Neuromuscular control and resistance training for people with chronic low back pain: a randomized controlled trial.

OBJECTIVE: To determine if adding lumbar neuromuscular control retraining exercises to a 12-week program of strengthening exercises has greater effect for improving disability than 12 weeks of strengthening exercises alone in people with chronic low back pain (LBP). DESIGN: Single centre, participant and assessor-blinded, comparative effectiveness randomized controlled trial. METHODS: 69 participants (31 females; 29 males; mean age 46.5 years) with non-specific chronic LBP were recruited for a twelve-week program involving lumbar extension neuromuscular retraining in addition to resistance exercises (intervention) or 12 weeks of resistance exercises alone (control). The primary outcome measure was the Oswestry Disability Index. Secondary outcome measures included the Numeric Rating Scale, Tampa Scale for Kinesiophobia, Pain Self-efficacy Questionnaire, and the International Physical Activity Questionnaire. Outcomes were measured at baseline, 6 and 12 weeks. RESULTS: Forty-three participants (22 control; 21 intervention) completed all outcome measures at 6 and 12 weeks. Fourteen participants were lost to follow-up and 12 participants discontinued due to COVID-19 restrictions. Both groups demonstrated clinically important changes in disability, pain intensity and kinesiophobia. The difference between groups with respect to disability was imprecise and not clinically meaningful (mean difference, -4.4, 95% CI [-10.2, 1.4]) at 12 weeks. Differences in secondary outcomes at 6 or 12 weeks were also small with wide confidence intervals. CONCLUSIONS: Adding lumbar neuromuscular control retraining to a series of resistance exercises offered no additional benefit over resistance exercises alone over a 12-week period.

The acute influence of amateur boxing on dynamic cerebral autoregulation and cerebrovascular reactivity to carbon dioxide.

PURPOSE: The purpose of this study was to investigate the acute effect of head impacts, sustained over the course of three rounds of amateur boxing, on indices of cerebrovascular function. METHODS: Eighteen university amateur boxers (six female) completed three experimental trials in a randomised order; (1) three rounds of boxing (BOX), (2) an equivalent bout of pad boxing (where no blows to the head were sustained; PAD), and (3) a time-matched seated control trial (CON). Indices of cerebrovascular function were determined immediately before and 45 min after each trial. Specifically, dynamic cerebral autoregulation (dCA) was determined by considering the relationship between changes in cerebral blood velocity and mean arterial pressure during 5 min of squat-stand manoeuvres at 0.05 and 0.10 Hz. Cerebrovascular reactivity was determined using serial breath holding and hyperventilation attempts. RESULTS: Participants received an average of 40 ± 16 punches to the head during the BOX trial. Diastolic, mean and systolic dCA phase during squat stand manoeuvres at 0.05 Hz was lower after BOX compared to pre BOX (P ≤ 0.02, effect size (d) ≥ 0.74). No other alterations in dCA outcomes were observed at 0.05 or 0.10 Hz. The number of head impacts received during the BOX trial was associated with the change in systolic phase (r = 0.50, P = 0.03). No differences in cerebrovascular reactivity to breath holding or hyperventilation were observed. CONCLUSIONS: A typical bout of amateur boxing (i.e., three rounds) can subtly alter cerebral pressure-flow dynamics, and the magnitude of this change may be related to head impact exposure.

Flexible tape-drive target system for secondary high-intensity laser-driven sources.

We present the development of a flexible tape-drive target system to generate and control secondary high-intensity laser-plasma sources. Its adjustable design permits the generation of relativistic MeV particles and x rays at high-intensity (i.e., ≥1 × 1018 W cm-2) laser facilities, at high repetition rates (>1 Hz). The compact and robust structure shows good mechanical stability and a high target placement accuracy (<4 µm RMS). Its compact and flexible design allows for mounting in both the horizontal and vertical planes, which makes it practical for use in cluttered laser-plasma experimental setups. The design permits ∼170° of access on the laser-driver side and 120° of diagnostic access at the rear. A range of adapted apertures have been designed and tested to be easily implemented to the targetry system. The design and performance testing of the tape-drive system in the context of two experiments performed at the COMET laser facility at the Lawrence Livermore National Laboratory and at the Advanced Lasers and Extreme Photonics (ALEPH) facility at Colorado State University are discussed. Experimental data showing that the designed prototype is also able to both generate and focus high-intensity laser-driven protons at high repetition rates are also presented.

Modified realist evaluation of a complex, multi-centred, multi-intervention programme.

Well North was a complex, multi-intervention health improvement programme spanning 10 sites across the North of England. The aim was to address inequalities by improving the health of the poorest fastest, increasing resilience and reducing levels of worklessness. The intention of the programme was for all sites to have freedom and flexibility to conduct different interventions reflecting local priorities. Evaluation ran concurrently with the programme, and an iterative approach was required to ensure constant feedback, allowing the programme to be adapted and improved as necessary. Realist methodology was chosen for evaluation, as it provides insight into what works, for whom and in what circumstances. Due to the complex nature of the programme and diverse approaches, it was necessary to adapt the methodology to meet the needs of the evaluation. The Evaluation Team utilized a range of qualitative and quantitative techniques within the context of a Rapid Cycle Evaluation framework. For each project, Contexts, Mechanisms and Outcomes (CMOs) were identified at three stages and were incorporated into the CMO configuration, leading to the development of a middle range theory. Validation and testing of theory took place at every stage. Realist methodology was the most appropriate existing method. However, it still necessitated modification.

A coded aperture with sub-mean free-path thickness for neutron implosion geometry imaging on inertial confinement fusion and inertial fusion energy experiments.

Inertial confinement fusion and inertial fusion energy experiments diagnose the geometry of the fusion region through imaging of the neutrons released through fusion reactions. Pinhole arrays typically used for such imaging require thick substrates to obtain high contrast along with a small pinhole diameter to obtain high resolution capability, resulting in pinholes that have large aspect ratios. This leads to expensive pinhole arrays that have small solid angles and are difficult to align. Here, we propose a coded aperture with scatter and partial attenuation (CASPA) for fusion neutron imaging that relaxes the thick substrate requirement for good image contrast. These coded apertures are expected to scale to larger solid angles and are easier to align without sacrificing imaging resolution or throughput. We use Monte Carlo simulations (Geant4) to explore a coded aperture design to measure neutron implosion asymmetries on fusion experiments at the National Ignition Facility (NIF) and discuss the viability of this technique, matching the current nominal resolution of 10 µm. The results show that a 10 mm thick tungsten CASPA can image NIF implosions with neutron yields above 1014 with quality comparable to unprocessed data from a current NIF neutron imaging aperture. This CASPA substrate is 20 times thinner than the current aperture arrays for fusion neutron imaging and less than one mean free-path of 14.1 MeV neutrons through the substrate. Since the resolution, solid angle, and throughput are decoupled in coded aperture imaging, the resolution and solid angle achievable with future designs will be limited primarily by manufacturing capability.

Phytoplanktonic community and bio-optical properties in coastal waters of an Argentinian Patagonian gulf.

The influence of the phytoplankton community in the light absorption budget was quantified in coastal waters of the North region of the San Jorge Gulf (Argentinian Patagonia). The phytoplanktonic composition and their absorption spectra were determined. Nanoflagellates and diatoms were the dominant groups. The toxigenic dinoflagellate Dinophysis acuminata was recorded in all the sampling sites. The optical characterization of the particulate material showed that 60 % of the absorption at 443 nm and 88 % of absorption at 675 nm was due to phytoplankton. The contributions of phytoplankton to total absorption at 443 nm wavelengths reached 50 %. The absorption by chromophoric dissolved organic matter (CDOM) and non-algal particles (NAP) was predominant in turbulent waters (>60 %). This study shows the influence of submesoscale physical-biological interactions in the light absorption budget. The field absorption spectra of active optical components are of interest in the assessment and development of regional ocean color satellite algorithms.

The Lifetime Burden of Schizophrenia as Estimated by a Government-Centric Fiscal Analytic Framework.

Objective: To estimate the fiscal consequences of schizophrenia compared to the general US population using a "government perspective" fiscal analytic modeling framework capturing lost tax revenue and broader government costs in 2021.Methods: Schizophrenia was modeled from age 23 using a cohort-based Markov chain with 6-week cycles, simulating the effect of antipsychotic treatment sequences on remission and relapse. Markov states were defined using efficacy and safety outcomes from short- and long-term clinical trials. Mortality was based on US lifetables, schizophrenia-related suicide, and cardiovascular risks. A semi-Markov model with annual cycles simulated the likelihood and costs of incarceration and homelessness in community-based individuals. Lifetime fiscal consequences were estimated conditionally to survival, remission/relapse status, and likelihood of socioeconomic outcomes. Costs and life years were discounted at 3.0% annually. Uncertainty was explored in 1-way and scenario analyses.Results: Unemployment, disability, incarceration, homelessness, health care use, and productivity losses were more common in people living with schizophrenia. Schizophrenia was associated with a $1,540,042 per person lifetime fiscal loss to the government, with $56,707 per life year lived with schizophrenia. Health care costs represented 41.9% of the fiscal losses, 39.4% were due to criminal and homelessness costs, and 17.5% related to foregone tax revenue. Considering a 1.19% prevalence of schizophrenia, the estimated annual fiscal burden in the US was $173.6 billion.Conclusions: The fiscal framework illustrates how schizophrenia influences taxation and government transfer payments over time. These findings can be used to augment cost-effectiveness analyses and inform stakeholders of the fiscal impact of schizophrenia to inform priority interventions.

Strategies of nanoparticles integration in polymer fibers to achieve antibacterial effect and enhance cell proliferation with collagen production in tissue engineering scaffolds.

Current design strategies for biomedical tissue scaffolds are focused on multifunctionality to provide beneficial microenvironments to support tissue growth. We have developed a simple yet effective approach to create core-shell fibers of poly(3-hydroxybuty-rate-co-3-hydroxyvalerate) (PHBV), which are homogenously covered with titanium dioxide (TiO2) nanoparticles. Unlike the blend process, co-axial electrospinning enabled the uniform distribution of nanoparticles without the formation of large aggregates. We observed 5 orders of magnitude reduction in Escherichia coli survival after contact with electrospun scaffolds compared to the non-material control. In addition, our hybrid cores-shell structure supported significantly higher osteoblast proliferation after 7 days of cell culture and profound generation of 3D networked collagen fibers after 14 days. The organic-inorganic composite scaffold produced in this study demonstrates a unique combination of antibacterial properties and increased bone regeneration properties. In summary, the multifunctionality of the presented core-shell cPHBV+sTiO2 scaffolds shows great promise for biomedical applications.

Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease.

Dopaminergic cell loss due to the accumulation of α-syn is a core feature of the pathogenesis of Parkinson disease. Neuroinflammation specifically induced by α-synuclein has been shown to exacerbate neurodegeneration, yet the role of central nervous system (CNS) resident macrophages in this process remains unclear. We found that a specific subset of CNS resident macrophages, border-associated macrophages (BAMs), play an essential role in mediating α-synuclein related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response whereas the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, α-synuclein expression led to an expansion in border-associated macrophage numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that border-associated macrophages played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, border-associated macrophages were identified in post-mortem PD brain in close proximity to T cells. These results point to a role for border-associated macrophages in mediating the pathogenesis of Parkinson disease through their role in the orchestration of the α-synuclein-mediated neuroinflammatory response.

Integrating the patients' voice in designing and delivering a research study: The Yorkshire Cancer Research funded PREHABS study's experience.

INTRODUCTION: Engaging with patients when designing a clinical or research project is beneficial; feedback from the intended audience provides invaluable insight form the patients' perspective. Working with patients can result in developing successful research grants and interventions. The benefit of including the voice of the patient in the Yorkshire Cancer Research funded PREHABS study is described in this article. METHODS: Patients were included in the PREHABS study from inception to completion. The Theory of Change methodology was used to provide a framework to implement patient feedback to refine the study intervention. RESULTS: In total, 69 patients engaged with the PREHABS project. Two patients were recruited as co-applicants on the grant and were members on the Trial Management Group. Six patients attended the pre application workshop and provided feedback on their lived experiences of being a lung cancer patient. Commentary from the patients influenced the interventions selected and the design of the prehabs study. Following ethical approval (21/EE/0048) and informed written consent, 61 patients were recruited into the PREHABS study between October 2021 and November 2022. The breakdown of recruited patients was 19 males: mean age 69.1 years (SD 8.91) and 41 females; mean age 74.9 years (SD 8.9). CONCLUSION: It is practicable and beneficial to include patients at all stages of designing and delivering a research study. Patient feedback can help refine the study interventions to allow for maximum acceptance, recruitment and retention. IMPLICATIONS FOR PRACTICE: Including patients in the design of radiotherapy research studies can provide invaluable insight that can support the selection and delivery of interventions that are acceptable to the patient cohort.

Integrating EM and Patch-seq data: Synaptic connectivity and target specificity of predicted Sst transcriptomic types.

Neural circuit function is shaped both by the cell types that comprise the circuit and the connections between those cell types 1 . Neural cell types have previously been defined by morphology 2, 3 , electrophysiology 4, 5 , transcriptomic expression 6-8 , connectivity 9-13 , or even a combination of such modalities 14-16 . More recently, the Patch-seq technique has enabled the characterization of morphology (M), electrophysiology (E), and transcriptomic (T) properties from individual cells 17-20 . Using this technique, these properties were integrated to define 28, inhibitory multimodal, MET-types in mouse primary visual cortex 21 . It is unknown how these MET-types connect within the broader cortical circuitry however. Here we show that we can predict the MET-type identity of inhibitory cells within a large-scale electron microscopy (EM) dataset and these MET-types have distinct ultrastructural features and synapse connectivity patterns. We found that EM Martinotti cells, a well defined morphological cell type 22, 23 known to be Somatostatin positive (Sst+) 24, 25 , were successfully predicted to belong to Sst+ MET-types. Each identified MET-type had distinct axon myelination patterns and synapsed onto specific excitatory targets. Our results demonstrate that morphological features can be used to link cell type identities across imaging modalities, which enables further comparison of connectivity in relation to transcriptomic or electrophysiological properties. Furthermore, our results show that MET-types have distinct connectivity patterns, supporting the use of MET-types and connectivity to meaningfully define cell types.

A flexible proton beam imaging energy spectrometer (PROBIES) for high repetition rate or single-shot high energy density (HED) experiments (invited).

The PROBIES diagnostic is a new, highly flexible, imaging and energy spectrometer designed for laser-accelerated protons. The diagnostic can detect low-mode spatial variations in the proton beam profile while resolving multiple energies on a single detector or more. When a radiochromic film stack is employed for "single-shot mode," the energy resolution of the stack can be greatly increased while reducing the need for large numbers of films; for example, a recently deployed version allowed for 180 unique energy measurements spanning ∼3 to 75 MeV with <0.4 MeV resolution using just 20 films vs 180 for a comparable traditional film and filter stack. When utilized with a scintillator, the diagnostic can be run in high-rep-rate (>Hz rate) mode to recover nine proton energy bins. We also demonstrate a deep learning-based method to analyze data from synthetic PROBIES images with greater than 95% accuracy on sub-millisecond timescales and retrained with experimental data to analyze real-world images on sub-millisecond time-scales with comparable accuracy.

The direct effect of fibroblast growth factor 23 on vascular smooth muscle cell phenotype and function.

BACKGROUND: In chronic kidney disease (CKD) patients, increased levels of fibroblast growth factor 23 (FGF23) are associated with cardiovascular mortality. The relationship between FGF23 and heart hypertrophy has been documented, however, it is not known whether FGF23 has an effect on vasculature. Vascular smooth muscle cells VSMCs may exhibit different phenotypes; our hypothesis is that FGF23 favours a switch from a contractile to synthetic phenotype that may cause vascular dysfunction. Our objective was to determine whether FGF23 may directly control a change in VSMC phenotype. METHODS: This study includes in vitro, in vivo and ex vivo experiments and evaluation of patients with CKD stages 2-3 studying a relationship between FGF23 and vascular dysfunction. RESULTS: In vitro studies show that high levels of FGF23, by acting on its specific receptor FGFR1 and Erk1/2, causes a change in the phenotype of VSMCs from contractile to synthetic. This change is mediated by a downregulation of miR-221/222, which augments the expression of MAP3K2 and PAK1. miR-221/222 transfections recovered the contractile phenotype of VSMCs. Infusion of recombinant FGF23 to rats increased vascular wall thickness, with VSMCs showing a synthetic phenotype with a reduction of miR-221 expression. Ex-vivo studies on aortic rings demonstrate also that high FGF23 increases arterial stiffening. In CKD 2-3 patients, elevation of FGF23 was associated with increased pulse wave velocity and reduced plasma levels of miR-221/222. CONCLUSION: In VSMCs, high levels of FGF23, through the downregulation of miR-221/222, causes a change to a synthetic phenotype. This change in VSMCs increases arterial stiffening and impairs vascular function, which might ultimately worsen cardiovascular disease.

Current issues and future directions in gymnastics research: biomechanics, motor control and coaching interface.

The sport of gymnastics is undergoing a global examination of its culture and the relationship between the gymnast, coach and environment is a central focus. The aim of this review is to explore biomechanics and motor control research in skill development and technique selection in artistic gymnastics with a focus on the underlying concepts and scientific principles that allow performance enhancement, skill development and injury risk reduction. The current review examines peer reviewed papers from 2000 onwards, with a focus on contemporary approaches in the field of gymnastics research, and highlights several key directions for future gymnastics research. Based on our review and the integration of the models of Newell (1986) and Irwin et al. (2005), we recommend that future gymnastics research should embrace at the very least a multidisciplinary approach and aim for an interdisciplinary paradigm.

Local delivery of tacrolimus using electrospun poly-ϵ-caprolactone nanofibres suppresses the T-cell response to peripheral nerve allografts.

Objective.Repair of nerve gap injuries can be achieved through nerve autografting, but this approach is restricted by limited tissue supply and donor site morbidity. The use of living nerve allografts would provide an abundant tissue source, improving outcomes following peripheral nerve injury. Currently this approach is not used due to the requirement for systemic immunosuppression, to prevent donor-derived cells within the transplanted nerve causing an immune response, which is associated with severe adverse effects. The aim of this study was to develop a method for delivering immunosuppression locally, then to test its effectiveness in reducing the immune response to transplanted tissue in a rat model of nerve allograft repair.Approach.A coaxial electrospinning approach was used to produce poly-ϵ-caprolactone fibre sheets loaded with the immunosuppressant tacrolimus. The material was characterised in terms of structure and tacrolimus release, then testedin vivothrough implantation in a rat sciatic nerve allograft model with immunologically mismatched host and donor tissue.Main results.Following successful drug encapsulation, the fibre sheets showed nanofibrous structure and controlled release of tacrolimus over several weeks. Materials containing tacrolimus (and blank material controls) were implanted around the nerve graft at the time of allograft or autograft repair. The fibre sheets were well tolerated by the animals and tacrolimus release resulted in a significant reduction in lymphocyte infiltration at 3 weeks post-transplantation.Significance.These findings demonstrate proof of concept for a novel nanofibrous biomaterial-based targeted drug delivery strategy for immunosuppression in peripheral nerve allografting.

Characterization of a 1D-imaging high-energy x-ray backlighter driven by the National Ignition Facility Advanced Radiographic Capability laser.

Plastic deformation of samples compressed to Mbar pressures at high strain rates at the National Ignition Facility (NIF) forms the basis of ongoing material strength experiments in conditions relevant to meteor impacts, geophysics, armor development, and inertial confinement fusion. Hard x-ray radiography is the primary means of measuring the evolution of these samples, typically employing a slit-collimated high-Z microdot driven by the NIF laser to generate >40 keV x rays [E. Gumbrell et al., Rev. Sci. Instrum. 89, 10G118 (2018) and C. M. Huntington et al., Rev. Sci. Instrum. 89, 10G121 (2018)]. Alternatively, a dysprosium "micro-flag" target driven by the Advanced Radiographic Capability laser (∼2 kJ, 10 ps) can deliver significantly higher spatiotemporal resolution [M. P. Hill et al., Rev. Sci. Instrum. 92, 033535 (2021)], especially in high-opacity samples. Initial experiments revealed problematic brightness and spectral gradients from this source, but by radiographing a set of diamond-turned, 105 µm-thick Pb test objects and supported by simulations using the 3D Monte Carlo code GEANT4, these geometry-dependent gradients across the field of view are quantified and mitigation strategies are assessed. In addition to significantly enhancing the modulation transfer function compared to the existing system, image stacking from multiple layers of image plate is shown to almost double the signal to noise ratio that will reduce uncertainties in future dynamic strength experiments.

Comparative economic outcomes in patients with focal seizures initiating eslicarbazepine acetate versus brivaracetam in the long-term care setting in the USA.

Aim: To compare all-cause and epilepsy-specific pharmacy and total costs associated with initiation of eslicarbazepine acetate (ESL) or brivaracetam (BRV) among patients with focal seizures in long-term care (LTC) in the US. Methods: This retrospective analysis used data from IQVIA's New Data Warehouse. Results: 298 patients initiated ESL and 282 patients initiated BRV. Initiation of ESL versus BRV was associated with 33.3% lower all-cause pharmacy costs, 34.4% lower epilepsy-specific pharmacy costs, 21.3% lower all-cause total costs and 30.9% lower epilepsy-specific total costs (all p < 0.0001). Conclusion: Among patients with focal seizures in LTC in the US, initiation of ESL versus BRV was associated with significant reductions in all-cause and epilepsy-specific pharmacy and total costs compared with initiation of BRV.