Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Safety was also assessed. RESULTS: In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Elevated liver aminotransferase levels were more common with ozanimod. CONCLUSIONS: Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992.).

Data Fusion of Acoustic and Optical Emission from Laser-Induced Plasma for In Situ Measurement of Rare Earth Elements in Molten LiCl-KCl.

Molten salts have a significant potential for use as next-generation nuclear reactor coolants and in pyroprocessing for the recycling of used nuclear fuel. However, the molten salt composition needs to be known at all times, and high temperatures and intense ionizing radiation pose challenges for the monitoring instrumentation. Although the technique of laser-induced breakdown spectroscopy (LIBS) has been studied for in situ measurements of molten salts, trials to improve its monitoring accuracy using chemometrics are lacking. In this study, a data fusion technique using the LIBS optical and laser-induced acoustic (LIA) signals was investigated to enhance the measurement accuracy for molten salt monitoring. Prediction models were constructed using the partial least-squares method, and the variable importance in projection scores was analyzed to evaluate the effect of incorporating the LIA signal into the analysis. This study investigates rare earth elements Eu, Er, and Pr found not only in nuclear but also in other settings such as laser and magnetic materials. The analysis of LIBS data without data fusion resulted in a root-mean-square error of prediction (RMSEP) of 0.0774-0.0913 wt %, whereas the prediction model using data fusion led to approximately 18-40% enhanced RMSEP (0.0461-0.0679 wt %). The results suggest that fusing the LIBS data with the simultaneously recorded LIA data can improve the monitoring accuracy of rare earth element composition in molten salts.

Filament-induced breakdown spectroscopy of solids through highly scattering media.

Ultrafast laser pulse filamentation in the air can be used for remote sensing by exciting a characteristic optical emission, which is usually referred to as filamentation-induced breakdown spectroscopy. In environments that impede light propagation, such as fog, haze, or clouds, scattering makes it challenging to propagate laser beams and retrieve generated optical signatures. We demonstrate the effectiveness of laser filamentation for simultaneously clearing the path for intense femtosecond pulse propagation in a highly scattering medium, generation of luminous plasma on a solid target, and counter-propagation of a characteristic spectroscopic signal over a cleared channel along the filament path. In a dense cloud, the counter-propagating signal predominantly transits the cleared on-axis path but is highly affected by the negative thermal lensing of a Gaussian beam. These insights enhance our understanding of laser filamentation in atmospheric sensing and could substantially improve remote detection capabilities in poor visibility conditions.

Long-wave-infrared pulse production at 11 µm via difference-frequency generation driven by femtosecond mid-infrared all-fluoride fiber laser.

We present an ultrafast long-wave infrared (LWIR) source driven by a mid-infrared fluoride fiber laser. It is based on a mode-locked Er:ZBLAN fiber oscillator and a nonlinear amplifier operating at 48 MHz. The amplified soliton pulses at ∼2.9 µm are shifted to ∼4 µm via the soliton self-frequency shifting process in an InF3 fiber. LWIR pulses with an average power of 1.25-mW centered at 11 µm with a spectral bandwidth of ∼1.3 µm are produced through difference-frequency generation (DFG) of the amplified soliton and its frequency-shifted replica in a ZnGeP2 crystal. Soliton-effect fluoride fiber sources operating in the mid-infrared for driving DFG conversion to LWIR enable higher pulse energies than with near-infrared sources, while maintaining relative simplicity and compactness, relevant for spectroscopy and other applications in LWIR.

Ultrafast Laser-Excited Optical Emission of Xe under Loose-Focusing Conditions.

The optical filament-based radioxenon sensing can potentially overcome the constraints of conventional detection techniques that are relevant for nuclear security applications. This study investigates the spectral signatures of pure xenon (Xe) when excited by ultrafast laser filaments at near-atmosphericpressure and in short and loose-focusing conditions. The two focusing conditions lead to laser intensity differences of several orders of magnitude and different plasma transient behavior. The gaseous sample was excited at atmospheric pressure using ∼7 mJ pulses with a 35 fs pulse duration at 800 nm wavelength. The optical signatures were studied by time-resolved spectrometry and imaging in orthogonal light collection configurations in the ∼400 nm (VIS) and ∼800 nm (NIR) spectral regions. The most prominent spectral lines of atomic Xe are observable in both focusing conditions. An on-axis light collection from an atmospheric air-Xe plasma mixture demonstrates the potential of femtosecond filamentation for the remote sensing of noble gases.

Impact of Glass Irradiation on Laser-Induced Breakdown Spectroscopy Data Analysis.

Increased absorption of optical materials arising from exposure to ionizing radiation must be accounted for to accurately analyze laser-induced breakdown spectroscopy (LIBS) data retrieved from high-radiation environments. We evaluate this effect on two examples that mimic the diagnostics placed within novel nuclear reactor designs. The analysis is performed on LIBS data measured with 1% Xe gas in an ambient He environment and 1% Eu in a molten LiCl-KCl matrix, along with the measured optical absorption from the gamma- and neutron-irradiated low-OH fused silica and sapphire glasses. Significant changes in the number of laser shots required to reach a 3σ detection level are observed for the Eu data, increasing by two orders of magnitude after exposure to a 1.7 × 1017 n/cm2 neutron fluence. For all cases examined, the spectral dependence of absorption results in the introduction of systematic errors. Moreover, if lines from different spectral regions are used to create Boltzmann plots, this attenuation leads to statistically significant changes in the temperatures calculated from the Xe II lines and Eu II lines, lowering them from 8000 ± 610 K to 6900 ± 810 K and from 15,800 ± 400 K to 7200 ± 800 K, respectively, for exposure to the 1.7 × 1017 n/cm2 fluence. The temperature range required for a 95% confidence interval for the calculated temperature is also broadened. In the case of measuring the Xe spectrum, these effects may be mitigated using only the longer-wavelength spectral region, where radiation attenuation is relatively small, or through analysis using the iterative Saha-Boltzmann method.

Alcohol, Inflammation, and Microbiota in Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is a consequence of excessive alcohol use. According to many studies, alcohol represents a significant socioeconomic and health risk factor in today's population. According to data from the World Health Organization, there are about 75 million people who have alcohol disorders, and it is well known that its use leads to serious health problems. ALD is a multimodality spectrum that includes alcoholic fatty liver disease (AFL) and alcoholic steatohepatitis (ASH), consequently leading to liver fibrosis and cirrhosis. In addition, the rapid progression of alcoholic liver disease can lead to alcoholic hepatitis (AH). Alcohol metabolism produces toxic metabolites that lead to tissue and organ damage through an inflammatory cascade that includes numerous cytokines, chemokines, and reactive oxygen species (ROS). In the process of inflammation, mediators are cells of the immune system, but also resident cells of the liver, such as hepatocytes, hepatic stellate cells, and Kupffer cells. These cells are activated by exogenous and endogenous antigens, which are called pathogen and damage-associated molecular patterns (PAMPs, DAMPs). Both are recognized by Toll-like receptors (TLRs), which activation triggers the inflammatory pathways. It has been proven that intestinal dysbiosis and disturbed integrity of the intestinal barrier perform a role in the promotion of inflammatory liver damage. These phenomena are also found in chronic excessive use of alcohol. The intestinal microbiota has an important role in maintaining the homeostasis of the organism, and its role in the treatment of ALD has been widely investigated. Prebiotics, probiotics, postbiotics, and symbiotics represent therapeutic interventions that can have a significant effect on the prevention and treatment of ALD.

Lipotoxicity as the Leading Cause of Non-Alcoholic Steatohepatitis.

The emerging issues nowadays are non-alcoholic fatty liver disease (NAFLD) and its advanced stage non-alcoholic steatohepatitis (NASH), which further can be a predisposing factor for chronic liver complications, such as cirrhosis and/or development of hepatocellular carcinoma (HCC). Liver lipotoxicity can influence the accumulation of reactive oxygen species (ROS), so oxidative stress is also crucial for the progression of NASH. Moreover, NASH is in strong connection with metabolic disorders, and supporting evidence shows that insulin resistance (IR) is in a close relation to NAFLD, as it is involved in the progression to NASH and further progression to hepatic fibrosis. The major issue is that, at the moment, NASH treatment is based on lifestyle changes only due to the fact that no approved therapeutic options are available. The development of new therapeutic strategies should be conducted towards the potential NAFLD and NASH treatment by the modulation of IR but also by dietary antioxidants. As it seems, NASH is going to be the leading indication for liver transplantation as a consequence of increased disease prevalence and the lack of approved treatment; thus, an effective solution is needed as soon as possible.

Aging of Liver in Its Different Diseases.

The proportion of elderly people in the world population is constantly increasing. With age, the risk of numerous chronic diseases and their complications also rises. Research on the subject of cellular senescence date back to the middle of the last century, and today we know that senescent cells have different morphology, metabolism, phenotypes and many other characteristics. Their main feature is the development of senescence-associated secretory phenotype (SASP), whose pro-inflammatory components affect tissues and organs, and increases the possibility of age-related diseases. The liver is the main metabolic organ of our body, and the results of previous research indicate that its regenerative capacity is greater and that it ages more slowly compared to other organs. With age, liver cells change under the influence of various stressors and the risk of developing chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH) and hepatocellular carcinoma (HCC) increases. It has been proven that these diseases progress faster in the elderly population and in some cases lead to end-stage liver disease that requires transplantation. The treatment of elderly people with chronic liver diseases is a challenge and requires an individual approach as well as new research that will reveal other safe and effective therapeutic modalities.

Factors Predicting Malignant Occurrence and Polyp Recurrence after the Endoscopic Resection of Large Colorectal Polyps: A Single Center Experience.

Background: The aim of this study was to identify risk factors contributing to the malignancy of colorectal polyps, as well as risk factors for recurrence after the successful endoscopic mucosal resection of large colorectal polyps in a referral center. Materials and Methods: This retrospective cohort study was performed in patients diagnosed with large (≥20 mm diameter) colorectal polyps and treated in the period from January 2014 to December 2019 at the University Hospital Medical Center Bezanijska Kosa, Belgrade, Serbia. Based on the endoscopic evaluation and classification of polyps, the following procedures were performed: en bloc resection, piecemeal resection or surgical treatment. Results: A total of 472 patients with large colorectal polyps were included in the study. The majority of the study population were male (62.9%), with a mean age of 65.7 ± 10.8 years. The majority of patients had one polyp (73.7%) less than 40 mm in size (74.6%) sessile morphology (46.4%), type IIA polyps (88.2%) or polyps localized in the descending colon (52.5%). The accessibility of the polyp was complicated in 17.4% of patients. En bloc resection was successfully performed in 61.0% of the patients, while the rate of piecemeal resection was 26.1%. Due to incomplete endoscopic resection, surgery was performed in 5.1% of the patients, while 7.8% of the patients were referred to surgery directly. Hematochezia (p = 0.001), type IIB polyps (p < 0.001) and complicated polyp accessibility (p = 0.002) were significant independent predictors of carcinoma presence in a multivariate logistic regression analysis. Out of the 472 patients enrolled in the study, 364 were followed after endoscopic resection for colorectal polyp recurrence, which was observed in 30 patients (8.2%) during follow-up. Piecemeal resection (p = 0.048) and incomplete resection success (p = 0.013) were significant independent predictors of polyp recurrence in the multivariate logistic regression analysis. Conclusions: Whenever an endoscopist encounters a complex colorectal lesion (i.e., a polyp with complicated accessibility), polyp size > 40 mm, the Laterally Spreading Tumor nongranular (LST-NG) morphological type, type IIB polyps or the presence of hematochezia, malignancy risk should be considered before making the decision to either resect, refer to an advanced endoscopist or perform surgery.

Elevated Transaminases as Predictors of COVID-19 Pneumonia Severity.

BACKGROUND: This study aimed to calculate the frequency of elevated liver enzymes in hospitalized patients with coronavirus disease 2019 (COVID-19) infection and to test if liver enzyme biochemistry levels on admission could predict the computed tomography (CT) scan severity score of bilateral interstitial pneumonia. METHODS: This single-center study comprised of 323 patients including their demographic data, laboratory analyses, and radiological findings. All the information was taken from electronic health records, followed by statistical analysis. RESULTS: Out of 323 patients, 115 of them (35.60%) had aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) over 40 U/L on admission. AST was the best predictor of CT scan severity score of bilateral interstitial pneumonia (R2 = 0.313, Adjusted R2 = 0.299). CT scan severity score in the peak of the infection could be predicted with the value of AST, neutrophils, platelets, and monocytes count (R2 = 0.535, Adjusted R2 = 0.495). CONCLUSION: AST, neutrophils, platelets, and monocytes count on admission can account for almost half (49.5%) of the variability in CT scan severity score at peak of the disease, predicting the extensiveness of interstitial pneumonia related to COVID-19 infection. Liver enzymes should be closely monitored in order to stratify COVID-19 patients with a higher risk of developing severe forms of the disease and to plan the beforehand step-up treatment.

Millisecond-long suppression of spectroscopic optical signals using laser filamentation.

Ultrashort laser pulse filamentation in air can extend the delivery of focused laser energy to distances greatly exceeding the Rayleigh length. In this way, remote measurements can be conducted using many standard methods of analytical spectroscopy. The performance of spectroscopic techniques can be enhanced by temporal gating, which rejects the unwanted noise and background. In the present work, we investigate the thermal relaxation of air in the wake of single-filament plasmas using shadowgraphy. We demonstrate that the transient change in refractive index associated with relaxation of the gas can be used to reject both continuous and time-varying spectroscopic signals, including emission from laser-produced plasmas. This method can augment temporal gating of simple optical detectors.

Demonstration of 0.67-mJ and 10-ns high-energy pulses at 2.72 µm from large core Er:ZBLAN fiber amplifiers.

We explored generation of high-energy nanosecond short pulses in the mid-IR wavelength range using 30-70-µm-core Er:ZBLAN fiber amplifiers. The highest energies achieved were ∼0.7mJ at 2.72 µm in 11.5-ns-long pulses, with the corresponding peak power of 60.3 kW, obtained with a 70-µm-diameter core fiber amplifier pumped at 976 nm and seeded by a KTiOAsO4-based optical parametric oscillator/optical parametric amplifier system. To the best of our knowledge, these pulse energies are the highest achieved to date from mid-IR fiber lasers at longer than 2-µm wavelengths with nanosecond pulses. The achieved highest pulse energies were limited by the surface damage of unprotected fiber output facets.

Patients with rheumatoid arthritis facing sick leave or work disability meet varying regulations: a study among rheumatologists and patients from 44 European countries.

OBJECTIVES: To describe and explore differences in formal regulations around sick leave and work disability (WD) for patients with rheumatoid arthritis (RA), as well as perceptions by rheumatologists and patients on the system's performance, across European countries. METHODS: We conducted three cross-sectional surveys in 50 European countries: one on work (re-)integration and social security (SS) system arrangements in case of sick leave and long-term WD due to RA (one rheumatologist per country), and two among approximately 15 rheumatologists and 15 patients per country on perceptions regarding SS arrangements on work participation. Differences in regulations and perceptions were compared across categories defined by gross domestic product (GDP), type of social welfare regime, European Union (EU) membership and country RA WD rates. RESULTS: Forty-four (88%) countries provided data on regulations, 33 (75%) on perceptions of rheumatologists (n=539) and 34 (77%) on perceptions of patients (n=719). While large variation was observed across all regulations across countries, no relationship was found between most of regulations or income compensation and GDP, type of SS system or rates of WD. Regarding perceptions, rheumatologists in high GDP and EU-member countries felt less confident in their role in the decision process towards WD (ß=-0.5 (95% CI -0.9 to -0.2) and ß=-0.5 (95% CI -1.0 to -0.1), respectively). The Scandinavian and Bismarckian system scored best on patients' and rheumatologists' perceptions of regulations and system performance. CONCLUSIONS: There is large heterogeneity in rules and regulations of SS systems across Europe in relation to WD of patients with RA, and it cannot be explained by existing welfare regimes, EU membership or country's wealth.

Evolution of uranium monoxide in femtosecond laser-induced uranium plasmas.

We report on the observation of uranium monoxide (UO) emission following fs laser ablation (LA) of a uranium metal sample. The formation and evolution of the molecular emission is studied under various ambient air pressures. Observation of UO emission spectra at a rarefied residual air pressure of ~1 Torr indicates that the UO molecule is readily formed in the expanding plasma with trace concentrations of oxygen present within the vacuum chamber. The persistence of the UO emission exceeded that of the atomic emission; however, the molecular emission was delayed in time compared to the atomic emission due to the necessary cooling and expansion of the plasma before the UO molecules can form.

Propagation distance-resolved characteristics of filament-induced copper plasma.

Copper plasma generated at different filament-copper interaction points was characterized by spectroscopic, acoustic, and imaging measurements. The longitudinal variation of the filament intensity was qualitatively determined by acoustic measurements in air. The maximum plasma temperature was measured at the location of peak filament intensity, corresponding to the maximum mean electron energy during plasma formation. The highest copper plasma density was measured past the location of the maximum electron density in the filament, where spectral broadening of the filament leads to enhanced ionization. Acoustic measurements in air and on solid target were correlated to reconstructed plasma properties. Optimal line emission is measured near the geometric focus of the lens used to produce the filament.

Parametric generation and characterization of femtosecond mid-infrared pulses in ZnGeP2.

Ultrafast mid-infrared (IR) coherent radiation plays an important role in strong-field physics, wherein the use of longer wavelengths has reduced the optical intensities needed to drive light-matter interactions by orders of magnitude in comparison to near-IR radiation. Optimizing parametric interactions for generation and characterization of mid-IR pulses is an enabling step for those applications. We report on the production of >50 µJ femtosecond pulses centered at 5 µm in a two-stage optical parametric amplifier (OPA) based on ZnGeP2, a high-performance optical material in this spectral region. The OPA is pumped by an ultrafast 2-µm source. Amplified pulses have been characterized by parametric upconversion, enabling the use of standard silicon detectors. A numerical model of the system has been developed and tested to control dispersion, group-velocity mismatch, and off-axis parametric fluorescence. The source architecture is suitable for production of mJ-level mid-IR ultrafast pulses without the use of chirped-pulse amplification, where convenient pumping could be realized directly by mid-IR laser sources based on materials such as Cr:ZnSe or Cr:ZnS.

Real-time thermographic analysis of low-density bone during implant placement: a randomized parallel-group clinical study comparing lateral condensation with bone drilling surgical technique.

OBJECTIVES: To compare the effect of two surgical techniques, lateral condensation and bone drilling, on changes in temperature of the adjacent low-density bone during implant placement into posterior maxilla and to investigate the influence of the host factors - age, gender, region of implantation, bone density, and thickness of the cortical bone at the recipient sites. MATERIAL AND METHODS: Local bone temperature was measured thermographically during implant placement into posterior maxilla following lateral bone condensing (test group) or bone drilling (controls). The main study outcomes were baseline bone temperature prior to implantation and maximum bone temperature recorded during implantation. Early implant success was evaluated after 6 months of healing. RESULTS: A total of 40 implants were randomly allocated to test and control groups and placed into maxillary premolar and/or molar region of 18 participants of both genders and average age of 51.74 years. All recorded bone temperatures were below the threshold for thermal necrosis. Although both groups showed significant increase in bone temperature during implant placement procedure (P ≤ 0.0005), it was significantly higher for bone condensing compared with drilling (P ≤ 0.0005; 3.79 ± 1.54°C; 1.91 ± 0.70°C respectively). No host factor was singled out as a significant predictor of bone temperature changes, although trend of higher increase was observed in young patients, regardless of gender, during implant placement procedure into maxillary first premolar region with bone density type 3 and cortical layer thicker than 1 mm. Early implant success rate after 6 months follow-up was 100%. CONCLUSION: Although both surgical techniques, bone condensing and bone drilling, can be considered safe regarding their thermal effect on the bone of posterior maxilla, bone drilling is associated with fewer local bone heating during implantation. Host factors do not affect the bone thermal changes significantly.

A Reliability Investigation of VDMOS Transistors: Performance and Degradation Caused by Bias Temperature Stress.

This study aimed to comprehensively understand the performance and degradation of both p- and n-channel vertical double diffused MOS (VDMOS) transistors under bias temperature stress. Conducted experimental investigations involved various stress conditions and annealing processes to analyze the impacts of BT stress on the formation of oxide trapped charge and interface traps, leading to threshold voltage shifts. Findings revealed meaningful threshold voltage shifts in both PMOS and NMOS devices due to stresses, and the subsequent annealing process was analyzed in detail. The study also examined the influence of stress history on self-heating behavior under real operating conditions. Additionally, the study elucidated the complex correlation between stress-induced degradation and device reliability. The insights contribute to optimizing the performance and permanence of VDMOS transistors in practical applications, advancing semiconductor technology. This study underscored the importance of considering stress-induced effects on device reliability and performance in the design and application of VDMOS transistors.

Angle-multiplexed spatial-spectral interferometry for simultaneous measurement of spectral phase and polarization state.

A novel method to simultaneously extract the polarization state and relative spectral phase of an ultrashort laser pulse from an angle-multiplexed spatial-spectral interferometric measurement is proposed and experimentally demonstrated. Spectral interference is produced between an arbitrary polarized signal pulse and two orthogonal linearly polarized reference pulses. The accuracy of this technique has been verified by reconstructing the known relative spectral phase arising from material dispersion and the known elliptical polarization state. Measurement of the relative spectral phase and the spatially variable polarization state of a radially polarized pulse is also demonstrated. An additional independent measurement of the spectral phase of reference pulses provides absolute spectral and temporal characteristics of the signal pulse.