Miracle-dz/UniFAR-FTUs huggingface dataset:
Intra-patient Inter-metastatic Genetic Heterogeneity in Colorectal Cancer as a Key Determinant of Survival after Curative Liver Resection

Chromosomal instability is a well-defined hallmark of tumor aggressiveness and metastatic progression in colorectal cancer. The magnitude of genetic heterogeneity among distinct liver metastases from the same patient at the copy number level, as well as its relationship with chemotherapy exposure and patient outcome, remains unknown. We performed high-resolution DNA copy number analyses of 134 liver metastatic deposits from 45 colorectal cancer patients to assess: (i) intra-patient inter-metastatic genetic heterogeneity using a heterogeneity score based on pair-wise genetic distances among tumor deposits; and (ii) genomic complexity, defined as the proportion of the genome harboring aberrant DNA copy numbers. Results were analyzed in relation to the patients’ clinical course; previous chemotherapy exposure and outcome after surgical resection of liver metastases. We observed substantial variation in the level of intra-patient inter-metastatic heterogeneity. Heterogeneity was not associated with the number of metastatic lesions or their genomic complexity. In metachronous disease, heterogeneity was higher in patients previously exposed to chemotherapy. Importantly, intra-patient inter-metastatic heterogeneity was a strong prognostic determinant, stronger than known clinicopathological prognostic parameters. Patients with a low level of heterogeneity (below the median level) had a three-year progression-free and overall survival rate of 23% and 66% respectively, versus 5% and 18% for patients with a high level (hazard ratio0.4, 95% confidence interval 0.2–0.8, P = 0.01; and hazard ratio0.3,95% confidence interval 0.1–0.7, P = 0.007). A low patient-wise level of genomic complexity (below 25%) was also a favorable prognostic factor; however, the prognostic association of intra-patient heterogeneity was independent of genomic complexity in multivariable analyses. In conclusion, intra-patient inter-metastatic genetic heterogeneity is a pronounced feature of metastatic colorectal cancer, and the strong prognostic association reinforces its clinical relevance and places it as a key feature to be explored in future patient cohorts.
Clinical Characteristics and Outcomes of Hospitalized Older Patients with Distinct Risk Profiles for Functional Decline: A Prospective Cohort Study

Background The aim of this research was to study the clinical characteristics and mortality and disability outcomes of patients who present distinct risk profiles for functional decline at admission. Methods Multicenter, prospective cohort study conducted between 2006 and 2009 in three hospitals in the Netherlands in consecutive patients of ≥65 years, acutely admitted and hospitalized for at least 48 hours. Nineteen geriatric conditions were assessed at hospital admission, and mortality and functional decline were assessed until twelve months after admission. Patients were divided into risk categories for functional decline (low, intermediate or high risk) according to the Identification of Seniors at Risk-Hospitalized Patients. Results A total of 639 patients were included, with a mean age of 78 years. Overall, 27%, 33% and 40% of the patients were at low, intermediate or high risk, respectively, for functional decline. Low-risk patients had fewer geriatric conditions (mean 2.2 [standard deviation [SD] 1.3]) compared with those at intermediate (mean 3.8 [SD 2.1]) or high risk (mean 5.1 [SD 1.8]) (p<0.001). Twelve months after admission, 39% of the low-risk group had an adverse outcome, compared with 50% in the intermediate risk group and 69% in the high risk group (p<0.001). Conclusion By using a simple risk assessment instrument at hospital admission, patients at low, intermediate or high risk for functional decline could be identified, with distinct clinical characteristics and outcomes. This approach should be tested in clinical practice and research and might help appropriately tailor patient care.
Adaptive Temporal Encoding Leads to a Background-Insensitive Cortical Representation of Speech

Speech recognition is remarkably robust to the listening background, even when the energy of background sounds strongly overlaps with that of speech. How the brain transforms the corrupted acoustic signal into a reliable neural representation suitable for speech recognition, however, remains elusive. Here, we hypothesize that this transformation is performed at the level of auditory cortex through adaptive neural encoding, and we test the hypothesis by recording, using MEG, the neural responses of human subjects listening to a narrated story. Spectrally matched stationary noise, which has maximal acoustic overlap with the speech, is mixed in at various intensity levels. Despite the severe acoustic interference caused by this noise, it is here demonstrated that low-frequency auditory cortical activity is reliably synchronized to the slow temporal modulations of speech, even when the noise is twice as strong as the speech. Such a reliable neural representation is maintained by intensity contrast gain control and by adaptive processing of temporal modulations at different time scales, corresponding to the neural δ and θ bands. Critically, the precision of this neural synchronization predicts how well a listener can recognize speech in noise, indicating that the precision of the auditory cortical representation limits the performance of speech recognition in noise. Together, these results suggest that, in a complex listening environment, auditory cortex can selectively encode a speech stream in a background insensitive manner, and this stable neural representation of speech provides a plausible basis for background-invariant recognition of speech.
The clock is ticking: the rate and timeliness of antiretroviral therapy initiation from the time of treatment eligibility in Kenya

Understanding the determinants of timely antiretroviral therapy (ART) initiation is useful for HIV programmes intent on developing models of care that reduce delays in treatment initiation while maintaining a high quality of care. We analysed patient‐ and facility‐level determinants of time to ART initiation among patients who initiated ART in Kenya.
Evaluation of Methods for Sampling, Recovery, and Enumeration of Bacteria Applied to the Phylloplane

Determining the fate and survival of genetically engineered microorganisms released into the environment requires the development and application of accurate and practical methods of detection and enumeration. Several experiments were performed to examine quantitative recovery methods that are commonly used or that have potential applications. In these experiments, Erwinia herbicola and Enterobacter cloacae were applied in greenhouses to Blue Lake bush beans (Phaseolus vulgaris) and Cayuse oats (Avena sativa). Sampling indicated that the variance in bacterial counts among leaves increased over time and that this increase caused an overestimation of the mean population size by bulk leaf samples relative to single leaf samples. An increase in the number of leaves in a bulk sample, above a minimum number, did not significantly reduce the variance between samples. Experiments evaluating recovery methods demonstrated that recovery of bacteria from leaves was significantly better with stomacher blending, than with blending, sonication, or washing and that the recovery efficiency was constant over a range of sample inoculum densities. Delayed processing of leaf samples, by storage in a freezer, did not significantly lower survival and recovery of microorganisms when storage was short term and leaves were not stored in buffer. The drop plate technique for enumeration of bacteria did not significantly differ from the spread plate method. Results of these sampling, recovery, and enumeration experiments indicate a need for increased development and standardization of methods used by researchers as there are significant differences among, and also important limitations to, some of the methods used.
Influence of Oxidative Stress on Stored Platelets

Platelet storage and its availability for transfusion are limited to 5-6 days. Oxidative stress (OS) is one of the causes for reduced efficacy and shelf-life of platelets. The studies on platelet storage have focused on improving the storage conditions by altering platelet storage solutions, temperature, and materials. Nevertheless, the role of OS on platelet survival during storage is still unclear. Hence, this study was conducted to investigate the influence of storage on platelets. Platelets were stored for 12 days at 22°C. OS markers such as aggregation, superoxides, reactive oxygen species, glucose, pH, lipid peroxidation, protein oxidation, and antioxidant enzymes were assessed. OS increased during storage as indicated by increments in aggregation, superoxides, pH, conjugate dienes, and superoxide dismutase and decrements in glucose and catalase. Thus, platelets could endure OS till 6 days during storage, due to the antioxidant defense system. An evident increase in OS was observed from day 8 of storage, which can diminish the platelet efficacy. The present study provides an insight into the gradual changes occurring during platelet storage. This lays the foundation towards new possibilities of employing various antioxidants as additives in storage solutions.
Evidence Implicating Nonmuscle Myosin in Restenosis: Use of In Situ Hybridization to Analyze Human Vascular Lesions Obtained by Directional Atherectomy

BackgroundIdentification of genes that are specifically activated in restenosis lesions after percutaneous transluminal angioplasty represents a necessary step toward molecular manipulation designed to inhibit cellular proliferation responsible for such lesions. Whereas quiescent smooth muscle cells (contractile phenotype) preferentially express smooth muscle myosin, proliferating smooth muscle cells (synthetic phenotype) have been shown to preferentially express nonmuscle myosin in vitro. Accordingly, we analyzed the expression of a recently cloned isoform of human nonmuscle myosin heavy chain (MHC-B) in fresh human restenotic lesions. Methods and ResultsA total of 10 lesions, including four restenosis (three superficial femoral arterial lesions and one saphenous vein bypass lesion) and six primary (four superficial femoral arterial lesions and two coronary arterial lesions) obtained percutaneously by directional atherectomy, were processed for examination by in situ hybridization. In total, 150 tissue sections of restenotic lesions (66 sections), primary lesions (78 sections), and normal internal mammary artery (six sections) were hybridized with the nonmuscle MHC-B probe. Restenotic lesions showed intense hybridization to the nonmuscle MHC-B cRNA probe, as demonstrated by a clustering of more than 20 grains per cell nucleus in 80% of the cells examined within a high-power field (×250); in contrast, an equivalent degree of hybridization was observed in only 7% of cells within primary lesions (p<0.001). Results of immunocytochemistry using monoclonal antibody to smooth muscle actin indicated that cells demonstrating strong hybridization were smooth muscle in origin. ConclusionsThese findings demonstrate that 1) human vascular tissue obtained by percutaneous directional atherectomy constitutes appropriate biopsy material for gene expression studies at the mRNA level, and 2) nonmuscle MHC-B mRNA is present in greater abundance among restenotic versus primary vascular stenoses. These observations thus provide a rational basis to explore restenotic lesions on a larger scale to identify genes that are activated in these lesions and establish potential targets for future gene therapy.
Third order nonlinear optical response of conjugated photoactive ligands

Generally, organic and organometallic materials containing π-conjugated chains are considered as promising candidates for nonlinear optical applications. In this work, we report on the third order nonlinear optical response of π-conjugated azo-conjugated azo-iminopyridine photoactive ligands containing electron donating or electron accepting fragments in their structure. The nonlinear optical investigation is performed by means of the Z-scan technique well as the Maker Fringes Third Harmonic Generation technique employing a 30 ps mode-locked Nd-YVO4 laser with a repetition rate of 10 Hz.
Retzius‐sparing robot‐assisted laparoscopic radical prostatectomy: Critical appraisal of the anatomic landmarks for a complete intrafascial approach

To provide an overview of the anatomical landmarks needed to guide a retropubic (Retzius)‐sparing robot‐assisted laparoscopic prostatectomy (RALP), and a step‐by‐step description of the surgical technique that maximizes preservation of the periprostatic neural network. The anatomy of the pelvic fossae is presented, including the recto‐vesical pouch (pouch of Douglas) created by the reflections of the peritoneum. The actual technique of the trans‐Douglas, intrafascial nerve‐sparing robotic radical prostatectomy is described. The technique allows the prostate gland to be shelled out from under the overlying detrusor apron and dorsal vascular complex (DVC‐Santorini plexus), entirely avoiding the pubovesical ligaments. There is no need to control the DVC, since the line of dissection passes beneath the plexus. Three key points to ensure enhanced nerve preservation should be respected: (1) the tips of the seminal vesicles, enclosed in a “cage” of neuronal tissue; a seminal vesicle‐sparing technique is therefore advised when oncologically safe; (2) the external prostate‐vesicular angle; (3) the lateral surface of the prostate gland and the apex. The principles of tension and energy‐free dissection should guide all the maneuvers in order to minimize neuropathy. Using robotic technology, a complete intrafascial dissection of the prostate gland can be achieved through the Douglas space, reducing surgical trauma and providing excellent functional and oncological outcomes. Clin. Anat. 28:896–902, 2015. © 2015 Wiley Periodicals, Inc.
Minimizing the number of one-paths in BDDs by an evolutionary algorithm

Ordered binary decision diagrams (BDDs) are used in VLSI CAD, especially for the canonical representation of Boolean functions. In the last decade, the method of choice for optimizing this data structure was minimizing the number of nodes in the associated graph. However, recent works have shown that the number of paths is also important. In this work, minimizing the number of one-paths of BDDs is accomplished by an evolutionary algorithm (EA) acting on the permutation of variables. The optimal operator weights for the EA were determined by a parameter study. Experimental results demonstrate the efficiency of our approach.
Performance assessment of age-adapted SOFA, qSOFA, and PELOD-2, PCIS, P-MODS for Hand, Foot and Mouth Disease

Objectives Hand, foot and mouth disease (HFMD) is a common infectious disease in children caused by intestinal virus and an important cause of child death. Early identification of critical HFMD and timely intervention are the key to reduce mortality. However, there is no available unified critical HFMD screening standard. This study aimed to explore the predictive evaluation of HFMD with critical illness scoring systems. Methods A total of 31 patients with mild HFMD, 30 with severe HFMD, and 25 with critical HFMD were included. The platelet index in age-adapted sequential organ failure assessment score (SOFA) was re-assigned to constitute the SOFA for HFMD (H-SOFA). The results of age-adapted SOFA, quick SOFA (qSOFA), and pediatric logistic organ dysfunction score-2 (PELOD-2), pediatric multiple organ dysfunction score (P-MODS), pediatric critical illness score (PCIS), H-SOFA of the three groups were compared. Results Significant differences in the following parameters were found between severe group and critical group: enterovirus 71 positive, heart rate, respiration, vomiting, cold sweat, moist rales, disturbance in consciousness, platelet, and blood glucose (P<0.05), as well as all critical illness scoring data (P<0.001). age-adapted SOFA, qSOFA, and PELOD-2, P-MODS, H-SOFA were positively correlated with critical HFMD (odds ratio (OR): 3.213, 8.66, 2.64, 2.56, and 4.297 respectively; P<0.01), with area under the curve (AUC) values of 0.938, 0.823, 0.848, 0.910, and 0.956, respectively. PCIS was negatively correlated with critical HFMD (OR=0.76, P<0.001), with an AUC value of 0.865. Conclusion Increase in platelet count was related to the severity of HFMD. Age-adapted SOFA, qSOFA, and PELOD-2, P-MODS, PCIS, H-SOFA had high predictive value on critical HFMD, with H-SOFA being the highest.
Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI)

Aim Despite prompt revascularization of acute myocardial infarction (AMI), substantial myocardial injury may occur, in part a consequence of ischaemia reperfusion injury (IRI). There has been considerable interest in therapies that may reduce IRI. In experimental models of AMI, sodium nitrite substantially reduces IRI. In this doubleblind randomized placebo controlled parallel-group trial, we investigated the effects of sodium nitrite administered immediately prior to reperfusion in patients with acute ST-elevation myocardial infarction (STEMI). Methods and results A total of 229 patients presenting with acute STEMI were randomized to receive either an i.v. infusion of 70 μmol sodium nitrite (n = 118) or matching placebo (n = 111) over 5 min immediately before primary percutaneous intervention (PPCI). Patients underwent cardiac magnetic resonance imaging (CMR) at 6–8 days and at 6 months and serial blood sampling was performed over 72 h for the measurement of plasma creatine kinase (CK) and Troponin I. Myocardial infarct size (extent of late gadolinium enhancement at 6–8 days by CMR-the primary endpoint) did not differ between nitrite and placebo groups after adjustment for area at risk, diabetes status, and centre (effect size −0.7% 95% CI: −2.2%, +0.7%; P = 0.34). There were no significant differences in any of the secondary endpoints, including plasma troponin I and CK area under the curve, left ventricular volumes (LV), and ejection fraction (EF) measured at 6–8 days and at 6 months and final infarct size (FIS) measured at 6 months. Conclusions Sodium nitrite administered intravenously immediately prior to reperfusion in patients with acute STEMI does not reduce infarct size.
Aging Increases Susceptibility to High Fat Diet-Induced Metabolic Syndrome in C57BL/6 Mice: Improvement in Glycemic and Lipid Profile after Antioxidant Therapy

Nonalcoholic fatty liver disease (NAFLD) has been considered a novel component of the metabolic syndrome (MetS), with the oxidative stress participating in its progression. This study aimed to evaluate the metabolic profile in young and old mice with MetS, and the effects of apocynin and tempol on glycemic and lipid parameters. Young and old C57BL/6 mice with high fat diet- (HFD-) induced MetS received apocynin and tempol 50 mg·kg−1/day in their drinking water for 10 weeks. After HFD, the young group showed elevated fasting glucose, worsened lipid profile in plasma, steatosis, and hepatic lipid peroxidation. Nevertheless, the old group presented significant increase in fasting insulin levels, insulin resistance, plasma and hepatic lipid peroxidation, and pronounced steatosis. The hepatic superoxide dismutase and catalase activity did not differ between the groups. Tempol and apocynin seemed to prevent hepatic lipid deposition in both groups. Furthermore, apocynin improved glucose tolerance and insulin sensitivity in old mice. In summary, old mice are more susceptible to HFD-induced metabolic changes than their young counterparts. Also, the antioxidant therapy improved insulin sensitivity and glucose tolerance, and in addition, apocynin seemed to prevent the HFD-induced hepatic fat deposition, suggesting an important role of oxidative stress in the induction of NAFLD.
Cyclopentenone Prostaglandins as Potential Inducers of Intracellular Oxidative Stress*

In the present study, we find that cyclopentenone prostaglandins (PGs) of the J2 series, naturally occurring derivatives of PGD2, are potential inducers of intracellular oxidative stress that mediates cell degeneration. Based on an extensive screening of diverse chemical agents on induction of intracellular production of reactive oxygen species (ROS), we found that the cyclopentenone PGs, such as PGA2, PGJ2, Δ12-PGJ2, and 15-deoxy-Δ12,14-PGJ2, showed the most potent pro-oxidant effect on SH-SY5Y human neuroblastoma cells. As the intracellular events that mediate the PG cytotoxicity, we observed (i) the cellular redox alteration represented by depletion of antioxidant defenses, such as glutathione and glutathione peroxidase; (ii) a transient decrease in the mitochondrial membrane potential (Δψ); (iii) the production of protein-bound lipid peroxidation products, such as acrolein and 4-hydroxy-2-nonenal; and (iv) the accumulation of ubiquitinated proteins. These events correlated well with the reduction in cell viability. In addition, the thiol compound,N-acetylcysteine, could significantly inhibit the PG-induced ROS production, thereby preventing cytotoxicity, suggesting that the redox alteration is closely related to the pro-oxidant effect of cyclopentenone PGs. More strikingly, the lipid peroxidation end products, acrolein and 4-hydroxy-2-nonenal, detected in the PG-treated cells potently induced the ROS production, which was accompanied by the accumulation of ubiquitinated proteins and cell death, suggesting that the membrane lipid peroxidation products may represent one of the causative factors that potentiate the cytotoxic effect of cyclopentenone PGs by accelerating intracellular oxidative stress. These data suggest that the intracellular oxidative stress, represented by ROS production/lipid peroxidation and redox alteration, may underlie the well documented biological effects, such as antiproliferative and antitumor activities, of cyclopentenone PGs.
Joint Optimization of Neural Network-based WPE Dereverberation and Acoustic Model for Robust Online ASR

Signal dereverberation using the Weighted Prediction Error (WPE) method has been proven to be an effective means to raise the accuracy of far-field speech recognition. First proposed as an iterative algorithm, follow-up works have reformulated it as a recursive least squares algorithm and therefore enabled its use in online applications. For this algorithm, the estimation of the power spectral density (PSD) of the anechoic signal plays an important role and strongly influences its performance. Recently, we showed that using a neural network PSD estimator leads to improved performance for online automatic speech recognition. This, however, comes at a price. To train the network, we require parallel data, i.e., utterances simultaneously available in clean and reverberated form. Here we propose to overcome this limitation by training the network jointly with the acoustic model of the speech recognizer. To be specific, the gradients computed from the cross-entropy loss between the target senone sequence and the acoustic model network output is backpropagated through the complex-valued dereverberation filter estimation to the neural network for PSD estimation. Evaluation on two databases demonstrates improved performance for on-line processing scenarios while imposing fewer requirements on the available training data and thus widening the range of applications.