Cardiac fibroblasts are critical to proper heart function through multiple interactions with the myocardial compartment, but appreciation of their contribution has suffered from incomplete ...characterization and lack of cell-specific markers.
To generate an unbiased comparative gene expression profile of the cardiac fibroblast pool, identify and characterize the role of key genes in cardiac fibroblast function, and determine their contribution to myocardial development and regeneration.
High-throughput cell surface and intracellular profiling of cardiac and tail fibroblasts identified canonical mesenchymal stem cell and a surprising number of cardiogenic genes, some expressed at higher levels than in whole heart. While genetically marked fibroblasts contributed heterogeneously to interstitial but not cardiomyocyte compartments in infarcted hearts, fibroblast-restricted depletion of one highly expressed cardiogenic marker, T-box 20, caused marked myocardial dysmorphology and perturbations in scar formation on myocardial infarction.
The surprising transcriptional identity of cardiac fibroblasts, the adoption of cardiogenic gene programs, and direct contribution to cardiac development and repair provoke alternative interpretations for studies on more specialized cardiac progenitors, offering a novel perspective for reinterpreting cardiac regenerative therapies.
Recent research has advanced two degree-of-freedom (DoF), simultaneous, independent and proportional control of hand-wrist prostheses using surface electromyogram signals from remnant muscles as the ...control input. We evaluated two such regression-based controllers, along with conventional, sequential two-site control with co-contraction mode switching (SeqCon), in box-block, refined-clothespin and door-knob tasks, on 10 able-bodied and 4 limb-absent subjects. Subjects operated a commercial hand and wrist using a socket bypass harness. One 2-DoF controller (DirCon) related the intuitive hand actions of open-close and pronation-supination to the associated prosthesis hand-wrist actions, respectively. The other (MapCon) mapped myoelectrically more distinct, but less intuitive, actions of wrist flexion-extension and ulnar-radial deviation. Each 2-DoF controller was calibrated from separate 90 s calibration contractions. SeqCon performed better statistically than MapCon in the predominantly 1-DoF box-block task (>20 blocks/minute vs. 8-18 blocks/minute, on average). In this task, SeqCon likely benefited from an ability to easily focus on 1-DoF and not inadvertently trigger co-contraction for mode switching. The remaining two tasks require 2-DoFs, and both 2-DoF controllers each performed better (factor of 2-4) than SeqCon. We also compared the use of 12 vs. 6 optimally-selected EMG electrodes as inputs, finding no statistical difference. Overall, we provide further evidence of the benefits of regression-based EMG prosthesis control of 2-DoFs in the hand-wrist.
Copper is the current interconnect metal of choice in integrated circuits. As interconnect dimensions decrease, the resistivity of copper increases dramatically because of electron scattering from ...surfaces, impurities, and grain boundaries (GBs) and threatens to stymie continued device scaling. Lacking direct measurements of individual scattering sources, understanding of the relative importance of these scattering mechanisms has largely relied on semiempirical modeling. Here we present the first ever attempt to measure and calculate individual GB resistances in copper nanowires with a one-to-one correspondence to the GB structure. Large resistance jumps are directly measured at the random GBs with a value far greater than at coincidence GBs and first-principles calculations. The high resistivity of the random GB appears to be intrinsic, arising from the scaling of electron mean free path with the size of the lattice relaxation region. The striking impact of random GB scattering adds vital information for understanding nanoscale conductors.
•1. Regression-based simultaneous, independent and proportional 2-DoF hand-wrist virtual myoelectric prosthesis control.•2. Automatic selectiion of best electrode sites based on backward stepwise ...selection.•3. Reduced calibration time with no force feedback needed.ss.
Most transradial prosthesis users with conventional “Sequential” myoelectric control have two electrode sites which control one degree of freedom (DoF) at a time. Rapid EMG co-activation toggles control between DoFs (e.g., hand and wrist), providing limited function. We implemented a regression-based EMG control method which achieved simultaneous and proportional control of two DoFs in a virtual task. We automated electrode site selection using a short-duration (90 s) calibration period, without force feedback. Backward stepwise selection located the best electrodes for either six or 12 electrodes (selected from a pool of 16). We additionally studied two, 2-DoF controllers: “Intuitive” control (hand open-close and wrist pronation-supination controlled virtual target size and rotation, respectively) and “Mapping” control (wrist flexion–extension and ulnar-radial deviation controlled virtual target left–right and up-down movement, respectively). In practice, a Mapping controller would be mapped to control prosthesis hand open-close and wrist pronation-supination. Eleven able-bodied subjects and 4 limb-absent subjects completed virtual target matching tasks (fixed target moves to a new location after being “matched,” and subject immediately pursues) and fixed (static) target tasks. For all subjects, both 2-DoF controllers with 6 optimally-sited electrodes had statistically better target matching performance than Sequential control in number of matches (average of 4–7 vs 2 matches, p < 0.001) and throughput (average of 0.75–1.25 vs 0.4 bits/s, p < 0.001), but not overshoot rate and path efficiency. There were no statistical differences between 6 and 12 optimally-sited electrodes for both 2-DoF controllers. These results support the feasibility of 2-DoF simultaneous, proportional myoelectric control.
In the CALGB (Alliance) 100104 study, lenalidomide versus placebo after autologous stem-cell transplantation (ASCT) was investigated for patients with newly diagnosed myeloma. That study showed ...improved time to progression and overall survival and an increase in second primary malignancies for lenalidomide at a median follow-up of 34 months. Here we report an updated intention-to-treat analysis of CALGB (Alliance) 100104 at a median follow-up of 91 months.
Patients were eligible for this randomised, double-blind, placebo-controlled, phase 3 trial if they had symptomatic disease requiring treatment; had received, at most, two induction regimens; and had achieved stable disease or better in the first 100 days after ASCT. We randomly assigned patients to either lenalidomide or placebo groups using permuted block randomisation, with a fixed block size of six. Randomisation was stratified by three factors: normal or elevated β2 microglobulin concentration at registration (≤2·5 mg/L vs >2·5 mg/L), previous use or non-use of thalidomide during induction therapy, and previous use or non-use of lenalidomide during induction therapy. The starting dose was two capsules (10 mg) per day, escalated to three capsules (15 mg) per day after 3 months. The primary endpoint was time to progression (time of progressive disease or death from any cause), with intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00114101. New patients are no longer being recruited, but some patients remain on treatment and in follow-up.
Between April 14, 2005, and July 2, 2009, 460 patients were randomly assigned to receive either lenalidomide (n=231) or placebo (n=229). After three interim analyses, the study was unblinded at a median follow-up of 18 months, at which point 86 (67%) of 128 patients without progressive disease in the placebo group chose to cross over to the lenalidomide group. The median follow-up for the updated survival analysis, as of Oct 19, 2016, was 91 months (IQR 83·6-103·1). The median time to progression was 57·3 months (95% CI 44·2-73·3) for the lenalidomide group and 28·9 months (23·0-36·3) for the placebo group (hazard ratio 0·57, 95% CI 0·46-0·71; p<0·0001). The most common grade 3-4 adverse events were neutropenia (116 50% patients in the lenalidomide group and 41 18% patients in the placebo group) and thrombocytopenia (34 15% patients in the lenalidomide group and 12 5% patients in the placebo group). 18 (8%) haematological and 14 (6%) solid tumour second primary malignancies were diagnosed after randomisation and before disease progression in the lenalidomide group, compared with three (1%) haematological and nine (4%) solid tumour second primary malignancies in the placebo group. Three haematological and five solid tumour second primary malignancies in the placebo group were in the crossover subgroup.
Despite an increase in haematological adverse events and second primary malignancies, lenalidomide maintenance therapy after ASCT significantly improved time to progression and could be considered a standard of care.
The National Cancer Institute.
Recently, improved metal-on-metal bearing technology has led to the reemergence of resurfacing as a reasonable option for total hip arthroplasty. During the course of a prospective multicenter ...FDA-IDE evaluation of metal-on-metal total hip resurfacings, we modified our indications and emphasized surgical technique where the femoral surface area was small due to femoral cysts and small component size. We assessed the influence of these changes on complication rates in the first cohort of 292 patients and the second of 724, and then compared these outcomes in the second cohort with historical reports of resurfacing. We had a minimum followup of 24 months (mean, 33 months; range, 24-60 months). After changes were made in the indications and technique, the overall complication rate decreased from 13.4% to 2.1% with the femoral neck fracture rate reduced from 7.2% to 0.8%. The outcomes of the second cohort compare with modern-day resurfacing devices and appear superior to historical results. The data suggest patients should be carefully selected and technique optimized to reduce complications. Long-term followup is required to see if these promising results will be maintained.
The biological determinants underlying the range of coronavirus 2019 (COVID-19) clinical manifestations are not fully understood. Here, over 1,400 plasma proteins and 2,600 single-cell immune ...features comprising cell phenotype, endogenous signaling activity, and signaling responses to inflammatory ligands are cross-sectionally assessed in peripheral blood from 97 patients with mild, moderate, and severe COVID-19 and 40 uninfected patients. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identify and independently validate a multi-variate model classifying COVID-19 severity (multi-class area under the curve AUC
= 0.799, p = 4.2e-6; multi-class AUC
= 0.773, p = 7.7e-6). Examination of informative model features reveals biological signatures of COVID-19 severity, including the dysregulation of JAK/STAT, MAPK/mTOR, and nuclear factor κB (NF-κB) immune signaling networks in addition to recapitulating known hallmarks of COVID-19. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for prevention and/or treatment of COVID-19 progression.
(1) The use of high-flow nasal cannula (HFNC) combined with frequent respiratory monitoring in patients with acute hypoxic respiratory failure due to COVID-19 has been shown to reduce intubation and ...mechanical ventilation. (2) This prospective, single-center, observational study included consecutive adult patients with COVID-19 pneumonia treated with a high-flow nasal cannula. Hemodynamic parameters, respiratory rate, inspiratory fraction of oxygen (F
O
), saturation of oxygen (S
O
), and the ratio of oxygen saturation to respiratory rate (ROX) were recorded prior to treatment initiation and every 2 h for 24 h. A 6-month follow-up questionnaire was also conducted. (3) Over the study period, 153 of 187 patients were eligible for HFNC. Of these patients, 80% required intubation and 37% of the intubated patients died in hospital. Male sex (OR = 4.65; 95% CI 1.28; 20.6,
= 0.03) and higher BMI (OR = 2.63; 95% CI 1.14; 6.76,
= 0.03) were associated with an increased risk for new limitations at 6-months after hospital discharge. (4) 20% of patients who received HFNC did not require intubation and were discharged alive from the hospital. Male sex and higher BMI were associated with poor long-term functional outcomes.
A small family of phenyl quinazolinone ureas is reported as potent modulators of Hedgehog protein function. Preliminary SAR studies of the urea substituent led to a nanomolar Hedgehog antagonist.
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