Publications by authors named "Martin James"

903 Publications

Targeting Oxidative Stress with Amobarbital to Prevent Intervertebral Disc Degeneration.

Spine J 2021 Feb 18. Epub 2021 Feb 18.

Roy J. Carver Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA.

Background: Mounting evidence that oxidative stress contributes to the pathogenesis of intervertebral disc (IVD) degeneration (IDD) suggests that therapies targeting oxidative stress may slow or prevent disease progression.

Purpose: The objective of this study was to investigate the inhibitory effects of amobarbital (Amo) on the mitochondria of nucleus pulposus (NP) cells under tert-butyl hydrogen peroxide (tBHP)-induced oxidative stress or in NP tissues under oxidative stress from tissue injury as a means of identifying therapeutic targets for IDD.

Study Design/setting: We tested the effects inhibiting mitochondria, a major source of oxidants, with Amo in NP cells subjected to two different forms of insult: exposure to tBHP, and physical injury induced by disc transection. N-acetylcysteine (NAC), an antioxidant known to protect NP cells, was compared to the complex I inhibitor, Amo.

Methods: NP cells were pre-treated for 2 hours with Amo, NAC, or both, and then exposed to tBHP for 1 hour. Apoptosis, necrosis, and reactive oxygen species (ROS) production were assessed using confocal microscopy and fluorescent probes (Annexin V, propidium iodide, and MitoSox Red, respectively). The activation of mitogen-activated protein kinases (MAPKs) involved in oxidative stress responses were interrogated by confocal imaging of immunofluorescence stains using phospho-specific antibodies to extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), and p38. Mitochondrial function was assessed by imaging JC-1 staining, a probe for membrane potential.

Results: Amo was modestly more protective than NAC by some measures, while both agents improved mitochondrial function and lowered tBHP-induced apoptosis, necrosis, and ROS production. Activation of MAPK by tBHP was significantly suppressed by both drugs. Physically injured IVDs were treated immediately after transection with Amo or NAC for 24 hours, and then stained with dihydroethidium (DHE), a fluorescent probe for ROS production. Immunofluorescence was used to track the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor that induces the expression of antioxidant genes. Amo and NAC significantly reduced ROS production and increased Nrf2 expression.

Conclusion: These findings suggest that the progression of IDD may be forestalled by Amo via protection of NP cells from oxidative stress following IVD injury.

Clinical Significance: This study will define the extent to which a novel, minimally invasive procedure targeting oxidative stress in NP cells can augment surgical interventions intended to retard IVD degeneration.
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http://dx.doi.org/10.1016/j.spinee.2021.02.008DOI Listing
February 2021

Reducing Medical Admissions and Presentations Into Hospital through Optimising Medicines (REMAIN HOME): a stepped wedge, cluster randomised controlled trial.

Med J Aust 2021 Feb 12. Epub 2021 Feb 12.

University of Queensland, Brisbane, QLD.

Objective: To investigate whether integrating pharmacists into general practices reduces the number of unplanned re-admissions of patients recently discharged from hospital.

Design, Setting: Stepped wedge, cluster randomised trial in 14 general practices in southeast Queensland.

Participants: Adults discharged from one of seven study hospitals during the seven days preceding recruitment (22 May 2017 - 14 March 2018) and prescribed five or more long term medicines, or having a primary discharge diagnosis of congestive heart failure or exacerbation of chronic obstructive pulmonary disease.

Intervention: Comprehensive face-to-face medicine management consultation with an integrated practice pharmacist within seven days of discharge, followed by a consultation with their general practitioner and further pharmacist consultations as needed.

Major Outcomes: Rates of unplanned, all-cause hospital re-admissions and emergency department (ED) presentations 12 months after hospital discharge; incremental net difference in overall costs.

Results: By 12 months, there had been 282 re-admissions among 177 control patients (incidence rate [IR], 1.65 per person-year) and 136 among 129 intervention patients (IR, 1.09 per person-year; fully adjusted IR ratio [IRR], 0.79; 95% CI, 0.52-1.18). ED presentation incidence (fully adjusted IRR, 0.46; 95% CI, 0.22-0.94) and combined re-admission and ED presentation incidence (fully adjusted IRR, 0.69; 95% CI, 0.48-0.99) were significantly lower for intervention patients. The estimated incremental net cost benefit of the intervention was $5072 per patient, with a benefit-cost ratio of 31:1.

Conclusion: A collaborative pharmacist-GP model of post-hospital discharge medicines management can reduce the incidence of hospital re-admissions and ED presentations, achieving substantial cost savings to the health system.

Trial Registration: Australian New Zealand Clinical Trials Registry, ACTRN12616001627448 (prospective).
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http://dx.doi.org/10.5694/mja2.50942DOI Listing
February 2021

Utility of palliative EUS-guided biliary drainage using lumen-apposing metal stents: a prospective multicenter feasibility study (with video).

Gastrointest Endosc 2021 Feb 2. Epub 2021 Feb 2.

NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, United Kingdom; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom.

Background And Aims: Biliary drainage with ERCP is successful in only 80% to 90% of extrahepatic cholangiocarcinoma and pancreatic cancer. We present the results of a multicenter prospective study assessing the safety, feasibility, and quality of life of patients after EUS-guided biliary drainage (EUS-BD) with lumen-apposing metal stents (LAMSs), after failed ERCP.

Methods: All consecutive adults with a dilated common bile duct (CBD) ≥14 mm secondary to inoperable malignant distal common bile duct (CBD) stricture and failed ERCP biliary drainage were screened and recruited from 3 tertiary U.K. centers. Technical success of EUS-BD using LAMSs was the primary endpoint. Improvement in serum bilirubin, 30-day mortality, procedure-related adverse events, and quality of life were secondary endpoints. The quality of life improvement was measured using a validated questionnaire (EORTC QLQ-BIL21).

Results: Twenty patients were included in analysis. EUS-BD was technically successful in all patients and the clinical success was 95% (19/20) at day 7 (>50% reduction in bilirubin) and 92.3% (12/13) at day 30 (bilirubin <50 μmol/L). There were significant improvements in overall quality of life score (49 vs 42, p=0.03) at day 30. All cause 30-day mortality was 20% and the moderate adverse event rate was 10% (1 cholangitis and 1 stent migration).

Conclusion: EUS-BD has acceptable technical success and safety as a second line palliative treatment for inoperable malignant distal CBD strictures. Randomized controlled studies comparing EUS-BD with percutaneous transhepatic biliary drainage (PTBD) are needed to determine their effectiveness in clinical practice.
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http://dx.doi.org/10.1016/j.gie.2021.01.029DOI Listing
February 2021

Magnetic flexible endoscope for colonoscopy: an initial learning curve analysis.

Endosc Int Open 2021 Feb 25;9(2):E171-E180. Epub 2021 Jan 25.

Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, United States.

Colonoscopy is a technically challenging procedure that requires extensive training to minimize discomfort and avoid trauma due to its drive mechanism. Our academic team developed a magnetic flexible endoscope (MFE) actuated by magnetic coupling under supervisory robotic control to enable a front-pull maneuvering mechanism, with a motion controller user interface, to minimize colon wall stress and potentially reduce the learning curve. We aimed to evaluate this learning curve and understand the user experience. Five novices (no endoscopy experience), five experienced endoscopists, and five experienced MFE users each performed 40 trials on a model colon using 1:1 block randomization between a pediatric colonoscope (PCF) and the MFE. Cecal intubation (CI) success, time to cecum, and user experience (NASA task load index) were measured. Learning curves were determined by the number of trials needed to reach minimum and average proficiency-defined as the slowest average CI time by an experienced user and the average CI time by all experienced users, respectively. MFE minimum proficiency was achieved by all five novices (median 3.92 trials) and five experienced endoscopists (median 2.65 trials). MFE average proficiency was achieved by four novices (median 14.21 trials) and four experienced endoscopists (median 7.00 trials). PCF minimum and average proficiency levels were achieved by only one novice. Novices' perceived workload with the MFE significantly improved after obtaining minimum proficiency. The MFE has a short learning curve for users with no prior experience-requiring relatively few attempts to reach proficiency and at a reduced perceived workload.
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http://dx.doi.org/10.1055/a-1314-9860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834699PMC
February 2021

Suppressing Hippo signaling in the stem cell niche promotes skeletal muscle regeneration.

Stem Cells 2021 Feb 2. Epub 2021 Feb 2.

Wafic Said Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, Texas, USA.

Lack of blood flow to the lower extremities in peripheral arterial disease causes oxygen and nutrient deprivation in ischemic skeletal muscles, leading to functional impairment. Treatment options for muscle regeneration in this scenario are lacking. Here, we selectively targeted the Hippo pathway in myofibers, which provide architectural support for muscle stem cell niches, to facilitate functional muscle recovery in ischemic extremities by promoting angiogenesis, neovascularization, and myogenesis. We knocked down the core Hippo pathway component, Salvador (SAV1), by using an adeno-associated virus 9 (AAV9) vector expressing a miR30-based triple short-hairpin RNA (shRNA), controlled by a muscle-specific promoter. In a mouse hindlimb-ischemia model, AAV9 SAV1 shRNA administration in ischemic muscles induced nuclear localization of the Hippo effector YAP, accelerated perfusion restoration, and increased exercise endurance. Intravascular lectin labeling of the vasculature revealed enhanced angiogenesis. Using 5-ethynyl-2'-deoxyuridine to label replicating cellular DNA in vivo, we found SAV1 knockdown concurrently increased paired box transcription factor Pax7+ muscle satellite cell and CD31+ endothelial cell proliferation in ischemic muscles. To further study Hippo suppression in skeletal muscle regeneration, we used a cardiotoxin-induced muscle damage model in adult (12-15 weeks old) and aged mice (26-month old). Two weeks after delivery of AAV9 SAV1 shRNA into injured muscles, the distribution of regenerative myofibers shifted toward a larger cross-sectional area and increased capillary density compared with mice receiving AAV9 control. Together, these findings suggest our approach may have clinical promise in regenerative therapy for leg ischemia and muscle injury.
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http://dx.doi.org/10.1002/stem.3343DOI Listing
February 2021

An opportunistic evaluation of a routine service improvement project to reduce falls in hospital.

BMC Health Serv Res 2021 Jan 22;21(1):79. Epub 2021 Jan 22.

Institute of Applied Health Research, University of Birmingham, Edgbaston, B15 2TT, UK.

Background: Preventing falls in hospital is a perennial patient safety issue. The University Hospital Coventry and Warwickshire initiated a programme to train ward staff in accordance with guidelines. The National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care West Midlands was asked to expedite an independent evaluation of the initiative. We set out to describe the intervention to implement the guidelines and to evaluate it by means of a step-wedge cluster study using routinely collected data.

Methods: The evaluation was set up as a partially randomised, step-wedge cluster study, but roll-out across wards was more rapid than planned. The study was therefore analysed as a time-series. Primary outcome was rate of falls per 1000 Occupied Bed Days (OBDs) collected monthly using routine data. Data was analysed using a mixed-effects Poisson regression model, with a fixed effect for intervention, time and post-intervention time. We allowed for random variations across clusters in initial fall rate, pre-intervention slope and post-intervention slope.

Results: There was an average of 6.62 falls per 1000 OBDs in the control phase, decreasing to an average of 5.89 falls per 1000 OBDs in the period after implementation to the study end. Regression models showed no significant step change in fall rates (IRR: 1.02, 95% CI: 0.92-1.14). However, there was a gradual decrease, of approximately 3%, after the intervention was introduced (IRR: 0.97 per month, 95% CI: 0.95-0.99).

Conclusion: The intervention was associated with a small but statistically significantly improvement in falls rates. Expedited roll-out of an intervention may vitiate a step-wedge cluster design, but the intervention can still be studied using a time-series analysis. Assuming that there is some value in time series analyses, this is better than no evaluation at all. However, care is needed in making causal inferences given the non-experimental nature of the design.
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http://dx.doi.org/10.1186/s12913-021-06073-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821491PMC
January 2021

Long-term outcomes of liver transplant recipients followed up in non-transplant centres: Care closer to home.

Clin Med (Lond) 2021 Jan;21(1):e32-e38

NIHR Nottingham Biomedical Research Centre, Nottingham, UK, Nottingham University Hospitals NHS Trust, Nottingham, UK and the University of Nottingham, Nottingham, UK

Introduction: Increasing rates of liver transplantation and improved outcomes have led to greater numbers of transplant recipients followed up in non-transplant centres. Our aim was to document long-term clinical outcomes of liver transplant recipients managed in this 'hub-and-spoke' healthcare model.

Methods: A retrospective analysis of all adult patients who underwent liver transplantation between 1987 and 2016, with post-transplant follow-up in two non-transplant centres in the UK (Nottingham) and Canada (Ottawa), was performed.

Results: The 1-, 5-, 10- and 20-year patient survival rates were 98%, 95%, 87% and 62%, and 100%, 96%, 88% and 62% in the Nottingham and Ottawa groups, respectively (p=0.87). There were no significant differences between the two centres in 1-, 5-, 10- and 20-year cumulative incidence of death-censored graft-survival (p=0.10), end-stage renal disease (p=0.29) or cancer (p=0.22). Nottingham had a lower incidence of major cardiovascular events (p=0.008).

Conclusion: Adopting a new model of healthcare provides a means of delivering post-transplant patient care close to home without compromising patient survival and long-term clinical outcomes.
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http://dx.doi.org/10.7861/clinmed.2020-0609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850197PMC
January 2021

Effects on childhood infections of promoting safe and hygienic complementary-food handling practices through a community-based programme: A cluster randomised controlled trial in a rural area of The Gambia.

PLoS Med 2021 Jan 11;18(1):e1003260. Epub 2021 Jan 11.

London School of Hygiene & Tropical Medicine, London, United Kingdom.

Background: The Gambia has high rates of under-5 mortality from diarrhoea and pneumonia, peaking during complementary-feeding age. Community-based interventions may reduce complementary-food contamination and disease rates.

Methods And Findings: A public health intervention using critical control points and motivational drivers, delivered February-April 2015 in The Gambia, was evaluated in a cluster randomised controlled trial at 6- and 32-month follow-up in September-October 2015 and October-December 2017, respectively. After consent for trial participation and baseline data were collected, 30 villages (clusters) were randomly assigned to intervention or control, stratified by population size and geography. The intervention included a community-wide campaign on days 1, 2, 17, and 25, a reminder visit at 5 months, plus informal community-volunteer home visits. It promoted 5 key complementary-food and 1 key drinking-water safety and hygiene behaviours through performing arts, public meetings, and certifications delivered by a team from local health and village structures to all villagers who attended the activities, to which mothers of 6- to 24-month-old children were specifically invited. Control villages received a 1-day campaign on domestic-garden water use. The background characteristics of mother and clusters (villages) were balanced between the trial arms. Outcomes were measured at 6 and 32 months in a random sample of 21-26 mothers per cluster. There were no intervention or research team visits to villages between 6 and 32 months. The primary outcome was a composite outcome of the number of times key complementary-food behaviours were observed as a proportion of the number of opportunities to perform the behaviours during the observation period at 6 months. Secondary outcomes included the rate of each recommended behaviour; microbiological growth from complementary food and drinking water (6 months only); and reported acute respiratory infections, diarrhoea, and diarrhoea hospitalisation. Analysis was by intention-to-treat analysis adjusted by clustering. (Registration: PACTR201410000859336). We found that 394/571 (69%) of mothers with complementary-feeding children in the intervention villages were actively involved in the campaign. No villages withdrew, and there were no changes in the implementation of the intervention. The intervention improved behaviour adoption significantly. For the primary outcome, the rate was 662/4,351(incidence rate [IR] = 0.15) in control villages versus 2,861/4,378 (IR = 0.65) in intervention villages (adjusted incidence rate ratio [aIRR] = 4.44, 95% CI 3.62-5.44, p < 0.001), and at 32 months the aIRR was 1.17 (95% CI 1.07-1.29, p = 0.001). Secondary health outcomes also improved with the intervention: (1) mother-reported diarrhoea at 6 months, with adjusted relative risk (aRR) = 0.39 (95% CI 0.32-0.48, p < 0.001), and at 32 months, with aRR = 0.68 (95% CI 0.48-0.96, p = 0.027); (2) mother-reported diarrhoea hospitalisation at 6 months, with aRR = 0.35 (95% CI 0.19-0.66, p = 0.001), and at 32 months, with aRR = 0.38 (95% CI 0.18-0.80, p = 0.011); and (3) mother-reported acute respiratory tract infections at 6 months, with aRR = 0.67 (95% CI 0.53-0.86, p = 0.001), though at 32 months improvement was not significant (p = 0.200). No adverse events were reported. The main limitations were that only medium to small rural villages were involved. Obtaining laboratory cultures from food at 32 months was not possible, and no stool microorganisms were investigated.

Conclusions: We found that low-cost and culturally embedded behaviour change interventions were acceptable to communities and led to short- and long-term improvements in complementary-food safety and hygiene practices, and reported diarrhoea and acute respiratory tract infections.

Trial Registration: The trial was registered on the 17th October 2014 with the Pan African Clinical Trial Registry in South Africa with number (PACTR201410000859336) and 32-month follow-up as an amendment to the trial.
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http://dx.doi.org/10.1371/journal.pmed.1003260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799804PMC
January 2021

The Impact of Observation Versus Parathyroidectomy on Bone Mineral Density and Fracture Risk Determined by FRAX Tool in Patients With Primary Hyperparathyroidism.

J Clin Densitom 2020 Dec 15. Epub 2020 Dec 15.

Consultant in Endocrinology, Prince Charles Hospital, Cwm Taf Morgannwg University Health Board, Merthyr Tydfil, United Kingdom. Electronic address:

To study impact of observation (OBV) vs parathyroidectomy (PTX) on biochemistry, bone mineral density (BMD) and fracture risk calculated by Fracture Risk Assessment (FRAX) tool in primary hyperparathyroidism (PHPT). Retrospective study of 60 patients (OBV - 26; PTX - 34 patients). Mean adjusted calcium improved in both groups [OBV - 2.76 ± 0.07 vs 2.51 ± 0.20 mmol/L; p < 0.00001, PTX - 2.87 ± 0.21 vs 2.36 ± 0.12 mmol/L; p < 0.00001]. Mean parathyroid hormone level declined in both but more in PTX group [OBV - 11.4 ± 5.2 vs. 9.7 ± 5.6 pmol/L; p = 0.04, PTX - 14.3 ± 8.2 vs 4.6 ± 2.2 pmol/L; p < 0.00001]. In OBV group, BMD and T scores declined at all sites. Mean percentage change of BMD was -5.8 % at femoral neck (FN), -4.9 % at total hip (TH), -6.2 % at lumbar spine (LS) and -10.0 % at lower 1/3 radius (LR). PTX led to stabilization of BMD at FN (3.0 %), TH (-0.6 %) and LS (2.2 %) but significant improvement at LR (13.9 %; p = 0.0005). In OBV group, 10 year risk of hip fracture (HF) (7.5 ± 9.0 % vs. 8.6 ± 9.0; p = 0.01) and major osteoporotic fracture (OF) (16.6 ± 10.9 % vs 18.3 ± 10.8 %; p = 0.002) worsened with time whereas in PTX group, risk of both type of fractures remained stable (HF; p = 0.48 and OF; p = 0.43). Comparison between groups showed greater improvement in median % change of fracture risk for both HF and OF in PTX group. OBV in PHPT lead to greater decline in BMD at all skeletal sites and imparted significant risk of HF and major OF. PTX offered stabilization of BMD at most sites but improvement at LR with unchanged fracture risk. FRAX tool should be used more frequently and universally.
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http://dx.doi.org/10.1016/j.jocd.2020.12.005DOI Listing
December 2020

Practicability of lower extremity functional performance tests and their measurement properties in elite athletes: protocol for a systematic review.

BMJ Open 2020 12 22;10(12):e042975. Epub 2020 Dec 22.

Centre of Precision Rehabilitation for Spinal Pain (CPR Spine), School of Sport, Exercise and Rehabilitation Sciences, College of Life and Environmental Sciences, University of Birmingham, Birmingham, UK.

Introduction: Lower extremity injury (LEI) is highly prevalent and its occurrence increases the risk of future injury in athletic populations. Identifying athletes at risk of injury is the key to target injury-prevention programmes. Functional performance tests (FPT) assess an athlete's ability to produce and accept forces during movement tasks reflective of those experienced in sport, and are used to identify deficits in physical qualities or neuromuscular control. This review aims to identify FPT which have potential to predict LEI and assess their measurement properties associated with reliability, validity, responsiveness and practicability (interpretability and feasibility).

Methods/analysis: This protocol will be reported using the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol and the COnsensus-based Standards for the selection of health Measurement INstruments Methodology. The search strategy has two stages: stage 1 will identify lower limb FPT used in athletic populations; and stage 2 will assess the measurement properties of the identified FPT. A sensitive search strategy will use MEDLINE, EMBASE, CINHAL and SPORTdiscus databases; from inception to June 2020. Hand searching reference lists, key journals and grey literature will be completed. One reviewer will complete search 1 and data extraction. Two reviewers will complete the search, data extraction and risk-of-bias assessment for search 2. Evidence will be pooled or summarised by individual measurement property by each individual study and grouped by FPT. Meta-analysis using a random effects model with subgroup analysis will be performed where possible. Pooled or summarised results for each FPT in relation to each measurement property will be rated against the criteria for good measurement properties. Two reviewers will assess the overall body of evidence per measurement property per FPT using the modified Grading of Recommendations, Assessment, Development and Evaluation guidelines. This review will enable clinicians to make an informed choice when selecting FPT.

Ethics And Dissemination: No ethical approval is required for this review and the results will be disseminated through peer-reviewed publications and submitted for conference presentation.

Prospero Registration Number: CRD42020188932.
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http://dx.doi.org/10.1136/bmjopen-2020-042975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757441PMC
December 2020

Metabolic power and efficiency for an amputee cyclist: implications for cycling technique.

J Appl Physiol (1985) 2021 Feb 24;130(2):479-484. Epub 2020 Dec 24.

Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah.

Cycling technique is steeped in cultural lore. One deeply held belief is that "pulling up" to lift the leg (increased muscular leg flexion) will optimize technique and improve efficiency. In contrast, scientific evidence suggests that when cyclists are instructed to pull-up efficiency decreases. However, such interventions may not have allowed sufficient time for cyclists to adapt and refine their technique. This case study documented how a cyclist with a complete unilateral limb amputation consumed metabolic power to produce mechanical power during single-leg cycling. The cyclist was a four time US National Paralympic Champion who performed single-leg cycling for 7 yr and thus was fully adapted to pull up. We hypothesized that a counterweight system, which reduced the requirement to pull up, would decrease metabolic power and increase efficiency for this cyclist. The cyclist performed submaximal cycling (100, 135, 170, 205 W, 80 rpm, 5 min) with and without a counterweight (10 kg) on the unused crank. Expired gases were measured, and metabolic power and gross efficiency were calculated. Metabolic power decreased on average by 87 ± 7 W ( < 0.001) and gross efficiency increased from 16.3 ± 1.9 to 18.0 ± 1.8% ( < 0.001) when cycling with the counterweight. During counterweighted single-leg cycling, the metabolic power of unloaded cycling decreased (317 vs. 238 W) and delta efficiency was similar (25.2 vs. 25.5%). Results demonstrated that significant metabolic power was associated with pulling up to produce muscular leg flexion power even in a cyclist who pulled up substantially during cycling. Our findings confirm observations from previous studies that altered pedaling technique acutely and indicate that pulling up during cycling is less efficient. This study offers unique insight into pedaling technique and provides the "final nail in the coffin" to the notion that pulling up improves cycling efficiency. When the requirement for pulling up was reduced with the counterweight, the cyclist immediately benefited as the cost to move the limb decreased and gross efficiency increased. These case study results along with previous research suggest that, in general, cyclists should not adopt pedaling techniques, which increase the action of pulling up.
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http://dx.doi.org/10.1152/japplphysiol.00661.2020DOI Listing
February 2021

Interferon-γ amplifies airway smooth muscle-mediated CD4+ T cell recruitment by promoting the secretion of C-X-C-motif chemokine receptor 3 ligands.

FASEB J 2021 Jan;35(1):e21228

Meakins-Christie Laboratories, The Research Institute of McGill University Health Centre, Montreal, QC, Canada.

Asthmatic airways feature increased ASM mass that is largely attributable to hyperplasia, and which potentially contributes to excessive airway narrowing. T cells induce ASMC proliferation via contact-dependent mechanisms in vitro that may have importance for asthmatic ASM growth, as CD4+ T cells infiltrate ASM bundles in asthmatic human airways. In this study, we used an in vitro migration assay to investigate the pathways responsible for the trafficking of human CD4+ T cells to ASM. ASMCs induced chemotaxis of activated CD4+ T cells, which was inhibited by the CXCR3 antagonist AMG487 and neutralizing antibodies against its ligands CXCL10 and 11, but not CCR3 or CCR5 antagonists. CXCR3 expression was upregulated among all T cells following anti-CD3/CD28-activation. CD4+ T cells upregulated CXCL9, 10, and 11 expression in ASMCs in an IFN-γ/STAT1-dependent manner. Disruption of IFN-γ-signaling resulted in reduced T cell migration, along with the inhibition of CD4+ T cell-mediated STAT1 activation and CXCR3 ligand secretion by ASMCs. ASMCs derived from healthy and asthmatic donors demonstrated similar T cell-recruiting capacities. In vivo CXCL10 and 11 expression by asthmatic ASM was confirmed by immunostaining. We conclude that the CXCL10/11-CXCR3 axis causes CD4+ T cell recruitment to ASM that is amplified by T cell-derived IFN-γ.
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http://dx.doi.org/10.1096/fj.202001480RDOI Listing
January 2021

Wild turkey contaminant burdens.

Environ Toxicol Chem 2020 Dec 17. Epub 2020 Dec 17.

University of Georgia, Savannah River Ecology Laboratory, Warnell School of Forestry and Natural Resources, Aiken, South Carolina, USA.

Despite their popularity as a game species across North America, little is known about contaminant burdens in wild turkeys (Meleagris gallopavo) inhabiting areas of environmental contamination, and their potential to expose human and wildlife consumers. We compared trace element concentrations and radionuclide activity in muscle and liver tissues of turkeys inhabiting the Savannah River Site (SRS), an area with known anthropogenic contaminant inputs, with turkeys from uncontaminated areas off-site. In addition, we tested breast feathers from a subset of individuals for mercury (Hg) to assess the viability of non-lethal sampling for quantifying Hg concentrations. Finally, we quantified arsenic (As), Hg, and selenium (Se) in blood of live-captured turkeys inhabiting a coal ash basin on the SRS. Compared to reference samples, we found turkeys inhabiting the SRS contained elevated Hg levels in both muscle and liver tissues, and lower concentrations of Chromium (Cr). Turkeys from the ash basin also had elevated levels of Se. We found a positive correlation between breast muscle and feather Hg concentrations (F = 267.5, R = 0.82, P < 0.001), suggesting feathers can potentially be used as a non-lethal sampling technique. All elements analyzed were below reference limits set by the Centers for Disease Control for safe consumption. Thus, our data suggest turkeys likely are not an important pathway of contaminant exposure on the SRS or other areas with similar contaminant distributions. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/etc.4967DOI Listing
December 2020

Examining Whether Student Participation in School-Sponsored Extracurricular Activities Is Represented in IEPs.

Intellect Dev Disabil 2020 12;58(6):472-485

James Martin, University of Oklahoma.

The purpose of this study was to investigate the extent to which extracurricular activities are included in Individualized Education Programs (IEPs) of secondary age students with intellectual disability (ID). Student characteristics (grade, disability, use of augmentative and alternative communication) were examined to explore potential group differences. Participants were 498 special education teachers who had at least one student with ID on their caseload who had participated in a school sponsored extracurricular activity. Data were collected through an online questionnaire sent to members of a national listserv for transition professionals. Findings reveal that 63.69% (n = 314) of teachers reported they included information about extracurricular activities in the IEP; however, only 59.61% (n = 186) of these teachers also reported their student worked on IEP goals during extracurricular activities. Student characteristics were related to the presence of extracurricular activities in the IEP, number of IEP goals students worked on during extracurricular activities, student's most important IEP goal, and whether students received instruction on their most important IEP goal during extracurricular activities.
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http://dx.doi.org/10.1352/1934-9556-58.6.472DOI Listing
December 2020

Enhancing Pace: Identifying and Validating the Cis-Regulatory Landscape of the Sinoatrial Node.

Circ Res 2020 Dec 3;127(12):1519-1521. Epub 2020 Dec 3.

Department of Molecular Physiology and Biophysics (J.D.S., C.-R.T., J.F.M.), Baylor College of Medicine, Houston, TX.

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http://dx.doi.org/10.1161/CIRCRESAHA.120.318385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721045PMC
December 2020

A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction.

Proc Natl Acad Sci U S A 2020 12 23;117(49):31353-31364. Epub 2020 Nov 23.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030;

Progressive remodeling of the heart, resulting in cardiomyocyte (CM) loss and increased inflammation, fibrosis, and a progressive decrease in cardiac function, are hallmarks of myocardial infarction (MI)-induced heart failure. We show that MCB-613, a potent small molecule stimulator of steroid receptor coactivators (SRCs) attenuates pathological remodeling post-MI. MCB-613 decreases infarct size, apoptosis, hypertrophy, and fibrosis while maintaining significant cardiac function. MCB-613, when given within hours post MI, induces lasting protection from adverse remodeling concomitant with: 1) inhibition of macrophage inflammatory signaling and interleukin 1 (IL-1) signaling, which attenuates the acute inflammatory response, 2) attenuation of fibroblast differentiation, and 3) promotion of Tsc22d3-expressing macrophages-all of which may limit inflammatory damage. SRC stimulation with MCB-613 (and derivatives) is a potential therapeutic approach for inhibiting cardiac dysfunction after MI.
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http://dx.doi.org/10.1073/pnas.2011614117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733826PMC
December 2020

Predicting unrecognized enhancer-mediated genome topology by an ensemble machine learning model.

Genome Res 2020 Dec 12;30(12):1835-1845. Epub 2020 Nov 12.

Hunan Provincial Key Lab on Bioinformatics, School of Computer Science and Engineering, Central South University, Changsha 410083, China.

Transcriptional enhancers commonly work over long genomic distances to precisely regulate spatiotemporal gene expression patterns. Dissecting the promoters physically contacted by these distal regulatory elements is essential for understanding developmental processes as well as the role of disease-associated risk variants. Modern proximity-ligation assays, like HiChIP and ChIA-PET, facilitate the accurate identification of long-range contacts between enhancers and promoters. However, these assays are technically challenging, expensive, and time-consuming, making it difficult to investigate enhancer topologies, especially in uncharacterized cell types. To overcome these shortcomings, we therefore designed LoopPredictor, an ensemble machine learning model, to predict genome topology for cell types which lack long-range contact maps. To enrich for functional enhancer-promoter loops over common structural genomic contacts, we trained LoopPredictor with both H3K27ac and YY1 HiChIP data. Moreover, the integration of several related multi-omics features facilitated identifying and annotating the predicted loops. LoopPredictor is able to efficiently identify cell type-specific enhancer-mediated loops, and promoter-promoter interactions, with a modest feature input requirement. Comparable to experimentally generated H3K27ac HiChIP data, we found that LoopPredictor was able to identify functional enhancer loops. Furthermore, to explore the cross-species prediction capability of LoopPredictor, we fed mouse multi-omics features into a model trained on human data and found that the predicted enhancer loops outputs were highly conserved. LoopPredictor enables the dissection of cell type-specific long-range gene regulation and can accelerate the identification of distal disease-associated risk variants.
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http://dx.doi.org/10.1101/gr.264606.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706734PMC
December 2020

Behavioral strategies during incubation influence nest and female survival of Wild Turkeys.

Ecol Evol 2020 Oct 24;10(20):11752-11765. Epub 2020 Sep 24.

Warnell School of Forestry and Natural Resources University of Georgia Athens GA USA.

Females must balance physiological and behavioral demands of producing offspring with associated expenditures, such as resource acquisition and predator avoidance. Nest success is an important parameter underlying avian population dynamics. Galliforms are particularly susceptible to low nest success due to exposure of ground nests to multiple predator guilds, lengthy incubation periods, and substantive reliance on crypsis for survival. Hence, it is plausible that nesting individuals prioritize productivity and survival differently, resulting in a gradient of reproductive strategies. Fine-scale movement patterns during incubation are not well documented in ground-nesting birds, and the influence of reproductive movements on survival is largely unknown. Using GPS data collected from female wild turkeys ( = 278) across the southeastern United States, we evaluated the influence of incubation recess behaviors on trade-offs between nest and female survival. We quantified daily recess behaviors including recess duration, recess frequency, total distance traveled, and incubation range size for each nest attempt as well as covariates for nest concealment, nest attempt, and nest age. Of 374 nests, 91 (24%) hatched and 39 (14%) females were depredated during incubation. Average nest survival during the incubation period was 0.19, whereas average female survival was 0.78. On average, females took 1.6 daily unique recesses ( = 1.2), spent 2.1 hr off the nest each day ( = 1.8), and traveled 357.6 m during recesses ( = 396.6). Average nest concealment was 92.5 cm ( = 47). We found that females who took longer recess bouts had higher individual survival, but had increased nest loss. Females who recessed more frequently had lower individual survival. Our findings suggest behavioral decisions made during incubation represent life-history trade-offs between predation risk and reproductive success on an unpredictable landscape.
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http://dx.doi.org/10.1002/ece3.6812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593161PMC
October 2020

A time series analysis of the ecologic relationship between acute and intermediate PM2.5 exposure duration on neonatal intensive care unit admissions in Florida.

Environ Res 2020 Oct 22:110374. Epub 2020 Oct 22.

University of Florida, College of Public Health and Health Professions, Department of Environmental and Global Health, University of Florida, Gainesville, FL, USA; University of Florida, Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, USA.

Admissions of newborn infants into Neonatal Intensive Care Units (NICU) has increased in the US over the last decade yet the role of environmental exposures as a risk factor for NICU admissions is under studied. Our study aims to determine the ecologic association between acute and intermediate ambient PM2.5 exposure durations and rates of NICU admissions, and to explore whether this association differs by area-level social stressors and meteorological factors. We conducted an ecologic time-series analysis of singleton neonates (N = 1,027,797) born in Florida hospitals between December 26, 2011 to April 30, 2019. We used electronic medical records (EMRs) in the OneFlorida Data Trust and included infants with a ZIP code in a Metropolitan Statistical Areas (MSA) and excluded extreme preterm births (<24wks gestation). The study outcome is the number of daily NICU admission at 28 days old or younger for each ZIP code in the study area. The exposures of interest are average same day, 1- and 2-day lags, and 1-3 weeks ambient PM2.5 concentration at the ZIP code-level estimated using inverse distance weighting (IDW) for each day of the study period. We used a zero-inflated Poisson regression mixed effects models to estimate adjusted associations between acute and intermediate PM2.5 exposure durations and NICU admissions rates. NICU admissions rates increased over time during the study period. Ambient 7-day average PM2.5 concentrations was significantly associated with incidence of NICU admissions, with an interquartile range (IQR = 2.37 μg/m) increase associated with a 1.4% (95% CI: 0.4%, 2.4%) higher adjusted incidence of daily NICU admissions. No other exposure duration metrics showed a significant association with daily NICU admission rates. The magnitude of the association between PM2.5 7-day average concentrations with NICU admissions was significantly (p < 0.05) higher among ZIP codes with higher proportions of non-Hispanic Blacks, ZIP codes with household incomes in the lowest quartile, and on days with higher relative humidity. Our data shows a positive relationship between acute (7-day average) PM2.5 concentrations and daily NICU admissions in Metropolitan Statistical Areas of Florida. The observed associations were stronger in socioeconomically disadvantaged areas, areas with higher proportions with non-Hispanic Blacks, and on days with higher relative humidity. Further research is warranted to study other air pollutants and multipollutant effects and identify health conditions that are driving these associations with NICU admissions.
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http://dx.doi.org/10.1016/j.envres.2020.110374DOI Listing
October 2020

Enabling the future of colonoscopy with intelligent and autonomous magnetic manipulation.

Nat Mach Intell 2020 Oct 12;2(10):595-606. Epub 2020 Oct 12.

STORM Lab UK, University of Leeds, Leeds, UK.

Early diagnosis of colorectal cancer significantly improves survival. However, over half of cases are diagnosed late due to demand exceeding the capacity for colonoscopy - the "gold standard" for screening. Colonoscopy is limited by the outdated design of conventional endoscopes, associated with high complexity of use, cost and pain. Magnetic endoscopes represent a promising alternative, overcoming drawbacks of pain and cost, but struggle to reach the translational stage as magnetic manipulation is complex and unintuitive. In this work, we use machine vision to develop intelligent and autonomous control of a magnetic endoscope, for the first time enabling non-expert users to effectively perform magnetic colonoscopy in-vivo. We combine the use of robotics, computer vision and advanced control to offer an intuitive and effective endoscopic system. Moreover, we define the characteristics required to achieve autonomy in robotic endoscopy. The paradigm described here can be adopted in a variety of applications where navigation in unstructured environments is required, such as catheters, pancreatic endoscopy, bronchoscopy, and gastroscopy. This work brings alternative endoscopic technologies closer to the translational stage, increasing availability of early-stage cancer treatments.
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http://dx.doi.org/10.1038/s42256-020-00231-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571595PMC
October 2020

In Support of CDK4/6 Inhibitors-A Meta-analysis of Available Randomized Data.

JAMA Netw Open 2020 10 1;3(10):e2021062. Epub 2020 Oct 1.

Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1001/jamanetworkopen.2020.21062DOI Listing
October 2020

ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration.

Nat Cell Biol 2020 11 12;22(11):1346-1356. Epub 2020 Oct 12.

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Cardiomyocyte loss after injury results in adverse remodelling and fibrosis, inevitably leading to heart failure. The ERBB2-Neuregulin and Hippo-YAP signalling pathways are key mediators of heart regeneration, yet the crosstalk between them is unclear. We demonstrate that transient overexpression of activated ERBB2 in cardiomyocytes (OE CMs) promotes cardiac regeneration in a heart failure model. OE CMs present an epithelial-mesenchymal transition (EMT)-like regenerative response manifested by cytoskeletal remodelling, junction dissolution, migration and extracellular matrix turnover. We identified YAP as a critical mediator of ERBB2 signalling. In OE CMs, YAP interacts with nuclear-envelope and cytoskeletal components, reflecting an altered mechanical state elicited by ERBB2. We identified two YAP-activating phosphorylations on S352 and S274 in OE CMs, which peak during metaphase, that are ERK dependent and Hippo independent. Viral overexpression of YAP phospho-mutants dampened the proliferative competence of OE CMs. Together, we reveal a potent ERBB2-mediated YAP mechanotransduction signalling, involving EMT-like characteristics, resulting in robust heart regeneration.
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http://dx.doi.org/10.1038/s41556-020-00588-4DOI Listing
November 2020

Missing or making the timely diagnosis of acute fatty liver of pregnancy (AFLP): lessons learned.

J Matern Fetal Neonatal Med 2020 Oct 9:1-7. Epub 2020 Oct 9.

Obstetrics and Gynecology, The Winfred L. Wiser Hospital for Women and Infants, The University of Mississippi Medical Center, Jackson, MS, USA.

Objective: To review the presenting signs, symptoms, laboratory findings, clinical courses, complications, and maternal outcomes in women determined on medicolegal review to have had acute fatty liver of pregnancy (AFLP).

Methods: We retrospectively studied case files from women with medical and/or hypertensive complications of pregnancy which had been reviewed by the first author, deidentified and divested of legal documents so that only medical-related information was retained for later research and teaching purposes. Main outcomes are 12 lessons learned from this review to be offered for the future benefit of clinicians encountering patients with AFLP.

Results: Eleven women with AFLP were identified within the 161 file database. Signs and symptoms present in 91-100% of women with AFLP were altered sensorium, a fast resting maternal pulse >100/min, gastrointestinal complaints, muscle pain and evidence of fetal compromise/stillbirth. Laboratory findings in 91-100% revealed abnormal liver, renal and coagulation tests, hyperuricemia, and very low serum glucose and albumin. A correct initial diagnosis of AFLP was made for only three women; the most common incorrect presumptive diagnosis was HELLP syndrome. Four women survived. Twelve major findings are discussed.

Conclusion: Rapid, timely and thorough evaluation of third trimester women presenting with (Altered mental status changes/extreme sleepiness), (Fast resting pulse >100 in the absence of fever or heart causation), (Liver-related gastrointestinal complaints) and (Pain as myalgias and body aches), often in association with evidence of fetal compromise or stillbirth, should initiate efforts to investigate a possible diagnosis of AFLP. Adoption of the concepts summarized including core initial laboratory testing, immediate patient transfer to tertiary care, and aggressive correction of consumptive coagulopathy could form the basis of a patient safety bundle to guide future management for patients with AFLP.
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http://dx.doi.org/10.1080/14767058.2020.1832075DOI Listing
October 2020

Anopheline and human drivers of malaria risk in northern coastal, Ecuador: a pilot study.

Malar J 2020 Oct 2;19(1):354. Epub 2020 Oct 2.

Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, 46556, USA.

Background: Understanding local anopheline vector species and their bionomic traits, as well as related human factors, can help combat gaps in protection.

Methods: In San José de Chamanga, Esmeraldas, at the Ecuadorian Pacific coast, anopheline mosquitoes were sampled by both human landing collections (HLCs) and indoor-resting aspirations (IAs) and identified using both morphological and molecular methods. Human behaviour observations (HBOs) (including temporal location and bed net use) were documented during HLCs as well as through community surveys to determine exposure to mosquito bites. A cross-sectional evaluation of Plasmodium falciparum and Plasmodium vivax infections was conducted alongside a malaria questionnaire.

Results: Among 222 anopheline specimens captured, based on molecular analysis, 218 were Nyssorhynchus albimanus, 3 Anopheles calderoni (n = 3), and one remains unidentified. Anopheline mean human-biting rate (HBR) outdoors was (13.69), and indoors (3.38) (p = 0.006). No anophelines were documented resting on walls during IAs. HBO-adjusted human landing rates suggested that the highest risk of being bitten was outdoors between 18.00 and 20.00 h. Human behaviour-adjusted biting rates suggest that overall, long-lasting insecticidal bed nets (LLINs) only protected against 13.2% of exposure to bites, with 86.8% of exposure during the night spent outside of bed net protection. The malaria survey found 2/398 individuals positive for asymptomatic P. falciparum infections. The questionnaire reported high (73.4%) bed net use, with low knowledge of malaria.

Conclusion: The exophagic feeding of anopheline vectors in San Jose de Chamanga, when analysed in conjunction with human behaviour, indicates a clear gap in protection even with high LLIN coverage. The lack of indoor-resting anophelines suggests that indoor residual spraying (IRS) may have limited effect. The presence of asymptomatic infections implies the presence of a human reservoir that may maintain transmission.
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http://dx.doi.org/10.1186/s12936-020-03426-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532652PMC
October 2020

Comparison of the reverse bevel versus Franseen type endoscopic ultrasound needle.

World J Gastrointest Endosc 2020 Sep;12(9):266-275

National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Hospitals National Health Service Trust and University of Nottingham, Nottingham NG2 7UH, United Kingdom.

Background: Reverse bevel (RB) needle is widely used for endoscopic ultrasound fine needle biopsy (EUS-FNB). A 3-plane symmetrical needle with Franseen geometry (FG) has recently become available.

Aim: To compare the clinical efficacy of FG to that of RB needle.

Methods: A retrospective cohort study of all adult patients who underwent EUS-FNB for solid and mixed lesions either with 22G RB needle or 22G FG needle between January 2016 and February 2019 was undertaken. All cytology slides were reviewed by an independent gastrointestinal cytopathologist blinded to the needle used and the initial cytology report. The primary and secondary outcomes were to assess the sample adequacy using Euro-cytology criteria and the number of cell clusters, respectively.

Results: Two hundred and twenty six procedures were included in the study. RB needle was used in 128 procedures and FG needle in 98 procedures. The baseline characteristics of both groups were comparable. On multivariable analysis, FG needle ( = 0.02) and location of the lesion ( < 0.01) were independently associated with adequate tissue. Further, the use of FG needle ( = 0.04) and the size of the lesion ( = 0.02) were independently associated with acquisition of increased number of cell clusters.

Conclusion: FG needle is superior to RB needle in acquiring adequate tissue and attaining higher number of cell clusters for solid and mixed lesions.
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http://dx.doi.org/10.4253/wjge.v12.i9.266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503614PMC
September 2020

NEUROlogical Prognosis After Cardiac Arrest in Kids (NEUROPACK) study: protocol for a prospective multicentre clinical prediction model derivation and validation study in children after cardiac arrest.

BMJ Open 2020 09 25;10(9):e037517. Epub 2020 Sep 25.

Birmingham Acute Care Research Group, University of Birmingham College of Medical and Dental Sciences, Birmingham, West Midlands, UK.

Introduction: Currently, we are unable to accurately predict mortality or neurological morbidity following resuscitation after paediatric out of hospital (OHCA) or in-hospital (IHCA) cardiac arrest. A clinical prediction model may improve communication with parents and families and risk stratification of patients for appropriate postcardiac arrest care. This study aims to the derive and validate a clinical prediction model to predict, within 1 hour of admission to the paediatric intensive care unit (PICU), neurodevelopmental outcome at 3 months after paediatric cardiac arrest.

Methods And Analysis: A prospective study of children (age: >24 hours and <16 years), admitted to 1 of the 24 participating PICUs in the UK and Ireland, following an OHCA or IHCA. Patients are included if requiring more than 1 min of cardiopulmonary resuscitation and mechanical ventilation at PICU admission Children who had cardiac arrests in PICU or neonatal intensive care unit will be excluded. Candidate variables will be identified from data submitted to the Paediatric Intensive Care Audit Network registry. Primary outcome is neurodevelopmental status, assessed at 3 months by telephone interview using the Vineland Adaptive Behavioural Score II questionnaire. A clinical prediction model will be derived using logistic regression with model performance and accuracy assessment. External validation will be performed using the Therapeutic Hypothermia After Paediatric Cardiac Arrest trial dataset. We aim to identify 370 patients, with successful consent and follow-up of 150 patients. Patient inclusion started 1 January 2018 and inclusion will continue over 18 months.

Ethics And Dissemination: Ethical review of this protocol was completed by 27 September 2017 at the Wales Research Ethics Committee 5, 17/WA/0306. The results of this study will be published in peer-reviewed journals and presented in conferences.

Trial Registration Number: NCT03574025.
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http://dx.doi.org/10.1136/bmjopen-2020-037517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520830PMC
September 2020

Embryonic ECM Protein SLIT2 and NPNT Promote Postnatal Cardiomyocyte Cytokinesis.

Circ Res 2020 Sep 10;127(7):908-910. Epub 2020 Sep 10.

From the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (F.M., J.F.M.).

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317798DOI Listing
September 2020

Equine Asthma: Current Understanding and Future Directions.

Front Vet Sci 2020 30;7:450. Epub 2020 Jul 30.

College of Veterinary Medicine, Mississippi State University, Starkville, MS, United States.

The 2019 Havemeyer Workshop brought together researchers and clinicians to discuss the latest information on Equine Asthma and provide future research directions. Current clinical and molecular asthma phenotypes and endotypes in humans were discussed and compared to asthma phenotypes in horses. The role of infectious and non-infectious causes of equine asthma, genetic factors and proposed disease pathophysiology were reviewed. Diagnostic limitations were evident by the limited number of tests and biomarkers available to field practitioners. The participants emphasized the need for more accessible, standardized diagnostics that would help identify specific phenotypes and endotypes in order to create more targeted treatments or management strategies. One important outcome of the workshop was the creation of the Equine Asthma Group that will facilitate communication between veterinary practice and research communities through published and easily accessible guidelines and foster research collaboration.
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http://dx.doi.org/10.3389/fvets.2020.00450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438831PMC
July 2020

Epigenetic Assays in Purified Cardiomyocyte Nuclei.

Methods Mol Biol 2021 ;2158:307-321

Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.

The adult mammalian heart's potential for regeneration is very inefficient. Importantly, adult mammalian cardiomyocytes (CMs) are characterized as a cell population with very limited mitotic potential. Conversely, the neonatal mouse heart possesses a brief, yet robust, regenerative capacity within the first week of life. Cell type-specific enrichment procedures are essential for characterizing the full spectrum of epigenomic landscapes and gene regulatory networks deployed by mammalian CMs. In this chapter, we describe a protocol useful for purifying CM nuclei from mammalian cardiac tissue. Furthermore, we detail a low-input procedure suitable for the parallel genome-wide profiling of chromatin accessibility, histone modifications, and transcription factor-binding sites. The CM nuclei purified using this process are suitable for multi-omic profiling approaches.
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http://dx.doi.org/10.1007/978-1-0716-0668-1_23DOI Listing
March 2021

Quantifying the Relationship between Conformational Dynamics and Enzymatic Activity in Ribonuclease HI Homologues.

Biochemistry 2020 Sep 24;59(35):3201-3205. Epub 2020 Aug 24.

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, United States.

Ribonuclease HI (RNHI), a ubiquitous, non-sequence-specific endonuclease, cleaves the RNA strand in RNA/DNA hybrids. RNHI functions in replication and genome maintenance, and retroviral reverse transcriptases contain an essential ribonuclease H domain. Nuclear magnetic resonance (NMR) spectroscopy combined with molecular dynamics (MD) simulations suggests a model in which the extended handle region domain of RNHI populates (substrate-binding-competent) "open" and (substrate-binding-incompetent) "closed" states, while the thermophilic RNHI mainly populates the closed state at 300 K [Stafford, K. A., Robustelli, P., and Palmer, A. G., III (2013) , 1-10]. In addition, an -designed mutant Val98Ala RNHI was predicted to populate primarily the closed state. The work presented here validates this model and confirms the predicted properties of the designed mutant. MD simulations suggest that the conformational preferences of the handle region correlate with the conformations of Trp85, Thr92, and Val101. NMR residual dipolar coupling constants, three-bond scalar coupling constants, and chemical shifts experimentally define the conformational states of these residues and hence of the handle domain. These NMR parameters correlate with the Michaelis constants for RNHI homologues, confirming the important role of the handle region in the modulation of substrate recognition and illustrating the power of NMR spectroscopy in dissecting the conformational preferences underlying enzyme function.
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http://dx.doi.org/10.1021/acs.biochem.0c00500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737441PMC
September 2020