Limited proteolysis of gasdermin D (GSDMD) generates an N-terminal pore-forming fragment that controls pyroptosis in macrophages. GSDMD is processed via inflammasome-activated caspase-1 or -11. It is ...currently unknown whether macrophage GSDMD can be processed by other mechanisms. Here, we describe an additional pathway controlling GSDMD processing. The inhibition of TAK1 or IκB kinase (IKK) by the
effector protein YopJ elicits RIPK1- and caspase-8-dependent cleavage of GSDMD, which subsequently results in cell death. GSDMD processing also contributes to the NLRP3 inflammasome-dependent release of interleukin-1β (IL-1β). Thus, caspase-8 acts as a regulator of GSDMD-driven cell death. Furthermore, this study establishes the importance of TAK1 and IKK activity in the control of GSDMD cleavage and cytotoxicity.
Human papillomavirus-positive oropharynx cancer incidence has increased rapidly in cohorts of US white men born during the 1930s to 1950s. It is unknown how the trajectory of the oropharynx cancer ...epidemic may be changing in the United States.
Using US cancer registry information, we investigated whether increases in oropharynx cancer have continued into recent birth cohorts and forecasted the future burden across age, sex, and race/ethnicity subgroups. Log-linear Joinpoint regression and age-period-cohort models were used to evaluate incidence trends during 1992 to 2015 and projections through 2029.
Among white men, oropharynx cancer incidence increased rapidly in individuals born during 1939 to 1955 (5.3% per 2-year birth cohort; 95% CI, 4.8% to 5.7%), but this rate of increase significantly moderated in individuals born during 1955 to 1969 (1.7% per 2-year birth cohort; 95% CI, 1.0% to 2.4%). Should these birth-cohort trends continue, from 2016 to 2029 we forecast that incidence will increase dramatically in older white men 65 to 74 years of age (from 40.7 to 71.2 per 100,000) and 75 to 84 years of age (from 25.7 to 50.1 per 100,000), moderately in white men 55 to 64 years of age (from 40.3 to 52.0 per 100,000), and remain stable in white men 45 to 54 years of age (approximately 18 per 100,000). Accounting for population growth, we project an increase in annual number of cases in the United States from 20,124 (95% CI, 19,779 to 20,469) in 2016 to 30,629 (95% CI, 29,413 to 31,845) in 2029, primarily driven by older individuals (age ≥ 65 years; from 7,976 95% CI, 7,782 to 8,172 to 18,072 95% CI, 17,271 to 18,895) and white men (from 14,453 95% CI, 14,142 to 14,764 to 22,241 95% CI, 21,119 to 23,364).
The exponential increase in oropharynx cancer incidence in young white US men has ebbed, and modest increases are occurring/anticipated in cohorts born after 1955. Continued strong increases in incidence in cohorts born before 1955, and an approximate 50% increase in size of the US population age 65 years or older through 2029, portend a substantial shift in burden to elderly white men.
Total elbow arthroplasty (TEA) is often used to manage advanced arthropathies of the elbow caused by inflammatory conditions such as rheumatoid arthritis (RA). Recent literature has shown that use of ...TEA is decreasing in patients with RA, part of which can be attributed to early medical management involving disease-modifying antirheumatic drugs (DMARDs). However, there is a significant economic barrier to accessing DMARD therapy. The purpose of this study was to compare the use of TEA between patients with and without DMARD therapy from 2010 to 2020.
A retrospective cohort analysis was performed using a national insurance claim database to investigate the trends of patients with RA undergoing TEA from 2010-2020. Patients who underwent TEA and had a diagnosis of RA were identified using Current Procedural Terminology (CPT) and International Classification of Diseases (ICD)-9 and ICD-10 codes between 2010 and 2020. These patients were then stratified into 2 cohorts: those with DMARD prescription claims and those without. A linear regression, compound annual growth rate (CAGR) analysis, and χ2 analysis were conducted to compare trends and demographic variables, including insurance type, between cohorts. Additionally, a multivariable logistic regression was subsequently performed to observe odds ratios (ORs) and 95% confidence intervals.
From 2010 to 2020, there has been no significant change in the incidence of TEA in RA patients without DMARD prescriptions, whereas there has been a statistically significantly decreasing rate of TEA observed in RA patients with DMARD prescription claims. The analysis showed that there was a CAGR of −4%. For patients with a diagnosis of RA and DMARD prescription claims, the highest incidence of undergoing TEA was seen in the age group of 60-69 years, whereas patients with a diagnosis of RA and no DMARD prescription claims had the highest incidence of undergoing TEA in the age group of 70-79 years.
The incidence of patients undergoing TEA with a diagnosis of RA and DMARD prescription claims has shown a statistically significant decrease from 2010 to 2020, whereas no significant difference was observed for patients without DMARD prescription claims. There were no statistically significant differences in the insurance plans between cohorts.
Avascular necrosis of the humeral head (AVN) is characterized by osteonecrosis secondary to disrupted blood flow to the glenohumeral joint. Following collapse of the humeral head, arthroplasty, ...namely total shoulder arthroplasty (TSA) or humeral head arthroplasty (hemiarthroplasty) is recommended standard of care. The literature is limited to underpowered and small sample sizes in comparing arthroplasty modalities. Therefore, the aims of this study were (1) to compare the 10-year survivorship of TSA and hemiarthroplasty in the treatment of AVN of the humeral head and (2) to identify differences in their revision etiologies.
Patients who underwent primary TSA and hemiarthroplasty for AVN were identified using the PearlDiver database. TSA patients were matched by age, gender, and Charlson Comorbidity Index (CCI) to the hemiarthroplasty cohort in a 4:1 ratio since TSA patients were generally older, sicker, and more often female. The 10-year cumulative incidence rate of all-cause revision was determined using Kaplan-Meier survival analysis. Multivariable analysis was conducted using Cox Proportional Hazard modeling. Chi-squared analysis was conducted to compare the indications for revisions between matched cohorts including periprosthetic joint infection (PJI), dislocation, mechanical loosening, broken implants, periprosthetic fracture, and stiffness.
In total, 4,825 patients undergoing TSA and 1,969 patients undergoing hemiarthroplasty for AVN were included in this study. The unmatched 10-year cumulative incidence of revision for patients who underwent TSA and hemiarthroplasty was 7.0% and 7.7%, respectively. The matched 10-year cumulative incidence of revision for patients who underwent TSA and hemiarthroplasty was 6.7% and 8.0%, respectively. When comparing the unmatched cohorts, TSA patients were at significantly higher risk of 10-year all-cause revision (HR: 1.39; P = 0.017) when compared to hemiarthroplasty patients. After matching, there was no significant difference in risk of 10-year all-cause revision (HR: 1.29; P = 0.148) and no difference in the observed etiologies for revision (P > 0.05 for all).
After controlling for confounders, only 6.7% of TSA and 8.0% hemiarthroplasties for humeral head AVN were revised within 10-years of index surgery. The demonstrated high and comparable long-term survivorship for both modalities supports the utilization of either for the AVN induced humeral head collapse.
Abstract
We present the identification of the second discovery from the COol Companions ON Ultrawide orbiTS (COCONUTS) program, the COCONUTS-2 system, composed of the M3 dwarf L 34-26 and the T9 ...dwarf WISEPA J075108.79−763449.6. Given their common proper motions and parallaxes, these two field objects constitute a physically bound pair with a projected separation of 594″ (6471au). The primary star COCONUTS-2A has strong stellar activity (H
α
, X-ray, and ultraviolet emission) and is rapidly rotating (P
rot
= 2.83 days), from which we estimate an age of 150–800 Myr. Comparing equatorial rotational velocity derived from the Transiting Exoplanet Survey Satellite (TESS) light curve to spectroscopic
v
sin
i
, we find that COCONUTS-2A has a nearly edge-on inclination. The wide exoplanet COCONUTS-2b has an effective temperature of
T
eff
= 434 ± 9 K, a surface gravity of
log
g
=
4.11
−
0.18
+
0.11
dex, and a mass of
M
=
6.3
−
1.9
+
1.5
M
Jup
based on hot-start evolutionary models, leading to a mass ratio of
0.016
−
0.005
+
0.004
for the COCONUTS-2 system. COCONUTS-2b is the second coldest (after WD 0806−661B), and the second widest (after TYC 9486-927-1 b) exoplanet imaged to date. Comparison of COCONUTS-2b’s infrared photometry with ultracool model atmospheres suggests the presence of both condensate clouds and non-equilibrium chemistry in its photosphere. Similar to 51 Eri b, COCONUTS-2b has a sufficiently low luminosity (
log
(
L
bol
/
L
⊙
)
=
−
6.384
±
0.028
dex) to be consistent with the cold-start process that may form gas-giant (exo)planets, though its large separation means that such formation would not have occurred in situ. Finally, at a distance of 10.9 pc, COCONUTS-2b is the nearest imaged exoplanet to Earth known to date.
The use of tranexamic acid (TXA) has become widespread in orthopedics to promote hemostasis and has been successfully used to reduce blood loss and infection risk in joint arthroplasty. However, the ...cost effectiveness of routine TXA use for the prevention of periprosthetic infections in total shoulder arthroplasty remains unknown.
The acquisition cost of TXA ($5.22) for our institution, along with values from the literature for the average cost of infection-related care ($55,243) and the baseline infection rates for patients without TXA use (0.70%),were used to perform a break-even analysis. The absolute risk reduction (ARR) of infection necessary to justify the prophylactic use of TXA in shoulder arthroplasty was calculated from the nontreated and break-even infection rates.
TXA is considered cost-effective if it prevents one infection out of 10,583 total shoulder arthroplasty's (ARR = 0.009%). It is economically justifiable with an ARR range of 0.001% at a cost of $0.50/g to 0.181% at $100/g. At varying costs of infection-related care ($10,000-$100,000) and varying baseline infection rates (0.50%-8.00%) and routine use of TXA remained cost-effective.
The use of TXA is an economically viable practice for infection prevention following shoulder arthroplasty if it reduces the infection rate by 0.009%. Future, prospective studies should be conducted to observe whether TXA reduces the infection rate by more than 0.009%, showing cost effectiveness.
Neuronal inclusions of aggregated RNA‐binding protein fused in sarcoma (FUS) are hallmarks of ALS and frontotemporal dementia subtypes. Intriguingly, FUS's nearly uncharged, aggregation‐prone, yeast ...prion‐like, low sequence‐complexity domain (LC) is known to be targeted for phosphorylation. Here we map in vitro and in‐cell phosphorylation sites across FUS LC. We show that both phosphorylation and phosphomimetic variants reduce its aggregation‐prone/prion‐like character, disrupting FUS phase separation in the presence of RNA or salt and reducing FUS propensity to aggregate. Nuclear magnetic resonance spectroscopy demonstrates the intrinsically disordered structure of FUS LC is preserved after phosphorylation; however, transient domain collapse and self‐interaction are reduced by phosphomimetics. Moreover, we show that phosphomimetic FUS reduces aggregation in human and yeast cell models, and can ameliorate FUS‐associated cytotoxicity. Hence, post‐translational modification may be a mechanism by which cells control physiological assembly and prevent pathological protein aggregation, suggesting a potential treatment pathway amenable to pharmacologic modulation.
Synopsis
Self‐association of the ALS and FTD neurodegenerative disease‐linked RNA‐binding protein FUS is regulated by phosphorylation of its low complexity domain.
FUS low complexity (LC) domain can be phosphorylated at several sites: by DNA‐PK at 12 sites in vitro, and in human cells after DNA damage at additional sites.
FUS LC phosphorylation and phosphomimetic substitution discourages phase separation and aggregation.
FUS LC phosphomimetic substitution decreases FUS aggregation in yeast and human cell models.
FUS LC phosphomimetic substitution reduces FUS toxicity in the yeast model.
Post‐translational modification emerges as a cellular mechanism for controlling physiological assembly of the ALS and FTD neurodegenerative disease‐linked RNA‐binding protein FUS.
The etiology and significance of coronary artery tortuosity (TCA) among patients with spontaneous coronary artery dissection (SCAD) are unknown. The aim of this prospective imaging cohort study was ...to report echocardiographic findings and evaluate whether TCA correlates with cardiac anatomy and function among patients with SCAD. Comorbidities including fibromuscular dysplasia (FMD) and outcomes were also assessed.
TCA was determined on coronary angiography performed during the diagnosis of SCAD, and cardiac structure and function were evaluated using prospective comprehensive echocardiography.
Among 116 patients with SCAD, the mean age at echocardiography was 50.8 ± 8.8 years, a median of 10.9 months after SCAD. Sixty-two patients (53.4%) had FMD, 41 (35.3%) had histories of hypertension, and 17 (14.8%) were hypertensive during echocardiography. Most patients (n = 78 69%) had normal left ventricular geometry with normal median ejection fraction (61%; interquartile range, 56% to 64%) and normal global longitudinal strain (-22.2%; interquartile range, -24.0% to -19.9%). Fifteen patients (13.4%) had diastolic dysfunction that was associated with hypertension at the time of echocardiography. Patients with TCA (n = 96 82.8%) were older (mean age, 52.1 ± 8.0 vs 44.7 ± 9.9 years; P < .001) with a higher prevalence of FMD (59.4% vs 25%, P = .007) but a similar prevalence of hypertension (35% vs 35%, P > .99) compared with patients without TCA. Across the age range (31.5 to 66.9 years), each decade of age was associated with an approximately 0.89-unit increase in coronary tortuosity score (P < .0001). Echocardiographic parameters were not significantly different between the two groups. Median follow-up duration was 4.4 years (95% CI, 3.8 to 5.2 years). The Kaplan-Meier 3-year SCAD recurrence rate was 9.4% (95% CI, 3.7% to 14.8%). There were no deaths.
The majority of patients with SCAD had normal or near normal echocardiographic results, including global longitudinal strain, with no differences according to TCA. However, patients with SCAD with TCA were older, with a higher prevalence of FMD.
Vision-based methods using RGB inputs for human pose estimation have grown in recent years but have undergone limited testing in clinical and biomechanics research areas like gait analysis. The ...purpose of the present study was to compare lower extremity kinematics during overground gait between a traditional marker-based approach and a commercial multi-view markerless system in a sample of subjects including young adults, older adults, and adults diagnosed with Parkinson’s disease. A convenience sample of 35 adults between the age of 18–85 years were included in this study, yielding a total of 114 trials and 228 gait cycles that were compared between systems. A total of 30 time normalized waveforms, including three-dimensional joint centers, segment angles, and joint angles were compared between systems using root mean-squared error (RMSE), range of motion difference (ΔROM), Pearson correlation coefficients (r), and interclass correlation coefficients (ICC). RMSEs for joint center positions were less than 28 mm in all joints with correlations indicating good to excellent agreement. RMSEs for segment and joint angles were in range of previous results, with highest agreement between systems in the sagittal plane. ΔROM differences were within reference values that characterize clinical groups like Parkinson’s disease, stroke, or knee osteoarthritis. Further improvements in pelvis tracking, markerless keypoint model definitions, and standardization of comparison study protocols are needed. Nevertheless, markerless solutions seem promising toward unrestricted motion analysis in biomechanics research and clinical settings.
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