Despite the use of digital technology in healthcare, telemedicine has not been readily adopted. During the COVID-19 pandemic, healthcare systems have begun crisis management planning. To ...appropriately allocate resources and prevent virus exposure while maintaining effective patient care, our orthopaedic surgery department rapidly introduced a robust telemedicine program during a 5-day period. Implementation requires attention to patient triage, technological resources, credentialing, education of providers and patients, scheduling, and regulatory considerations. This article provides practical instruction based on our experience for physicians who wish to implement telemedicine during the COVID-19 pandemic. Between telemedicine encounters and necessary in-person visits, providers may be able to achieve 50% of their typical clinic volume within 2 weeks. When handling the massive disruption to the routine patient care workflow, it is critical to understand the key factors associated with an accelerated introduction of telemedicine for the safe and effective continuation of orthopaedic care during this pandemic. LEVEL OF EVIDENCE:: V.
The optimization of ionic conductivity and lithium-ion battery stability can be achieved by independently tuning the ion transport and mechanical robustness of block polymer (BP) electrolytes. ...However, the ionic conductivity of BP electrolytes is inherently limited by the covalent attachment of the ionically conductive block to the mechanically robust block, among other factors. Herein, the BP electrolyte polystyrene-block-poly(oligo-oxyethylene methacrylate) PS-b-POEM was blended with POEM homopolymers of varying molecular weights. The incorporation of a higher molecular weight homopolymer additive (α > 1 state) promoted a “dry brush-like” homopolymer distribution within the BP self-assembly and led to higher lithium salt concentrations in the more mobile homopolymer-rich region, increasing overall ionic conductivity relative to the “wet brush-like” (α < 1 state) and unblended composites, where α is the molecular weight ratio between the POEM homopolymer and the POEM block in the copolymer. Neutron and X-ray reflectometry (NR and XRR, respectively) provided additional details on the lithium salt and polymer distributions. From XRR, the α > 1 blends showed increased interfacial widths in comparison to their BP (unblended) or α < 1 counterparts because of the more central distribution of the homopolymer. This result, paired with NR data that suggested even salt concentrations across the POEM domains, implied that there was a higher salt concentration in the homopolymer POEM-rich regions in the dry brush blend than in the wet brush blend. Furthermore, using 7Li solid-state nuclear magnetic resonance spectroscopy, we found a temperature corresponding to a transition in lithium mobility (T Li mobility) that was a function of blend type. T Li mobility was found to be 39 °C above T g in all cases. Interestingly, the ionic conductivity of the blended BPs was highest in the α > 1 composites, even though these composites had higher T gs than the α < 1 composites, demonstrating that homopolymer-rich conducting pathways formed in the α > 1 assemblies had a larger influence on conductivity than the greater lithium ion mobility in the α < 1 blends.
Characterizing the TCRα and TCRβ chains expressed by T cells responding to a given pathogen or underlying autoimmunity helps in the development of vaccines and immunotherapies, respectively. However, ...our understanding of complementary TCRα and TCRβ chain utilization is very limited for pathogen- and autoantigen-induced immunity. To address this problem, we have developed a multiplex nested RT-PCR method for the simultaneous amplification of transcripts encoding the TCRα and TCRβ chains from single cells. This multiplex method circumvented the lack of antibodies specific for variable regions of mouse TCRα chains and the need for prior knowledge of variable region usage in the TCRβ chain, resulting in a comprehensive, unbiased TCR repertoire analysis with paired coexpression of TCRα and TCRβ chains with single-cell resolution. Using CD8+ CTLs specific for an influenza epitope recovered directly from the pneumonic lungs of mice, this technique determined that 25% of such effectors expressed a dominant, nonproductively rearranged Tcra transcript. T cells with these out-of-frame Tcra mRNAs also expressed an alternate, in-frame Tcra, whereas approximately 10% of T cells had 2 productive Tcra transcripts. The proportion of cells with biallelic transcription increased over the course of a response, a finding that has implications for immune memory and autoimmunity. This technique may have broad applications in mouse models of human disease.
The use of systemic prostanoids in severe pulmonary arterial hypertension (PAH) is often limited by patient/physician dissatisfaction with the delivery methods. Complications associated with external ...pump-delivered continuous therapy include IV catheter-related bloodstream infections and subcutaneous infusion site pain. We therefore investigated a fully implantable intravascular delivery system for treprostinil infusion.
A multicenter, prospective, single-arm, clinical trial (DelIVery for Pulmonary Arterial Hypertension) was conducted by using an implantable intravascular delivery system. The implanted pumps were refilled percutaneously at least every 12 weeks. The primary end point was the rate of catheter-related complications using the new model 10642 catheter compared with a predefined objective performance criterion of 2.5 per 1,000 patient-days based on the literature.
Patients (n = 60) with severe PAH (World Health Organization group 1) receiving a stable dose of IV treprostinil for at least 4 weeks received an implant device and were followed up for 12.1 ± 4.4 months. Six catheter-related complications occurred, corresponding to a complication rate of 0.27 per 1,000 patient-days. The 97.5% upper one-sided confidence bound of 0.59 was less than the predefined criterion of 2.5 per 1,000 patient-days (P < .0001). Plasma treprostinil levels at 1 week postimplantation were highly correlated with baseline levels (r = 0.91; P < .0001). The delivery system management time as reported by the patients was 2.5 ± 1.7 hours per week preimplantation, and this time decreased to 0.6 ± 0.8 hour per week at 6 months' postimplantation (P < .0001). All patients rated overall satisfaction with the implantable system as good, very good, or excellent at 6 weeks and 6 months. There were no catheter-related bloodstream infections or catheter occlusions.
The implantable intravascular delivery system delivered treprostinil to patients with PAH with a low rate of catheter-related complications and a high rate of patient satisfaction.
ClinicalTrials.gov; No.: NCT01321073; URL: www.clinicaltrials.gov.
Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing beta cells. The mechanisms governing replication of terminally differentiated beta cells and neogenesis ...from progenitor cells are unclear. Mice lacking insulin receptor substrate-2 (Irs2) develop beta cell failure, suggesting that insulin signaling is required to maintain an adequate beta cell mass. We report that haploinsufficiency for the forkhead transcription factor Foxo1 reverses beta cell failure in Irs2(-/-) mice through partial restoration of beta cell proliferation and increased expression of the pancreatic transcription factor pancreas/duodenum homeobox gene-1 (Pdx1). Foxo1 and Pdx1 exhibit mutually exclusive patterns of nuclear localization in beta cells, and constitutive nuclear expression of a mutant Foxo1 is associated with lack of Pdx1 expression. We show that Foxo1 acts as a repressor of Foxa2-dependent (Hnf-3beta-dependent) expression from the Pdx1 promoter. We propose that insulin/IGFs regulate beta cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset of cells embedded within pancreatic ducts.
Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder and is one of the most common muscular dystrophies. There are currently few effective therapies to treat the disease, although ...many small-molecule approaches are being pursued. Certain histone deacetylase inhibitors (HDACi) have been shown to ameliorate DMD phenotypes in mouse and zebrafish animal models. The HDACi givinostat has shown promise for DMD in clinical trials. However, beyond a small group of HDACi, other classes of epigenetic small molecules have not been broadly and systematically studied for their benefits for DMD.
We used an established animal model for DMD, the zebrafish dmd mutant strain sapje. A commercially available library of epigenetic small molecules was used to treat embryonic-larval stages of dmd mutant zebrafish. We used a quantitative muscle birefringence assay in order to assess and compare the effects of small-molecule treatments on dmd mutant zebrafish skeletal muscle structure.
We performed a novel chemical-combination screen of a library of epigenetic compounds using the zebrafish dmd model. We identified candidate pools of epigenetic compounds that improve skeletal muscle structure in dmd mutant zebrafish. We then identified a specific combination of two HDACi compounds, oxamflatin and salermide, that ameliorated dmd mutant zebrafish skeletal muscle degeneration. We validated the effects of oxamflatin and salermide on dmd mutant zebrafish in an independent laboratory. Furthermore, we showed that the combination of oxamflatin and salermide caused increased levels of histone H4 acetylation in zebrafish larvae.
Our results provide novel, effective methods for performing a combination of small-molecule screen in zebrafish. Our results also add to the growing evidence that epigenetic small molecules may be promising candidates for treating DMD.
In adults, myocardial infarction (MI) results in a brisk inflammatory response, myocardium loss, and scar formation. We have recently reported the first mammalian large-animal model of cardiac ...regeneration after MI in fetal sheep. We hypothesize that the ability of the fetus to regenerate functional myocardium after MI is owing to differential gene expression regulating the response to MI in the fetus compared with the adult.
Myocardial infarction was created in adult (n=4) or early gestation fetal (n=4) sheep. Tissue was harvested after 3 or 30 days, and RNA was extracted for microarray, followed by principal component analysis and global gene expression analysis for the following gene ontology terms: response to wounding, inflammatory response, extracellular matrix, cell cycle, cell migration, cell proliferation, and apoptosis.
Principal component analysis demonstrated that the global gene expression pattern in adult infarcts was distinctly different from the uninfarcted region at 3 days and remained different at 30 days after MI. In contrast, gene expression in the fetal infarct was different from the uninfarcted region at 3 days, but by 30 days it returned to a baseline expression pattern similar to the uninfarcted region. Three days after MI there was an increase in the expression of genes related to all gene ontology terms in fetal and adult infarcts, but this increase was much more pronounced in adults. By 30 days, the fetal gene expression returned to baseline, whereas in the adult it remained significantly elevated.
These data demonstrate that the global gene expression pattern is dramatically different in the fetal regenerative response to MI compared with the adult response and may partly be responsible for the regeneration.
Ultrasonication of toluene solutions of the heteropolynuclear cluster complex, Pt3Fe3(CO)15, in the presence of oleic acid and oleylamine affords surface-capped fcc FePt nanoparticles having an ...average diameter of ca. 2 nm. Self-assembled arrays of these nanoparticles on oxidized Si wafers undergo a fcc-to-fct phase transition at 775 °C to form ferromagnetic FePt nanocrystals ca. 5.8 nm in diameter well dispersed on the Si wafer surface. Room-temperature coercivity measurements of these annealed FePt nanoparticles confirm a high coercivity of ca. 22.3 kOe. Such high coercivity for fct FePt nanoparticles might result from use of a heterpolynuclear complex as a single-source precursor of Fe and Pt neutral atoms or from use of ultrasonication to form fcc FePt nanoparticles under conditions of exceptionally rapid heating. Experiments to determine the critical experimental conditions required to achieve such high room-temperature coercivities in ferromagnetic nanoparticles are underway.
Seven patients who had pain in the anterior aspect of the ankle were found to have a thickened distal fascicle of the anteroinferior tibiofibular ligament. Each patient had a history of an inversion ...sprain of the ankle followed by chronic pain in the anterior aspect of the ankle. The thickened distal fascicle was resected without loss of stability of the ankle. Five patients needed débridement of an area of abraded hyaline cartilage on the anterolateral aspect of the talus. Six patients were followed for a mean of thirty-nine months (range, twenty-four to fifty-nine months). Four of them had no pain in the ankle or limitation in activities, and two reported marked improvement, with only occasional pain in the ankle related to overuse. A separate distal fascicle of the anteroinferior tibiofibular ligament is present in most human ankles and can be a cause of talar impingement, abrasion of the articular cartilage, and pain in the anterior aspect of the ankle. Resection of this ligament usually will alleviate the pain caused by the impingement.
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