Background
Kinematically aligned TKA restores function by aligning the femoral and tibial components to the normal or prearthritic joint lines of the knee. However, aligning the components to the ...joint lines of the normal knee also aligns the tibial component in varus, creating concern that varus alignment might result in poor function and early catastrophic failure.
Questions/Purposes
We therefore determined whether function and the incidence of catastrophic failure were different when the tibial component, knee, and limb alignment were in a specified normal range, varus outlier, or valgus outlier.
Methods
We prospectively followed all 198 patients (214 knees) who underwent TKAs between February and October 2008. We treated each knee in this cohort of patients with a kinematically aligned, cruciate-retaining prosthesis implanted using patient-specific guides. From a long-leg scanogram, we measured and categorized alignment of the tibial component as in range (≤ 0°) or a varus outlier (> 0°), alignment of the knee as in range (between −2.5° to −7.4° valgus) or a varus (> −2.5°) or valgus (< −7.4°) outlier, and alignment of the limb as in range (0° ± 3°) or a varus (> 3°) or valgus (< −3°) outlier. We assessed function using the Oxford Knee Score and WOMAC™ score, and reported catastrophic failure as the incidence of revision attributable to loosening, wear, and instability of the femoral or tibial components. The minimum followup was 31 months (mean, 38 months; range, 31–43 months).
Results
The mean Oxford Knee Score of 43 and WOMAC™ score of 92 were similar between the three alignment categories. The incidence of catastrophic failure in each alignment category was zero.
Conclusions
Kinematically aligned TKA restores function without catastrophic failure regardless of the alignment category. Because 75% of patients had their tibial component categorized as a varus outlier and also had high function and a zero incidence of catastrophic failure, the concern that kinematic alignment compromises function and places the components at a high risk for catastrophic failure is unfounded and should be of interest to surgeons committed to cutting the tibia perpendicular to the mechanical axis of the tibia.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
We present an analysis of , O iii88, N ii122, and far-infrared (FIR) fine-structure line observations obtained with Herschel/PACS, for ∼240 local luminous infrared galaxies (LIRGs) in the Great ...Observatories All-sky LIRG Survey. We find pronounced declines ("deficits") of line-to-FIR continuum emission for N ii122, , and as a function of FIR color and infrared luminosity surface density, . The median electron density of the ionized gas in LIRGs, based on the N ii122/N ii205 ratio, is = 41 cm−3. We find that the dispersion in the deficit of LIRGs is attributed to a varying fractional contribution of photodissociation regions (PDRs) to the observed emission, f( ) = / , which increases from ∼60% to ∼95% in the warmest LIRGs. The / ratio is tightly correlated with the PDR gas kinetic temperature in sources where is not optically thick or self-absorbed. For each galaxy, we derive the average PDR hydrogen density, , and intensity of the interstellar radiation field, G, in units of and find G/ ratios of ∼0.1-50 cm3, with ULIRGs populating the upper end of the distribution. There is a relation between G/ and , showing a critical break at 5 × 1010 L kpc−2. Below , G/ remains constant, 0.32 cm3, and variations in are driven by the number density of star-forming regions within a galaxy, with no change in their PDR properties. Above , G/ increases rapidly with , signaling a departure from the typical PDR conditions found in normal star-forming galaxies toward more intense/harder radiation fields and compact geometries typical of starbursting sources.
A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of ...diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling.
Cellular growth signals stimulate anabolic processes. The mechanistic target of rapamycin complex 1 (mTORC1) is a protein kinase that senses growth signals to regulate anabolic growth and ...proliferation. Activation of mTORC1 led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. Growth signaling through mTORC1 thus stimulates the production of new nucleotides to accommodate an increase in RNA and DNA synthesis needed for ribosome biogenesis and anabolic growth.
The current research synthesis integrates the findings of 111 independent samples from 54 economically developing countries that examined the relation between economic status and subjective ...well-being (SWB). The average economic status-SWB effect size was strongest among low-income developing economies (
r
= .28) and for samples that were least educated (
r
= .36). The relation was weakest among high-income developing economies (
r
= .10) and for highly educated samples (
r
= .13). Controlling for numerous covariates, the partial
r
effect size remained significant for the least-educated samples (
pr
= .18). Moderator analyses showed the economic status-SWB relation to be strongest when (a) economic status was defined as wealth (a stock variable), instead of as income (a flow variable), and (b) SWB was measured as life satisfaction (a cognitive assessment), instead of as happiness (an emotional assessment). Findings were replicated with a meta-analysis of the World Values Survey data. Discussion centers on the plausibility of need theory, alternative explanations of results, interpretation of moderators, and directions for future research.
Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. However, knowledge of the full effects of metformin on biochemical pathways and processes in its primary target ...tissue, the liver, is limited. One established effect of metformin is to decrease cellular energy levels. The AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are key regulators of metabolism that are respectively activated and inhibited in acute response to cellular energy depletion. Here we show that metformin robustly inhibits mTORC1 in mouse liver tissue and primary hepatocytes. Using mouse genetics, we find that at the lowest concentrations of metformin that inhibit hepatic mTORC1 signaling, this inhibition is dependent on AMPK and the tuberous sclerosis complex (TSC) protein complex (TSC complex). Finally, we show that metformin profoundly inhibits hepatocyte protein synthesis in a manner that is largely dependent on its ability to suppress mTORC1 signaling.
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•Metformin strongly inhibits mTORC1 in mouse liver and mouse and human hepatocytes•AMPK is required for inhibition of hepatic mTORC1 signaling with low-dose metformin•The TSC complex is required for inhibition of hepatic mTORC1 with low-dose metformin•Metformin attenuates protein synthesis in hepatocytes through the TSC complex
Howell et al. address the controversy around mechanisms of metformin action using mouse genetics and show that metformin inhibits mTORC1 signaling in the liver through the AMPK-TSC axis in a dose- and time-dependent manner. AMPK is required for metformin to inhibit mTORC1 only when a low dose is used.
Gravitational-wave (GW) detectors can contribute to the measurement of cosmological parameters and to testing the dark-energy sector of alternatives to ΛCDM, by using standard sirens. In this paper ...we focus on binary neutron stars with a counterpart detected through a gamma-ray burst (GRB), both at a second-generation network made by advanced LIGO+advanced Virgo+LIGO India+Kagra, and at third-generation (3G) detectors, discussing in particular the cases of a single Einstein Telescope (ET), and of a network of ET plus two Cosmic Explorer (CE). We construct mock catalogs of standard sirens, using different scenarios for the local merger rate and for the detection of the electromagnetic counterpart. For 3G detectors we estimate the coincidences with a GRB detector with the characteristics of the proposed THESEUS mission. We discuss how these standard sirens with a GRB counterpart can improve the determination of cosmological parameters (and particularly of H0) in ΛCDM, and we then study how to extract information on dark energy, considering both a non-trivial dark energy equation of state and modified GW propagation. We find that a 2G detector network can already reach, over several years of data taking, an interesting sensitivity to modified GW propagation, while a single ET detector would have a remarkable potential for discovery. We also find that, to fully exploit the potential of a ET+CE+CE network, it is necessary a much stronger program of search for electromagnetic counterparts (or else to resort to statistical methods for standard sirens), and furthermore gravitational lensing can become a limiting factor.
This paper reports a comprehensive study on the gravitational wave (GW) background from compact binary coalescences. We consider in our calculations newly available observation-based neutron star and ...black hole mass distributions and complete analytical waveforms that include post-Newtonian amplitude corrections. Our results show that: (i) post-Newtonian effects cause a small reduction in the GW background signal; (ii) below 100 Hz the background depends primarily on the local coalescence rate r
0 and the average chirp mass and is independent of the chirp mass distribution; (iii) the effects of cosmic star formation rates and delay times between the formation and merger of binaries are linear below 100 Hz and can be represented by a single parameter within a factor of ∼2; (iv) a simple power-law model of the energy density parameter ΩGW(f ) ∼ f 2/3 up to 50-100 Hz is sufficient to be used as a search template for ground-based interferometers. In terms of detection prospects of this background signal, we show that: (i) detection (a signal-to-noise ratio of 3) within one year of observation by the Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) detectors (H1-L1) requires a coalescence rate of r
0 = 3 (0.2) Mpc−3 Myr−1 for binary neutron stars (binary black holes); (ii) this limit on r
0 could be reduced threefold for two co-located and co-aligned detectors, whereas the currently proposed worldwide network of advanced instruments gives only ∼30 per cent improvement in detectability; (iii) the improved sensitivity of the planned Einstein Telescope allows not only confident detection of the background but also the high-frequency components of the spectrum to be measured, possibly enabling rate evolutionary histories and mass distributions to be probed. Finally, we show that sub-threshold binary neutron star merger events produce a strong foreground, which could be an issue for future terrestrial stochastic searches of primordial GWs.
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