Miracle-dz/UniFAR-FTUs huggingface dataset:
Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer

Abstract Background In the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1. Patients and methods Randomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes. Results Of 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50–0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33–0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37–0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29–1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28–0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31–0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat ‘Good’ versus ‘Poor’ [2.7 versus 1.5 months; HR 0.71 (0.49–0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35). Conclusions Subgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative, EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings. Clinical trial registration NCT01345682.
Expression of CD163 in hereditary gingival fibromatosis: A possible association with TGF‐&bgr;1

BACKGROUND Although several studies have discussed some of the molecular and cellular changes associated with hereditary gingival fibromatosis (HGF), its pathogenesis is still largely unclear. This study was directed to detect and outline the degree of relationship between the immunophenotyped macrophages (M2) expressing CD163 and TGF-β1 in patients with gingival overgrowth due to HGF. METHODS Biopsies from 20 patients suffering from HGF and 20 normal control subjects were harvested, histologically and immunohistochemically stained then, analyzed and statistically compared and correlated for CD163 immunoexpression and TGF-β1. RESULTS All HGF specimens expressed TGF-β1 by most of the connective tissue fibroblasts, with statistically high significant mean of area % (2.61 ± 0.41) compared to normal controls (0.11 ± 0.06; P = .001). All control specimens revealed negligible CD163 immunostaining of the few inflammatory cells found with a mean area of % (0.69 ± 0.12), while the specimens of HGF cases showed statistically significant higher CD163 expression (3.39 ± 0.75) at (P = .007). A statistically significant higher mean % of M2 cells expressing CD163 in relation to the total number of the inflammatory cells was revealed in HGF (34.46 ± 2.04) compared to the control group (16.36 ± 2.39; P-value ≤ .05). Moderate correlation between CD163 and TGF-β1 was detected in HGF (r = .451; P-value < .05). CONCLUSIONS CD163 and TGF-β1 were clearly expressed in HGF cases compared to healthy control patients, with significant correlation. In HGF, the increase in CD 163-positive cells was specific and not dependent on the chronic gingival inflammation.
Incidence of Venous Thromboembolism in Families with Inherited Thrombophilia

Summary The risk of spontaneous or risk-period related venous thromboembolism in family members of symptomatic carriers of antithrombin (AT), protein C (PC) or protein S (PS) defects, as well as of the Factor V Leiden mutation is still undefined. We performed a retrospective cohort study in family members (n = 793) of unselected patients with a documented venous thromboembolism and one of these deficiencies to make an estimate of this risk. The annual incidences of total and spontaneous venous thromboembolic events in carriers of AT, PC or PS defects (n = 181) were 1.01% and 0.40%, respectively, as compared to 0.10% and 0.04% in non-carriers, respectively (relative risks both 10.6). In carriers of Factor V Leiden (n = 224), the annual incidences of total and spontaneous venous thromboembolism were 0.28% and 0.11%, respectively, as compared to 0.09% and 0.04% in non-carriers, respectively (relative risks 2.8 and 2.5). Additional risk factors (immobilisation, surgery and trauma; oral contraceptive use; and pregnancy/ post-partum) increased the risk of thrombosis in carriers of AT, PC and PS defects as compared to non-carriers (relative risks 8.3, 6.4 and 8.2, respectively). Oral contraceptive use and pregnancy/ post-partum period increased the risk of thrombosis in carriers of Factor V Leiden to 3.3-fold and 4.2-fold, respectively, whereas other risk factors had only a minor effect. These data lend some support to the practice of screening family members of symptomatic carriers of a AT, PC and PS deficiency. For family members of symptomatic carriers of Factor V Leiden, screening does not seem to be justified except for women in fertile age.
Enhancement of Data Rate and Packet Size in Image Sensor Communications by Employing Constant Power 4-PAM

Image sensor communications (ISC) is a scheme to make the LED lamp replace access points or beacons in indoor environments. Its application has been limited, however, due to its low data rate and small packet size. To resolve these problems, we propose a new ISC scheme using 4-PAM modulation and a parallel packet structure. The constant power 4-PAM signal was designed to have constant optical power in each symbol to eliminate the flickering effect. The experiments show that a data rate more than 2.6 times higher than the existing on-off keying schemes was achieved. In addition, it is demonstrated that the packet length can reach more than several frames while it is limited to less than a frame using the existing schemes. The limiting factors of N-PAM levels and packet size are analyzed in this paper to further improvement. All these results are demonstrated through simulations and experiments.
Results from a large-scale study of performance optimization techniques for source code analyses based on graph reachability algorithms

Internally, many source code analysis tools make use of graphs. For example, one of the oldest and most widely used internal graphs is the control-flow graph developed for use within a compiler. Work on compilation has also led to the development of the call graph, the procedure dependence graph (PDG), and the static-single assignment (SSA) graph. Compilers are not the only source-code analysis tools to use internal graphs. A variety of software engineering tools incorporate a variety of different graphs. A study of techniques that improve graph-based program analysis is presented. Several different techniques are considered, including forming strongly-connected components, topological sorting, and removing transitive edges. Graph reachability, a pervasive graph analysis operation, is used as a representative graph analysis operation in the study. Data collected from a test bed of just over 1000000 lines of code is presented. This data illustrates the impact on computation time of the improvement techniques. Overall, the combination of all techniques produces a 71% reduction in run-time (and 64% reduction in memory usage). In other words, they increase the size of the problem that can be effectively handled by factor of over three times.
Serum matrix metalloproteinase 9 (MMP9) as a biochemical marker for wasting marmoset syndrome

Use of the common marmoset (Callithrix jacchus) as a non-human primate experimental animal has increased in recent years. Although wasting marmoset syndrome (WMS) is one of the biggest problems in captive marmoset colonies, the molecular mechanisms, biochemical markers for accurate diagnosis and a reliable treatment remain unknown. In this study, as a first step to finding biochemical marker(s) for the accurate diagnosis of WMS, we conducted blood cell counts, including hematocrit, hemoglobin and platelets, and examined serum chemistry values, including albumin, calcium and levels of serum matrix metalloproteinase 9 (MMP9), using a colony of marmosets with and without weight loss. MMP9 is thought to be an enzyme responsible for the degradation of extracellular matrix components and participates in the pathogenesis of inflammatory conditions, such as human and murine inflammatory bowel disease, which, like WMS, are characterized histologically by inflammatory cell infiltrations in the intestines. The values of hematocrit and hemoglobin and levels of serum albumin and calcium in the WMS group were significantly decreased versus the control group. The platelet values and serum MMP9 concentrations were increased significantly in the WMS group compared with the control group. MMP9 could be a new and useful marker for the diagnosis of WMS in addition to hematocrit, hemoglobin, serum albumin and calcium. Our results also indicate that MMP9 could be a useful molecular candidate for treatment.
MARCH6 and TRC8 facilitate the quality control of cytosolic and tail‐anchored proteins

Misfolded or damaged proteins are typically targeted for destruction by proteasome‐mediated degradation, but the mammalian ubiquitin machinery involved is incompletely understood. Here, using forward genetic screens in human cells, we find that the proteasome‐mediated degradation of the soluble misfolded reporter, mCherry‐CL1, involves two ER‐resident E3 ligases, MARCH6 and TRC8. mCherry‐CL1 degradation is routed via the ER membrane and dependent on the hydrophobicity of the substrate, with complete stabilisation only observed in double knockout MARCH6/TRC8 cells. To identify a more physiological correlate, we used quantitative mass spectrometry and found that TRC8 and MARCH6 depletion altered the turnover of the tail‐anchored protein heme oxygenase‐1 (HO‐1). These E3 ligases associate with the intramembrane cleaving signal peptide peptidase (SPP) and facilitate the degradation of HO‐1 following intramembrane proteolysis. Our results highlight how ER‐resident ligases may target the same substrates, but work independently of each other, to optimise the protein quality control of selected soluble and tail‐anchored proteins.
Robust estimation of the sample mean variance for Gaussian processes with long-range dependence

We introduce a method to robustly estimate the variance of the sample mean for two Gaussian processes exhibiting Long-Range Dependence (LRD): fractional Gaussian noise, fGn(H), and fractional autoregressive integrated moving average, FARIMA(0, H, 0) processes. Our method is based on a combination of two estimators of H which are functions of a multitaper estimator of the log spectral density: a robust estimator which uses a limited number of frequencies near the origin, and an estimator which uses (almost) all of the frequencies. An important feature of our method is a test to differentiate between fGn(H) and FARIMA(0, H, 0) which, under a correct decision, allows us to estimate the Hurst parameter H using the correct model specification. Differentiating between fGn(H) and FARIMA(0, H, 0) with Gaussian innovations is important to estimate the sample mean variance and for statistical inference about the process location parameter. Numerical comparisons are made against existing estimators including parametric and semi-parametric methods in Fourier frequency and wavelet domains.
A simple visual system without neurons in jellyfish larvae

Earlier detailed studies of cnidarian planula larvae have revealed a simple nervous system but no eyes or identifiable light sensing structures. Here, we describe the planula of a box jellyfish, Tripedalia cystophora, and report that these larvae have an extremely simple organization with no nervous system at all. Their only advanced feature is the presence of 10–15 pigment–cup ocelli, evenly spaced across the posterior half of the larval ectoderm. The ocelli are single cell structures containing a cup of screening pigment filled with presumably photosensory microvilli. These rhabdomeric photoreceptors have no neural connections to any other cells, but each has a well–developed motor-cilium, appearing to be the only means by which light can control the behaviour of the larva. The ocelli are thus self–contained sensory–motor entities, making a nervous system superfluous.
Web-Based Physician Ratings for California Physicians on Probation

Background Web-based physician ratings systems are a popular tool to help patients evaluate physicians. Websites help patients find information regarding physician licensure, office hours, and disciplinary records along with ratings and reviews. Whether higher patient ratings are associated with higher quality of care is unclear. Objective The aim of this study was to characterize the impact of physician probation on consumer ratings by comparing website ratings between doctors on probation against matched controls. Methods A retrospective review of data from the Medical Board of California for physicians placed on probation from December 1989 to September 2015 was performed. Violations were categorized into nine types. Nonprobation controls were matched by zip code and specialty with probation cases in a 2:1 ratio using the California Department of Consumer Affairs website. Web-based reviews were recorded from vitals.com, healthgrades.com, and ratemds.com (ratings range from 1-5). Results A total of 410 physicians were placed on probation for 866 violations. The mean (standard deviation [SD]) number of ratings per doctor was 5.2 (7.8) for cases and 4 (6.3) for controls (P=.003). The mean rating for physicians on probation was 3.7 (1.6) compared with 4.0 (1.0) for controls when all three rating websites were pooled (P<.001). Violations for medical documentation, incompetence, prescription negligence, and fraud were found to have statistically significant lower rating scores. Conversely, scores for professionalism, drugs or alcohol, crime, sexual misconduct, and personal illness were similar between cases and controls. In a univariate analysis, probation was found to be associated with lower rating, odds ratio=1.5 (95% CI 1.0-2.2). This association was not significant in a multivariate model when we included age and gender. Conclusions Web-based physician ratings were lower for doctors on probation indicating that patients may perceive a difference. Despite these statistical findings, the absolute difference was quite small. Physician rating websites have utility but are imperfect proxies for competence. Further research on physician Web-based ratings is warranted to understand what they measure and how they are associated with quality.
A Blended Web-Based Gaming Intervention on Changes in Physical Activity for Overweight and Obese Employees: Influence and Usage in an Experimental Pilot Study

Background Addressing the obesity epidemic requires the development of effective interventions aimed at increasing physical activity (PA). eHealth interventions with the use of accelerometers and gaming elements, such as rewarding or social bonding, seem promising. These eHealth elements, blended with face-to-face contacts, have the potential to help people adopt and maintain a physically active lifestyle. Objective The aim of this study was to assess the influence and usage of a blended Web-based gaming intervention on PA, body mass index (BMI), and waist circumference among overweight and obese employees. Methods In an uncontrolled before-after study, we observed 52 health care employees with BMI more than 25 kg/m2, who were recruited via the company’s intranet and who voluntarily participated in a 23-week Web-based gaming intervention, supplemented (blended) with non-eHealth components. These non-eHealth components were an individual session with an occupational health physician involving motivational interviewing and 5 multidisciplinary group sessions. The game was played by teams in 5 time periods, aiming to gain points by being physically active, as measured by an accelerometer. Data were collected in 2014 and 2015. Primary outcome was PA, defined as length of time at MET (metabolic equivalent task) ≥3, as measured by the accelerometer during the game. Secondary outcomes were reductions in BMI and waist circumference, measured at baseline and 10 and 23 weeks after the start of the program. Gaming elements such as “compliance” with the game (ie, days of accelerometer wear), “engagement” with the game (ie, frequency of reaching a personal monthly target), and “eHealth teams” (ie, social influence of eHealth teams) were measured as potential determinants of the outcomes. Linear mixed models were used to evaluate the effects on all outcome measures. Results The mean age of participants was 48.1 years; most participants were female (42/51, 82%). The mean PA was 86 minutes per day, ranging from 6.5 to 223 minutes, which was on average 26.2 minutes per day more than self-reported PA at baseline and remained fairly constant during the game. Mean BMI was reduced by 1.87 kg/m2 (5.6%) and waist circumference by 5.6 cm (4.8%). The univariable model showed that compliance, engagement, and eHealth team were significantly associated with more PA, which remained significant for eHealth team in the multivariable model. Conclusions This blended Web-based gaming intervention was beneficial for overweight workers in becoming physically active above the recommended activity levels during the entire intervention period, and a favorable influence on BMI and waist circumference was observed. Promising components in the intervention, and thus targets for upscaling, are eHealth teams and engagement with the game. Broader implementation and long-term follow-up can provide insights into the sustainable effects on PA and weight loss and into who benefits the most from this approach.
The association of volumetric response and long-term survival after cardiac resynchronization therapy

Aims Clinical experience indicates that limited or no reverse left ventricular (LV) remodelling may not necessarily imply non-response to cardiac resynchronization therapy (CRT). We investigated the association of the extent of LV remodelling, mechanical dyssynchrony, and survival in patients undergoing CRT. Methods and results In 356 CRT candidates, three blinded readers visually assessed the presence of mechanical dyssynchrony (either apical rocking and/or septal flash) before device implantation and also its correction by CRT 12 ± 3 months post-implantation. To assess LV reverse remodelling, end-systolic volumes (ESV) were measured at the same time points. Patients were divided into four subgroups: no LV remodelling (ESV change 0 ± 5%), mild LV reverse remodelling (ESV reduction 5-15%), significant LV reverse remodelling (ESV reduction ≥15%), and LV volume expansion (ESV increase ≥5%). Patients were followed for all-cause mortality during the median follow-up of 36 months. Patients with LV remodelling as in the above defined groups showed 58, 54, and 84% reduction in all-cause mortality compared to patients with volume expansion. In multivariable analysis, LVESV change remained independently associated with survival, with an 8% reduction in mortality for every 10% decrease in LVESV (P = 0.0039), but an optimal cut-off point could not be established. In comparison, patients with corrected mechanical dyssynchrony showed 71% reduction in all-cause mortality (P < 0.001). Conclusion Volumetric response assessed at 1-year after CRT is strongly associated with long-term mortality. However, an optimal cut-off cannot be established. The association of the correction of mechanical dyssynchrony with survival was stronger than that of any volumetric cut-off.
Two Novel Cognitive Behavioral Therapy–Based Mobile Apps for Agoraphobia: Randomized Controlled Trial

Background Despite the large body of literature demonstrating the effectiveness of cognitive behavioral treatments for agoraphobia, many patients remain untreated because of various barriers to treatment. Web-based and mobile-based interventions targeting agoraphobia may provide a solution to this problem, but there is a lack of research investigating the efficacy of such interventions. Objective The objective of our study was to evaluate for the first time the effectiveness of a self-guided mobile-based intervention primarily targeting agoraphobic symptoms, with respect to a generic mobile app targeting anxiety. Methods A Web-based randomized controlled trial (RCT) compared a novel mobile app designed to target agoraphobia (called Agoraphobia Free) with a mobile app designed to help with symptoms of anxiety in general (called Stress Free). Both interventions were based on established cognitive behavioral principles. We recruited participants (N=170) who self-identified as having agoraphobia and assessed them online at baseline, midpoint, and end point (posttreatment) over a period of 12 weeks. The primary outcome was symptom severity measured by the Panic and Agoraphobia Scale. Results Both groups had statistically significant improvements in symptom severity over time (difference –5.97, 95% CI –8.49 to –3.44, P<.001 for Agoraphobia Free and –6.35, 95% CI –8.82 to –3.87, P<.001 for Stress Free), but there were no significant between-group differences on the primary outcome (difference 0.38, 95% CI –1.96 to 3.20, P=.64). Conclusions This is, to our knowledge, the first RCT to provide evidence that people who identify as having agoraphobia may equally benefit from a diagnosis-specific and a transdiagnostic mobile-based intervention. We also discuss clinical and research implications for the development and dissemination of mobile mental health apps. Trial Registration International Standard Randomized Controlled Trial Number (ISRCTN): 98453199; http://www.isrctn. com /ISRCTN98453199 (Archived by WebCite at http://www.webcitation.org/6uR5vsdZw)