A comprehensive review of phase 2/3 trials in osteoarthritis: an expert opinion.

INTRODUCTION: Osteoarthritis (OA) is a chronic, degenerative, and debilitating disease associated with significant long-term morbidity and disability. The pathogenesis of OA is not completely understood but involves an interplay between environmental risk factors, joint mechanics, abnormal pain pathways and upregulation of inflammatory signaling pathways. Current therapeutic options for patients are limited to conservative management, minimal pharmacological options or surgical management, with significant caveats to all approaches. AREAS COVERED: In this review, we have set out to investigate current phase II/III clinical trials by undertaking a PubMed search. Examined clinical trials have explored a myriad of potential therapeutics from conventional disease-modifying anti-rheumatic drugs and biologics usually used in the treatment of inflammatory arthritides, to more novel approaches targeting inflammatory pathways implicated in OA, cartilage degeneration or pain pathways. EXPERT OPINION: Unfortunately, most completed phase II/III clinical trials have shown little impact on patient pain scores, with the exception of the traditional DMARD methotrexate and Sprifermin. Methotrexate has been shown to be beneficial when used in the correct patient cohort (MRI proven synovitis). Sprifermin has the longest follow-up data of 5 years and has been shown to reduce loss of MRI-measured cartilage thickness and pain scores.

Base-Mediated Synthesis of Unsymmetrical 1,3,5-Triazin-2-amines via Three-Component Reaction of Imidates, Guanidines, and Amides or Aldehydes.

A simple and efficient method for the base-mediated synthesis of unsymmetrical 1,3,5-triazin-2-amines has been developed. The protocol uses readily available imidates, guanidines, and amides or aldehydes as the starting materials, cesium carbonate as the base, no catalyst or additive is required, and the three-component reaction provides diverse 1,3,5-triazin-2-amines in moderate to good yields with tolerance of wide functional groups.

Thyroid Hormone Biomonitoring: A Review on Their Metabolism and Machine-Learning Based Analysis on Effects of Endocrine Disrupting Chemicals.

The thyroid is an essential endocrine organ in human body, and thyroid hormones (THs) are pivotal signaling molecules and mediators in various physiological processes. THs, particularly in their free form, play a critical role in regulating body temperature and in the metabolism of lipid and glucose, making the maintenance of TH levels crucial for human health. THs undergo a series of metabolic processes, producing TH metabolites (THMs). THMs are significant in endocrine regulation, such as 3,5-diiothyronine (3,5-T2) and 3-iodothyronamine (3-T1AM), which exhibit activities akin to THs. The production and distribution of THMs are intricately linked to the function of specific organs and tissues, highlighting the need for advanced research into the determination and mechanisms of THMs in body. Exposure to endocrine disrupting chemicals (EDCs) can significantly affect the levels of thyroid stimulating hormone (TSH) and THs. This review utilizes machine learning to analyze epidemiological data, identifying potential EDCs that pose risks of hyperthyroidism and hypothyroidism. Additionally, it delves into the toxicological mechanisms of these EDCs, examining their effects on TH production, binding processes, related proteins, and metabolic enzymes. This approach effectively bridges the gap between epidemiological studies and toxicological researches, laying the groundwork for future research trends. By integrating epidemiological studies with machine learning, this review offers insightful perspectives on the potential risks associated with chemical exposure and underscores the necessity for further research in understanding the impact of EDCs on TH metabolism and TH-related health effects.

A Biomimetic Nociceptor Based on a Vertical Multigate, Multichannel Neuromorphic Transistor.

Nociceptors, crucial sensory receptors within biological systems, are essential for survival in diverse and potentially hazardous environments. Efforts to replicate nociceptors through advanced electronic devices, such as memristors and neuromorphic transistors, have achieved limited success, capturing basic nociceptive functions while more advanced characteristics like various forms of central sensitization and analgesic effect remain out of reach. Here, we introduce a vertical multigate, multichannel electrolyte-gated transistor (Vm-EGT), designed to mimic nociceptors. Utilizing the hybrid mechanism combining electric-double-layer (EDL) with ion intercalation/deintercalation in EGTs, our approach successfully replicates peripheral sensitization and desensitization characteristics of nociceptors. The intricate multigate and multichannel design of the Vm-EGT enables the emulation of more advanced nociceptive functionalities, including central sensitization and analgesic effect. Furthermore, we demonstrate that by exploiting the inherent current-voltage relationship, the Vm-EGT can simulate these advanced nociceptive features and seamlessly transition between them. Integrating a Vm-EGT with a thermistor and a heating plate, we have developed an artificial thermal nociceptor that closely mirrors the sensory attributes of its biological counterpart. Our approach significantly advances the emulation of nociceptors, providing a basis for the development of sophisticated artificial sensory systems and intelligent robotics.

A low-power vertical dual-gate neurotransistor with short-term memory for high energy-efficient neuromorphic computing.

Neuromorphic computing aims to emulate the computing processes of the brain by replicating the functions of biological neural networks using electronic counterparts. One promising approach is dendritic computing, which takes inspiration from the multi-dendritic branch structure of neurons to enhance the processing capability of artificial neural networks. While there has been a recent surge of interest in implementing dendritic computing using emerging devices, achieving artificial dendrites with throughputs and energy efficiency comparable to those of the human brain has proven challenging. In this study, we report on the development of a compact and low-power neurotransistor based on a vertical dual-gate electrolyte-gated transistor (EGT) with short-term memory characteristics, a 30 nm channel length, a record-low read power of ~3.16 fW and a biology-comparable read energy of ~30 fJ. Leveraging this neurotransistor, we demonstrate dendrite integration as well as digital and analog dendritic computing for coincidence detection. We also showcase the potential of neurotransistors in realizing advanced brain-like functions by developing a hardware neural network and demonstrating bio-inspired sound localization. Our results suggest that the neurotransistor-based approach may pave the way for next-generation neuromorphic computing with energy efficiency on par with those of the brain.

Exposure to organophosphate ester flame retardants and plasticizers during pregnancy: Thyroid endocrine disruption and mediation role of oxidative stress.

Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers in consumer and industrial products. Human exposure to OPEs raises concerns due to their endocrine disruptive potentials. Till now, the effects of OPEs on thyroid hormones (THs) and the mediating role of oxidative stress in pregnant women have not been studied. In this study, prenatal urinary concentrations of OPE metabolites (mOPEs), levels of free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and oxidative stress levels of 8-hydroxy-2-deoxy guanosine (8-OHdG) and malondialdehyde (MDA) were measured in pregnant women (n = 360) from a coastal urbanized region and moderate socioeconomic status. Neonatal TSH in heel blood was also measured in newborns (n = 309). Dibutyl phosphate (DBP) and diphenyl phosphate (DPHP) were extensively detected with a median creatinine-adjusted level of 0.19 µg/g and 0.66 µg/g, respectively, and the median of ∑mOPEs was 1.82 µg/g. DBP and DPHP were included in the analysis. The concentrations of DBP and DPHP were positively associated with either maternal or neonatal TSH levels, while not for maternal FT3 and FT4 levels. Positive associations for maternal and neonatal TSH were particularly observed in girls as stratified by newborn sex suggesting a sex-selective difference. Furthermore, 8-OHdG, the biomarker of DNA damage, was found to be a major mediator (>60%) for the association between neonatal TSH and DPHP, suggesting that DNA damage is involved in fetal thyroid function disruption. On the other hand, MDA showed a partially suppressing effect (<40%) for the associations between mOPEs and neonatal TSH, which needs further clarification. For maternal TSH, both 8-OHdG and MDA showed moderate mediating effects while the direct effects of mOPEs on maternal TSH also contributed. These results suggest thyroid disrupting effects of OPE exposure on mothers and fetuses during pregnancy and the potential influence mediated by the oxidative stresses of DNA damage and lipid peroxidation.

Application of the Effect of Latitude on the Starting of Hand, Foot, and Mouth Disease Epidemic on Early Warning in Dalian, Liaoning Province, China.

Hand, foot, and mouth disease (HFMD) is a common infectious gastrointestinal disease in children under the age of 5. Many studies have documented that meteorological variables, especially temperature, are associated with HFMD. Since the general climate patterns occur as latitude increases, so latitude may indirectly influence the peak time of HFMD. The objective of this study was to explore the effect of latitude on the starting of an HFMD epidemic in Dalian, which can help in the development of an early warning model of HFMD in difference latitude districts. Spearman's rank correlation coefficient was used to analyze the tendency of HFMD incidence rate over the year. A circular distribution method was used to calculate the gold standard of beginning of the HFMD epidemic. A negative binomial regression model was used to establish the early warning of the starting of the HFMD epidemic. The annualized crude incidence rate of HFMD disease in Dalian, Liaoning Province, China as a whole was 169.14 per 100,000 from 2009 to 2013.The incidence rate of HFMD varied considerably by district during the study period, but there was no significant declining or rising trend in disease incidence over the years by district of Dalian. The circular statistical analysis results showed that there was latitudinal gradient in the starting of the HFMD epidemic except for region B; the starting time of HFMD epidemic of Region A was earlier than other regions range 9 days to 18 days. The starting time of the HFMD epidemic differs from region to region with different latitudes in Dalian, Liaoning Province, China. This result can provide a scientific basis for early warning of HFMD.

Using a Negative Binomial Regression Model for Early Warning at the Start of a Hand Foot Mouth Disease Epidemic in Dalian, Liaoning Province, China.

BACKGROUND: The hand foot and mouth disease (HFMD) is a human syndrome caused by intestinal viruses like that coxsackie A virus 16, enterovirus 71 and easily developed into outbreak in kindergarten and school. Scientifically and accurately early detection of the start time of HFMD epidemic is a key principle in planning of control measures and minimizing the impact of HFMD. The objective of this study was to establish a reliable early detection model for start timing of hand foot mouth disease epidemic in Dalian and to evaluate the performance of model by analyzing the sensitivity in detectability. METHODS: The negative binomial regression model was used to estimate the weekly baseline case number of HFMD and identified the optimal alerting threshold between tested difference threshold values during the epidemic and non-epidemic year. Circular distribution method was used to calculate the gold standard of start timing of HFMD epidemic. RESULTS: From 2009 to 2014, a total of 62022 HFMD cases were reported (36879 males and 25143 females) in Dalian, Liaoning Province, China, including 15 fatal cases. The median age of the patients was 3 years. The incidence rate of epidemic year ranged from 137.54 per 100,000 population to 231.44 per 100,000population, the incidence rate of non-epidemic year was lower than 112 per 100,000 population. The negative binomial regression model with AIC value 147.28 was finally selected to construct the baseline level. The threshold value was 100 for the epidemic year and 50 for the non- epidemic year had the highest sensitivity(100%) both in retrospective and prospective early warning and the detection time-consuming was 2 weeks before the actual starting of HFMD epidemic. CONCLUSIONS: The negative binomial regression model could early warning the start of a HFMD epidemic with good sensitivity and appropriate detection time in Dalian.

Total ionizing dose (TID) effects of γ ray radiation on switching behaviors of Ag/AlO x /Pt RRAM device.

The total ionizing dose (TID) effects of (60)Co γ ray radiation on the resistive random access memory (RRAM) devices with the structure of Ag/AlO x /Pt were studied. The resistance in low resistance state (LRS), set voltage, and reset voltage are almost immune to radiation, whereas the initial resistance, resistance at high resistance state (HRS), and forming voltage were significantly impacted after radiation due to the radiation-induced holes. A novel hybrid filament model is proposed to explain the radiation effects, presuming that holes are co-operated with Ag ions to build filaments. In addition, the thermal coefficients of the resistivity in LRS can support this hybrid filament model. The Ag/AlO x /Pt RRAM devices exhibit radiation immunity to a TID up to 1 Mrad(Si) and are highly suitable for radiation-hard electronics applications.