Abstract Robotic assisted orthopaedic surgery has been available clinically in some form for over two decades, claiming to improve total joint arthroplasty by enhancing the surgeon’s ability to ...reproduce alignment, and therefore better restore normal kinematics. Various current systems include a robotic arm, robotic guided cutting jigs, and robotic milling systems with a diversity of different navigation strategies using active, semi-active, or passive control systems. Semi-active systems have become dominant, providing a haptic window through which the surgeon is able to consistently prepare an arthroplasty based on preoperative planning. A review of previous designs and clinical studies demonstrate that these robotic systems decrease variability and increase precision, primarily focusing on component positioning and alignment. Some early clinical results indicate decreased revision rates and improved patient satisfaction with robotic assisted arthroplasty. The future design objectives include precise planning and even further improved consistent intra-operative execution. Despite this cautious optimism, many still wonder whether robotics will ultimately increase cost and operative time without objectively improving outcomes. Over the long term, every industry that has seen robotic technology be introduced, ultimately has shown an increase in production capacity, improved accuracy and precision, and lower cost. A new generation of robotic systems is now being introduced into the arthroplasty arena and early results with unicompartmental knee arthroplasty and total hip arthroplasty have demonstrated improved accuracy of placement, improved satisfaction, and reduced complications. Further studies are needed to confirm the cost-effectiveness of these technologies.
Abstract Background In patients with aortic stenosis undergoing transcatheter aortic valve replacement (TAVR), studies have suggested that reduced left ventricular (LV) ejection fraction (LVEF) and ...low aortic valve gradient (AVG) are associated with worse long-term outcomes. Because these conditions commonly coexist, the extent to which they are independently associated with outcomes after TAVR is unknown. Objectives The purpose of this study was to evaluate the impact of LVEF and AVG on clinical outcomes after TAVR and to determine whether the effect of AVG on outcomes is modified by LVEF. Methods Using data from 11,292 patients who underwent TAVR as part of the Transcatheter Valve Therapies Registry, we examined rates of 1-year mortality and recurrent heart failure in patients with varying levels of LV dysfunction (LVEF <30% vs. 30% to 50% vs. >50%) and AVG (<40 mm Hg vs. ≥40 mm Hg). Multivariable models were used to estimate the independent effect of AVG and LVEF on outcomes. Results During the first year of follow-up after TAVR, patients with LV dysfunction and low AVG had higher rates of death and recurrent heart failure. After adjustment for other clinical factors, only low AVG was associated with higher mortality (hazard ratio: 1.21; 95% confidence interval: 1.11 to 1.32; p < 0.001) and higher rates of heart failure (hazard ratio: 1.52; 95% confidence interval: 1.36 to 1.69; p <0.001), whereas the effect of LVEF was no longer significant. There was no evidence of effect modification between AVG and LVEF with respect to either endpoint. Conclusions In this series of real-world patients undergoing TAVR, low AVG, but not LV dysfunction, was associated with higher rates of mortality and recurrent heart failure. Although these findings suggest that AVG should be considered when evaluating the risks and benefits of TAVR for individual patients, neither severe LV dysfunction nor low AVG alone or in combination provide sufficient prognostic discrimination to preclude treatment with TAVR.
After a prolonged response, an anaplastic thyroid cancer developed resistance to mammalian target of rapamycin (mTOR) inhibition by somatic mutation of mTOR at the everolimus binding site. The mutant ...enzyme retained in vitro responsiveness to an mTOR kinase inhibitor.
A better understanding of the mechanisms of sensitivity and resistance to anticancer therapies may improve patient selection and allow the development of rational treatment designs. One approach involves studying paired biopsy samples of pretreatment and drug-resistant tumors obtained from patients with exquisite sensitivity or unusually durable responses to therapy.
Everolimus is a Food and Drug Administration–approved oral allosteric inhibitor of mTOR. Tumors that exhibit a dependency on the mTOR pathway might have enhanced sensitivity to mTOR inhibition. Inactivating mutations in the tumor-suppressor genes
TSC1, TSC2,
and
STK11
result in mTOR-pathway activation and are targetable by TOR inhibitors in hamartoma syndromes . . .
Myogenesis is a crucial process governing skeletal muscle development and homeostasis. Differentiation of primitive myoblasts into mature myotubes requires a metabolic switch to support the increased ...energetic demand of contractile muscle. Skeletal myoblasts specifically shift from a highly glycolytic state to relying predominantly on oxidative phosphorylation (OXPHOS) upon differentiation. We have found that this phenomenon requires dramatic remodeling of the mitochondrial network involving both mitochondrial clearance and biogenesis. During early myogenic differentiation, autophagy is robustly upregulated and this coincides with DNM1L/DRP1 (dynamin 1-like)-mediated fragmentation and subsequent removal of mitochondria via SQSTM1 (sequestosome 1)-mediated mitophagy. Mitochondria are then repopulated via PPARGC1A/PGC-1α (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha)-mediated biogenesis. Mitochondrial fusion protein OPA1 (optic atrophy 1 autosomal dominant) is then briskly upregulated, resulting in the reformation of mitochondrial networks. The final product is a myotube replete with new mitochondria. Respirometry reveals that the constituents of these newly established mitochondrial networks are better primed for OXPHOS and are more tightly coupled than those in myoblasts. Additionally, we have found that suppressing autophagy with various inhibitors during differentiation interferes with myogenic differentiation. Together these data highlight the integral role of autophagy and mitophagy in myogenic differentiation.
Objective:
A study was undertaken to determine whether psychiatric disorders associated with suicide are more common in incident epilepsy than in matched controls without epilepsy, before and after ...epilepsy diagnosis.
Methods:
A matched, longitudinal cohort study was conducted in the UK General Practice Research Database. A total of 3,773 cases diagnosed with epilepsy between the ages of 10 and 60 years were compared to 14,025 controls matched by year of birth, sex, general practice, and years of medical records before the index date. We examined first diagnosis of psychosis, depression, anxiety, and suicidality in each of the 3 years before and after the index date and annual prevalence of suicide. Referent diagnoses were eczema and acute surgery. The incidence rate ratio (IRR) was calculated for each year in the study period; the prevalence ratio (PR) was calculated for suicidality.
Results:
The IRR of psychosis, depression, and anxiety was significantly increased for all years before epilepsy diagnosis (IRR, 1.5–15.7) and after diagnosis (IRR, 2.2–10.9) and for suicidality before epilepsy diagnosis (IRR, 3.1–4.5) and 1 year after diagnosis (IRR, 5.3). The PR was increased for suicide attempt before epilepsy onset (PR, 2.6–5.2) and after onset (PR, 2.4–5.6). Eczema and acute surgery were both associated with epilepsy in the first and third year after diagnosis.
Interpretation:
Epilepsy is associated with an increased onset of psychiatric disorders and suicide before and after epilepsy diagnosis. These relations suggest common underlying pathophysiological mechanisms that both lower seizure threshold and increase risk for psychiatric disorders and suicide. ANN NEUROL 2012
Abstract
The first few 100 Myr at
z
> 10 mark the last major uncharted epoch in the history of the universe, where only a single galaxy (GN-z11 at
z
≈ 11) is currently spectroscopically confirmed. ...Here we present a search for luminous
z
> 10 galaxies with JWST/NIRCam photometry spanning ≈1–5
μ
m and covering 49 arcmin
2
from the public JWST Early Release Science programs (CEERS and GLASS). Our most secure candidates are two
M
UV
≈ −21 systems: GLASS-z12 and GLASS-z10. These galaxies display abrupt ≳1.8 mag breaks in their spectral energy distributions (SEDs), consistent with complete absorption of flux bluewards of Ly
α
that is redshifted to
z
=
12.4
−
0.3
+
0.1
and
z
=
10.4
−
0.5
+
0.4
. Lower redshift interlopers such as quiescent galaxies with strong Balmer breaks would be comfortably detected at >5
σ
in multiple bands where instead we find no flux. From SED modeling we infer that these galaxies have already built up ∼10
9
solar masses in stars over the ≲300–400 Myr after the Big Bang. The brightness of these sources enable morphological constraints. Tantalizingly, GLASS-z10 shows a clearly extended exponential light profile, potentially consistent with a disk galaxy of
r
50
≈ 0.7 kpc. These sources, if confirmed, join GN-z11 in defying number density forecasts for luminous galaxies based on Schechter UV luminosity functions, which require a survey area >10× larger than we have studied here to find such luminous sources at such high redshifts. They extend evidence from lower redshifts for little or no evolution in the bright end of the UV luminosity function into the cosmic dawn epoch, with implications for just how early these galaxies began forming. This, in turn, suggests that future deep JWST observations may identify relatively bright galaxies to much earlier epochs than might have been anticipated.
JASPAR (http://jaspar.genereg.net) is an open-access database storing curated, non-redundant transcription factor (TF) binding profiles representing transcription factor binding preferences as ...position frequency matrices for multiple species in six taxonomic groups. For this 2016 release, we expanded the JASPAR CORE collection with 494 new TF binding profiles (315 in vertebrates, 11 in nematodes, 3 in insects, 1 in fungi and 164 in plants) and updated 59 profiles (58 in vertebrates and 1 in fungi). The introduced profiles represent an 83% expansion and 10% update when compared to the previous release. We updated the structural annotation of the TF DNA binding domains (DBDs) following a published hierarchical structural classification. In addition, we introduced 130 transcription factor flexible models trained on ChIP-seq data for vertebrates, which capture dinucleotide dependencies within TF binding sites. This new JASPAR release is accompanied by a new web tool to infer JASPAR TF binding profiles recognized by a given TF protein sequence. Moreover, we provide the users with a Ruby module complementing the JASPAR API to ease programmatic access and use of the JASPAR collection of profiles. Finally, we provide the JASPAR2016 R/Bioconductor data package with the data of this release.
Background
IgE‐mediated egg allergy presents as one of the most common food allergies in children. Measurement of egg white specific IgE (sIgE) levels in serum or skin prick test has been shown to be ...a poor predictor of clinical allergy to raw egg white, and also to baked or cooked egg. Recent developments in component resolved diagnostic (CRD) technology have enabled us to improve the way in which we diagnose and predict peanut allergy by examining IgE specificity to individual peptides.
Objectives
We aimed to investigate whether egg CRD could improve current methods to diagnose various egg allergy phenotypes as well as predict the development of tolerance to egg.
Methods
Using the HealthNuts cohort of food challenge‐proven egg allergic and egg‐sensitized and egg‐tolerant, age‐matched 12‐month infants with longitudinal follow‐up at 2 and 4 years (n = 451), we measured serum egg white, Gal d 1, 2, 3 and 5 sIgE using ImmunoCAP.
Results
Gal d 1 sensitization increased the risk of persistent egg allergy by 2.5‐fold. The production of sIgE to all four egg allergens (Gal d 1, 2, 3 or 5) increased the risk of having persistent raw egg allergy fourfold (OR 4.19 (95% CI: 1.25‐14.07). We did not find any improvements of using Gal d 1, 2, 3 or 5 to diagnose current egg allergy compared to egg white sIgE.
Conclusion
Sensitization to multiple egg allergens Gal d 1, 2, 3 or 5 may be a prognostic marker that could be useful for patient management and identifying individuals at risk of developing persistent egg allergy.
Sensitisation to Gal d 1 increases the risk of persistent egg allergy later in life (OR 2.5). Sensitisation to any of the 3 or 4 major egg allergens Gal d 1, 2, 3 or 5, increases the risk of persistent egg allergy (OR 4.19). The use of egg CRD does not improve the accuracy of egg allergy diagnosis compared to current whole egg sIgE 95% PPV.
BACKGROUND—Valve-in-valve (VIV) transcatheter aortic valve replacement (TAVR) may be less effective in small surgical valves because of patient/prosthesis mismatch. Bioprosthetic valve fracture (BVF) ...using a high-pressure balloon can be performed to facilitate VIV TAVR.
METHODS AND RESULTS—We report data from 20 consecutive clinical cases in which BVF was successfully performed before or after VIV TAVR by inflation of a high-pressure balloon positioned across the valve ring during rapid ventricular pacing. Hemodynamic measurements and calculation of the valve effective orifice area were performed at baseline, immediately after VIV TAVR, and after BVF. BVF was successfully performed in 20 patients undergoing VIV TAVR with balloon-expandable (n=8) or self-expanding (n=12) transcatheter valves in Mitroflow, Carpentier-Edwards Perimount, Magna and Magna Ease, Biocor Epic and Biocor Epic Supra, and Mosaic surgical valves. Successful fracture was noted fluoroscopically when the waist of the balloon released and by a sudden drop in inflation pressure, often accompanied by an audible snap. BVF resulted in a reduction in the mean transvalvular gradient (from 20.5±7.4 to 6.7±3.7 mm Hg, P<0.001) and an increase in valve effective orifice area (from 1.0±0.4 to 1.8±0.6 cm, P<0.001). No procedural complications were reported.
CONCLUSIONS—BVF can be performed safely in small surgical valves to facilitate VIV TAVR with either balloon-expandable or self-expanding transcatheter valves and results in reduced residual transvalvular gradients and increased valve effective orifice area.
Summary
Since previous reviews of epidemiologic studies of premature mortality among people with epilepsy were completed several years ago, a large body of new evidence about this subject has been ...published. We aim to update prior reviews of mortality in epilepsy and to reevaluate and quantify the risks, potential risk factors, and causes of these deaths. We systematically searched the Medline and Embase databases to identify published reports describing mortality risks in cohorts and populations of people with epilepsy. We reviewed relevant reports and applied criteria to identify those studies likely to accurately quantify these risks in representative populations. From these we extracted and summarized the reported data. All population‐based studies reported an increased risk of premature mortality among people with epilepsy compared to general populations. Standard mortality ratios are especially high among people with epilepsy aged <50 years, among those whose epilepsy is categorized as structural/metabolic, those whose seizures do not fully remit under treatment, and those with convulsive seizures. Among deaths directly attributable to epilepsy or seizures, important immediate causes include sudden unexpected death in epilepsy (SUDEP), status epilepticus, unintentional injuries, and suicide. Epilepsy‐associated premature mortality imposes a significant public health burden, and many of the specific causes of death are potentially preventable. These require increased attention from healthcare providers, researchers, and public health professionals.
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