR and CERT guidelines should improve intervention reporting as use increases. Trials would be improved by consistent blinded outcome assessor use and with consensus on which mobility outcomes should be assessed

Synthesis of Triple-Stranded Diruthenium(II) Compounds

A series of ligands containing a 1,4-disubstituted 1,2,3-triazole unit have been used for the formation of triple-stranded dinuclear Ru(II) complexes. In contrast to the previously reported complexes of labile metals, the use of inert Ru(II) enabled stereoisomeric mixtures of triple-stranded diruthenium(II) complexes to be accessed. The chromatographic resolution of the enantiomers of a reported helicate containing a more rigid 1,4-xylyl spacer was carried out on cellulose. The ligand spacer was modified and as the flexibility increased the production of isomeric mixtures was detected; the mesocate and helicate forms were separated when an n-propyl spacer was used. This pair of diastereomers was found to exhibit photoconversion, a unique observation for Ru(II) compounds of this type. Partial separation via chromatographic resolution was achieved for compounds containing an n-butyl spacer, and the presence of a mesocate/helicate pair confirmed

Comparing air-sea flux measurements from a new unmanned surface vehicle and proven platforms during the SPURS-2 field campaign.

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Zhang, D., Cronin, M. F., Meinig, C., Farrar, J. T., Jenkins, R., Peacock, D., Keene, J., Sutton, A., & Yang, Q. Comparing air-sea flux measurements from a new unmanned surface vehicle and proven platforms during the SPURS-2 field campaign. Oceanography, 32(2), (2019): 122-133, doi:10.5670/oceanog.2019.220.Two saildrones participated in the Salinity Processes in the Upper-ocean Regional Study 2 (SPURS-2) field campaign at 10°N, 125°W, as part of their more than six-month Tropical Pacific Observing System (TPOS)-2020 pilot study in the eastern tropical Pacific. The two saildrones were launched from San Francisco, California, on September 1, 2017, and arrived at the SPURS-2 region on October 15, one week before R/V Revelle. Upon arrival at the SPURS-2 site, they each began a two-week repeat pattern, sailing around the program’s central moored surface buoy. The heavily instrumented Woods Hole Oceanographic Institution (WHOI) SPURS-2 buoy serves as a benchmark for validating the saildrone measurements for air-sea fluxes. The data collected by the WHOI buoy and the saildrones were found to be in reasonably good agreement. Although of short duration, these ship-saildrone-buoy comparisons are encouraging as they provide enhanced understanding of measurements by various platforms in a rapidly changing subsynoptic weather system. The saildrones were generally able to navigate the challenging Intertropical Convergence Zone, where winds are low and currents can be strong, demonstrating that the saildrone is an effective platform for observing a wide range of oceanographic variables important to air-sea interaction studies.The TPOS-2020 saildrone pilot study was funded by the NOAA Ocean Observations and Monitoring Division of the Climate Programs Office. The WHOI flux mooring was funded by NASA as part of the SPURS-2 program. This work is partially funded by the Joint Institute for the Study of the Atmosphere and Ocean (JISAO) under NOAA Cooperative Agreement NA15OAR4320063. We thank SPURS-2 cruise Chief Scientist Kyla Drushka of APL/University of Washington, Fred Bingham of the University of North Carolina, and Dave Rivera of PMEL onboard R/V Revelle for close coordination between ship operation and saildrone piloting. High-quality shipboard air-sea flux measurements by Carol Anne Clayson and James Edson of WHOI are greatly appreciated. We also thank the editors and two anonymous reviewers for their thoughtful suggestions that helped to improve this manuscript. This is PMEL contribution #4899

Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part II: Physiologically Based Pharmacokinetic Modeling and Manganese Risk Assessment

Recently, a variety of physiologically based pharmacokinetic (PBPK) models have been developed for the essential element manganese. This paper reviews the development of PBPK models (e.g., adult, pregnant, lactating, and neonatal rats, nonhuman primates, and adult, pregnant, lactating, and neonatal humans) and relevant risk assessment applications. Each PBPK model incorporates critical features including dose-dependent saturable tissue capacities and asymmetrical diffusional flux of manganese into brain and other tissues. Varied influx and efflux diffusion rate and binding constants for different brain regions account for the differential increases in regional brain manganese concentrations observed experimentally. We also present novel PBPK simulations to predict manganese tissue concentrations in fetal, neonatal, pregnant, or aged individuals, as well as individuals with liver disease or chronic manganese inhalation. The results of these simulations could help guide risk assessors in the application of uncertainty factors as they establish exposure guidelines for the general public or workers

Development and implementation of the physiotherapy-led exercise interventions for the treatment of rotator cuff disorders for the ‘Getting it Right:Addressing Shoulder Pain’ (GRASP) trial

The Getting it Right: Addressing Shoulder Pain (GRASP) trial is a large-scale, multicentre, randomised controlled trial investigating the clinical and cost-effectiveness of a progressive exercise intervention versus a best-practice advice intervention, with or without corticosteroid injection, for treating people with a rotator cuff disorder. Interventions were developed using the Medical Research Council guidance on complex interventions, and included a stakeholder meeting of 26 clinicians, researchers, and patient representatives. The best-practice advice (1 session) and progressive exercise (≤6 sessions over 16 weeks) interventions both involve face-to-face, one-to-one physiotherapist appointments and include self-management advice, home-exercise instruction, and behaviour-change strategies to target exercise adherence. The results of the GRASP trial are anticipated in 2020. This large scale evaluation on 704 participants will provide high quality evidence to best inform clinical practice for the management of people with shoulder pain due to a rotator cuff disorder. A critical stage of evaluating the complex interventions in the GRASP trial is ensuring details of the development and content of the interventions are available to clinicians and researchers to facilitate their implementation

SHAPE reveals transcript-wide interactions, complex structural domains, and protein interactions across the Xist lncRNA in living cells

Long noncoding RNAs (lncRNAs) are important regulators of gene expression, but their structural features are largely unknown. We used structure-selective chemical probing to examine the structure of the Xist lncRNA in living cells and found that the RNA adopts well-defined and complex structures throughout its entire 18-kb length. By looking for changes in reactivity induced by the cellular environment, we were able to identify numerous previously unknown hubs of protein interaction. We also found that the Xist structure governs specific protein interactions in multiple distinct ways. Our results provide a detailed structural context for Xist function and lay a foundation for understanding structure–function relationships in all lncRNAs

Longitudinal Cognitive Performance of Alzheimer\u27s Disease Neuropathological Subtypes

Introduction: Alzheimer\u27s disease (AD) neuropathological subtypes (limbic predominant [lpAD], hippocampal sparing [HpSpAD], and typical [tAD]), defined by relative neurofibrillary tangle (NFT) burden in limbic and cortical regions, have not been studied in prospectively characterized epidemiological cohorts with robust cognitive assessments. Methods: Two hundred ninety-two participants with neuropathologically confirmed AD from the Religious Orders Study and Memory and Aging Project were categorized by neuropathological subtype based on previously specified diagnostic criteria using quantitative regional NFT counts. Rates of cognitive decline were compared across subtypes using linear mixed-effects models that included subtype, time, and a subtype-time interaction as predictors and four cognitive domain factor scores (memory, executive function, language, visuospatial) and a global score as outcomes. To assess if memory was relatively preserved in HpSpAD, non-memory factor scores were included as covariates in the mixed-effects model with memory as the outcome. Results: There were 57 (20%) with lpAD, 22 (8%) with HpSpAD and 213 (73%) with tAD. LpAD died significantly later than the participants with tAD (2.4 years, P = .01) and with HpSpAD (3.8 years, P = .03). Compared to tAD, HpSpAD, but not lpAD, performed significantly worse in all cognitive domains at the time of initial impairment and declined significantly faster in memory, language, and globally. HpSpAD did not have relatively preserved memory performance at any time point. Conclusion: The relative frequencies of AD neuropathological subtypes in an epidemiological sample were consistent with a previous report in a convenience sample. People with HpSpAD decline rapidly, but may not have a memory-sparing clinical syndrome. Cohort-specific differences in regional tau burden and comorbid neuropathology may explain the lack of clinicopathological correlation

A systematic review of outcome reporting in clinical trials of distal tibia and ankle fractures : the need for a core outcome set

Aim: To describe outcome reporting variation and trends in non-pharmacological randomised clinical trials (RCT) of distal tibia and/or ankle fractures. Method: Five electronic databases and three clinical trial registries were searched (January 2000-February 2022). Trials including patients with distal tibia and/or ankle fractures without concomitant injuries were included. One reviewer conducted all searches, screened titles, and abstracts, assessed eligibility, and completed data extraction; a random 10% subset were independently assessed and extracted by a second reviewer at each stage. All extracted outcomes were mapped to a modified version of the International Classification of Functioning, Disability and Health framework. The quality of outcome reporting (reproducibility) was assessed. Results: 105 trials (n=16 to 669 participants) from 27 countries were included. Trials compared surgical interventions (62), post-surgical management options (17), rehabilitative interventions (14), surgical versus non-surgical interventions (6), and pre-surgical management strategies (5). In total, 888 outcome assessments were reported across seven domains: 263 assessed body structure or function (85.7% of trials), 136 activities (68.6% of trials), 34 participation (23.8% of trials), 159 health-related quality of life (61.9% of trials), 247 processes of care (80% of trials), 21 patient experiences (15.2% of trials), and 28 economic impact (8.6% of trials). From these, 337 discrete outcomes were described. Outcome reporting was inconsistent across trials. The quality of reporting varied widely (reproducibility ranged 4.8% patient experience to 100% complications). Conclusion: Substantial heterogeneity in outcome selection, assessment methods and reporting quality were described. Despite the large number of outcomes, few are reported across multiple trials. Most outcomes are clinically focused, with little attention to the long-term consequences important to patients. Poor reporting quality reduces confidence in data quality, inhibiting data synthesis by which to inform care decisions. Outcome reporting guidance and standardisation, that captures the outcomes that matter to multiple stakeholders, is urgently required

Understanding patient experience of distal tibia or ankle fracture : a qualitative systematic review

Aims To systematically review qualitative studies of patients with distal tibia or ankle fracture, and explore their experience of injury and recovery. Methods We undertook a systematic review of qualitative studies. Five databases were searched from inception to 1 February 2022. All titles and abstracts were screened, and a subset were independently assessed. Methodological quality was appraised using the Critical Appraisal Skills Programme (CASP) checklist. The GRADE-CERQual checklist was used to assign confidence ratings. Thematic synthesis was used to analyze data with the identification of codes which were drawn together to form subthemes and then themes. Results From 2,682 records, 15 studies were reviewed in full and four included in the review. A total of 72 patients were included across the four studies (47 female; mean age 50 years (17 to 80)). Methodological quality was high for all studies, and the GRADE-CERQual checklist provided confidence that the findings were an adequate representation of patient experience of distal tibia or ankle fracture. A central concept of ‘being the same but different’ conveyed the substantial disruption to patients’ self-identity caused by their injury. Patient experience of ‘being the same but different’ was expressed through three interrelated themes, with seven subthemes: i) being proactive where persistence, doing things differently and keeping busy prevailed; ii) living with change including symptoms, and living differently due to challenges at work and leisure; and iii) striving for normality, adapting while lacking in confidence, and feeling fearful and concerned about the future. Conclusion Ankle injuries were disruptive, draining, and impacted on patients’ wellbeing. Substantial short- and longer-term challenges were experienced during recovery. Rehabilitation and psychosocial treatment strategies may help to ameliorate these challenges. Patients may benefit from clinicians being cognisant of patient experience when assessing, treating, and discussing expectations and outcomes with patients

Detection of astrocytic tau pathology facilitates recognition of chronic traumatic encephalopathy neuropathologic change

Traumatic brain injury (TBI) is associated with the development of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy (CTE). Current consensus diagnostic criteria define the pathognomonic cortical lesion of CTE neuropathologic change (CTE-NC) as a patchy deposition of hyperphosphorylated tau in neurons, with or without glial tau in thorn-shaped astrocytes, typically towards the depths of sulci and clustered around small blood vessels. Nevertheless, although incorporated into consensus diagnostic criteria, the contribution of the individual cellular components to identification of CTE-NC has not been formally evaluated. To address this, from the Glasgow TBI Archive, cortical tissue blocks were selected from consecutive brain donations from contact sports athletes in which there was known to be either CTE-NC (n = 12) or Alzheimer’s disease neuropathologic change (n = 4). From these tissue blocks, adjacent tissue sections were stained for tau antibodies selected to reveal either solely neuronal pathology (3R tau; GT-38) or mixed neuronal and astroglial pathologies (4R tau; PHF-1). These stained sections were then randomised and independently assessed by a panel of expert neuropathologists, blind to patient clinical history and primary antibody applied to each section, who were asked to record whether CTE-NC was present. Results demonstrate that, in sections stained for either 4R tau or PHF-1, consensus recognition of CTE-NC was high. In contrast, recognition of CTE-NC in sections stained for 3R tau or GT-38 was poor; in the former no better than chance. Our observations demonstrate that the presence of both neuronal and astroglial tau pathologies facilitates detection of CTE-NC, with its detection less consistent when neuronal tau pathology alone is visible. The combination of both glial and neuronal pathologies, therefore, may be required for detection of CTE-NC