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Retrospective review.Intraoperative motor evoked potential (MEP) monitoring in spine surgery may assist surgeons in taking corrective measures to prevent neurologic deficits. The efficacy of monitoring MEPs intraoperatively in patients with myelopathy from

Background: Total joint replacement is an accepted, cost-effective, and underutilized treatment for moderate-to-severe hip and knee arthritis. Yet, research has suggested that many patients with arthritis are unwilling to consider total joint replacement surgery. We sought to understand these patients' unwillingness by exploring the nature of their decision-making processes.Methods: In-depth interviews were conducted with seventeen individuals with moderate-to-severe arthritis who were appropriate candidates for, but unwilling to consider, total joint replacement. The interviews were analyzed with use of qualitative methods and content analysis techniques.Results: Symptoms and information sources were the two main factors influencing patient decision-making. Participants engaged in individualized processes of trading off perceived costs and benefits. Accommodation to pain and disability and minimization of the quality-of-life benefit, in view of decreasing life span, led to a process whereby the threshold at which the benefits compared with the risks would tilt in favor of total joint replacement was constantly shifting, a phenomenon we called "the moving target."Conclusions and Clinical Relevance: The moving-target characterization sheds light on patients' conceptions of their arthritis and on their unwillingness to consider total joint replacement. This process needs to be considered when developing ways to aid decision-making. [ABSTRACT FROM AUTHOR]

Pathogens implicated in community-acquired respiratory tract infections are becoming increasingly resistant to anti-bacterial therapies. Thus, there is an urgent need for new agents with activity against current resistant respiratory tract pathogens and a low potential to select for resistance or induce cross-resistance to existing antibacterial agents. Telithromycin, the first ketolide antibacterial agent to undergo clinical development, has enhanced binding to bacterial ribosomal RNA. Through its unique structure, telithromycin retains activity against resistant respiratory pathogens and has shown high efficacy in the treatment of respiratory tract infections. On the basis of phase 3 clinical trial experience, telithromycin appears safe and well tolerated across various patient populations, including high-risk groups. [ABSTRACT FROM AUTHOR]

Objective: The Canadian Public Health Association, along with other professional organizations, has identified intimate partner violence (IPV) as a priority health issue to which the health professions must respond. This study synthesizes Canadian studies on the prevalence of IPV against women, focusing in particular on the stated implications for women's health and health care.Methods: Medical and social science databases were searched for all articles pertaining to IPV in Canada for 1974 through September 2000. Reference lists of these and other related publications were consulted to supplement the literature review. Data on study characteristics, methods, and results were extracted by two independent reviewers. Discrepancies were resolved by consensus.Results: Sixteen studies were identified in this review, 11 population-based and 5 conducted in clinical settings. Age, ethnicity, and socioeconomic status were not consistently documented, making comparisons and evaluations of generalizability difficult. Annual prevalence of IPV in Canada was found to range from 0.4% to 23%, with severe violence occurring from 2% to 10% annually. Less than two fifths (37.5%) of the studies incorporated a health-related measure.Interpretation: This review reveals a paucity of Canadian prevalence data on IPV, marked by design and methodological issues. Poor quality data may pose a challenge to articulating and establishing a coordinated health care response to eliminating IPV in Canada. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To explore the process by which elderly persons make decisions about a surgical treatment, total joint arthroplasty (TJA). METHODS: In-depth interviews with 17 elderly individuals identified as potential candidates for TJA who were unwilling to undergo the procedure. RESULTS: For the majority of participants, decision making involved ongoing deliberation of the surgical option, often resulting in a deferral of the treatment decision. Three assumptions may constrain elderly persons from making a decision about surgery. First, some participants viewed osteoarthritis not as a disease but as a normal part of aging. Second, despite being candidates for TJA according to medical criteria, many participants believed candidacy required a level of pain and disability higher than their current level. Third, some participants believed that if they either required or would benefit from TJA, their physicians would advise surgery. CONCLUSION: These assumptions may limit the possibility for shared decision making. CLINICAL IMPLICATIONS: Emphasis should be directed toward thinking about ways in which discussions about TJA might be initiated (and by whom) and considering how patients' views on and knowledge of osteoarthritis in general might be addressed. [ABSTRACT FROM AUTHOR]

The health and safety of women who work as exotic dancers are firmly embedded within the social organization of the strip club and the broader social, economic and political context of the work of exotic dancing. Exotic dancers in this study expressed health concerns associated with: the effects of costuming and appearance requirements; dirty work environments; problems due to stigmatization, sexual harassment and assault; and police disinterest or victim blaming. The balance between benefits and hazards related to exotic dancing is influenced not only by the personal choices made by dancers, but also by the organization of the strip club and the broader context within which exotic dancing takes place. [ABSTRACT FROM AUTHOR]

Changes in brain mitochondrial metabolism are coincident with functional decline; however, direct links between the two have not been established. Here, we show that mitochondrial targeting via the adiponectin receptor activator AdipoRon (AR) clears neurofibrillary tangles (NFTs) and rescues neuronal tauopathy-associated defects. AR reduced levels of phospho-tau and lowered NFT burden by a mechanism involving the energy-sensing kinase AMPK and the growth-sensing kinase GSK3b. The transcriptional response to AR included broad metabolic and functional pathways. Induction of lysosomal pathways involved activation of LC3 and p62, and restoration of neuronal outgrowth required the stress-responsive kinase JNK. Negative consequences of NFTs on mitochondrial activity, ATP production, and lipid stores were corrected. Defects in electrophysiological measures (e.g., resting potential, resistance, spiking profiles) were also corrected. These findings reveal a network linking mitochondrial function, cellular maintenance processes, and electrical aspects of neuronal function that can be targeted via adiponectin receptor activation., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Various studies have demonstrated gender disparities in workplace settings and the need for further intervention. This study identifies and examines evidence from randomized controlled trials (RCTs) on interventions examining gender equity in workplace or volunteer settings. An additional aim was to determine whether interventions considered intersection of gender and other variables, including PROGRESS-Plus equity variables (e.g., race/ethnicity)., Methods: Scoping review conducted using the JBI guide. Literature was searched in MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, ERIC, Index to Legal Periodicals and Books, PAIS Index, Policy Index File, and the Canadian Business & Current Affairs Database from inception to May 9, 2022, with an updated search on October 17, 2022. Results were reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension to scoping reviews (PRISMA-ScR), Sex and Gender Equity in Research (SAGER) guidance, Strengthening the Integration of Intersectionality Theory in Health Inequality Analysis (SIITHIA) checklist, and Guidance for Reporting Involvement of Patients and the Public (GRIPP) version 2 checklist. All employment or volunteer sectors settings were included. Included interventions were designed to promote workplace gender equity that targeted: (a) individuals, (b) organizations, or (c) systems. Any comparator was eligible. Outcomes measures included any gender equity related outcome, whether it was measuring intervention effectiveness (as defined by included studies) or implementation. Data analyses were descriptive in nature. As recommended in the JBI guide to scoping reviews, only high-level content analysis was conducted to categorize the interventions, which were reported using a previously published framework., Results: We screened 8855 citations, 803 grey literature sources, and 663 full-text articles, resulting in 24 unique RCTs and one companion report that met inclusion criteria. Most studies (91.7%) failed to report how they established sex or gender. Twenty-three of 24 (95.8%) studies reported at least one PROGRESS-Plus variable: typically sex or gender or occupation. Two RCTs (8.3%) identified a non-binary gender identity. None of the RCTs reported on relationships between gender and other characteristics (e.g., disability, age, etc.). We identified 24 gender equity promoting interventions in the workplace that were evaluated and categorized into one or more of the following themes: (i) quantifying gender impacts; (ii) behavioural or systemic changes; (iii) career flexibility; (iv) increased visibility, recognition, and representation; (v) creating opportunities for development, mentorship, and sponsorship; and (vi) financial support. Of these interventions, 20/24 (83.3%) had positive conclusion statements for their primary outcomes (e.g., improved academic productivity, increased self-esteem) across heterogeneous outcomes., Conclusions: There is a paucity of literature on interventions to promote workplace gender equity. While some interventions elicited positive conclusions across a variety of outcomes, standardized outcome measures considering specific contexts and cultures are required. Few PROGRESS-Plus items were reported. Non-binary gender identities and issues related to intersectionality were not adequately considered. Future research should provide consistent and contemporary definitions of gender and sex., Trial Registration: Open Science Framework https://osf.io/x8yae ., (© 2024. The Author(s).)

Objective: The objectives of this study were to describe the authors' clinical methodology and outcomes for mapping the laryngeal motor cortex (LMC) and define localization of the LMC in a cohort of neurosurgical patients undergoing intraoperative brain mapping. Because of mapping variability across patients, the authors aimed to define the probabilistic distribution of cortical sites that evoke laryngeal movement, as well as adjacent cortical somatotopic representations for the face (mouth), tongue, and hand., Methods: Thirty-six patients underwent left (n = 18) or right (n = 18) craniotomy with asleep motor mapping. For each patient, electromyography (EMG) electrodes were placed in the face, tongue, and hand; a nerve integrity monitor (NIM) endotracheal tube with surface electrodes detected EMG activity from the bilateral vocal folds. After dense cortical stimulation was delivered throughout the sensorimotor cortex, motor responses were then mapped onto a three-dimensional reconstruction of the patient's cortical surfaces for location characterization of the evoked responses. Finally, stimulation sites were transformed into a two-dimensional coordinate system for probabilistic mapping of the stimulation site relative to the central sulcus and sylvian fissure., Results: The authors found that the LMC was predominantly localized to a mid precentral gyrus region, dorsal to face representation and surrounding a transverse sulcus ventral to the hand knob. In 14 of 36 patients, the authors identified additional laryngeal responses located ventral to all orofacial representations, providing evidence for dual LMC representations., Conclusions: The authors determined the probabilistic distribution of the LMC. Cortical stimulation mapping with an NIM endotracheal tube is an easy and effective method for mapping the LMC and is simply integrated into the current neuromonitoring methods for brain mapping.

Objective: Maximal safe resection of gliomas near motor pathways is facilitated by intraoperative mapping. Here, the authors review their results with triple-modality asleep motor mapping with motor evoked potentials and bipolar and monopolar stimulation for cortical and subcortical mapping during glioma surgery in an expanded cohort., Methods: This was a retrospective analysis of patients who underwent resection of a perirolandic glioma near motor pathways. Clinical and neuromonitoring data were extracted from the electronic medical records for review. All patients with new or worsened postoperative motor deficits were followed for at least 6 months. Regression analyses were performed to assess factors associated with a persistent motor deficit., Results: Between January 2018 and December 2021, 160 operations were performed in 151 patients with perirolandic glioma. Sixty-four patients (40%) had preoperative motor deficits, and the median extent of resection was 98%. Overall, patients in 38 cases (23.8%) had new or worse immediate postoperative deficits by discharge, and persistent deficits by 6 months were seen in 6 cases (3.8%), all in patients with high-grade gliomas. There were no new persistent deficits in low-grade glioma patients (0%). The risk factors for a persistent deficit included an insular tumor component (OR 8.6, p = 0.01), preoperative motor weakness (OR 8.1, p = 0.03), intraoperative motor evoked potential (MEP) changes (OR 36.5, p < 0.0001), and peri-resection cavity ischemia (OR 7.5, p = 0.04). Most persistent deficits were attributable to ischemic injury despite structural preservation of the descending motor tracts. For patients with persistent motor deficits, there were 3 cases (50%) in which a change in MEP was noted but subsequent subcortical monopolar stimulation still elicited a response in the corresponding muscle groups, suggesting axonal activation distal to a point of injury., Conclusions: Asleep triple motor mapping results in a low rate of permanent deficits, especially for low-grade gliomas. Peri-resection cavity ischemia continues to be a significant risk factor for permanent deficit despite maintaining appropriate distance for subcortical tracts based on monopolar feedback.

Haptic cues delivered via wearable devices have great potential to enhance a user's experience by transmitting task information and touch sensations in domains such as virtual reality, teleoperation, and prosthetics. Much is still unknown on how haptic perception, and consequently optimal haptic cue design, varies between individuals. In this work we present three contributions. First, we propose a new metric, the Allowable Stimulus Range (ASR), as a way to capture subject-specific magnitudes for a given cue, using the method of adjustments and the staircase method. Second, we present a modular, grounded, 2-DOF, haptic testbed designed to conduct psychophysical experiments in multiple control schemes and with rapidly-interchangeable haptic interfaces. Third, we demonstrate an application of the testbed and our ASR metric, together with just noticeable differences (JND) measurements, to compare perception of haptic cues delivered via position or force control schemes. Our findings show that users demonstrate higher perceptual resolution in the position-control case, though survey results suggest that force-controlled haptic cues are more comfortable. The results of this work outline a framework to define perceptible and comfortable cue magnitudes for an individual, providing the groundwork to understand haptic variability, and compare the effectiveness of different types of haptic cues.

Lower-body robotic exoskeletons can be used to reduce the energy demand of locomotion and increase the endurance of wearers. Understanding how motor fatigue affects walking performance may lead to better exoskeleton designs to support the changing physical capacity of an individual due to motor fatigue. The purpose of this study was to investigate the effects of motor fatigue on walking mechanics and energetics. Treadmill walking with progressively increased incline gradient was used to induce motor fatigue. Twenty healthy young participants walked on an instrumented treadmill at 1.25 m/s and 0° of incline for 5 min before (PRE) and after (POST) motor fatigue. We examined lower-limb joint mechanics, metabolic cost, and the efficiency of positive mechanical work (η + work ). Compared to PRE, participants had increased net metabolic power by ∼14% (p < 0.001) during POST. Participants also had increased total-limb positive mechanical power (Total P + mech ) by ∼4% during POST (p < 0.001), resulting in a reduced η + work by ∼8% (p < 0.001). In addition, the positive mechanical work contribution of the lower-limb joints during POST was shifted from the ankle to the knee while the negative mechanical work contribution was shifted from the knee to the ankle (all p < 0.017). Although greater knee positive mechanical power was generated to compensate for the reduction in ankle positive power after motor fatigue, the disproportionate increase in metabolic cost resulted in a reduced walking efficiency. The findings of this study suggest that powering the ankle joint may help delay the onset of the lower-limb joint work redistribution observed during motor fatigue., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: To chart the global literature on gender equity in academic health research., Design: Scoping review., Participants: Quantitative studies were eligible if they examined gender equity within academic institutions including health researchers., Primary and Secondary Outcome Measures: Outcomes related to equity across gender and other social identities in academia: (1) faculty workforce: representation of all genders in university/faculty departments, academic rank or position and salary; (2) service: teaching obligations and administrative/non-teaching activities; (3) recruitment and hiring data: number of applicants by gender, interviews and new hires for various rank; (4) promotion: opportunities for promotion and time to progress through academic ranks; (5) academic leadership: type of leadership positions, opportunities for leadership promotion or training, opportunities to supervise/mentor and support for leadership bids; (6) scholarly output or productivity: number/type of publications and presentations, position of authorship, number/value of grants or awards and intellectual property ownership; (7) contextual factors of universities; (8) infrastructure; (9) knowledge and technology translation activities; (10) availability of maternity/paternity/parental/family leave; (11) collaboration activities/opportunities for collaboration; (12) qualitative considerations: perceptions around promotion, finances and support., Results: Literature search yielded 94 798 citations; 4753 full-text articles were screened, and 562 studies were included. Most studies originated from North America (462/562, 82.2%). Few studies (27/562, 4.8%) reported race and fewer reported sex/gender (which were used interchangeably in most studies) other than male/female (11/562, 2.0%). Only one study provided data on religion. No other PROGRESS-PLUS variables were reported. A total of 2996 outcomes were reported, with most studies examining academic output (371/562, 66.0%)., Conclusions: Reviewed literature suggest a lack in analytic approaches that consider genders beyond the binary categories of man and woman, additional social identities (race, religion, social capital and disability) and an intersectionality lens examining the interconnection of multiple social identities in understanding discrimination and disadvantage. All of these are necessary to tailor strategies that promote gender equity., Trial Registration Number: Open Science Framework: https://osf.io/8wk7e/., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We report the first inorganic/organic hybrids that show outstanding mechanical properties (withstanding cyclic loading) and bone bioactivity. This new hybrid material may fulfil the unmet clinical need for bioactive synthetic bone grafts that can withstand cyclic loading. A SiO 2 /PTHF/PCL-diCOOH sol-gel hybrid system, that combined inorganic and organic conetworks at the molecular level, previously demonstrated unprecedented synergy of properties, with excellent flexibility and promoted formation of articular cartilage matrix in vitro . Here, for the first time, calcium and phosphate ions were incorporated into the inorganic component of the hybrid network, to impart osteogenic properties. Calcium methoxyethoxide and triethyl phosphate were the calcium and phosphate precursors because they allow for incorporation into the silicate network at low temperature. The hybrid network was characterised with ATR-FTIR, XRD and solid-state Nuclear Magnetic Resonance, which proved calcium and phosphate incorporation and suggested the Ca 2+ ions also interacted with PCL-diCOOH through ionic bonds. This resulted in an increased strength (17-64 MPa) and modulus of toughness (2.5-14 MPa) compared to the original SiO 2 /PTHF/PCL-diCOOH hybrid material (which showed strength of ~3 MPa and modulus of toughness of ~0.35 MPa), while also maintaining the ability to withstand cyclic loading. The presence of calcium and phosphates in the silicate network resulted in a more congruent dissolution of the inorganic and organic co-networks in TRIS buffer. This was shown by the presence of silicon, calcium and phosphate ions along with PCL in the TRIS buffer after 1 week, whereas Ca-free hybrids mainly released PCL with negligible Si dissolution. The presence of calcium and phosphates also enabled deposition of hydroxycarbonate apatite following immersion in simulated body fluid, which was not seen on Ca-free hybrid. All hybrids passed cell cytotoxicity tests and supported preosteoblast cell attachment. The phosphate-free hybrid showed the best mechanical behaviour and supported better cell attachment, spreading and potentially differentiation of cells. Therefore, the SiO 2 -CaO/PTHF/PCL-diCOOH hybrid represents a promising biomaterial for use in bone regeneration., Competing Interests: Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Study Design: Case report., Objective: The aim of this study was to present how computed tomographic angiography (CTA) and intraoperative neurophysiologic monitoring (IONM) detect spinal cord ischemia during anterior spine surgery. These data directed expedient surgical and anesthetic interventions that restored IONM signals and prevented neurologic sequalæ., Summary of Background Data: Anterior vertebral tethering (AVT) is a fusionless surgical treatment of adolescent idiopathic scoliosis (AIS)., Methods: AVT was performed on a skeletally immature patient with AIS. Preoperative CTA detailed location of the dominant radicular artery (DRA). Transcranial motor (tcMEP) and somatosensory (SEP) evoked potentials were monitored during operation., Results: There was significant decline in tcMEP, but not SEP, after compression of the DRA during cable tensioning of AVT. There was complete tcMEP recovery following release of instrumentation., Conclusion: This article identifies a rare but potentially catastrophic vascular hazard associated with anterior spine operation, including AVT. Sacrifice of multiple unilateral segmental vessels may overwhelm the capacity of collateral spinal cord perfusion to compensate for DRA blood supply. This vascular risk may be eliminated by identifying the DRA in order that it may be preserved during the procedure., Level of Evidence: 5.

Objective: The objective of this review is to describe the global evidence of gender inequity among individuals with appointments at academic institutions that conduct health research, and examine how gender intersects with other social identities to influence outcomes., Introduction: The gender demographics of universities have shifted, yet the characteristics of those who lead academic health research institutions have not reflected this change. Synthesized evidence will guide decision-making and policy development to support the progress of gender and other under-represented social identities in academia., Inclusion Criteria: This review will consider any quantitative, qualitative, or mixed methods primary research that reports outcome data related to gender equity and other social identities among individuals affiliated with academic or research institutions that conduct health research, originating from any country., Methods: The JBI Manual for Evidence Synthesis and the Cochrane Collaboration's guidance on living reviews will inform the review methods. Information sources will include electronic databases, unpublished literature sources, reference scanning of relevant systematic reviews, and sources provided by experts on the research team. Searches will be run regularly to monitor the development of new literature and determine when the review will be updated. Study selection and data extraction will be conducted by two reviewers working independently, and all discrepancies will be resolved by discussion or a third reviewer. Data synthesis will summarize information using descriptive frequencies and simple thematic analysis. Results will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension to scoping reviews., Registration: Open Science Framework: https://osf.io/8wk7e/.

Caloric restriction (CR) improves survival in nonhuman primates and delays the onset of age-related morbidities including sarcopenia, which is characterized by the age-related loss of muscle mass and function. A shift in metabolism anticipates the onset of muscle-aging phenotypes in nonhuman primates, suggesting a potential role for metabolism in the protective effects of CR. Here, we show that CR induced profound changes in muscle composition and the cellular metabolic environment. Bioinformatic analysis linked these adaptations to proteostasis, RNA processing, and lipid synthetic pathways. At the tissue level, CR maintained contractile content and attenuated age-related metabolic shifts among individual fiber types with higher mitochondrial activity, altered redox metabolism, and smaller lipid droplet size. Biometric and metabolic rate data confirm preserved metabolic efficiency in CR animals that correlated with the attenuation of age-related muscle mass and physical activity. These data suggest that CR-induced reprogramming of metabolism plays a role in delayed aging of skeletal muscle in rhesus monkeys., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

An electrospinning technique was used to produce three-dimensional (3D) bioactive glass fibrous scaffolds, in the SiO 2 -CaO sol-gel system, for wound healing applications. Previously, it was thought that 3D cotton wool-like structures could only be produced from sol-gel when the sol contained calcium nitrate, implying that the Ca 2+ and its electronic charge had a significant effect on the structure produced. Here, fibres with a 3D appearance were also electrospun from compositions containing only silica. A polymer binding agent was added to inorganic sol-gel solutions, enabling electrospinning prior to bioactive glass network formation and the polymer was removed by calcination. While the addition of Ca 2+ contributes to the 3D morphology, here we show that other factors, such as relative humidity, play an important role in producing the 3D cotton-wool-like macrostructure of the fibres. A human dermal fibroblast cell line (CD-18CO) was exposed to dissolution products of the samples. Cell proliferation and metabolic activity tests were carried out and a VEGF ELISA showed a significant increase in VEGF production in cells exposed to the bioactive glass samples compared to control in DMEM. A novel SiO 2 -CaO nanofibrous scaffold was created that showed tailorable physical and dissolution properties, the control and composition of these release products are important for directing desirable wound healing interactions.

Restoring hand function in individuals with upper limb loss is a challenging task, made difficult by the complexity of human hands from both a functional and sensory point of view. Users of commercial prostheses, even sophisticated devices, must visually attend to the hand to know its state, since in most cases they are not provided with any direct sensory information. Among the different types of haptic feedback that can be delivered, particularly information on hand opening is likely to reduce the requirement of constant visual attention. In recent years, there has been a trend of using underactuated, compliant multi-fingered hands as upper limb prostheses, in part due to their simplicity and ease of use attributed to low degree-of-freedom (d.o.f.) actuation. The trend toward underactuation encourages the design of one d.o.f. haptic devices to provide intuitive sensory feedback from the prosthesis. However, mapping the closure of a multi-d.o.f. prosthetic hand to a simple and intuitive haptic cue is not a trivial task. In this paper, we explore the use of a one d.o.f. skin stretch haptic device, the rice haptic rocker, to provide intuitive proprioceptive feedback indicating overall hand closure of an underactuated prosthesis. The benefits and challenges of the system are assessed in multi-tasking and reduced vision scenarios for an object-size discrimination task, in an effort to simulate challenges in daily life, and are compared against the haptic resolution of the device using the just noticeable difference. Finally, an evaluation done with a prosthesis user, in the form of a truncated version of the Activities Measure for Upper Limb Amputees (AM-ULA), shows possible benefits of the addition of haptic feedback in tasks with reduced visual attention.

Deleterious changes in energy metabolism have been linked to aging and disease vulnerability, while activation of mitochondrial pathways has been linked to delayed aging by caloric restriction (CR). The basis for these associations is poorly understood, and the scope of impact of mitochondrial activation on cellular function has yet to be defined. Here, we show that mitochondrial regulator PGC-1a is induced by CR in multiple tissues, and at the cellular level, CR-like activation of PGC-1a impacts a network that integrates mitochondrial status with metabolism and growth parameters. Transcriptional profiling reveals that diverse functions, including immune pathways, growth, structure, and macromolecule homeostasis, are responsive to PGC-1a. Mechanistically, these changes in gene expression were linked to chromatin remodeling and RNA processing. Metabolic changes implicated in the transcriptional data were confirmed functionally including shifts in NAD metabolism, lipid metabolism, and membrane lipid composition. Delayed cellular proliferation, altered cytoskeleton, and attenuated growth signaling through post-transcriptional and post-translational mechanisms were also identified as outcomes of PGC-1a-directed mitochondrial activation. Furthermore, in vivo in tissues from a genetically heterogeneous mouse population, endogenous PGC-1a expression was correlated with this same metabolism and growth network. These data show that small changes in metabolism have broad consequences that arguably would profoundly alter cell function. We suggest that this PGC-1a sensitive network may be the basis for the association between mitochondrial function and aging where small deficiencies precipitate loss of function across a spectrum of cellular activities., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Introduction: When developing control strategies for robotic rehabilitation, it is important that end-users who train with those strategies retain what they learn. Within the current state-of-the-art, however, it remains unclear what types of robotic controllers are best suited for promoting retention. In this work, we experimentally compare short-term retention in able-bodied end-users after training with two common types of robotic control strategies: fixed- and variable-gain controllers., Methods: Our approach is based on recent motor learning research, where reward signals are employed to reinforce the learning process. We extend this approach to now include robotic controllers, so that participants are trained with a robotic control strategy and auditory reward-based reinforcement on tasks of different difficulty. We then explore retention after the robotic feedback is removed., Results: Overall, our results indicate that fixed-gain control strategies better stabilize able-bodied users' motor adaptation than either a no controller baseline or variable-gain strategy. When breaking these results down by task difficulty, we find that assistive and resistive fixed-gain controllers lead to better short-term retention on less challenging tasks but have opposite effects on the learning and forgetting rates., Conclusions: This suggests that we can improve short-term retention after robotic training with consistent controllers that match the task difficulty.

Falsified and substandard medicines are associated with tens of thousands of deaths, mainly in young children in poor countries. Poor-quality drugs exact an annual economic toll of up to US$200 billion and contribute to the increasing peril of antimicrobial resistance. The WHO has emerged recently as the global leader in the battle against poor-quality drugs, and pharmaceutical companies have increased their roles in assuring the integrity of drug supply chains. Despite advances in drug quality surveillance and detection technology, more efforts are urgently required in research, policy, and field monitoring to halt the pandemic of bad drugs. In addition to strengthening international and national pharmaceutical governance, in part by national implementation of the Model Law on Medicines and Crime, a quantifiable Sustainable Development Goal target and an international convention to insure drug quality and safety are urgent priorities.

Amino acid δ 15 N values of foliage of various plant taxa, grown at the experimental farm stations of North Wyke, UK and Bad Lauchstädt, Germany were determined by GC-C-IRMS. The difference between δ 15 N values of glutamate (Glx) and phenylalanine (Phe) were found to differ significantly between woody and herbaceous plants, with mean Δ 15 N Glx-Phe (i.e. δ 15 N Phe - δ 15 N Glx ) values of -9.3 ± 1.6‰ and -5.8 ± 2.1‰, respectively. These differences in values are hypothesised to be due to the involvement of Phe in the phenylpropanoid pathway, by which lignin and other phenolic secondary metabolites are produced, leading to isotopic fractionation and enrichment of the remaining Phe pool available for protein biosynthesis. This results in the more negative Δ 15 N Glx-Phe values observed in woody plants relative to herbaceous plants, as the former are assumed to produce more lignin. To test this assumption, plant leaf tissue lignin concentrations were estimated by solid state 13 C cross-polarisation, magic-angle-spinning (CPMAS) NMR spectroscopy for a subset of plants, which showed that tree foliage has a higher concentration of lignin (12.6 wt%) than herbaceous foliage (6.3 wt%). The correlation of lignin concentration with Δ 15 N Glx-Phe values demonstrates that the difference in these values with plant type is indeed due to differential production of lignin. The ability to estimate the lignin content of plants from amino acid δ 15 N values will, to give one example, allow refinement of estimates of herbivore diet in present and past ecosystems, enabling more accurate environmental niche modelling., (Copyright © 2019. Published by Elsevier Ltd.)

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a) is a central regulator of metabolism that is poised at the intersection of myriad intracellular signaling pathways. In this brief update, we discuss regulation of PGC-1a at multiple levels, including transcriptional, post-transcriptional, and post-translational modifications. We discuss recently identified small molecule effectors of PGC-1a that offer translational potential and promise new insight into PGC-1a biology. We highlight novel mechanistic insights relating to PGC-1a's interactions with RNA to enhance transcription and potentially influence transcript processing. Finally, we place these exciting new data in the context of aging biology, offering PGC-1a as a candidate target with terrific potential in anti-aging interventions., Competing Interests: Conflict of interest statement Nothing declared.

GSK3β is a serine threonine kinase implicated in the progression of Alzheimer's disease. Although the role of GSK3β in growth and pathology has been extensively studied, little is known about the metabolic consequences of GSK3β manipulation, particularly in the brain. Here, we show that GSK3β regulates mitochondrial energy metabolism in human H4 neuroglioma cells and rat PC12-derived neuronal cells and that inhibition of GSK3β in mice in vivo alters metabolism in the hippocampus in a region-specific manner. We demonstrate that GSK3β inhibition increases mitochondrial respiration and membrane potential and alters NAD(P)H metabolism. These metabolic effects are associated with increased PGC-1α protein stabilization, enhanced nuclear localization, and increased transcriptional co-activation. In mice treated with the GSK3β inhibitor lithium carbonate, changes in hippocampal energy metabolism are linked to increased PGC-1α. These data highlight a metabolic role for brain GSK3β and suggest that the GSK3β/PGC-1α axis may be important in neuronal metabolic integrity., (Published by Elsevier Inc.)

Caloric restriction (CR) extends lifespan and delays the onset of age-related disorders in diverse species. Metabolic regulatory pathways have been implicated in the mechanisms of CR, but the molecular details have not been elucidated. Here, we show that CR engages RNA processing of genes associated with a highly integrated reprogramming of hepatic metabolism. We conducted molecular profiling of liver biopsies collected from adult male rhesus monkeys (Macaca mulatta) at baseline and after 2 years on control or CR (30% restricted) diet. Quantitation of over 20,000 molecules from the hepatic transcriptome, proteome, and metabolome indicated that metabolism and RNA processing are major features of the response to CR. Predictive models identified lipid, branched-chain amino acid, and short-chain carbon metabolic pathways, with alternate transcript use for over half of the genes in the CR network. We conclude that RNA-based mechanisms are central to the CR response and integral in metabolic reprogramming., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Caloric restriction (CR) is one of the most robust interventions shown to delay aging in diverse species, including rhesus monkeys (Macaca mulatta). Identification of factors involved in CR brings a promise of translatability to human health and aging. Here, we show that CR induced a profound change in abundance of circulating microRNAs (miRNAs) linked to growth and insulin signaling pathway, suggesting that miRNAs are involved in CR's mechanisms of action in primates. Deep sequencing of plasma RNA extracts enriched for short species revealed a total of 243 unique species of miRNAs including 47 novel species. Approximately 70% of the plasma miRNAs detected were conserved between rhesus monkeys and humans. CR induced or repressed 24 known and 10 novel miRNA species. Regression analysis revealed correlations between bodyweight, adiposity, and insulin sensitivity for 10 of the CR-regulated known miRNAs. Sequence alignment and target identification for these 10 miRNAs identify a role in signaling downstream of the insulin receptor. The highly abundant miR-125a-5p correlated positively with adiposity and negatively with insulin sensitivity and was negatively regulated by CR. Putative target pathways of CR-associated miRNAs were highly enriched for growth and insulin signaling that have previously been implicated in delayed aging. Clustering analysis further pointed to CR-induced miRNA regulation of ribosomal, mitochondrial, and spliceosomal pathways. These data are consistent with a model where CR recruits miRNA-based homeostatic mechanisms to coordinate a program of delayed aging., (© 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

To test the directness of factors in initiating PIWI-directed gene silencing, we employed a Piwi-interacting RNA (piRNA)-targeted reporter assay in Drosophila ovary somatic sheet (OSS) cells [1]. This assay confirmed direct silencing roles for piRNA biogenesis factors and PIWI-associated factors [2-12] but suggested that chromatin-modifying proteins may act downstream of the initial silencing event. Our data also revealed that RNA-polymerase-II-associated proteins like PAF1 and RTF1 antagonize PIWI-directed silencing. PAF1 knockdown enhances PIWI silencing of reporters when piRNAs target the transcript region proximal to the promoter. Loss of PAF1 suppresses endogenous transposable element (TE) transcript maturation, whereas a subset of gene transcripts and long-non-coding RNAs adjacent to TE insertions are affected by PAF1 knockdown in a similar fashion to piRNA-targeted reporters. Additionally, transcription activation at specific TEs and TE-adjacent loci during PIWI knockdown is suppressed when PIWI and PAF1 levels are both reduced. Our study suggests a mechanistic conservation between fission yeast PAF1 repressing AGO1/small interfering RNA (siRNA)-directed silencing [13, 14] and Drosophila PAF1 opposing PIWI/piRNA-directed silencing., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Adipose tissue expansion has been associated with system-wide metabolic dysfunction and increased vulnerability to diabetes, cancer, and cardiovascular disease. A reduction in adiposity is a hallmark of caloric restriction (CR), an intervention that extends longevity and delays the onset of these same age-related conditions. Despite these parallels, the role of adipose tissue in coordinating the metabolism of aging is poorly defined. Here, we show that adipose tissue metabolism and secretory profiles change with age and are responsive to CR. We conducted a cross-sectional study of CR in adult, late-middle-aged, and advanced-aged mice. Adiposity and the relationship between adiposity and circulating levels of the adipose-derived peptide hormone adiponectin were age-sensitive. CR impacted adiposity but only levels of the high molecular weight isoform of adiponectin responded to CR. Activators of metabolism including PGC-1a, SIRT1, and NAMPT were differentially expressed with CR in adipose tissues. Although age had a significant impact on NAD metabolism, as detected by biochemical assay and multiphoton imaging, the impact of CR was subtle and related to differences in reliance on oxidative metabolism. The impact of age on circulating lipids was limited to composition of circulating phospholipids. In contrast, the impact of CR was detected in all lipid classes regardless of age, suggesting a profound difference in lipid metabolism. These data demonstrate that aspects of adipose tissue metabolism are life phase specific and that CR is associated with a distinct metabolic state, suggesting that adipose tissue signaling presents a suitable target for interventions to delay aging., (© 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Study Design: Retrospective review., Objective: Intraoperative motor evoked potential (MEP) monitoring in spine surgery may assist surgeons in taking corrective measures to prevent neurologic deficits. The efficacy of monitoring MEPs intraoperatively in patients with myelopathy from nondegenerative causes has not been quantified. We compared the sensitivity and specificity of intraoperative MEP monitoring in patients with myelopathy caused by nondegenerative processes to patients with degenerative cervicothoracic spondylotic myelopathy (CSM)., Methods: We retrospectively reviewed our myelopathy surgical cases during a 1-year period to identify patients with degenerative CSM and CSM of nondegenerative causes and collected data on intraoperative MEP changes and postoperative new deficits. Categorical variables were analyzed by Fisher exact test. Receiver operator curves assessed intraoperative MEP monitoring performance in the two groups., Results: In all, 144 patients were identified: 102 had degenerative CSM and 42 had CSM of nondegenerative causes (24 extra-axial tumors, 12 infectious processes, 5 traumatic fractures, and 1 rheumatoid arthritis). For degenerative CSM, there were 11 intraoperative MEP alerts and 7 new deficits (p < 0.001). The corresponding sensitivity was 71% and the specificity was 94%. In the nondegenerative group, there were 11 intraoperative MEP alerts and 3 deficits, which was not significant (p > 0.99). The sensitivity (33%) and specificity (74%) were lower. Among patients with degenerative CSM, the model performed well for predicting postoperative deficits (area under the curve [AUC] 0.826), which appeared better than the nondegenerative group, although it did not reach statistical significance (AUC 0.538, p = 0.16)., Conclusions: Based on this large retrospective analysis, intraoperative MEP monitoring in surgery for nondegenerative CSM cases appears to be less sensitive to cord injury and less predictive of postoperative deficits when compared with degenerative CSM cases.

The state of protein folding in the endoplasmic reticulum (ER), via the unfolded protein response (UPR), regulates a pro- or anti-apoptotic cell fate. Hypoxic preconditioning (HPC) is a potent anti-apoptotic stimulus, wherein ischemic neural injury is averted by a non-damaging exposure to hypoxia. We tested if UPR modulation contributes to the pro-survival/anti-apoptotic phenotype in neurons preconditioned with hypoxia, using organotypic cultures of rat hippocampus as a model system. Pharmacologic induction of the UPR with tunicamycin increased mRNA of 79 of 84 UPR genes and replicated the pro-survival phenotype of HPC, whereas only small numbers of the same mRNAs were upregulated at 0, 6 and 24h after HPC. During the first 24h after HPC, protein signals in all 3 UPR pathways increased at various times: increased ATF4, phosphorylation of eif2α and IRE1, cleavage of xbb1 mRNA and cleavage of ATF6. Pharmacologic inhibition of ATF6 and IRE1 blocked HPC. Ischemia-like conditions (oxygen/glucose deprivation, OGD) caused extensive neuron cell damage and involved some of the same UPR protein signals as HPC. In distinction to HPC and tunicamycin, OGD caused widespread suppression of UPR genes: 55 of 84 UPR gene mRNAs were numerically downregulated. We conclude that although HPC and ischemic cell death in hippocampal neurons involve protein-based signaling in all 3 UPR pathways, these processes co-opt only a subset of the genomic response elicited by agents known to cause protein misfolding, possibly because of persistent transcription/translation arrest induced by hypoxia and especially OGD., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Over the past decade, the number of countries reporting falsified (fake, spurious/falsely labeled/counterfeit) medicines and the types and quantities of fraudulent drugs being distributed have increased greatly. The obstacles in combatting falsified pharmaceuticals include 1) lack of consensus on definitions, 2) paucity of reliable and scalable technology to detect fakes before they reach patients, 3) poor global and national leadership and accountability systems for combating this scourge, and 4) deficient manufacturing and regulatory challenges, especially in China and India where fake products often originate. The major needs to improve the quality of the world's medicines fall into three main areas: 1) research to develop and compare accurate and affordable tools to identify high-quality drugs at all levels of distribution; 2) an international convention and national legislation to facilitate production and utilization of high-quality drugs and protect all countries from the criminal and the negligent who make, distribute, and sell life-threatening products; and 3) a highly qualified, well-supported international science and public health organization that will establish standards, drug-quality surveillance, and training programs like the U.S. Food and Drug Administration. Such leadership would give authoritative guidance for countries in cooperation with national medical regulatory agencies, pharmaceutical companies, and international agencies, all of which have an urgent interest and investment in ensuring that patients throughout the world have access to good quality medicines. The organization would also advocate strongly for including targets for achieving good quality medicines in the United Nations Millennium Development Goals and Sustainable Development Goals., (© The American Society of Tropical Medicine and Hygiene.)

Leukemias with MLL translocations are often found in infants and are associated with poor outcomes. The pathogenesis of MLL-fusion leukemias has been linked to upregulation of HOX/MEIS1 genes. The functions of the Hox/Meis1 complex in leukemia, however, remain elusive. Here, we used inducible Meis1-knockout mice coupled with MLL-AF9 knockin mice to decipher the mechanistic role of Meis1 in established MLL leukemia. We demonstrate that Meis1 is essential for maintenance of established leukemia. In addition, in both the murine model and human leukemia cells, we found that Meis1 loss led to increased oxidative stress, oxygen flux, and apoptosis. Gene expression and chromatin immunoprecipitation studies revealed hepatic leukemia factor (HLF) as a target gene of Meis1. Hypoxia or HLF expression reversed the oxidative stress, rescuing leukemia development in Meis1-deficient cells. Thus, the leukemia-promoting properties of Meis1 are at least partly mediated by a low-oxidative state, aided by HLF. These results suggest that stimulants of oxidative metabolism could have therapeutic potential in leukemia treatment., (© 2015 by The American Society of Hematology.)

Although Piwi proteins and Piwi-interacting RNAs (piRNAs) genetically repress transposable elements (TEs), it is unclear how the highly diverse piRNA populations direct Piwi proteins to silence TE targets without silencing the entire transcriptome. To determine the capacity of piRNA-mediated silencing, we introduced reporter genes into Drosophila OSS cells, which express microRNAs (miRNAs) and piRNAs, and compared the Piwi pathway to the Argonaute pathway in gene regulation. Reporter constructs containing several target sites that were robustly silenced by miRNAs were not silenced to the same degrees by piRNAs. However, another set of reporters we designed to enable a large number of both TE-directed and genic piRNAs to bind were robustly silenced by the PIWI/piRNA complex in OSS cells. These reporters show that a bulk of piRNAs are required to pair to the reporter's transcripts and not the reporter's DNA sequence to engage PIWI-mediated silencing. Following our genome-wide study of PIWI-regulated targets in OSS cells, we assessed candidate gene elements with our reporter platform. These results suggest TE sequences are the most direct of PIWI regulatory targets while coding genes are less directly affected by PIWI targeting. Finally, our study suggests that the PIWI transcriptional silencing mechanism triggers robust chromatin changes on targets with sufficient piRNA binding, and preferentially regulates TE transcripts because protein-coding transcripts lack a threshold of targeting by piRNA populations. This reporter platform will facilitate future dissections of the PIWI-targeting mechanism., (© 2014 Post et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)