Disease progression and clinical outcomes in latent osteoarthritis phenotypes: Data from the Osteoarthritis Initiative.

The prevalence of knee osteoarthritis (OA) is widespread and the heterogeneous patient factors and clinical symptoms in OA patients impede developing personalized treatments for OA patients. In this study, we used unsupervised and supervised machine learning to organize the heterogeneity in knee OA patients and predict disease progression in individuals from the Osteoarthritis Initiative (OAI) dataset. We identified four distinct knee OA phenotypes using unsupervised learning that were defined by nutrition, disability, stiffness, and pain (knee and back) and were strongly related to disease fate. Interestingly, the absence of supplemental vitamins from an individual's diet was protective from disease progression. Moreover, we established a phenotyping tool and prognostic model from 5 variables (WOMAC disability score of the right knee, WOMAC total score of the right knee, WOMAC total score of the left knee, supplemental vitamins and minerals frequency, and antioxidant combination multivitamins frequency) that can be utilized in clinical practice to determine the risk of knee OA progression in individual patients. We also developed a prognostic model to estimate the risk for total knee replacement and provide suggestions for modifiable variables to improve long-term knee health. This combination of unsupervised and supervised data-driven tools provides a framework to identify knee OA phenotype in a clinical scenario and personalize treatment strategies.

Disease progression and clinical outcomes in latent osteoarthritis phenotypes: Data from the Osteoarthritis Initiative.

The prevalence of knee osteoarthritis (OA) is widespread and the heterogeneous patient factors and clinical symptoms in OA patients impede developing personalized treatments for OA patients. In this study, we used unsupervised and supervised machine learning to organize the heterogeneity in knee OA patients and predict disease progression in individuals from the Osteoarthritis Initiative (OAI) dataset. We identified four distinct knee OA phenotypes using unsupervised learning that were defined by nutrition, disability, stiffness, and pain (knee and back) and were strongly related to disease fate. Interestingly, the absence of supplemental vitamins from an individual's diet was protective from disease progression. Moreover, we established a phenotyping tool and prognostic model from 5 variables (WOMAC disability score of the right knee, WOMAC total score of the right knee, WOMAC total score of the left knee, supplemental vitamins and minerals frequency, and antioxidant combination multivitamins frequency) that can be utilized in clinical practice to determine the risk of knee OA progression in individual patients. We also developed a prognostic model to estimate the risk for total knee replacement and provide suggestions for modifiable variables to improve long-term knee health. This combination of unsupervised and supervised data-driven tools provides a framework to identify knee OA phenotype in a clinical scenario and personalize treatment strategies.

Developing an integrated multilevel model of uncertainty in health care: a qualitative systematic review and thematic synthesis.

INTRODUCTION: Uncertainty is an inevitable part of healthcare and a source of confusion and challenge to decision-making. Several taxonomies of uncertainty have been developed, but mainly focus on decisions in clinical settings. Our goal was to develop a holistic model of uncertainty that can be applied to both clinical as well as public and global health scenarios. METHODS: We searched Medline, Embase, CINAHL, Scopus and Google scholar in March 2021 for literature reviews, qualitative studies and case studies related to classifications or models of uncertainty in healthcare. Empirical articles were assessed for study limitations using the Critical Appraisal Skills Programme (CASP) checklist. We synthesised the literature using a thematic analysis and developed a dynamic multilevel model of uncertainty. We sought patient input to assess relatability of the model and applied it to two case examples. RESULTS: We screened 4125 studies and included 15 empirical studies, 13 literature reviews and 5 case studies. We identified 77 codes and organised these into 26 descriptive and 11 analytical themes of uncertainty. The themes identified are global, public health, healthcare system, clinical, ethical, relational, personal, knowledge exchange, epistemic, aleatoric and parameter uncertainty. The themes were included in a model, which captures the macro, meso and microlevels and the inter-relatedness of uncertainty. We successfully piloted the model on one public health example and an environmental topic. The main limitations are that the research input into our model predominantly came from North America and Europe, and that we have not yet tested the model in a real-life setting. CONCLUSION: We developed a model that can comprehensively capture uncertainty in public and global health scenarios. It builds on models that focus solely on clinical settings by including social and political contexts and emphasising the dynamic interplay between different areas of uncertainty.

Body-size dependent foraging strategies in the Christmas Island flying-fox: implications for seed and pollen dispersal within a threatened island ecosystem.

BACKGROUND: Animals are important vectors for the dispersal of a wide variety of plant species, and thus play a key role in maintaining the health and biodiversity of natural ecosystems. On oceanic islands, flying-foxes are often the only seed dispersers or pollinators. However, many flying-fox populations are currently in decline, particularly those of insular species, and this has consequences for the ecological services they provide. Knowledge of the drivers and the scale of flying-fox movements is important in determining the ecological roles that flying-foxes play on islands. This information is also useful for understanding the potential long-term consequences for forest dynamics resulting from population declines or extinction, and so can aid in the development of evidence-based ecological management strategies. To these ends, we examined the foraging movements, floral resource use, and social interactions of the Critically Endangered Christmas Island flying-fox (Pteropus natalis). METHODS: Utilization distributions, using movement-based kernel estimates (MBKE) were generated to determine nightly foraging movements of GPS-tracked P. natalis (n = 24). Generalized linear models (GLMs), linear mixed-effect models (LMMs), and Generalized linear mixed-effects model (GLMMs) were constructed to explain how intrinsic factors (body mass, skeletal size, and sex) affected the extent of foraging movements. In addition, we identified pollen collected from facial and body swabs of P. natalis (n = 216) to determine foraging resource use. Direct observations (n = 272) of foraging P. natalis enabled us to assess the various behaviors used to defend foraging resources. RESULTS: Larger P. natalis individuals spent more time foraging and less time traveling between foraging patches, traveled shorter nightly distances, and had smaller overall foraging ranges than smaller conspecifics. Additionally, larger individuals visited a lower diversity of floral resources. CONCLUSIONS: Our findings suggest that smaller P. natalis individuals are the primary vectors of long-distance dispersal of pollen and digested seeds in this species, providing a vital mechanism for maintaining the flow of plant genetic diversity across Christmas Island. Overall, our study highlights the need for more holistic research approaches that incorporate population demographics when assessing a species' ecological services.

A Systematic Review of the Effect of Centella asiatica on Wound Healing.

BACKGROUND: Under metabolic stress conditions, there is a higher demand for nutrients which needs to be met. This is to reduce the risk of delay in wound healing which could lead to chronic wound. AIM: This is a systematic review of the effect of Centella asiatica on wound healing. C. asiatica is a traditional medicinal plant used due to its antimicrobial, antioxidant, anti-inflammatory, neuroprotective, and wound healing properties. METHODS: PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed for the systematic review and four electronic databases were used. RESULTS: Four clinical trials met the inclusion criteria. The following distinct areas were identified under C. asiatica: wound contraction and granulation; healing/bleeding time and re-epithelialization; VAS (visual analogue scale) scores; skin erythema and wound appearance. CONCLUSIONS: C. asiatica might enhance wound healing resulting from improved angiogenesis. This might occur due to its stimulating effect on collagen I, Fibroblast Growth Factor (FGF) and Vascular Endothelial Growth Factor (VEGF) production. Besides, C. asiatica has shown an anti-inflammatory effect observed by the reduction in Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6) and Tumour Necrosis Factor α (TNFα), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), and lipoxygenase (LOX) activity. Delivery systems such as nanoencapsulation could be used to increase C. asiatica bioavailability. Nevertheless, more studies are needed in order to perform a meta-analysis and ascertain the effects of C. asiatica on wound healing and its different parameters.

Management of Primary Aggressive Tumors of the Knee.

Primary bone sarcomas and aggressive benign bone tumors are relatively rare. It is essential to recognize features that are concerning for these aggressive tumors based on a patient's history, physical exam, and radiographs. Physicians and other health care providers should have a high suspicion for these tumors and promptly refer these patients to orthopaedic oncologists. A multidisciplinary, team-based approach is required to obtain an accurate diagnosis and provide comprehensive care. This review discussed the appropriate work-up, biopsy principles, relevant peri-operative medical management, and surgical treatment options for patients with aggressive primary bone tumors around the knee. Primary bone sarcomas (osteosarcoma and chondrosarcoma) and aggressive benign bone tumors (giant cell tumor, chondroblastoma, and chondromyxoid fibroma) that have a predilection to the distal femur and proximal tibia are the focus of this review.

Risk of hospitalization and mortality associated with uncontrolled blood pressure in patients with hypertension and COVID-19.

OBJECTIVE: The role of uncontrolled blood pressure (BP) in COVID-19 severity among patients with hypertension is unclear. We evaluated the association between uncontrolled BP and the risk of hospitalization and/or mortality in patients with hypertension from a large US integrated healthcare system. METHODS: We identified patients with hypertension and a positive RT-PCR test result or a diagnosis of COVID-19 between March 1 - September 1, 2020 from Kaiser Permanente Southern California. BP categories was defined using the most recent outpatient BP measurement during 12 months prior to COVID-19 infection. The primary outcome of interest was all-cause hospitalization or mortality within 30 days from COVID-19 infection. RESULTS: Among 12,548 patients with hypertension and COVID-19 (mean age = 60 years, 47% male), 63% had uncontrolled BP (≥130/80 mm Hg) prior to COVID-19. Twenty-one percent were hospitalized or died within 30 days of COVID-19 infection. Uncontrolled BP was not associated with higher hospitalization or mortality (adjusted rate ratios for BP ≥ 160/100 mm Hg vs < 130/80 mm Hg = 1.00 [95% CI: 0.87, 1.14]; BP 140-159/90-99 mm Hg vs < 130/80 mm Hg = 1.02 [95% CI: 0.93, 1.11]). These findings were consistent across different age groups, treatment for antihypertensive medications, as well as atherosclerotic cardiovascular disease risk. CONCLUSION: Among patients with hypertension, uncontrolled BP prior to COVID-19 infection did not appear to be an important risk factor for 30-day mortality or hospitalization.

The Effect of Amino Acids on Wound Healing: A Systematic Review and Meta-Analysis on Arginine and Glutamine.

Under stress conditions, the metabolic demand for nutrients increases, which, if not met, may slow down or indeed stop the wound from healing, thus, becoming chronic wounds. This study aims to perform a systematic review and meta-analysis of the effect of arginine and glutamine supplementation on wound healing. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed for the systematic review and ten electronic databases were used. Five and 39 human studies met the inclusion criteria for arginine and glutamine, respectively. The overall meta-analysis demonstrated a significant effect of arginine supplementation on hydroxyproline content (MD: 4.49, 95% CI: 3.54, 4.45, p < 0.00001). Regarding glutamine supplementation, there was significant effect on nitrogen balance levels (MD: 0.39, 95% CI: 0.21, 0.58, p < 0.0001), IL-6 levels (MD: -5.78, 95% CI: -8.71, -2.86, p = 0.0001), TNFα levels (MD: -8.15, 95% CI: -9.34, -6.96, p < 0.00001), lactulose/mannitol (L/M) ratio (MD: -0.01, 95% CI: -0.02, -0.01, p < 0.00001), patient mortality (OR: 0.48, 95% CI: 0.32, 0.72, p = 0.0004), C-reactive protein (CRP) levels (MD: -1.10, 95% CI: -1.26, -0.93, p < 0.00001) and length of hospital stay (LOS) (MD: -2.65, 95% CI: -3.10, -2.21, p < 0.00001). Regarding T-cell lymphocytes, a slight decrease was observed, although it failed to reach significance (MD: -0.16, 95% CI: -0.33, 0.01, p = 0.07). Conclusion: The wound healing might be enhanced in one or at various stages by nutritional supplementation in the right dose.

Ultrasound-on-chip platform for medical imaging, analysis, and collective intelligence.

Over the past half-century, ultrasound imaging has become a key technology for assessing an ever-widening range of medical conditions at all stages of life. Despite ultrasound's proven value, expensive systems that require domain expertise in image acquisition and interpretation have limited its broad adoption. The proliferation of portable and low-cost ultrasound imaging can improve global health and also enable broad clinical and academic studies with great impact on the fields of medicine. Here, we describe the design of a complete ultrasound-on-chip, the first to be cleared by the Food and Drug Administration for 13 indications, comprising a two-dimensional array of silicon-based microelectromechanical systems (MEMS) ultrasonic sensors directly integrated into complementary metal-oxide-semiconductor-based control and processing electronics to enable an inexpensive whole-body imaging probe. The fabrication and design of the transducer array with on-chip analog and digital circuits, having an operating power consumption of 3 W or less, are described, in which approximately 9,000 seven-level feedback-based pulsers are individually addressable to each MEMS element and more than 11,000 amplifiers, more than 1,100 analog-to-digital converters, and more than 1 trillion operations per second are implemented. We quantify the measured performance and the ability to image areas of the body that traditionally takes three separate probes. Additionally, two applications of this platform are described-augmented reality assistance that guides the user in the acquisition of diagnostic-quality images of the heart and algorithms that automate the measurement of cardiac ejection fraction, an indicator of heart health.

COVID-19 morbidity and mortality associated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers use among 14,129 patients with hypertension from a US integrated healthcare system.

OBJECTIVE: Although recent evidence suggests no increased risk of severe COVID-19 outcomes associated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) use, the relationship is less clear among patients with hypertension and diverse racial/ethnic groups. This study evaluates the risk of hospitalization and mortality among patients with hypertension and COVID-19 in a large US integrated healthcare system. METHODS: Patients with hypertension and COVID-19 (between March 1- September 1, 2020) on ACEIs or ARBs were compared with patients on other frequently used antihypertensive medications. RESULTS: Among 14,129 patients with hypertension and COVID-19 infection (mean age 60 years, 48% men, 58% Hispanic), 21% were admitted to the hospital within 30 days of COVID-19 infection. Of the hospitalized patients, 24% were admitted to intensive care units, 17% required mechanical ventilation, and 10% died within 30 days of COVID-19 infection. Exposure to ACEIs or ARBs prior to COVID-19 infection was not associated with an increased risk of hospitalization or all-cause mortality (rate ratios for ACEIs vs other antihypertensive medications â€‹= â€‹0.98, 95% CI: 0.88, 1.08; ARBs vs others â€‹= â€‹1.00, 95% CI: 0.90, 1.11) after applying inverse probability of treatment weights. These associations were consistent across racial/ethnic groups. Use of ACEIs or ARBs during hospitalization was associated with a lower risk of all-cause mortality (odds ratios for ACEIs or ARBs vs others â€‹= â€‹0.50, 95% CI: 0.34, 0.72). CONCLUSION: Our study findings support continuation of ACEI or ARB use for patients with hypertension during the COVID-19 pandemic and after COVID-19 infection.

Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers Use and COVID-19 Infection Among 824 650 Patients With Hypertension From a US Integrated Healthcare System.

Background Previous reports suggest that the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) may upregulate angiotensin-converting enzyme 2 receptors and increase severe acute respiratory syndrome coronavirus 2 infectivity. We evaluated the association between ACEI or ARB use and coronavirus disease 2019 (COVID-19) infection among patients with hypertension. Methods and Results We identified patients with hypertension as of March 1, 2020 (index date) from Kaiser Permanente Southern California. Patients who received ACEIs, ARBs, calcium channel blockers, beta blockers, thiazide diuretics (TD), or no therapy were identified using outpatient pharmacy data covering the index date. Outcome of interest was a positive reverse transcription polymerase chain reaction test for COVID-19 between March 1 and May 6, 2020. Patient sociodemographic and clinical characteristics were identified within 1 year preindex date. Among 824 650 patients with hypertension, 16 898 (2.0%) were tested for COVID-19. Of those tested, 1794 (10.6%) had a positive result. Overall, exposure to ACEIs or ARBs was not statistically significantly associated with COVID-19 infection after propensity score adjustment (odds ratio [OR], 1.06; 95% CI, 0.90-1.25) for ACEIs versus calcium channel blockers/beta blockers/TD; OR, 1.10; 95% CI, 0.91-1.31 for ARBs versus calcium channel blockers/beta blockers/TD). The associations between ACEI use and COVID-19 infection varied in different age groups (P-interaction=0.03). ACEI use was associated with lower odds of COVID-19 among those aged ≥85 years (OR, 0.30; 95% CI, 0.12-0.77). Use of no antihypertensive medication was significantly associated with increased odds of COVID-19 infection compared with calcium channel blockers/beta blockers/TD (OR, 1.32; 95% CI, 1.11-1.56). Conclusions Neither ACEI nor ARB use was associated with increased likelihood of COVID-19 infection. Decreased odds of COVID-19 infection among adults ≥85 years using ACEIs warrants further investigation.

Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening.

The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.

Spinal cord direct current stimulation differentially modulates neuronal activity in the dorsal and ventral spinal cord.

Spinal cord direct current stimulation (sDCS) has the potential for promoting motor function after injury through its modulatory actions on sensory processing, reflex functions, the motor cortex (M1) motor map, and motor output. Here we addressed systems-level mechanisms underlying sDCS neuromodulation of spinal circuits activated by M1 and peripheral forelimb electrical stimulation in anesthetized healthy rats. We determined the effects of cathodal and anodal sDCS (c- and a-sDCS) on local field potentials (LFP) and single-unit activity recorded at 32 sites simultaneously within the sixth cervical segment using a silicon multielectrode array. M1 stimulation produced distinctive dorsomedial and ventral LFP responses that showed polarity-dependent sDCS modulation. c-sDCS enhanced and a-sDCS depressed significantly ventral M1 responses; neither modulated dorsal responses significantly. Using evoked changes in ß- and γ-oscillations to assay network function, c-sDCS enhanced and a-sDCS reduced oscillation power ventrally. c-sDCS increased and a-sDCS decreased background firing and firing synchrony of recorded pairs of single units. Peripheral stimulation produced a region-dependent response that showed polarity-dependent sDCS modulation. The dorsomedial LFP was unaffected by c-sDCS and weakly suppressed with a-sDCS. Peripheral-evoked unit responses showed limited polarity dependence. Our findings stress that ventral motor network behavior is enhanced by the neuromodulatory actions of c-sDCS. The combined actions of c-sDCS on M1-evoked neural responses and network behavior in the cervical spinal cord help explain the reported enhanced motor effects of this neuromodulation approach and inform the mechanisms of sDCS for promoting motor rehabilitation after spinal cord or brain injury.NEW & NOTEWORTHY Spinal cord direct current stimulation (sDCS) modulates spinal functions and shows potential for neural rehabilitation after motor systems injury. Using a multichannel electrode array, we found that cathodal DCS enhanced, and anodal depressed, M1-evoked local field potentials, network oscillations, neuronal activity, and neuronal synchrony, especially in the ventral horn. With this new understanding, it is hoped that sDCS can be developed into a tunable spinal neuromodulatory tool for promoting function after brain or spinal injury.

Orbitide Composition of the Flax Core Collection (FCC).

The flax (Linum usitatissimum L.) core collection (FCC) was regenerated in Saskatoon, Saskatchewan and Morden, Manitoba in 2009. Seed orbitide content and composition from successfully propagated plants of 391 accessions were analyzed using high-throughput analyses employing high-performance liquid chromatography (HPLC) with reverse-phase monolithic HPLC columns and diode array detection (HPLC-DAD). Seed from plants regenerated in Morden had comparatively higher orbitide content than those grown in Saskatoon. Concentrations of orbitides encoded by contig AFSQ01016651.1 (1, 3, and 8) were higher than those encoded by AFSQ01025165.1 (6, 13, and 17) for most accessions in both locations. The cultivar 'Primus' from Poland and an unnamed accession (CN 101580 of unknown origin) exhibited the highest ratio of sum of [1,3,8] to a sum of [6,13,17]. Conversely, the lowest orbitide concentrations and ratio of [1,3,8] to [6,13,17] were observed in cultivars 'Hollandia' and 'Z 11637', both from The Netherlands. Orbitide expression did not correlate with flax morphological and other chemical traits.

A picture of health? Animal use and the Faraday traditional medicine market, South Africa.

ETHNOPHARMACOLOGICAL RELEVANCE: The use of animals and plants as traditional remedies for both medical afflictions and social or cultural issues (symbolism) has a long history in South Africa and a reasonably large proportion of the population will consult a traditional healer during their life-time. Compared to plants, the use of animal parts in traditional medicine and folklore is poorly documented. METHODS: We interviewed 32 traders from South Africa's largest traditional medicine market, the Faraday Street market in Johannesburg, of which only 20 consented to supplying some species use information. Traders are particularly protective of the medicinal properties of their wares. Given the sensitive nature of this information (12 traders declined to be interviewed), we were only able to gather data on their perceived uses and no data on dosages, efficacy, or individual turn-over of products. We assessed the trade of animal parts from the perspective of consumer needs by analysing use-categories (e.g. headaches, strokes, skin problems, bad luck, etc.) and the degree of informant consensus in the selection of fauna to treat certain conditions. RESULTS: We documented 301 uses for animal parts from 52 species and 18 'morphospecies' that we allocated to 122 broad-use categories. Overall, reptiles and mammals were the most frequently used taxa in traditional medicine and some species had multiple uses (i.e., appeared in multiple use-categories) including crocodiles, lizards generally, chameleons, striped polecats, elephants and jackals. Animals were mostly used for 'strength' (physical or overcoming fear), but also as love charms, warding off bad luck or bad spirits or improving one's luck. Only 36% of our categories were medicinal (e.g., headaches, skin problems, swollen feet, etc.). We also found a high rate of non-disclosure of uses per species (a mean 86% of traders did not reveal information on the use of a species), and a variable degree of consensus between the traders on what particular species are actually used for. CONCLUSIONS: We suggest that traditional medicine markets provide a unique opportunity to gauge the health and symbolic or personal issues representative of a large sector of society. What's more, we recommend that researchers be more mindful in the way that use information is reported. We also highlight the potentially serious threat of traditional medicine to species that may be particularly vulnerable by virtue of their restricted distribution or predictable behaviour.

Combined motor cortex and spinal cord neuromodulation promotes corticospinal system functional and structural plasticity and motor function after injury.

An important strategy for promoting voluntary movements after motor system injury is to harness activity-dependent corticospinal tract (CST) plasticity. We combine forelimb motor cortex (M1) activation with co-activation of its cervical spinal targets in rats to promote CST sprouting and skilled limb movement after pyramidal tract lesion (PTX). We used a two-step experimental design in which we first established the optimal combined stimulation protocol in intact rats and then used the optimal protocol in injured animals to promote CST repair and motor recovery. M1 was activated epidurally using an electrical analog of intermittent theta burst stimulation (iTBS). The cervical spinal cord was co-activated by trans-spinal direct current stimulation (tsDCS) that was targeted to the cervical enlargement, simulated from finite element method. In intact rats, forelimb motor evoked potentials (MEPs) were strongly facilitated during iTBS and for 10 min after cessation of stimulation. Cathodal, not anodal, tsDCS alone facilitated MEPs and also produced a facilitatory aftereffect that peaked at 10 min. Combined iTBS and cathodal tsDCS (c-tsDCS) produced further MEP enhancement during stimulation, but without further aftereffect enhancement. Correlations between forelimb M1 local field potentials and forelimb electromyogram (EMG) during locomotion increased after electrical iTBS alone and further increased with combined stimulation (iTBS+c-tsDCS). This optimized combined stimulation was then used to promote function after PTX because it enhanced functional connections between M1 and spinal circuits and greater M1 engagement in muscle contraction than either stimulation alone. Daily application of combined M1 iTBS on the intact side and c-tsDCS after PTX (10 days, 27 min/day) significantly restored skilled movements during horizontal ladder walking. Stimulation produced a 5.4-fold increase in spared ipsilateral CST terminations. Combined neuromodulation achieves optimal motor recovery and substantial CST outgrowth with only 27 min of daily stimulation compared with 6h, as in our prior study, making it a potential therapy for humans with spinal cord injury.

ROS-responsive microspheres for on demand antioxidant therapy in a model of diabetic peripheral arterial disease.

A new microparticle-based delivery system was synthesized from reactive oxygen species (ROS)-responsive poly(propylene sulfide) (PPS) and tested for "on demand" antioxidant therapy. PPS is hydrophobic but undergoes a phase change to become hydrophilic upon oxidation and thus provides a useful platform for ROS-demanded drug release. This platform was tested for delivery of the promising anti-inflammatory and antioxidant therapeutic molecule curcumin, which is currently limited in use in its free form due to poor pharmacokinetic properties. PPS microspheres efficiently encapsulated curcumin through oil-in-water emulsion and provided sustained, on demand release that was modulated in vitro by hydrogen peroxide concentration. The cytocompatible, curcumin-loaded microspheres preferentially targeted and scavenged intracellular ROS in activated macrophages, reduced in vitro cell death in the presence of cytotoxic levels of ROS, and decreased tissue-level ROS in vivo in the diabetic mouse hind limb ischemia model of peripheral arterial disease. Interestingly, due to the ROS scavenging behavior of PPS, the blank microparticles also showed inherent therapeutic properties that were synergistic with the effects of curcumin in these assays. Functionally, local delivery of curcumin-PPS microspheres accelerated recovery from hind limb ischemia in diabetic mice, as demonstrated using non-invasive imaging techniques. This work demonstrates the potential for PPS microspheres as a generalizable vehicle for ROS-demanded drug release and establishes the utility of this platform for improving local curcumin bioavailability for treatment of chronic inflammatory diseases.

Electrical stimulation of motor cortex in the uninjured hemisphere after chronic unilateral injury promotes recovery of skilled locomotion through ipsilateral control.

Partial injury to the corticospinal tract (CST) causes sprouting of intact axons at their targets, and this sprouting correlates with functional improvement. Electrical stimulation of motor cortex augments sprouting of intact CST axons and promotes functional recovery when applied soon after injury. We hypothesized that electrical stimulation of motor cortex in the intact hemisphere after chronic lesion of the CST in the other hemisphere would restore function through ipsilateral control. To test motor skill, rats were trained and tested to walk on a horizontal ladder with irregularly spaced rungs. Eight weeks after injury, produced by pyramidal tract transection, half of the rats received forelimb motor cortex stimulation of the intact hemisphere. Rats with injury and stimulation had significantly improved forelimb control compared with rats with injury alone and achieved a level of proficiency similar to uninjured rats. To test whether recovery of forelimb function was attributable to ipsilateral control, we selectively inactivated the stimulated motor cortex using the GABA agonist muscimol. The dose of muscimol we used produces strong contralateral but no ipsilateral impairments in naive rats. In rats with injury and stimulation, but not those with injury alone, inactivation caused worsening of forelimb function; the initial deficit was reinstated. These results demonstrate that electrical stimulation can promote recovery of motor function when applied late after injury and that motor control can be exerted from the ipsilateral motor cortex. These results suggest that the uninjured motor cortex could be targeted for brain stimulation in people with large unilateral CST lesions.

Developing a pathway for high-value, patient-centered total joint arthroplasty.

BACKGROUND: Total joint arthroplasty (TJA) is one of the most widely performed elective procedures; however, there are wide variations in cost and quality among facilities where the procedure is performed. QUESTIONS/PURPOSES: The purposes of this study were to (1) develop a generalizable clinical care pathway for primary TJA using inputs from clinical, academic, and patient stakeholders; and (2) identify system- and patient-level processes to provide safe, effective, efficient, and patient-centered care for patients undergoing TJA. METHODS: We used a combination of quantitative and qualitative methods to design a care pathway that spans 14 months beginning with the presurgical office visit and concluding 12 months after discharge. We derived care suggestions from interviews with 16 hospitals selected based on readmission rates, cost, and quality (n = 10) and author opinion (n = 6). A 32-member multistakeholder panel refined the pathway during a 1-day workshop. Participants were selected based on leadership in orthopaedic (n = 4) and anesthesia (n = 1) specialty societies; involvement in organizations specializing in safety and high reliability care (n = 3), lean production/consumption of care (n = 3), and patient experience of care (n = 3); membership in an interdisciplinary care team of a hospital selected for interviewing (n = 8); recent receipt of a TJA (n = 1); and participation in the pathway development team (n = 9). RESULTS: The care pathway includes 40 suggested processes to improve care, 37 techniques to reduce waste, and 55 techniques to improve communication. Central themes include standardization and process improvement, interdisciplinary communication and collaboration, and patient/family engagement and education. Selected recommendations include standardizing care protocols and staff roles; aligning information flow with patient and process flow; identifying a role accountable for care delivery and communication; managing patient expectations; and stratifying patients into the most appropriate care level. CONCLUSIONS: We developed a multidisciplinary clinical care pathway for patients undergoing TJA based on principles of high-value care. The pathway is ready for clinical testing and context-specific adaptation. LEVEL OF EVIDENCE: Level V, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.