U.S. estimates of the natural rate of interest – the real short-term interest rate that would prevail absent transitory disturbances – have declined dramatically since the start of the global ...financial crisis. For example, estimates using the Laubach–Williams (2003) model indicate the natural rate in the United States fell to close to zero during the crisis and has remained there into 2016. Explanations for this decline include shifts in demographics, a slowdown in trend productivity growth, and global factors affecting real interest rates. This paper applies the Laubach–Williams methodology to the United States and three other advanced economies – Canada, the Euro Area, and the United Kingdom. We find that large declines in trend GDP growth and natural rates of interest have occurred over the past 25years in all four economies. These country-by-country estimates are found to display a substantial amount of comovement over time, suggesting an important role for global factors in shaping trend growth and natural rates of interest.
According to standard macroeconomic models, the zero lower bound greatly reduces the effectiveness of monetary policy and increases the efficacy of fiscal policy. However, private-sector decisions ...depend on the entire path of expected future short-term interest rates, not just the current short-term rate. Put differently, longer-term yields matter. We show how to measure the zero bound's effects on yields of any maturity. Indeed, 1- and 2-year Treasury yields were surprisingly unconstrained throughout 2008 to 2010, suggesting that monetary and fiscal policy were about as effective as usual during this period. Only beginning in late 2011 did these yields become more constrained.
Optogenetics provides an alternative to electrical stimulation to manipulate membrane voltage, and trigger or modify action potentials (APs) in excitable cells. We compare biophysically and ...energetically the cellular responses to direct electrical current injection versus optical stimulation mediated by genetically expressed light-sensitive ion channels, e.g., Channelrhodopsin-2 (ChR2). Using a computational model of ChR2(H134R mutant), we show that both stimulation modalities produce similar-in-morphology APs in human cardiomyocytes, and that electrical and optical excitability vary with cell type in a similar fashion. However, whereas the strength-duration curves for electrical excitation in ventricular and atrial cardiomyocytes closely follow the theoretical exponential relationship for an equivalent RC circuit, the respective optical strength-duration curves significantly deviate, exhibiting higher nonlinearity. We trace the origin of this deviation to the waveform of the excitatory current—a nonrectangular self-terminating inward current produced in optical stimulation due to ChR2 kinetics and voltage-dependent rectification. Using a unifying charge measure to compare energy needed for electrical and optical stimulation, we reveal that direct electrical current injection (rectangular pulse) is more efficient at short pulses, whereas voltage-mediated negative feedback leads to self-termination of ChR2 current and renders optical stimulation more efficient for long low-intensity pulses. This applies to cardiomyocytes but not to neuronal cells (with much shorter APs). Furthermore, we demonstrate the cell-specific use of ChR2 current as a unique modulator of intrinsic activity, allowing for optical control of AP duration in atrial and, to a lesser degree, in ventricular myocytes. For self-oscillatory cells, such as Purkinje, constant light at extremely low irradiance can be used for fine control of oscillatory frequency, whereas constant electrical stimulation is not feasible due to electrochemical limitations. Our analysis offers insights for designing future new energy-efficient stimulation strategies in heart or brain.
Clinical studies are ongoing to assess whether existing vaccines may afford protection against SARS-CoV-2 infection through trained immunity. In this exploratory study, we analyze immunization ...records from 137,037 individuals who received SARS-CoV-2 PCR tests. We find that polio, Haemophilus influenzae type-B (HIB), measles-mumps-rubella (MMR), Varicella, pneumococcal conjugate (PCV13), Geriatric Flu, and hepatitis A/hepatitis B (HepA-HepB) vaccines administered in the past 1, 2, and 5 years are associated with decreased SARS-CoV-2 infection rates, even after adjusting for geographic SARS-CoV-2 incidence and testing rates, demographics, comorbidities, and number of other vaccinations. Furthermore, age, race/ethnicity, and blood group stratified analyses reveal significantly lower SARS-CoV-2 rate among black individuals who have taken the PCV13 vaccine, with relative risk of 0.45 at the 5 year time horizon (n: 653, 95% CI (0.32, 0.64), p-value: 6.9e-05). Overall, this study identifies existing approved vaccines which can be promising candidates for pre-clinical research and Randomized Clinical Trials towards combating COVID-19.
Lymphomas arising from NK or γδ-T cells are very aggressive diseases and little is known regarding their pathogenesis. Here we report frequent activating mutations of STAT3 and STAT5B in NK/T-cell ...lymphomas (n=51), γδ-T-cell lymphomas (n=43) and their cell lines (n=9) through next generation and/or Sanger sequencing. STAT5B N642H is particularly frequent in all forms of γδ-T-cell lymphomas. STAT3 and STAT5B mutations are associated with increased phosphorylated protein and a growth advantage to transduced cell lines or normal NK cells. Growth-promoting activity of the mutants can be partially inhibited by a JAK1/2 inhibitor. Molecular modelling and surface plasmon resonance measurements of the N642H mutant indicate a marked increase in binding affinity of the phosphotyrosine-Y699 with the mutant histidine. This is associated with the prolonged persistence of the mutant phosphoSTAT5B and marked increase of binding to target sites. Our findings suggest that JAK-STAT pathway inhibition may represent a therapeutic strategy.
Persistently low real interest rates have prompted the question whether low interest rates are here to stay. This essay assesses the empirical evidence regarding the natural rate of interest in the ...United States using the Laubach-Williams model. Since the start of the Great Recession, the estimated natural rate of interest fell sharply and shows no sign of recovering. These results are robust to alternative model specifications. If the natural rate remains low, future episodes of hitting the zero lower bound are likely to be frequent and longlasting. In addition, uncertainty about the natural rate argues for policy approaches that are more robust to mismeasurement of natural rates.
Channelrhodospin-2 (ChR2), a light-sensitive ion channel, and its variants have emerged as new excitatory optogenetic tools not only in neuroscience, but also in other areas, including cardiac ...electrophysiology. An accurate quantitative model of ChR2 is necessary for in silico prediction of the response to optical stimulation in realistic tissue/organ settings. Such a model can guide the rational design of new ion channel functionality tailored to different cell types/tissues. Focusing on one of the most widely used ChR2 mutants (H134R) with enhanced current, we collected a comprehensive experimental data set of the response of this ion channel to different irradiances and voltages, and used these data to develop a model of ChR2 with empirically-derived voltage- and irradiance- dependence, where parameters were fine-tuned via simulated annealing optimization. This ChR2 model offers: 1) accurate inward rectification in the current-voltage response across irradiances; 2) empirically-derived voltage- and light-dependent kinetics (activation, deactivation and recovery from inactivation); and 3) accurate amplitude and morphology of the response across voltage and irradiance settings. Temperature-scaling factors (Q10) were derived and model kinetics was adjusted to physiological temperatures. Using optical action potential clamp, we experimentally validated model-predicted ChR2 behavior in guinea pig ventricular myocytes. The model was then incorporated in a variety of cardiac myocytes, including human ventricular, atrial and Purkinje cell models. We demonstrate the ability of ChR2 to trigger action potentials in human cardiomyocytes at relatively low light levels, as well as the differential response of these cells to light, with the Purkinje cells being most easily excitable and ventricular cells requiring the highest irradiance at all pulse durations. This new experimentally-validated ChR2 model will facilitate virtual experimentation in neural and cardiac optogenetics at the cell and organ level and provide guidance for the development of in vivo tools.
The improvement of preclinical cardiotoxicity testing, discovery of new ion-channel-targeted drugs, and phenotyping and use of stem cell-derived cardiomyocytes and other biologics all necessitate ...high-throughput (HT), cellular-level electrophysiological interrogation tools. Optical techniques for actuation and sensing provide instant parallelism, enabling contactless dynamic HT testing of cells and small-tissue constructs, not affordable by other means. Here we show, computationally and experimentally, the limits of all-optical electrophysiology when applied to drug testing, then implement and validate OptoDyCE, a fully automated system for all-optical cardiac electrophysiology. We validate optical actuation by virally introducing optogenetic drivers in rat and human cardiomyocytes or through the modular use of dedicated light-sensitive somatic 'spark' cells. We show that this automated all-optical approach provides HT means of cellular interrogation, that is, allows for dynamic testing of >600 multicellular samples or compounds per hour, and yields high-content information about the action of a drug over time, space and doses.
Practice-based collaborative care is a complex evidence-based practice that is difficult to implement in smaller primary care practices that lack on-site mental health staff. Telemedicine-based ...collaborative care virtually co-locates and integrates mental health providers into primary care settings. The objective of this multisite randomized pragmatic comparative effectiveness trial was to compare the outcomes of patients assigned to practice-based and telemedicine-based collaborative care.
From 2007 to 2009, patients at federally qualified health centers serving medically underserved populations were screened for depression, and 364 patients who screened positive were enrolled and followed for 18 months. Those assigned to practice-based collaborative care received evidence-based care from an on-site primary care provider and a nurse care manager. Those assigned to telemedicine-based collaborative care received evidence-based care from an on-site primary care provider and an off-site team: a nurse care manager and a pharmacist by telephone, and a psychologist and a psychiatrist via videoconferencing. The primary clinical outcome measures were treatment response, remission, and change in depression severity.
Significant group main effects were observed for both response (odds ratio=7.74, 95% CI=3.94-15.20) and remission (odds ratio=12.69, 95% CI=4.81-33.46), and a significant overall group-by-time interaction effect was observed for depression severity on the Hopkins Symptom Checklist, with greater reductions in severity over time for patients in the telemedicine-based group. Improvements in outcomes appeared to be attributable to higher fidelity to the collaborative care evidence base in the telemedicine-based group.
Contracting with an off-site telemedicine-based collaborative care team can yield better outcomes than implementing practice-based collaborative care with locally available staff.
Stone composition as a function of age and sex Lieske, John C; Rule, Andrew D; Krambeck, Amy E ...
Clinical journal of the American Society of Nephrology,
12/2014, Letnik:
9, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Kidney stones are heterogeneous but often grouped together. The potential effects of patient demographics and calendar month (season) on stone composition are not widely appreciated.
The first stone ...submitted by patients for analysis to the Mayo Clinic Metals Laboratory during 2010 was studied (n=43,545). Stones were classified in the following order: any struvite, any cystine, any uric acid, any brushite, majority (≥50%) calcium oxalate, or majority (≥50%) hydroxyapatite.
Calcium oxalate (67%) was the most common followed by hydroxyapatite (16%), uric acid (8%), struvite (3%), brushite (0.9%), and cystine (0.35%). Men accounted for more stone submissions (58%) than women. However, women submitted more stones than men between the ages of 10-19 (63%) and 20-29 (62%) years. Women submitted the majority of hydroxyapatite (65%) and struvite (65%) stones, whereas men submitted the majority of calcium oxalate (64%) and uric acid (72%) stones (P<0.001). Although calcium oxalate stones were the most common type of stone overall, hydroxyapatite stones were the second most common before age 55 years, whereas uric acid stones were the second most common after age 55 years. More calcium oxalate and uric acid stones were submitted in the summer months (July and August; P<0.001), whereas the season did not influence other stone types.
It is well known that calcium oxalate stones are the most common stone type. However, age and sex have a marked influence on the type of stone formed. The higher number of stones submitted by women compared with men between the ages of 10 and 29 years old and the change in composition among the elderly favoring uric acid have not been widely appreciated. These data also suggest increases in stone risk during the summer, although this is restricted to calcium oxalate and uric acid stones.
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