COBALT: A Confirmatory Trial of Obeticholic Acid in Primary Biliary Cholangitis With Placebo and External Controls

Copyright \ua9 2024 The Author(s).Objectives: Obeticholic acid (OCA) treatment for primary biliary cholangitis (PBC) was conditionally approved in the phase 3 POISE trial. The COBALT confirmatory trial assessed whether clinical outcomes in PBC patients improve with OCA therapy. Methods: Patients randomized to OCA (5–10 mg) were compared with placebo (randomized controlled trial [RCT]) or external control (EC). The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation. A prespecified propensity score–weighted EC group was derived from a US healthcare claims database. Results: In the RCT, the primary endpoint occurred in 28.6% of OCA (n=168) and 28.9% of placebo patients (n=166; intent-to-treat [ITT] analysis hazard ratio [HR]=1.01, 95% CI=0.68–1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Correcting for these using inverse probability of censoring weighting (IPCW) and as-treated analyses shifted the HR to favor OCA. In the EC (n=1051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR=0.39; 95% CI=0.22–0.69; P=0.001). No new safety signals were identified in the RCT. Conclusions: Functional unblinding and treatment crossover, particularly in the placebo arm, confounded the ITT estimate of outcomes associated with OCA in the RCT. Comparison with the real-world EC showed that OCA treatment significantly reduced the risk of negative clinical outcomes. These analyses demonstrate the value of EC data in confirmatory trials and suggest that treatment with OCA improves clinical outcomes in patients with PBC

KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo

Abstract Histone deacetylase (HDAC) inhibitors have garnered significant attention as cancer drugs. These therapeutic agents have recently been clinically validated with the market approval of vorinostat (SAHA, Zolinza) for treatment of cutaneous T-cell lymphoma. Like vorinostat, most of the small-molecule HDAC inhibitors in clinical development are hydroxamic acids, whose inhibitory activity stems from their ability to coordinate the catalytic Zn 2+ in the active site of HDACs. We sought to identify novel, nonhydroxamate-based HDAC inhibitors with potentially distinct pharmaceutical properties via an ultra-high throughput small molecule biochemical screen against the HDAC activity in a HeLa cell nuclear extract. An A-mercaptoketone series was identified and chemically optimized. The lead compound, KD5170, exhibits HDAC inhibitory activity with an IC 50 of 0.045 Mmol/L in the screening biochemical assay and an EC 50 of 0.025 Mmol/L in HeLa cell -based assays that monitor histone H3 acetylation. KD5170 also exhibits broad spectrum classe

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Integration of optoelectronic components with LTCC (low temperature co-fired ceramic) microfluidic structure

Investigations on integration of optoelectronic components with LTCC (low temperature co-fired ceramics) microfluidic module are presented. Design, fabrication and characterization of the ceramic structure for optical absorbance is described as well. The geometry of the microfluidic channels has been designed according to results of the CFD (computational fluid dynamics) analysis. A fabricated LTCC-based microfluidic module consists of an U-shaped microchannel, two optical fibers and integrated light source (light emitting diode) and photodetector (light-to-voltage converter). Properties of the fabricated microfluidic system have been investigated experimentally. Several concentrations of potassium permanganate (KMnO4) in water were used for absorbance/transmittance measurements. The test has shown a linear detection range for various concentrations of heavy metal ions in distilled water. The fabricated microfluidic structure is found to be a very useful system in chemical analysis

Selected aspects of developing microwave elements in LTCC modules

Artykuł prezentuje aspekty techniczne, które są istotne podczas wykonywania oraz projektowania zintegrowanych układów mikroprzepływowo-mikrofalowych. Zastosowanie techniki mikrofalowej w układach mikroprzepływowych otwiera nowe możliwości, które stanowią rozwiązanie części problemów występujących w układach mikroprzepływowych, takich jak wykorzystanie i dostarczanie energii cieplnej. Ponadto, mikrofale stanowią atrakcyjną alternatywę dla spotykanych obecnie metod charakteryzacji parametrów substancji umieszczonych w kanale mikroukładu. W związku z tym, przedstawiono typowe obszary zastosowań techniki mikrofalowej w modułach mikroprzepływowych. Opisano typowe podłoża, które są stosowane podczas wytwarzania wspomnianych układów, wraz z wyszczególnieniem ich cech charakterystycznych i porównaniem. Wskazano na korzyści płynące z zastosowania ceramiki LTCC (ang. Low temperature cofired ceramics, niskotemperaturowa ceramika współwypalana), jako materiału podłożowego pod układy mikroprzepływowo-mikrofalowe. Wyszczególniono możliwe do wykonania techniką LTCC typy prowadnic falowych wraz z odpowiednim położeniem mikrokanału w ceramicznym podłożu oraz dokonano krótkiego podsumowania.This paper descries aspects, which are significant during the process of designing and developing of integrated microfluidic-microwave modules. The application of microwaves in microfluidic modules ensures the new possibilities, such as a providing a heat to the selected parts of a microsystem. Furthermore, the microwaves are the alternative solution of characterization of parameters the substance in the microchannel. Therefore, the usual fields of microwave technique in microfluidic modules are presented. The most used substrates in mentioned devices are described and compared. The benefits of using the LTCC as the substrate of microfluidic-microwave devices are indicated. Furthermore, the most common used wave guides integrated with the geometry of microchannels in LTCC modules are presented

The possibility to use the low-temperature co-fired ceramics (LTCC) in the mining industry

W artykule opisano technologię LTCC (niskotemperaturowa współwypalana ceramika, ang. Low Temperature Co-fired Ceramic) pod względem możliwości jej wykorzystania w przemyśle górniczym. Wskazano unikalne cechy technologii LTCC, które są istotne w przypadku wytwarzania układów elektronicznych przeznaczonych do pracy w trudnych warunkach środowiskowych, takich jak podwyższona temperatura, ciśnienie oraz wilgotność. Opisano przykładowe rozwiązania bazujące na technice LTCC obecne w literaturze przedmiotu, wskazujące na możliwość ich zastosowania w przemyśle wydobywczym.This article presents LTCC (Low Temperature Co-Fired Ceramic) in terms of using ceramic substrates as base of electronic devices in the mining industry. Technological attributes of substrate material are significant aspects of the perspective of choosing type of electronic systems in harsh environment (such as elevated temperatures, pressures and humidity). Technological process of manufacturing LTCC multilayer was described. Examples of LTCC-based solutions are presented, with particular emphasis on wireless sensor system tested in coalmine

Neurotransmitters detection using a fluorescence-based sensor with graphene quantum dots

In the paper, the development and performance of an optical sensor for detection of neurotransmitters (dopamine) is presented. The concentration of dopamine is measured basing on fluorescence quenching of graphene quantum dots. In the sensor, the dopamine molecules coat the graphene quantum dots surface – in result, the quenching of fluorescence occurs due to the Förster resonance energy transfer. The changes in fluorescence correspond to specific concentrations of the neurotransmitter in tested samples, so it is possible to accurately determine the concentration of dopamine in the sample

Badanie właściwości termistorów wykonanych na podłożach LTCC

The work is conducted on NTC (Negative Temperature Coefficient) thermistors. An influence of different type of the substrate (DP 951 and lead free ESL 41020) on basic electrical properties: sheet resistance at a room temperature, R = f(T) dependence, B constant and a long-term stability is analyzed. The resistance values are measured twenty times in the range from 25°C to 125°C at 5°C intervals, while temperature is recorded using Pt-100 resistor. Long-term stability is investigated by annealing at 150°C for 200 h.W pracy przedstawiono wyniki badań związanych z elementami termistorowymi NTC (Negative Temperature Coefficient). Zbadano wpływ rodzaju podłoża (DP 951 i bezołowiowego ESL 41020) oraz konfiguracji elementów (zagrzebane, powierzchniowe) na podstawowe parametry elektryczne: rezystancję na kwadrat, zależność rezystancji od temperatury, stałą termistorową B, stabilność długo terminową. Wartości rezystancji były mierzone 20 razy w zakresie od 25°C do 125°C ze skokiem 5°C temperatura była mierzona za pomocą rezystora PT-100. Stabilność długoterminowa była badana przez wygrzewanie w 150°C przez 200 h