Functional range of motion of the cervical spine in cervical fusion patients during activities of daily living.

Following cervical spine fusion there is a reduction in maximum range of motion (ROM) but how this impacts activity of daily living (ADLs) and quality of life is unknown. This study's purpose is to quantify maximum and functional cervical spine ROM in patients with multi-level cervical fusion (>3 levels) compared to controls during ADLs and to correlate functional range of motion with scores from patient reported outcomes measures (PROs) including the Comparative Pain Scale (CPS), Fear Avoidance Belief Questionnaire (FABQ), and Neck Disability Index (NDI). An inertial measurement unit (IMU) system quantified ROM during ADLs in the extension/flexion, lateral bending, and axial rotation directions of motion. The reliability of this system was compared to standard optical motion tracking. Fourteen participants (8 females, age = 60.0 years (18.7) (median, (interquartile range)) with a history of multi-level cervical fusion (years post-op 0.9 (0.7)) were compared to 16 controls (13 females, age = 52.1 years (15.8)). PROs were collected for each participant. Fusion participants had significantly decreased maximum ROM in all directions of motion. Fusion participants had decreased ROM for some ADLs (backing up a car, using a phone, donning socks, negotiating stairs). CPS, FABQ, and NDI scores were significantly increased in fusion participants. Reductions in two activities (backing up a car, stair negotiation) correlated with a combination of increased PRO scores. Cervical fusion decreases maximum ROM and is correlated with increased PROs in some ADLs, however there is minimal impact on functional ROM. Investigation into velocity and acceleration may yield categorization of pathologic movement.

Glucocorticoid induced loss of oestrogen receptor alpha gene methylation and restoration of sensitivity to fulvestrant in triple negative breast cancer.

The response to psychological stress can differ depending on the type and duration of the stressor. Acute stress can facilitate a "fight or flight response" and aid survival, whereas chronic long-term stress with the persistent release of stress hormones such as cortisol has been shown to be detrimental to health. We are now beginning to understand how this stress hormone response impacts important processes such as DNA repair and cell proliferation processes in breast cancer. However, it is not known what epigenetic changes stress hormones induce in breast cancer. Epigenetic mechanisms include modification of DNA and histones within chromatin that may be involved in governing the transcriptional processes in cancer cells in response to changes by endogenous stress hormones. The contribution of endogenous acute or long-term exposure of glucocorticoid stress hormones, and exogenous glucocorticoids to methylation patterns in breast cancer tissues with different aetiologies remains to be evaluated. In vitro and in vivo models were developed to investigate the epigenetic modifications and their contribution to breast cancer progression and aetiology. A panel of triple negative breast cancer cell lines were treated with the glucocorticoid, cortisol which resulted in epigenetic alteration characterised by loss of methylation on promoter regions of tumour suppressor genes including ESR1, and loss of methylation on LINE-1 repetitive element used as a surrogate marker for global methylation. This was verified in vivo in MDA-MB-231 xenografts; the model verified the loss of methylation on ESR1 promoter, and subsequent increase in ESR1 expression in primary tumours in mice subjected to restraint stress. Our study highlights that DNA methylation landscape in breast cancer can be altered in response to stress and glucocorticoid treatment.

The function of BK channels extracted and purified within SMALPs.

Human BK channels are large voltage and Ca2+-activated K+ channels, involved in several important functions within the body. The core channel is a tetramer of α subunits, and its function is modulated by the presence of ß and γ accessory subunits. BK channels composed of α subunits, as well as BK channels composed of α and ß1 subunits, were successfully solubilised from HEK cells with styrene maleic acid (SMA) polymer and purified by nickel affinity chromatography. Native SMA-PAGE analysis of the purified proteins showed the α subunits were extracted as a tetramer. In the presence of ß1 subunits, they were co-extracted with the α subunits as a heteromeric complex. Purified SMA lipid particles (SMALPs) containing BK channel could be inserted into planar lipid bilayers (PLB) and single channel currents recorded, showing a high conductance (≈260 pS), as expected. The open probability was increased in the presence of co-purified ß1 subunits. However, voltage-dependent gating of the channel was restricted. In conclusion, we have demonstrated that SMA can be used to effectively extract and purify large, complex, human ion channels, from low expressing sources. That these large channels can be incorporated into PLB from SMALPs and display voltage-dependent channel activity. However, the SMA appears to reduce the voltage dependent gating of the channels.

Stability testing of the Pfizer-BioNTech BNT162b2 COVID-19 vaccine: a translational study in UK vaccination centres.

OBJECTIVE: The roll-out of the Pfizer-BioNTech BNT162b2 COVID-19 vaccine has brought many logistical challenges, such as the absence of comprehensive stability data leading to strict handling instructions during dilution and administration. Accidental mishandling therefore presents challenging clinical dilemmas, which often led vaccine providers to err on the side of caution and discard mishandled vials rather than risk administering ineffective vaccine. This study aims to answer key questions about the vaccine's stability to allow for a more informed decision-making process should a non-conformity occur. METHODS: Residual vaccine in freshly used, but appropriately stored vials collected from vaccination centres in Brighton, UK, were tested after exposure to various handling conditions and analysed by dynamic light scattering to determine the size of the lipid-mRNA nanoparticles, and gel electrophoresis to visualise the mRNA integrity and separation from the lipid formulation. RESULTS: Knocking or dropping vaccine samples from small heights resulted in lowest levels of instability, indicating low risk of compromising clinical efficacy. However, repeated drawing and injecting through 23 G needles at high speed and, more significantly, shaking and vortexing led to progressive increase in the size and polydispersity index of the lipid-mRNA nanoparticles, coupled with or caused by up to ~50% release of mRNA from the lipid formulation. This is thought to impact the vaccine's efficacy due to lack of free mRNA protection and cellular internalisation. CONCLUSIONS: These results reiterate the importance of adhering to the manufacturer's instructions on handling, especially with regard to shaking and exposing the vaccine to excessive vibration.

Advances in motion and electromyography based wearable technology for upper extremity function rehabilitation: A review.

STUDY DESIGN: Scoping review. INTRODUCTION: With the recent advances in technologies, interactive wearable technologies including inertial motion sensors and e-textiles are emerging in the field of rehabilitation to monitor and provide feedback and therapy remotely. PURPOSE OF THE STUDY: This review article focuses on inertial measurement unit motion sensor and e-textiles-based technologies and proposes approaches to augment these interactive wearable technologies. METHODS: We conducted a comprehensive search of relevant electronic databases (eg, PubMed, the Cumulative Index to Nursing and Allied Health Literature, Embase, PsycINFO, The Cochrane Central Register of Controlled Trial, and the Physiotherapy Evidence Database). The scoping review included all study designs. RESULTS: Currently, there are a numerous research groups and companies investigating inertial motion sensors and e-textiles-based interactive wearable technologies. However, translation of these technologies to the clinic would need further research to increase ease of use and improve clinical validity of the outcomes of these technologies. DISCUSSION: The current review discusses the limitations of the interactive wearable technologies such as, limited clinical utility, bulky equipment, difficulty in setting up equipment inertial motion sensors and e-textiles. CONCLUSION: There is tremendous potential for interactive wearable technologies in rehabilitation. With the evolution of cloud computing, interactive wearable systems can remotely provide intervention and monitor patient progress using models of telerehabilitation. This will revolutionize the delivery of rehabilitation and make rehabilitation more accessible and affordable to millions of individuals.

Estimating a drug's elimination rate-constant or half-life from a single blood sample: a practical approach with particular benefits for critically ill/vulnerable patients.

In this paper we present a mathematical solution that allows the elimination rate-constant or half life of a drug to be estimated from a single blood drug measurement. This is of great utility in clinical areas involving care of criticallly ill or vulnerable patients, where providing more than one blood sample can involve significant risks. The calculations used in our approach, based solely on a single sample, do not require complex pharmacokinetic software, but instead can be simply performed at the patient's bedside using standard personal computing tools. The proposed method allows a personalised estimate of the drug's half life, which is preferable to using population averages, or using estimates based on proxy markers of lagging organ function, which are both indirect and generally inaccurate for a patient with confounding factors.

Biomechanical Analysis of Wide Posterior Releases Compared With Inferior Facetectomy and Discectomy in the Thoracolumbar and Lumbar Spine.

STUDY DESIGN: In vitro biomechanical analysis. OBJECTIVES: Compare the destabilizing effects of anterior discectomy to posterior spinal releases. SUMMARY OF BACKGROUND DATA: Posterior release and pedicle screw fixation has become the accepted form of treatment for lumbar and thoracolumbar pediatric scoliotic spinal deformity. A biomechanical evaluation of posterior releases with comparison to traditional anterior releases has not been reported in the lumbar spine. METHODS: Eleven fresh-frozen human thoracolumbar specimens (T9-L5) were tested by a robotic manipulator (Staubli RX90; moment target of 5.0 Nm, force target of 50 N) in axial rotation (AR), plus lateral and anterior translation (LT and AT). Specimens underwent either sequential anterior release (partial and full discectomy) or posterior release (inferior facetectomy and wide posterior release) from T10 to L4. Partial discectomy retained the posterior 50% of disc and posterior longitudinal ligament, whereas full discectomy removed all of the disc and PLL. Wide posterior release included total facetectomy plus ligamentum flavum and spinous process resection. RESULTS: Inferior facetectomy produced an average increase of 1.5° ± 1.0° (p = .0625), 1.0 ± 0.8 mm (p = .0313), and 0.2 ± 0.3 mm (p = .156) in AR, LT, and AT, respectively. Compared with partial facetectomy, wide posterior release produced an average additional increase of 8.1° ± 4.0° (p = .0312), 2.0 ± 2.2 mm (p = .4062), and 1.1 ± 1.0 mm (p = .0625) in AR, LT, and AT, respectively. Full discectomy produced 201%, 161%, and 153% of the motion relative to wide posterior release in AR, LT, and AT, respectively (p = .0043, .0087, and .0173). Partial discectomy and wide posterior release proved statistically equivalent. CONCLUSIONS: Wide posterior release of the thoracolumbar spine allows significant correction and may be superior to inferior facetectomy in axial rotation. Although complete discectomy with PLL resection would likely allow greater correction, a more clinically realistic partial discectomy confers similar corrective potential in vitro compared with wide posterior release. LEVEL OF EVIDENCE: Not applicable.

Stress hormone-mediated acceleration of breast cancer metastasis is halted by inhibition of nitric oxide synthase.

Stress hormones have been shown to be important mediators in driving malignant growth and reducing treatment efficacy in breast cancer. Glucocorticoids can induce DNA damage through an inducible nitric oxide synthase (iNOS) mediated pathway to increase levels of nitric oxide (NO). Using an immune competent mouse breast cancer model and 66CL4 breast cancer cells we identified a novel role of NOS inhibition to reduce stress-induced breast cancer metastasis. On a mechanistic level we show that the glucocorticoid cortisol induces expression of keys genes associated with angiogenesis, as well as pro-tumourigenic immunomodulation. Transcriptomics analysis confirmed that in the lungs of tumour-bearing mice, stress significantly enriched pathways associated with tumourigenesis, some of which could be regulated with NOS inhibition. These results demonstrate the detrimental involvement of NOS in stress hormone signalling, and the potential future benefits of NOS inhibition in highly stressed patients.

Verification of a Portable Motion Tracking System for Remote Management of Physical Rehabilitation of the Knee.

Rehabilitation following knee injury or surgery is critical for recovery of function and independence. However, patient non-adherence remains a significant barrier to success. Remote rehabilitation using mobile health (mHealth) technologies have potential for improving adherence to and execution of home exercise. We developed a remote rehabilitation management system combining two wireless inertial measurement units (IMUs) with an interactive mobile application and a web-based clinician portal (interACTION). However, in order to translate interACTION into the clinical setting, it was first necessary to verify the efficacy of measuring knee motion during rehabilitation exercises for physical therapy and determine if visual feedback significantly improves the participant's ability to perform the exercises correctly. Therefore, the aim of this study was to verify the accuracy of the IMU-based knee angle measurement system during three common physical therapy exercises, quantify the effect of visual feedback on exercise performance, and understand the qualitative experience of the user interface through survey data. A convenience sample of ten healthy control participants were recruited for an IRB-approved protocol. Using the interACTION application in a controlled laboratory environment, participants performed ten repetitions of three knee rehabilitation exercises: heel slides, short arc quadriceps contractions, and sit-to-stand. The heel slide exercise was completed without feedback from the mobile application, then all exercises were performed with visual feedback. Exercises were recorded simultaneously by the IMU motion tracking sensors and a video-based motion tracking system. Validation showed moderate to good agreement between the two systems for all exercises and accuracy was within three degrees. Based on custom usability survey results, interACTION was well received. Overall, this study demonstrated the potential of interACTION to measure range of motion during rehabilitation exercises for physical therapy and visual feedback significantly improved the participant's ability to perform the exercises correctly.

Towards translational health policy: Findings from a state evaluation of programs targeting children with special health care needs.

PURPOSE: Current evidence-based research suggests that early evaluation, comprehensive care plans, and appropriate referrals for childhood and adolescent behavioral and development needs is critical for successful family-centered outcomes. The overall purpose of this study was to conduct an assessment of a state public health program that offers diagnostic evaluation and coordination for children with behavioral and developmental disorders in the state of Virginia (Child Development Center programs, or CDC). A secondary purpose was to provide translational policy and advocacy targets based on key findings. DESIGN AND METHOD: The evaluation of the scope of services of the CDC programs was done using qualitative interviews with a focus group interview (n = 23), interviews from representatives from individual centers ( n = 5 centers), and descriptive quantitative data elements for the fiscal year 2015. RESULTS: After conducting the state public health evaluation, several translational health policy priorities emerged, including: (a) the need for integrated data standards, (b) Lack of developmental pediatric workforce, particularly in rural sectors of the state, and (c) Need for enhanced program support for care coordination. CONCLUSION: Academic nurse and public health partnerships can aid in translation from research to policy among vulnerable populations and assist in communication to key stakeholders and legislators for iterative action and reassessment.

Using Geospatial Analysis to Determine Access Gaps Among Children with Special Healthcare Needs.

Purpose: To examine geospatial gaps in identification and evaluation of children with special healthcare needs (CSHCN) within public child development centers (CDCs). Methods: A descriptive geospatial design was used to visually depict service gaps, proximity, and clustering of area-level sociodemographic attributes of Virginia counties, and patient-level data within each CDC. Results: Geospatial analysis shows population density of uninsured children against CDC resources. Data visualization facilitates policy advocacy based on the identification of care and screening gaps for CSHCN. Conclusion: This project illustrates the collaborative potential between researchers and Health Department members to identify gaps in access to care.

Planar lipid bilayers in recombinant ion channel research.

There are a number of methods of investigating the function of recombinant proteins such as ion channels. However, after channel purification there are few methods to guarantee that the protein still functions. For ion channels, reconstituting back into planar lipid bilayers and demonstrating preserved function is a convenient and trusted method. It is cell free and even inaccessible, intracellular ion channels can be studied. We have used this method to study the function of recombinant channels of known subunit composition and have found it convenient for investigating the mode of action of ion channel modulators.

Impact of insulin signaling and proteasomal activity on physiological output of a neuronal circuit in aging Drosophila melanogaster.

The insulin family of growth factors plays an important role in development and function of the nervous system. Reduced insulin and insulin-growth-factor signaling (IIS), however, can improve symptoms of neurodegenerative diseases in laboratory model organisms and protect against age-associated decline in neuronal function. Recently, we showed that chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber escape response circuit. Here, we expand our initial findings by demonstrating that reduced functional output in the giant fiber system of aging flies can be prevented by increasing proteasomal activity within the circuit. Manipulations of IIS in neurons can also affect longevity, underscoring the relevance of the nervous system for aging.

Transfer of care - a randomised control trial investigating the effect of sending the details of patients' discharge medication to their community pharmacist on discharge from hospital.

OBJECTIVE: There is substantial evidence demonstrating that transferring patients between care providers is a high-risk area for medicines management. This study aimed to investigate the effect of sending patients' hospital discharge letters to their nominated community pharmacists on the number of discrepancies between the patient's general practitioner (GP) records and the discharge letter and between the patient's self-described medication regime and the discharge letter. METHODS: In a randomised, controlled trial, 33 participants in two groups, control and intervention, had their discharge letter sent to either their GP only or their GP and nominated community pharmacy after hospital discharge. At least 3 weeks after hospital discharge, the participant's current GP's medication record and their self-described medication regime was obtained. Discrepancies between their GP medication record and their discharge letter and between the participant's self-described medication regime and their discharge letter were counted. The number of discrepancies (relative to the number of drugs prescribed) in the intervention group was compared with the control group for each of the above two categories, using the chi-squared test to determine the statistical significance of any differences between the two groups. RESULTS: The intervention group had statistically fewer discrepancies than the control group for both data sets: GP records compared with the discharge letters (P < 0.0005); participants' self-described medication regimes compared with the discharge letters (P < 0.00005). CONCLUSIONS: Sending a copy of patients' discharge letters to their community pharmacists could be beneficial in reducing post-discharge prescribing discrepancies and improving patient understanding of the changes made to their medicines.

Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies.

Lowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the "insulin paradox"). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders.

A Nonlinear Dynamics-Based Estimator for Functional Electrical Stimulation: Preliminary Results From Lower-Leg Extension Experiments.

Miniature inertial measurement units (IMUs) are wearable sensors that measure limb segment or joint angles during dynamic movements. However, IMUs are generally prone to drift, external magnetic interference, and measurement noise. This paper presents a new class of nonlinear state estimation technique called state-dependent coefficient (SDC) estimation to accurately predict joint angles from IMU measurements. The SDC estimation method uses limb dynamics, instead of limb kinematics, to estimate the limb state. Importantly, the nonlinear limb dynamic model is formulated into state-dependent matrices that facilitate the estimator design without performing a Jacobian linearization. The estimation method is experimentally demonstrated to predict knee joint angle measurements during functional electrical stimulation of the quadriceps muscle. The nonlinear knee musculoskeletal model was identified through a series of experiments. The SDC estimator was then compared with an extended kalman filter (EKF), which uses a Jacobian linearization and a rotation matrix method, which uses a kinematic model instead of the dynamic model. Each estimator's performance was evaluated against the true value of the joint angle, which was measured through a rotary encoder. The experimental results showed that the SDC estimator, the rotation matrix method, and EKF had root mean square errors of 2.70°, 2.86°, and 4.42°, respectively. Our preliminary experimental results show the new estimator's advantage over the EKF method but a slight advantage over the rotation matrix method. However, the information from the dynamic model allows the SDC method to use only one IMU to measure the knee angle compared with the rotation matrix method that uses two IMUs to estimate the angle.

Mapping Geospatial Gaps in Early Identification of Children With Autism Spectrum Disorder.

Despite the known developmental benefits of early intervention for autism spectrum disorder (ASD), diagnosis before age 5 years is often not achieved. Research suggests that lack of health insurance and living in rural areas and areas of severe provider shortages contribute significantly to these delays. The purpose of this project was to conduct a geospatial evaluation of potential gaps in early ASD diagnosis of uninsured children in Virginia. A secondary purpose was to show the use of geospatial analysis by pediatric nurse practitioners for policy advocacy. We mapped data from a statewide provider of ASD evaluative services associated with the Virginia Department of Health and found several communities with high numbers of uninsured children where children may not be receiving early diagnostic services. Pediatric nurse practitioners can help address community-level gaps in early identification of ASD for uninsured young children living in rural areas by conducting outreach programs to providers and families within rural communities and concurrently partnering with nurse-scientists to develop visually impactful geospatial analyses to educate legislators and further advocate for policy positions.

Glucocorticoids induce production of reactive oxygen species/reactive nitrogen species and DNA damage through an iNOS mediated pathway in breast cancer.

BACKGROUND: Psychological stress increases the circulating levels of the stress hormones cortisol and norepinephrine (NE). Chronic exposure to elevated stress hormones has been linked to a reduced response to chemotherapy through induction of DNA damage. We hypothesize that stress hormone signalling may induce DNA damage through the production of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and interference in DNA repair processes, promoting tumourigenesis. METHODS: Breast cancer cell lines were incubated with physiological levels of cortisol and NE in the presence and absence of receptor antagonists and inducible nitric oxide synthase (iNOS) inhibitors and DNA damage measured using phosphorylated γ-H2AX. The rate of DNA repair was measured using comet assays and electrochemical sensors were used to detect ROS/RNS in the cell lysates from cells exposed to stress hormones. A syngeneic mouse model was used to assess the presence of iNOS in mammary tumours in stressed versus control animals and expression of iNOS was examined using western blotting and qRT-PCR. RESULTS: Acute exposure to cortisol and NE significantly increased levels of ROS/RNS and DNA damage and this effect was diminished in the presence of receptor antagonists. Cortisol induced DNA damage and the production of RNS was further attenuated in the presence of an iNOS inhibitor. An increase in the expression of iNOS in response to psychological stress was observed in vivo and in cortisol-treated cells. Inhibition of glucocorticoid receptor-associated Src kinase also produced a decrease in cortisol-induced RNS. CONCLUSION: These results demonstrate that glucocorticoids may interact with iNOS in a non-genomic manner to produce damaging levels of RNS, thus allowing an insight into the potential mechanisms by which psychological stress may impact breast cancer.

Acute paraquat exposure impairs colonic motility by selectively attenuating nitrergic signalling in the mouse.

Paraquat, a common herbicide, is responsible for large numbers of deaths worldwide through both deliberate and accidental ingestion. Previous studies have eluded that the bioavailability of paraquat increases substantially with increasing dose and that these changes may in part be due to the effects that these high concentrations have on the gastrointestinal tract (GI tract). To date, the actions of acute, high concentrations (20mM for 60 min) of paraquat on the GI tract, particularly the colon which is a major site of paraquat absorption, are unknown. This study examined the effects of acute paraquat administration on colonic motility in the C57BL/6 mouse. Acute paraquat exposure decreased colonic motility and the amplitude of colonic migrating motor complexes (CMMCs), which are major motor patterns involved in faecal pellet propulsion. In isolated segments of distal colon, paraquat increased resting tension and markedly attenuated electrical field stimulation-evoked relaxations. Pharmacological dissection of paraquat's mechanism of action on both the CMMCs and field stimulated tissue using the nitric oxide synthase inhibitor NG-nitro-L-arginine and direct measurement of NO release from the myenteric plexus, demonstrated that paraquat selectively attenuates nitrergic signalling pathways. These changes did not appear to be due to alterations in colonic oxidative stress, inflammation or complex 1 activity, but were most likely caused by paraquat's ability to act as a redox couple. In summary, these data demonstrate that acute paraquat exposure attenuates colonic transit. These changes may facilitate the absorption of paraquat into the circulation and so facilitate its toxicity.

A switch in the mode of the sodium/calcium exchanger underlies an age-related increase in the slow afterhyperpolarization.

During aging, the Ca(2+)-sensitive slow afterhyperpolarization (sAHP) of hippocampal neurons is known to increase in duration. This change has also been observed in the serotonergic cerebral giant cells (CGCs) of the pond snail Lymnaea stagnalis, but has yet to be characterized. In this article, we confirm that there is a reduction in firing rate, an increase in the duration of the sAHP, and an alteration in the strength and speed of spike frequency adaptation in the CGCs during aging, a finding that is compatible with an increase in the sAHP current. We go on to show that age-related changes in the kinetics of spike frequency adaptation are consistent with a reduction in Ca(2+) clearance from the cell, which we confirm with Ca(2+) imaging and pharmacological manipulation of the sodium calcium exchanger. These experiments suggest that the sodium calcium exchanger may be switching to a reverse-mode configuration in the CGCs during aging.