Many early universe theories predict the creation of Primordial Black Holes (PBHs). PBHs could have masses ranging from the Planck mass to 105 solar masses or higher depending on the size of the ...universe at formation. A Black Hole (BH) has a Hawking temperature which is inversely proportional to its mass. Hence a sufficiently small BH will quasi-thermally radiate particles at an ever-increasing rate as emission lowers its mass and raises its temperature. The final moments of this evaporation phase should be explosive and its description is dependent on the particle physics model. In this work we investigate the final few seconds of BH evaporation, using the Standard Model and incorporating the most recent Large Hadron Collider (LHC) results, and provide a new parameterization for the instantaneous emission spectrum. We calculate for the first time energy-dependent PBH burst light curves in the GeV/TeV energy range. Moreover, we explore PBH burst search methods and potential observational PBH burst signatures. We have found a unique signature in the PBH burst light curves that may be detectable by GeV/TeV gamma-ray observatories such as the High Altitude Water Cerenkov (HAWC) observatory. The implications of beyond the Standard Model theories on the PBH burst observational characteristics are also discussed, including potential sensitivity of the instantaneous photon detection rate to a squark threshold in the 5–10 TeV range.
Background
The purpose of this study was to identify the ten most frequent complications after surgery for stage I–III colon cancer and to assess the association between these complications and ...overall survival, conditional overall survival, and recurrences.
Methods
All patients who underwent surgery for stage I–III colon cancer in five hospitals in the Western region of the Netherlands were identified. Crude and adjusted Cox proportional hazards models were used to study the association between complications and 1-year overall survival, 5-year overall survival, 5-year conditional overall survival, and 5-year disease-free period.
Results
Data from 761 patients were used for the analyses. Complications were associated with decreased 1-year overall survival (hazard ratio (HR) 2.87, 95 % confidence interval (CI) 1.82–4.51;
p
< 0.001), 5-year overall survival (HR 1.59, 95 % CI 1.25–2.04;
p
< 0.001), and 5-year conditional overall survival (HR 1.34, 95 % CI 1.06–1.69;
p
= 0.016), whereas an increasing number of complications had no additional impact. Anastomotic leakage, excessive blood loss, and (abdominal) sepsis were associated with reduced 1-year overall survival, anastomotic leakage, delirium, abscess, and (abdominal) sepsis with reduced 5-year overall survival, and anastomotic leakage, delirium, and abscess with reduced 5-year conditional overall survival. Anastomotic leakage, electrolyte disorders, and abscess were risk factors for recurrence within five years.
Conclusions
Our results demonstrate the serious impact of the most frequent complications after surgery for colon cancer on short-term and long-term outcomes. This study confirms the prolonged impact of surgery and demonstrates that complications result not only in reduced 1-year survival, but also in reduced long-term outcomes.
Objective: The bidirectional communication between the user and the prosthesis is an important requirement when developing prosthetic hands. Proprioceptive feedback is fundamental to perceiving ...prosthesis movement without the need for constant visual attention. We propose a novel solution to encode wrist rotation using a vibromotor array and Gaussian interpolation of vibration intensity. The approach generates tactile sensation that smoothly rotates around the forearm congruently with prosthetic wrist rotation. The performance of this scheme was systematically assessed for a range of parameter values (number of motors and Gaussian standard deviation). Methods: Fifteen able-bodied subjects and one individual with congenital limb deficiency used vibrational feedback to control the virtual hand in the target-achievement test. Performance was assessed by end-point error and efficiency as well as subjective impressions. Results: The results showed a preference for smooth feedback and a higher number of motors (8 and 6 versus 4). With 8 and 6 motors, the standard deviation, determining the sensation spread and continuity, could be modulated through a broad range of values (0.1 - 2) without a significant performance loss (error: ∼ 10%; efficiency: ∼ 30%). For low values of standard deviation (0.1-0.5), the number of motors could be reduced to 4 without a significant performance decrease. Conclusion: The study demonstrated that the developed strategy provided meaningful rotation feedback. Moreover, the Gaussian standard deviation can be used as an independent parameter to encode an additional feedback variable. Significance: The proposed method is a flexible and effective approach to providing proprioceptive feedback while adjusting the trade-off between sensation quality and the number of vibromotors.
Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes ...immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy.
KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study.
On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes.
This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.
•Coexisting alterations in KEAP1, PBRM1, SMARCA4 and STK11 define a subset of lung adenocarcinoma unresponsive to immunotherapy.•Tumors harboring co-mutations had inferior survival outcomes compared with both single-mutant and wild-type tumors.•Tumors with co-occurring alterations are misclassified as immunoresponsive by tumor mutational burden.•An immunologically cold phenotype characterizes lung adenocarcinoma with coexisting mutations.
PET/MRI of Inflammation in Myocardial Infarction Lee, Won Woo, MD, PhD; Marinelli, Brett, BA; van der Laan, Anja M., MD ...
Journal of the American College of Cardiology,
01/2012, Letnik:
59, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Objectives The aim of this study was to explore post–myocardial infarction (MI) myocardial inflammation. Background Innate immune cells are centrally involved in infarct healing and are emerging ...therapeutic targets in cardiovascular disease; however, clinical tools to assess their presence in tissue are scarce. Furthermore, it is currently not known if the nonischemic remote zone recruits monocytes. Methods Acute inflammation was followed in mice with coronary ligation by 18-fluorodeoxyglucose (18 FDG) positron emission tomography/magnetic resonance imaging, fluorescence-activated cell sorting, polymerase chain reaction, and histology. Results Gd-DTPA–enhanced infarcts showed high18 FDG uptake on day 5 after MI. Cell depletion and isolation data confirmed that this largely reflected inflammation; CD11b+ cells had 4-fold higher18 FDG uptake than the infarct tissue from which they were isolated (p < 0.01). Surprisingly, there was considerable monocyte recruitment in the remote myocardium (approximately 104 /mg of myocardium, 5.6-fold increase; p < 0.01), a finding mirrored by macrophage infiltration in the remote myocardium of patients with acute MI. Temporal kinetics of cell recruitment were slower than in the infarct, with peak numbers on day 10 after ischemia. Quantitative polymerase chain reaction showed a robust increase of recruiting adhesion molecules and chemokines in the remote myocardium (e.g., 12-fold increase of monocyte chemoattractant protein-1), although levels were always lower than in the infarct. Finally, matrix metalloproteinase activity was significantly increased in noninfarcted myocardium, suggesting that monocyte recruitment to the remote zone may contribute to post-MI dilation. Conclusions This study shed light on the innate inflammatory response in remote myocardium after MI.
Damage evolution during low- and high-cycle fatigue in an embrittled duplex stainless steel is characterized in this paper. Moreover, scanning electron microscopy observations (SEM) in combination ...with electron backscattered diffraction (EBSD) measurements and transmission electron microscopy (TEM) were employed in order to analyze microcracks formation and propagation. During low-cycle fatigue, microcracks initiate the ferrite phase either along slip planes with the highest Schmid factor (SF) inside the grains or at the α/α grain boundary. Then, microcracks propagation take place in ferrite or austenite grains with the highest SF. An analysis of the dislocation structure in the near-surface and in ferritic grains in the bulk of the specimen has shown that dislocation microbands are associated with microcrack initiation.
In the high-cycle fatigue regime, damage generally initiates in the austenite by slip band formation followed by crack initiation either at an α–α boundary or at an α–γ boundary in the intersection of slip bands in the austenite. The microstructure in the austenite consists of a low density of dislocation pile-ups while the ferrite is practically inactive or develops only micro-yielding at boundaries.
Despite the differences in both fatigue regimes, phase boundaries are an effective barrier against crack propagation because they delay the advance of the crack tip.
Breastfeeding and the place of sleep for the mother and the infant have been controversial internationally due to reported concerns regarding infant deaths despite the known benefits of exclusive and ...prolonged breastfeeding, which are increased by breastfeeding at night. The aims of this integrated analysis were to (a) review breastfeeding and maternal and infant sleep research literature via historical, epidemiological, anthropological, and methodological lenses; (b) use this information to determine where we are currently in safeguarding both infant lives and breastfeeding; and (c) postulate the direction that research might take from this point forward to improve our knowledge and inform our policy and practice. Despite well-meaning but unsuccessful campaigns in some countries to dissuade parents from sleeping with their babies, many breastfeeding mothers and caregivers do sleep with their infants whether intentionally or unintentionally. Taking cultural contexts and socio-ecological circumstances into consideration, data supports policies to counsel parents and caregivers on safe sleep practices, including bed-sharing in non-hazardous circumstances, particularly in the absence of parental smoking, recent parental alcohol consumption, or sleeping next to an adult on a sofa. Further research with appropriate methodology is needed to drill down on actual rates of infant deaths, paying close attention to the definitions of deaths, the circumstances of the deaths, and confounding factors, in order to ensure we have the best information with which to derive public health policy. Introduction and use of the concept of “breastsleeping” is a plausible way to remove the negative connotations of “co-sleeping” and redirect ongoing data-driven discussions and education of best practices of breastfeeding and sleep.
A scheme for generating two simultaneous hard-x-ray free-electron laser pulses with a controllable difference in photon energy is described and then demonstrated using the self-seeding setup at the ...Linac Coherent Light Source (LCLS). The scheme takes advantage of the existing LCLS equipment, which allows two independent rotations of the self-seeding diamond crystal. The two degrees of freedom are used to select two nearby crystal reflections, causing two wavelengths to be present in the forward transmitted seeding x-ray pulse. The free-electron laser system must support amplification at both desired wavelengths.
We conducted a phase I-II study to evaluate Nilotinib (NIL) safety and pharmacokinetics in 22 SR-cGVHD patients; we also evaluated ORR by using in parallel NIH criteria and an exploratory approach, ...combining objective improvement (OI) without failure criteria (GITMO criteria). Results: 22 patients were enrolled. After dose escalation up to 600 mg/day, MTD was not reached. Main toxicities were asthenia, headache, nausea, pruritus, cramps, and mild anemia. Mean and median plasma concentrations of NIL (C-NIL) were 817 (SD ± 450) and 773 ng/ml. ORR at 6 months, according to 2005 and 2014 NIH and GITMO criteria were 27.8%, 22.2%, and 55.6% respectively; close correspondence has been observed for ORR, according to 2014 NIH criteria, both assessed in a conventional way and assisted by dedicated software (CROSY). At 48 months OS was 75% while FFS, according to NIH and GITMO criteria, was 30 and 25%. In conclusion the safety profile of NIL and long-term outcome makes NIL an attractive option in SR-cGVHD. Exploratory GITMO criteria could represent an alternative tool for easy response evaluation in patients with prevalent skin and lung involvement, but require validation in a larger population; CROSY software showed excellent reliability in capturing ORR according to the 2014 NIH criteria.
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