Miracle-dz/UniFAR-FTUs huggingface dataset:
Senescent T-Cells Promote Bone Loss in Rheumatoid Arthritis

Objective T-cells are critical players in the pathogenesis of osteoporosis in patients with rheumatoid arthritis (RA). Premature senescence of lymphocytes including the accumulation of senescent CD4+ T-cells is a hallmark feature of RA. Whether T-cell senescence is associated with bone loss in RA patients is elusive so far. Methods This includes a prospective study of consecutive patients with RA (n = 107), patients with primary osteopenia/-porosis (n = 75), and healthy individuals (n = 38). Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry scan. Flow cytometry, magnetic-associated cell sorting, and cell culture experiments were performed to analyze the pro-osteoclastic phenotype and the function of senescent CD4+CD28− T-cells. Results Patients with osteopenia/-porosis yielded a higher prevalence of senescent CD4+CD28− T-cells than individuals with normal BMD, in the RA, as well as in the non-RA cohort. Receptor activator of nuclear factor kappa-B ligand (RANKL) was expressed at higher levels on CD4+CD28− T-cells as compared to CD28+ T-cells. Stimulation with interleukin-15 led to an up-regulation of RANKL expression, particularly on CD28− T-cells. CD4+CD28− T-cells induced osteoclastogenesis more efficiently than CD28+ T-cells. Conclusion Our data indicate that senescent T-cells promote osteoclastogenesis more efficiently than conventional CD28+ T-cells, which might contribute to the pathogenesis of systemic bone loss in RA and primary osteoporosis.
Variations in the medical treatment of inflammatory bowel disease among gastroenterologists

Abstract Background and aims With expanding available treatment options and evolving understanding of the risks and benefits of medical therapies for inflammatory bowel disease (IBD), there is the possibility of significant variations in treatment and outcomes. Little is known about the variation in treatment between IBD specialists and other gastroenterology (GI) physicians. Evaluating possible variations is an important first step to help address standardized care and optimize treatment. We studied the differences in use of biologics and immunomodulators in the management of IBD patients at a tertiary care hospital between IBD-trained physicians and other gastroenterologists. Methods A total of 325 IBD patients were included in the analysis. Of these, 216 patients received care with an IBD physician and 109 had other GI/non-IBD physicians as their main caregivers. Results The unadjusted use of immunomodulators (35.6% vs 16.5%, p = 0.001), biologics (45.8% vs 22.9%, p =0.001) and dual therapy (biologics and immunomodulator) (14.4% vs 3.7%, p =0.001) was significantly higher in the IBD-physician group. These differences in therapy between the two groups remained after adjusting for patient and disease characteristics. Conclusion There are significant variations in the treatment of patients with IBD by GI physicians. The use of biologics and immunomodulators is higher in GI physicians with dedicated IBD interest and training.
Using permutation tests to enhance causal inference in interrupted time series analysis

RATIONALE, AIMS AND OBJECTIVES Interrupted time series analysis (ITSA) is an evaluation methodology in which a single treatment unit's outcome is studied serially over time and the intervention is expected to "interrupt" the level and/or trend of that outcome. The internal validity is strengthened considerably when the treated unit is contrasted with a comparable control group. In this paper, we introduce a robustness check based on permutation tests to further improve causal inference. METHOD We evaluate the effect of California's Proposition 99 for reducing cigarette sales by iteratively casting each nontreated state into the role of "treated," creating a comparable control group using the ITSAMATCH package in Stata, and then evaluating treatment effects using ITSA regression. If statistically significant "treatment effects" are estimated for pseudotreated states, then any significant changes in the outcome of the actual treatment unit (California) cannot be attributed to the intervention. We perform these analyses setting the cutpoint significance level to P > . 40 for identifying balanced matches (the highest threshold possible for which controls could still be found for California) and use the difference in differences of trends as the treatment effect estimator. RESULTS Only California attained a statistically significant treatment effect, strengthening confidence in the conclusion that Proposition 99 reduced cigarette sales. CONCLUSIONS The proposed permutation testing framework provides an additional robustness check to either support or refute a treatment effect identified in for the true treated unit in ITSA. Given its value and ease of implementation, this framework should be considered as a standard robustness test in all multiple group interrupted time series analyses.
β-glucans and cholesterol (Review)

Hypercholesterolemia is one of primary risk factors of cardiovascular disease, together with metabolic syndrome, hypertension and diabetes. Although progress has been made, the search for novel methods of preventing and treating dyslipidemia is ongoing and current therapies for cardiovascular disease induce various side effects. β-glucans are linear unbranched polysaccharides found in various natural sources, such as mushrooms. Due to their structure they are able to interact with innate immunity receptors, however they also act as dietary fibers in the digestive tract. As there are two forms of β-glucans, insoluble and soluble forms, they are able to interact with lipids and biliary salts in the bowel and consequently reduce cholesterol levels. Therefore, they may be developed as a suitable therapeutic option to treat patients with dyslipidemia, as they are natural molecules that do not induce any significant side effects. The current review discusses the evidence supporting the effects of β-glucans on cholesterol levels.
Multiple Acquisitions of Pathogen-Derived Francisella Endosymbionts in Soft Ticks

Abstract Bacterial endosymbionts of ticks are of interest due to their close evolutionary relationships with tick-vectored pathogens. For instance, whereas many ticks contain Francisella-like endosymbionts (FLEs), others transmit the mammalian pathogen Francisella tularensis. We recently sequenced the genome of an FLE present in the hard tick Amblyomma maculatum (FLE-Am) and showed that it likely evolved from a pathogenic ancestor. In order to expand our understanding of FLEs, in the current study we sequenced the genome of an FLE in the soft tick Ornithodoros moubata and compared it to the genomes of FLE-Am, Francisella persica—an FLE in the soft tick Argus (Persicargas) arboreus, Francisella sp. MA067296—a clinical isolate responsible for an opportunistic human infection, and F. tularensis, the established human pathogen. We determined that FLEs and MA067296 belonged to a sister taxon of mammalian pathogens, and contained inactivated versions of virulence genes present in F. tularensis, indicating that the most recent common ancestor shared by FLEs and F. tularensis was a potential mammalian pathogen. Our analyses also revealed that the two soft ticks (O. moubata and A. arboreus) probably acquired their FLEs separately, suggesting that the virulence attenuation observed in FLEs are not the consequence of a single acquisition event followed by speciation, but probably due to independent transitions of pathogenic francisellae into nonpathogenic FLEs within separate tick lineages. Additionally, we show that FLEs encode intact pathways for the production of several B vitamins and cofactors, denoting that they could function as nutrient-provisioning endosymbionts in ticks.
MicroSpec: Speculation-centric fine-grained parallelization for FSM computations

Finite state machines (FSMs) are basic computation models that play essential roles in many applications. Enabling efficient parallel FSM execution is critical to the performance of these applications. However, they are very challenging to parallelize due to their inherent data dependencies that occur at each step of computations. Existing efforts on FSM parallelization either explore coarse-grained speculative parallelism or leverage parallel prefixsum. The former ignores prevalent fine-grained hardware parallelism on modern processors (such as ILP or SIMD parallelism) while the latter limits the benefits of fine-grained parallelism mainly to state enumeration. This work presents MicroSpec, a set of parallelization techniques that, for the first time, expose fine-grained speculative parallelism to FSM computations. Based on a rigorous analysis of three types of parallelism at fine-grained level, MicroSpec consists of a list of four fine-grained speculative parallelization approaches along with a speculation-oriented data transformation. Experiments on a large set of realworld FSM benchmarks show that MicroSpec achieves substantial performance improvement over the state-of-the-art.
Reinforcement’s incidental effects on reproductive isolation between conspecifics

Abstract Reinforcement—the process whereby maladaptive hybridization leads to the strengthening of prezygotic isolation between species—has a long history in the study of speciation. Because reinforcement affects traits involved in mate choice and fertility, it can have indirect effects on reproductive isolation between populations within species. Here we review examples of these “cascading effects of reinforcement” (CER) and discuss different mechanisms through which they can arise. We discuss three factors that are predicted to influence the potential occurrence of CER: rates of gene flow among populations, the strength of selection acting on the traits involved in reinforcement, and the genetic basis of those traits. We suggest that CER is likely if (1) the rate of gene flow between conspecific populations is low; (2) divergent selection acts on phenotypes involved in reinforcement between sympatric and allopatric populations; and (3) the genetic response to reinforcement differs among conspecific populations subject to parallel reinforcing selection. Future work continuing to address gene flow, selection, and the genetic basis of the traits involved in the reinforcement will help develop a better understanding of reinforcement as a process driving the production of species diversity, both directly and incidentally.
Event and Cost Offsets of Switching 20% of the Type 1 Diabetes Population in Germany From Multiple Daily Injections to Continuous Subcutaneous Insulin Infusion

Background: Most patients with type 1 diabetes (T1D) administer insulin by multiple daily injections (MDI). However, continuous subcutaneous insulin infusion (CSII) therapy has been shown to improve glycemic control compared with MDI. Objective: The objective was to determine the key medical event and cost offsets generated over a 4-year period by introducing CSII to T1D patients who have inadequately controlled glucose metabolism on MDI in Germany. Methods: A decision-analytic budget impact model, simulating a treatment switch scenario, was developed. In the base case, all T1D patients received MDI, while in the switch scenario, 20% of the eligible T1D population, randomly selected, moved to CSII. The model focused on 2 medical endpoints and their corresponding cost offsets: severe hypoglycemic events requiring hospitalization (SHEH) and complication-borne diabetic events (CDEs) avoided. Event rates and costs were taken from the literature and official sources, adopting a health insurance perspective. Results: Compared with the base case, treating 20% of patients with CSII in the switch scenario resulted in 47 864 fewer SHEH and 5543 fewer CDEs. This led to total cost offsets of €183 085 281 within the 4-year time horizon. Of these, 92% were driven by avoided SHEH. Compared to an expected budget impact (cost increase) of 83%, only treatment costs considered, the total impact of the switch scenario amounted merely to a 24.5% increase in costs (reduction by 58.5% points; a factor of 3.4). Conclusion: The use of CSII resulted in fewer SHEH and CDEs compared to MDI. The incurred CSII implementation costs are hence offset to a substantial degree by cost savings in complication treatment.
Prevalence of sleep deprivation in patients with chronic neck and back pain: a retrospective evaluation of 1016 patients

Background Chronic low back pain (CLBP) and chronic neck pain (CNP) have become a serious medical and socioeconomic problem in recent decades. Patients suffering from chronic pain seem to have a higher prevalence of sleep disorders. Purpose To calculate the prevalence of sleep deprivation in patients with CLBP and CNP and to evaluate the factors that may contribute to sleep impairment. Methods This study was a retrospective evaluation of 1016 patients with CNP and CLBP who consulted an orthopedic department at a university hospital. Factors assessed were gender, age, diagnosis, grade of sleep deprivation, pain intensity, chronification grade, and migrational background. Pearson’s chi-squared test was performed to calculate the relationship between these factors and the grade of sleep deprivation. Regression analysis was performed to explore the correlation between the grade of sleep deprivation and age, pain intensity, and chronification grade. Results A high prevalence of sleep deprivation (42.22%) was calculated in patients with CNP and CLBP, even when analgesics had been taken. About 19.88% of the patients reported serious sleep impairments (ie, <4 hours of sleep per night). The grade of sleep deprivation did not correlate with the gender or age distribution. A significant relationship was found between the grade of sleep deprivation and pain intensity, failed back surgery syndrome, and patients with a migrational background. There was a moderate relationship with intervertebral disc disease and no relationship with spinal stenosis. Conclusion Sleep disturbance should be assessed when treating patients with CNP or CLBP, especially in patients with higher pain intensity, failed back surgery syndrome, and a migrational background. Further research is needed to explore the complex relationship of sleep disturbance and chronic pain.
Engineering Growth: Innovative Capacity and Development in the Americas

This paper offers the first systematic historical evidence on the role of a central actor in modern growth theory - the engineer. It collects cross-country and state level data on the labor share of engineers for the Americas, and county level data on engineering and patenting for the US during the Second Industrial Revolution. These are robustly correlated with income today after controlling for literacy, other types of higher order human capital (e.g. lawyers, physicians), demand side factors, and after instrumenting engineering using the Land Grant Colleges program. A one standard deviation increase in engineers in 1880 accounts for a 16% increase in US county income today, and patenting capacity contributes another 10%. We further show engineering density supported technological adoption and structural transformation across intermediate time periods. Our estimates help explain why countries with similar levels of income in 1900, but tenfold differences in engineers diverged in their growth trajectories over the next century. The results are supported by historical case studies from the US and Latin America.
Shadow-driven Document Representation A summarizationbased summarizationbased summarizationbased strategy to represent noninteroperable noninteroperable noninteroperable documents

Document production tools are present everywhere, resulting in an exponential growth of increasingly complex, distributed and heterogeneous documents. This hampers document exchange, as well as their annotation, indexing and retrieval. Existing approaches to these tasks either concentrate on specific formats or require representing document’s content using interoperable standards or schema. This work presents our effort to handle this problem. Rather than trying to modify or convert the document itself, our strategy defines an intermediate and interoperable descriptor – shadow – that summarizes key aspects and elements of a given document, improving its annotation, indexation and retrieval process regardless of its format. Shadows can be used with different purposes, from semantic annotations and contextsensitive annotations, to content indexation and clustering.
Transdermal Optical Imaging Reveal Basal Stress via Heart Rate Variability Analysis: A Novel Methodology Comparable to Electrocardiography

The present study examined the validity of a novel physiological measurement technology called transdermal optical imaging (TOI) technology at assessing basal stress. This technology conveniently, contactlessly, and remotely measures facial blood flow changes using a conventional digital video camera. We compared data from TOI against the pulse data collected from the FDA approved BIOPAC system. One hundred thirty-six healthy adults participated in the study. We found that TOI measurements of heart rate and heart rate variability (HRV), which reflects basal stress, corresponded strongly to those obtained from BIOPAC. These findings indicate that TOI technology is a viable method to monitor heart rate and HRV not only accurately but also conveniently, contactlessly, and remotely. Further, measures of HRV obtained via TOI serves as a valid index of basal stress. Potential applications of this technology in psychological research and other fields are discussed.
LISA: nová naděje lovců gravitačních vln

Již brzy uplyne 100 let od pobytu Alberta Einsteina v Praze. Mezi 1. dubnem 1911 a 25. červencem 1912 zde působil jako řádný profesor teoretické fyziky na německé části Karlo-Ferdinandovy univerzity. Pro fyziku a astronomii to bude významné jubileum. Během pražského pobytu se Einstein vydal na náročnou intelektuální cestu, jejímž cílem bylo uvést teorii gravitace do souladu s principy relativity. Jak je podrobně popsáno v monografiích [1], [2] a [3], úkol to byl obtížný a Einstein ho po mnoha peripetiích triumfálně završil formulací obecné teorie relativity v listopadu 1915. Koncepční kořeny této fascinující teorie, která se stala pilířem moderní fyziky, však sahají právě do jeho pobytu v Praze. Einsteinova obecná relativita, mnohokrát experimentálně ověřená [4], dodnes zůstává nejlepší gravitační teorií. V jejím rámci byly poprvé v historii sestrojeny realistické kosmologické modely rozpínajícího se vesmíru vzniklého při velkém třesku. Einsteinova teorie se stala i nezbytným nástrojem astrofyziky: sehrála klíčovou roli v pochopení vzniku prvků, struktury a vývoje hvězd i procesů odehrávajících se na konci jejich života, kdy kolabují v bílé trpaslíky, neutronové hvězdy či dokonce singulární černé díry. Po objevu pulsarů, kvasarů a aktivních galaxií, jichž jsou zmíněné rotující objekty hnacím motorem, se v 60. letech obecná relativita stala integrální součástí astronomie.
Cell cycle arrest induced by inhibitors of epigenetic modifications in maize (Zea mays) seedling leaves: characterization of the process and possible mechanisms involved.

Epigenetic modifications play crucial roles in the regulation of chromatin architecture and are involved in cell cycle progression, including mitosis and meiosis. To explore the relationship between epigenetic modifications and the cell cycle, we treated maize (Zea mays) seedlings with six different epigenetic modification-related inhibitors and identified the postsynthetic phase (G2 ) arrest via flow cytometry analysis. Total H4K5ac levels were significantly increased and the distribution of H3S10ph signalling was obviously changed in mitosis under various treatments. Further statistics of the cells in different periods of mitosis confirmed that the cell cycle was arrested at preprophase. Concentrations of hydrogen peroxide were relatively higher in the treated plants and the antioxidant thiourea could negate the influence of the inhibitors. Moreover, all of the treated plants displayed negative results in the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) and γ-H2AX immunostaining assays after exposure for 3 d. Additionally, the expression level of topoisomerase genes in the treated plants was relatively lower than that in the untreated plants. These results suggest that these inhibitors of epigenetic modifications could cause preprophase arrest via reactive oxygen species formation inhibiting the expression of DNA topoisomerase genes, accompanied by changes in the H4K5ac and H3S10ph histone modifications.
Hybrid Closed-Loop Insulin Delivery in Type 1 Diabetes During Supervised Outpatient Conditions

Background: Efficacy and safety of the Medtronic Hybrid Closed-Loop (HCL) system were tested in subjects with type 1 diabetes in a supervised outpatient setting. Methods: The HCL system is a prototype research platform that includes a sensor-augmented insulin pump in communication with a control algorithm housed on an Android-based cellular device. Nine subjects with type 1 diabetes (5 female, mean age 53.3 years, mean A1C 7.2%) underwent 9 studies totaling 571 hours of closed-loop control using either default or personalized parameters. The system required meal announcements with estimates of carbohydrate (CHO) intake that were based on metabolic kitchen quantification (MK), dietician estimates (D), or subject estimates (Control). Postprandial glycemia was compared for MK, D, and Control meals. Results: The overall sensor glucose mean was 145 ± 43, the overall percentage time in the range 70-180 mg/dL was 80%, the overall percentage time <70 mg/dL was 0.79%. Compared to intervals of default parameter use (225 hours), intervals of personalized parameter use (346 hours), sensor glucose mean was 158 ± 49 and 137 ± 37 mg/dL (P < .001), respectively, and included more time in range (87% vs 68%) and less time below range (0.54% vs 1.18%). Most subjects underestimated the CHO content of meals, but postprandial glycemia was not significantly different between MK and matched Control meals (P = .16) or between D and matched Control meals (P = .76). There were no episodes of severe hypoglycemia. Conclusions: The HCL system was efficacious and safe during this study. Personally adapted HCL parameters were associated with more time in range and less time below range than default parameters. Accurate estimates of meal CHO did not contribute to improved postprandial glycemia.