Effects of Training Intensity on Locomotor Performance in Individuals With Chronic Spinal Cord Injury: A Randomized Crossover Study

Background. Many physical interventions can improve locomotor function in individuals with motor incomplete spinal cord injury (iSCI), although the training parameters that maximize recovery are not clear. Previous studies in individuals with other neurologic injuries suggest the intensity of locomotor training (LT) may positively influence walking outcomes. However, the effects of intensity during training of individuals with iSCI have not been tested. Objective. The purpose of this pilot, blinded-assessor randomized trial was to evaluate the effects of LT intensity on walking outcomes in individuals with iSCI. Methods. Using a crossover design, ambulatory participants with iSCI \u3e1 year duration performed either high- or low-intensity LT for ≤20 sessions over 4 to 6 weeks. Four weeks following completion, the training interventions were alternated. Targeted intensities focused on achieving specific ranges of heart rate (HR) or ratings of perceived exertion (RPE), with intensity manipulated by increasing speeds or applying loads. Results. Significantly greater increases in peak treadmill speeds (0.18 vs 0.02 m/s) and secondary measures of metabolic function and overground speed were observed following high- versus low-intensity training, with no effects of intervention order. Moderate to high correlations were observed between differences in walking speed or distances and differences in HRs or RPEs during high- versus low-intensity training. Conclusion. This pilot study provides the first evidence that the intensity of stepping practice may be an important determinant of LT outcomes in individuals with iSCI. Whether such training is feasible in larger patient populations and contributes to improved locomotor outcomes deserves further consideration

High intensity variable stepping training in persons with motor incomplete spinal cord injury: a case series

Background and Purpose: Previous data suggest that large amounts of high intensity stepping training in variable contexts (tasks and environments) may improve locomotor function, aerobic capacity and treadmill gait kinematics in individuals post-stroke. Whether similar training strategies are tolerated and efficacious for patients with other acute-onset neurological diagnoses, such as motor incomplete spinal cord injury (iSCI) is unknown, particularly with potentially greater, bilateral impairments. This case series evaluated the feasibility and preliminary short and long-term efficacy of high intensity variable stepping practice in ambulatory participants >1 year post-iSCI. Case Series Description: Four participants with iSCI (neurological levels C5-T3) completed up to 40 1-hr sessions over 3–4 months. Stepping training in variable contexts was performed at up to 85% maximum predicted heart rate, with feasibility measures of patient tolerance, total steps/session, and intensity of training. Clinical measures of locomotor function, balance, peak metabolic capacity and gait kinematics during graded treadmill assessments were performed at baseline and post-training, with >1 year follow-up. Outcomes: Participants completed 24–40 sessions over 8–15 weeks, averaging 2222±653 steps/session, with primary adverse events of fatigue and muscle soreness. Modest improvements in locomotor capacity where observed at post-training, with variable changes in lower extremity kinematics during treadmill walking. Discussion: High intensity, variable stepping training was feasible and tolerated by participants with iSCI although only modest gains in gait function or quality were observed. The utility of this intervention in patients with more profound impairments may be limited

Cell-free DNA screening for rare autosomal trisomies and segmental chromosome imbalances

Funding Information: Ben W. Mol is supported by a NHMRC Investigator grant (GNT1176437). Ben W. Mol reports consultancy for ObsEva and Merck and travel support and research grants from Merck. The authors declare no conflict of interest. The authors wish to acknowledge the staff of Monash Ultrasound for Women, Sydney Ultrasound for Women, and Ultrasound Care for their diligent and compassionate care of the women involved in this study. Open access publishing facilitated by Monash University, as part of the Wiley - Monash University agreement via the Council of Australian University Librarians.Peer reviewedPublisher PD

The IKKâ related kinase TBK1 activates mTORC1 directly in response to growth factors and innate immune agonists

The innate immune kinase TBK1 initiates inflammatory responses to combat infectious pathogens by driving production of type I interferons. TBK1 also controls metabolic processes and promotes oncogeneâ induced cell proliferation and survival. Here, we demonstrate that TBK1 activates mTOR complex 1 (mTORC1) directly. In cultured cells, TBK1 associates with and activates mTORC1 through siteâ specific mTOR phosphorylation (on S2159) in response to certain growth factor receptors (i.e., EGFâ receptor but not insulin receptor) and pathogen recognition receptors (PRRs) (i.e., TLR3; TLR4), revealing a stimulusâ selective role for TBK1 in mTORC1 regulation. By studying cultured macrophages and those isolated from genome edited mTOR S2159A knockâ in mice, we show that mTOR S2159 phosphorylation promotes mTORC1 signaling, IRF3 nuclear translocation, and IFNâ β production. These data demonstrate a direct mechanistic link between TBK1 and mTORC1 function as well as physiologic significance of the TBK1â mTORC1 axis in control of innate immune function. These data unveil TBK1 as a direct mTORC1 activator and suggest unanticipated roles for mTORC1 downstream of TBK1 in control of innate immunity, tumorigenesis, and disorders linked to chronic inflammation.SynopsisTBK1, an IKKâ related kinase that drives interferon production as well cancer cell proliferation and survival, phosphorylates mTOR to activate mTORC1 in response to EGF and innate immune agonists, suggesting unanticipated roles for mTORC1 downstream of TBK1 in control of innate immunity and tumorigenesis.TBK1 interacts with mTORC1 and phosphorylates mTOR on S2159 to increase its catalytic activity.Cells lacking TBK1 or expressing a mTOR S2159A allele exhibit reduced mTORC1 signaling in response to EGFâ receptor and TLR3/4 activation.Primary macrophages derived from genome edited mTOR S2159A mice exhibit reduced mTORC1 signaling in response to TLR3/4 activation.Primary macrophages treated with rapamycin as well as those derived from mTORS2159A mice produce reduced levels of IFNâ β due to impaired nuclear translocation of the transcription factor IRF3.Innate immune kinase TBK1â dependent activation of mTORC1 occurs in response to pathogen recognition and EGF receptor activation and drives interferon production, thus highlighting the role of mTOR for innate immunity.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141029/1/embj201696164.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141029/2/embj201696164.reviewer_comments.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141029/3/embj201696164_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141029/4/embj201696164-sup-0001-EVFigs.pd

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Detection of Diffuse Sea Floor Venting Using Structured Light Imaging

Efficiently identifying and localizing diffuse sea floor venting at hydrothermal and cold seep sites is often difficult. Actively venting fluids are usually identified by a temperature induced optical shimmering seen during direct visual inspections or in video data collected by vehicles working close to the sea floor. Relying on such direct methods complicates establishing spatial relations between areas within a survey covering a broad area. Our recent work with a structured light laser system has shown that venting can also be detected in the image data in an automated fashion. A structured light laser system consists of a camera and sheet laser projected at the sea floor. The camera and laser are fixed to a rigid calibrated mount such that the optical axis of the camera and the laser plane intersect at some distance away from the camera, typically 2 to 5 meters. The position of the laser line, visible on the sea floor in the image, can be extracted using standard computer vision techniques (Fig. 1) and used to determine the height of the bottom along the laser line. By collecting images in a survey pattern at a high frame rate, typically 20 to 30 Hz, a bathymetric map can be produced using the individual profiles. In the presence of venting, temperature anomalies refract the laser sheet such that it does not project a crisp and clear line on the sea floor. The laser will instead appear blurred and visible over a larger section of the image. By processing the images to segment out clear laser lines from refracted lines it is possible to identify areas of venting. Our initial approach uses calculated image moments relative to the peak intensity level detected in each column of the image matrix. In the presence of venting the calculated moments differ from those of the undistorted laser shining on the sea floor. Test results from the Kolumbo submarine volcano near Santorini, Greece demonstrate this approach and show the utility of the method for survey work. Test images over active vents are compared to typical sea floor images, allowing for allowing areas of venting to be identified from sequences of images taken during a standard grid survey over the vent field. The use of structured light laser image offers potential for broad area vehicle surveys. The method would also complement direct visual surveys and other acoustic coherence methods that are used to identify the location of fluid flow. AGU session number OS11B-1473

The silence around schizophrenia

ABC broadcast. What’s the scariest word in the English language? Still highly stigmatised, schizophre the illness that we dare not speak about openly, and this silence may get in the way o recovery. We hear from an author who’s listening to family stories, and an anthropol whose research shows that focusing on the social and cultural aspects of schizophren could significantly improve rates of recovery