An Energy-Efficient FD-fNIRS Readout Circuit Employing a Mixer-First Analog Frontend and a Σ-Δ Phase-to-Digital Converter.

This paper presents a low-power frequency-domain functional near-infrared spectroscopy (FD-fNIRS) readout circuit for the absolute value measurement of tissue optical characteristics. The paper proposes a mixer-first analog front-end (AFE) structure and a 1-bit Σ-Δ phase-to-digital converter (PDC) to reduce the required circuit bandwidth and the laser modulation frequency, thereby saving power while maintaining high resolution. The proposed chip achieves sub-0.01° phase resolution and consumes 6.8 mW of power. Nine optical solid phantoms are produced to evaluate the chip. Compared to a self-built high-precision measurement platform that combines a network analyzer with an avalanche photodiode (APD) module, the maximum measuring errors of the absorption coefficient and reduced scattering coefficient are 10.6% and 12.3%, respectively.

Self-Adaptive Perception of Object's Deformability with Multiple Deformation Attributes Utilizing Biomimetic Mechanoreceptors.

The perception of object's deformability in unstructured interactions relies on both kinesthetic and cutaneous cues to adapt the uncertainties of an object. However, the existing tactile sensors cannot provide adequate cutaneous cues to self-adaptively estimate the material softness, especially in non-standard contact scenarios where the interacting object deviates from the assumption of an elastic half-infinite body. This paper proposes an innovative design of a tactile sensor that integrates the capabilities of two slow-adapting mechanoreceptors within a soft medium, allowing self-decoupled sensing of local pressure and strain at specific locations within the contact interface. By leveraging these localized cutaneous cues, the sensor can accurately and self-adaptively measure the material softness of an object, accommodating variations in thicknesses and applied forces. Furthermore, when combined with a kinesthetic cue from the robot, the sensor can enhance tactile expression by the synergy of two relevant deformation attributes, including material softness and compliance. It is demonstrated that the biomimetic fusion of tactile information can fully comprehend the deformability of an object, hence facilitating robotic decision-making and dexterous manipulation.

COMPARISON AMONG PRESEPSIN, PROCALCITONIN, AND C-REACTIVE PROTEIN IN PREDICTING BLOOD CULTURE POSITIVITY AND PATHOGEN IN SEPSIS PATIENTS.

ABSTRACT: Background: Sepsis is caused by the invasion of the bloodstream by microorganisms from local sites of infection, leading to high mortality. This study aimed to compare the predictive ability of the biomarkers presepsin, procalcitonin (PCT), and C-reactive protein for bacteraemia. Methods: In this retrospective, multicentre study, a dataset of patients with sepsis who were prospectively enrolled between November 2017 and June 2021 was analyzed. The performances of the biomarkers for predicting positive blood cultures and infection with specific pathogens were assessed by the areas under the receiver operating characteristic curves (AUCs). The independent effects of the pathogen and foci of infection on presepsin and PCT levels were assessed by linear logistic regression models. Results: A total of 577 patients with 170 positive blood cultures (29.5%) were enrolled. The AUC achieved using PCT levels (0.856) was significantly higher than that achieved using presepsin (0.786, P = 0.0200) and C-reactive protein (0.550, P < 0.0001) levels in predicting bacteraemia. The combined analysis of PCT and presepsin levels led to a significantly higher AUC than the analysis of PCT levels alone for predicting blood culture positivity (0.877 vs. 0.856, P = 0.0344) and gram-negative bacteraemia (0.900 vs. 0.875, P = 0.0216). In a linear regression model, the elevated concentrations of presepsin and PCT were both independently related to Escherichia coli , Klebsiella species, Pseudomonas species, and Streptococcus species infections and Sequential Organ Failure Assessment score. Presepsin levels were also associated with Acinetobacter species and abdominal infection, and PCT levels were positively associated with other Enterobacteriaceae and negatively associated with respiratory infection. Combined analysis of presepsin and PCT levels provided a high sensitivity and specificity in identifying E. coli or Klebsiella species infection. Conclusions: Presepsin and PCT were promising markers for predicting bacteraemia and common pathogens at the time of sepsis onset with a synergistic effect.

Diagnosis of colorectal cancer based on folate receptor-positive circulating tumor cell analysis: a retrospective cohort study.

BACKGROUND: Early diagnosis and treatment are crucial to improve the prognosis of colorectal cancer (CRC). At present, there is a lack of an accurate CRC screening factor. We conducted folate receptor-positive circulating tumor cell analysis (FR + CTC analysis) in distinguishing CRC from benign colorectal diseases to evaluate the diagnostic efficiency. METHODS: Clinical data of patients admitted to The First Affiliated Hospital of Anhui Medical University from January 2021 to July 2022 were retrospectively collected. Levels of FR + CTC and other indicators were analyzed. Receiver operating characteristic (ROC) analysis was performed to assess the diagnostic performance of these molecular biomarkers. RESULTS: Data of 103 patients with CRC and 54 patients with benign colorectal diseases were collected. FR + CTC levels were observed significantly higher in CRC patients than in patients with benign colorectal diseases (P < 0.001). FR + CTC level was correlated with tumor diameter, differentiation, T-stage, pathological stage, clinical stage, and intravascular tumor thrombus in patients with CRC (P < 0.05). The optimal cutoff value of FR + CTC level for diagnosing CRC patients was 7.66 FU/3 ml, with a sensitivity of 85.4%, a specificity of 74.1%, and an Area Under Curve (AUC) of 0.855 (95% CI 0.77-0.923). In < 50-years old patients with CRC, the diagnostic efficiency of FR + CTC was excellent, with an AUC of 0.936 (95% CI 0.877-0.995). CONCLUSION: FR + CTC counting has excellent diagnostic efficiency in screening of CRC. FR + CTC count can also predict the tumor stage of CRC patients before surgery, and guide the choice of treatment.

Meta-Analysis of Pulse Transition Features in Non-Invasive Blood Pressure Estimation Systems: Bridging Physiology and Engineering Perspectives.

The pulse transition features (PTFs), including pulse arrival time (PAT) and pulse transition time (PTT), hold significant importance in estimating non-invasive blood pressure (NIBP). However, the literature showcases considerable variations in terms of PTFs' correlation with blood pressure (BP), accuracy in NIBP estimation, and the comprehension of the relationship between PTFs and BP. This inconsistency is exemplified by the wide-ranging correlations reported across studies investigating the same feature. Furthermore, investigations comparing PAT and PTT have yielded conflicting outcomes. Additionally, PTFs have been derived from various bio-signals, capturing distinct characteristic points like the pulse's foot and peak. To address these inconsistencies, this study meticulously reviews a selection of such research endeavors while aligning them with the biological intricacies of blood pressure and the human cardiovascular system (CVS). Each study underwent evaluation, considering the specific signal acquisition locale and the corresponding recording procedure. Moreover, a comprehensive meta-analysis was conducted, yielding multiple conclusions that could significantly enhance the design and accuracy of NIBP systems. Grounded in these dual aspects, the study systematically examines PTFs in correlation with the specific study conditions and the underlying factors influencing the CVS. This approach serves as a valuable resource for researchers aiming to optimize the design of BP recording experiments, bio-signal acquisition systems, and the fine-tuning of feature engineering methodologies, ultimately advancing PTF-based NIBP estimation.

Construction and validation of a immune-related prognostic gene DHRS1 in hepatocellular carcinoma based on bioinformatic analysis.

A member of the short-chain dehydrogenase/reductase superfamily (DHRS1, SDR19C1) is a member of the short-chain dehydrogenase/reductase superfamily and a potential predictor of hepatocellular carcinoma (HCC). However, the role of DHRS1 in HCC immunity remains unclear. We systematically analyzed the association between DHRS1 and HCC immunity with transcriptional and clinical data from the Tumor Immune Estimation Resource, an integrated repository portal for tumor immune system interactions, and cBioPortal databases. Six DHRS1-associated immunomodulators strongly correlated with survival and were uncovered by exploiting univariate and multivariate Cox analyses. We created a risk score for each patient by adding the points from each immunomodulator and then classified them into high and low risk categories. Survival analysis were used to compare the overall survival between the 2 groups, and the receiver operating characteristic curve was applied to assess the accuracy of the risk score. Data from our center were adopted as the external validation set, the risk score was calculated using the risk coefficient of the 6 genes in the training cohort, and survival analysis were executed to verify the experimental group results. A nomogram was ultimately constructed with the R package. Our data revealed a correlation between the levels of immune cell infiltration and either the DHRS1 gene copy numbers or mRNA levels in HCC. Second, we generated a signature based on the 6 DHRS1-related immunomodulators (KDR, TNFRSF4, CD276, TNFSF4, SLAMF6, and SIGLEC9). We postulate that the generated risk scores would serve as an independent indicator of HCC prognosis, with an area under the receiver operating characteristic curve for the risk score of 0.743. We further established external validation sets to reconfirm the predictive validity of the risk score. Finally, a prognostic nomogram and calibration curve were created. The DHRS1 gene may exert an impact on HCC immunity. We posit that the nominated immune signature based on DHRS1-associated immunomodulators could constitute a promising prognostic biomarker in HCC.

Discovery of Novel Tryptanthrin Derivatives with Benzenesulfonamide Substituents as Multi-Target-Directed Ligands for the Treatment of Alzheimer's Disease.

Based on the multi-target-directed ligands (MTDLs) approach, two series of tryptanthrin derivatives with benzenesulfonamide substituents were evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro biological assays indicated most of the derivatives had good cholinesterase inhibitory activity and neuroprotective properties. Among them, the target compound 4h was considered as a mixed reversible dual inhibitor of acetylcholinesterase (AChE, IC50 = 0.13 ± 0.04 µM) and butyrylcholinesterase (BuChE, IC50 = 6.11 ± 0.15 µM). And it could also potentially prevent the generation of amyloid plaques by inhibiting self-induced Aß aggregation (63.16 ± 2.33%). Molecular docking studies were used to explore the interactions of AChE, BuChE, and Aß. Furthermore, possessing significant anti-neuroinflammatory potency (NO, IL-1ß, TNF-α; IC50 = 0.62 ± 0.07 µM, 1.78 ± 0.21 µM, 1.31 ± 0.28 µM, respectively) reduced ROS production, and chelated biometals were also found in compound 4h. Further studies showed that 4h had proper blood-brain barrier (BBB) permeability and suitable in vitro metabolic stability. In in vivo study, 4h effectively ameliorated the learning and memory impairment of the scopolamine-induced AD mice model. These findings suggested that 4h may be a promising compound for further development as a multifunctional agent for the treatment of AD.

High-normal free thyroxine level is related with decreased bone mineral density in nonobese male patients with type 2 diabetes over 50 years old.

Background: The prevalence of 'low bone mineral density (BMD)' in Type 2 diabetes (T2DM), especially stratified by body mass index, is seldom reported. The relation of the euthyroid range and low BMD in T2DM remains to be further elucidated. Objectives: We aim to investigate the thyroid hormones' impact on BMD among euthyroid patients with T2DM. Design and methods: A total of 1452 hospitalized T2DM patients with normal thyroid function (43.6% males aged over 50 and 56.4% postmenopausal females) were enrolled in this cross-sectional study. BMD was measured at lumbar spine by GE lunar dual-energy X-ray absorptiometry system, and 'low BMD' was defined as T-score <-1.0 SD. The prevalence of 'low BMD' was compared between obese and nonobese (body mass index < 25 kg/m2) groups for both sexes, and the relation of low BMD and free T4 quartiles was explored by multiple logistic regression. Results: The general prevalence of 'low BMD' was 12.3% for male patients aged over 50 (15.5% in the nonobese group and 8.0% in the obese group) and 49.8% for postmenopausal females (56.7% in the nonobese group and 48.9% in the obese group). After adjustment in multiple linear regression, free T4 level remained significantly related to decreased BMD in nonobese male subgroup. Multiple logistic regression revealed that BMD of the highest free T4 quartile (1.12-1.48 ng/dL) decreased significantly than other three quartiles after adjusting for confounding factors including age, body mass index, serum calcium and creatinine level, fasting glucose, alkaline phosphatase, glycosylated hemoglobin, total cholesterol, and smoking history (OR = 2.724, 95% CI = 1.085-6.840, p = 0.033). No significant relation was found in obese male or postmenopausal female groups. Conclusion: High-normal free T4 is a potential independent risk factor for 'low BMD' in nonobese male T2DM patients aged over 50. Close attention should be paid to thyroid function profile, even within normal range, in nonobese men with underlying higher fracture risks on diabetes status.

Controllability of the Conductive Filament in Porous SiOx Memristors by Humidity-Mediated Silver Ion Migration.

Oxide-based memristors composed of Ag/porous SiOx/Si stacks are fabricated using different etching time durations between 0 and 90 s, and the memristive properties are analyzed in the relative humidity (RH) range of 30-60%. The combination of humidity and porous structure provides binding sites to control silver filament formation with a confined nanoscale channel. The memristive properties of devices show high on/off ratios up to 108 and a dispersion coefficient of 0.1% of the high resistance state (CHRS) when the RH increases to 60%. Humidity-mediated silver ion migration in the porous SiOx memristors is investigated, and the mechanism leading to the synergistic effects between the porous structure and environmental humidity is elucidated. The artificial neural network constructed theoretically shows that the recognition rate increases from 60.9 to 85.29% in the RH range of 30-60%. The results and theoretical understanding provide insights into the design and optimization of oxide-based memristors in neuromorphic computing applications.

CLINICAL CHARACTERISTICS AND PREDICTORS OF MORTALITY DIFFER BETWEEN PULMONARY AND ABDOMINAL SEPSIS.

ABSTRACT: Background: Pulmonary sepsis and abdominal sepsis have pathophysiologically distinct phenotypes. This study aimed to compare their clinical characteristics and predictors of mortality. Methods: In this multicenter retrospective trial, 1,359 adult patients who fulfilled the Sepsis-3 criteria were enrolled and classified into the pulmonary sepsis or abdominal sepsis groups. Plasma presepsin was measured, and the scores of Acute Physiology and Chronic Health Evaluation (APACHE) II, Mortality in Emergency Department Sepsis (MEDS), and Simplified Acute Physiology Score (SAPS) II were calculated at enrollment. Data on 28-day mortality were collected for all patients. Results: Compared with patients with abdominal sepsis (n = 464), patients with pulmonary sepsis (n = 895) had higher 28-day mortality rate, illness severity scores, incidence of shock and acute kidney injury, and hospitalization costs. Lactate level and APACHE II and MEDS scores were independently associated with 28-day mortality in both sepsis types. Independent predictors of 28-day mortality included Pa o2 /F io2 ratio (hazard ratio [HR], 0.998; P < 0.001) and acute kidney injury (HR, 1.312; P = 0.039) in pulmonary sepsis, and SAPS II (HR, 1.037; P = 0.017) in abdominal sepsis. A model that combined APACHE II score, lactate, and MEDS score or SAPS II score had the best area under the receiver operating characteristic curve in predicting mortality in patients with pulmonary sepsis or abdominal sepsis, respectively. Interaction term analysis confirmed the association between 28-day mortality and lactate, APACHE II score, MEDS score, SAPS II score, and shock according to the sepsis subgroups. The mortality of patients with pulmonary sepsis was higher than that of patients with abdominal sepsis among patients without shock (32.9% vs. 8.8%; P < 0.001) but not among patients with shock (63.7 vs. 48.4%; P = 0.118). Conclusions: Patients with pulmonary sepsis had higher 28-day mortality than patients with abdominal sepsis. The study identified sepsis subgroup-specific mortality predictors. Shock had a larger effect on mortality in patients with abdominal sepsis than in those with pulmonary sepsis.

A Re-Configurable Body Channel Transceiver Towards Wearable and Flexible Biomedical Sensor Networks.

Body channel communication (BCC) has become a promising candidate in wireless body area networks (WBAN) due to its advantages in energy efficiency and security. However, BCC transceivers face two challenges: diverse application requirements and varying channel conditions. To overcome these challenges, this article proposes a re-configurable architecture for BCC transceivers (TRXs), whose key parameters and communication protocols can be software-defined (SD) according to the requirements. In the proposed TRX, the programmable direct-sampling receiver (RX) is a combination of a programmable low-noise amplifier (LNA) and a fast-convergent successive approaching register analog-to-digital converter (SAR ADC), to achieve simple but energy-efficient data reception. The programmable digital transmitter (TX) is essentially implemented by a 2-bit DAC array to transmit either wide-band carrier-free signals like 4-level pulse amplitude modulation (PAM-4) or non-return-to-zero (NRZ) or narrow-band carrier-based signals like on-off keying (OOK) or frequency shift keying (FSK). The proposed BCC TRX is fabricated in a 180-nm CMOS process. Through an in-vivo experiment, it achieves up to 10-Mbps data rate and 119.2 pJ/bit energy efficiency. Moreover, the TRX is able to communicate under long-distance (1.5 m) and body-shielding conditions by switching its protocols, which shows the potential to be deployed in all categories of WBAN applications.

Optimal antiplatelet therapy for patients after antiplatelet therapy induced gastrointestinal bleeding: timing.

Adjusting antiplatelet strategies after antiplatelet-associated gastrointestinal bleeding (GIB) is a complex clinical challenge. To assess the risk of outcomes at different times of resumption of antiplatelet therapy in an attempt to find the optimal time to resume therapy. The study analyzed consecutive patients with antiplatelet-associated GIB from Beijing Friendship Hospital Information System between October 2019 and June 2022. The primary outcomes were recurrent bleeding, major adverse cardiovascular and cerebrovascular events (MACE), and all-cause death. Multivariate-adjusted Cox proportional hazards models were used to evaluate the risks of these outcomes. The receiver operating characteristic curve was used to find the optimal time to resume treatment. Of the 617 patients with GIB after antiplatelet therapy successfully followed up, the median follow-up was 246 (interquartile range: 120-466) days, most patients (87.36%) interrupted therapy after GIB and 45.22% resumed within 90 days, of which 35.13% resumed within 7 days and 64.87% resumed after 7 days. Resumption therapy had a low risk of recurrent bleeding (uninterrupted as a reference: HR 0.32, 95% CI 0.15-0.67, p = 0.003), MACE (no resumption as a reference: HR 0.66, 95% CI 0.45-0.98, p = 0.037), and all-cause death (no resumption as a reference: HR 0.18, 95% CI 0.08-0.40, p < 0.001). And resuming therapy within 7 days had a lower risk of MACE (HR 0.18, 95% CI 0.08-0.44, p < 0.001) than after 7 days without a significantly higher risk of re-bleeding. The optimal time point for resuming therapy in this study was 8.5 days. Resuming antiplatelet therapy after GIB provides better clinical benefits compared to discontinued and uninterrupted therapy, especially compared with resuming after 7 days, resuming within 7 days is associated with a lower risk of MACE and a less significant increased risk of recurrent bleeding, leading to a higher net clinical benefit. China Clinical Trial Registration: ChiCTR2200064063.

Predictive value of presepsin and acylcarnitines for severity and biliary drainage in acute cholangitis.

BACKGROUND: Bacteremia, which is a major cause of mortality in patients with acute cholangitis, induces hyperactive immune response and mitochondrial dysfunction. Presepsin is responsible for pathogen recognition by innate immunity. Acylcarnitines are established mitochondrial biomarkers. AIM: To clarify the early predictive value of presepsin and acylcarnitines as biomarkers of severity of acute cholangitis and the need for biliary drainage. METHODS: Of 280 patients with acute cholangitis were included and the severity was stratified according to the Tokyo Guidelines 2018. Blood presepsin and plasma acylcarnitines were tested at enrollment by chemiluminescent enzyme immunoassay and ultra-high-performance liquid chromatography-mass spectrometry, respectively. RESULTS: The concentrations of presepsin, procalcitonin, short- and medium-chain acylcarnitines increased, while long-chain acylcarnitines decreased with the severity of acute cholangitis. The areas under the receiver operating characteristic curves (AUC) of presepsin for diagnosing moderate/severe and severe cholangitis (0.823 and 0.801, respectively) were greater than those of conventional markers. The combination of presepsin, direct bilirubin, alanine aminotransferase, temperature, and butyryl-L-carnitine showed good predictive ability for biliary drainage (AUC: 0.723). Presepsin, procalcitonin, acetyl-L-carnitine, hydroxydodecenoyl-L-carnitine, and temperature were independent predictors of bloodstream infection. After adjusting for severity classification, acetyl-L-carnitine was the only acylcarnitine independently associated with 28-d mortality (hazard ratio 14.396; P < 0.001) (AUC: 0.880). Presepsin concentration showed positive correlation with direct bilirubin or acetyl-L-carnitine. CONCLUSION: Presepsin could serve as a specific biomarker to predict the severity of acute cholangitis and need for biliary drainage. Acetyl-L-carnitine is a potential prognostic factor for patients with acute cholangitis. Innate immune response was associated with mitochondrial metabolic dysfunction in acute cholangitis.

Atrial Fibrillation (AFIB) in the ICU: Incidence, Risk Factors, and Outcomes: The International AFIB-ICU Cohort Study.

OBJECTIVES: To assess the incidence, risk factors, and outcomes of atrial fibrillation (AF) in the ICU and to describe current practice in the management of AF. DESIGN: Multicenter, prospective, inception cohort study. SETTING: Forty-four ICUs in 12 countries in four geographical regions. SUBJECTS: Adult, acutely admitted ICU patients without a history of persistent/permanent AF or recent cardiac surgery were enrolled; inception periods were from October 2020 to June 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We included 1,423 ICU patients and analyzed 1,415 (99.4%), among whom 221 patients had 539 episodes of AF. Most (59%) episodes were diagnosed with continuous electrocardiogram monitoring. The incidence of AF was 15.6% (95% CI, 13.8-17.6), of which newly developed AF was 13.3% (11.5-15.1). A history of arterial hypertension, paroxysmal AF, sepsis, or high disease severity at ICU admission was associated with AF. Used interventions to manage AF were fluid bolus 19% (95% CI 16-23), magnesium 16% (13-20), potassium 15% (12-19), amiodarone 51% (47-55), beta-1 selective blockers 34% (30-38), calcium channel blockers 4% (2-6), digoxin 16% (12-19), and direct current cardioversion in 4% (2-6). Patients with AF had more ischemic, thromboembolic (13.6% vs 7.9%), and severe bleeding events (5.9% vs 2.1%), and higher mortality (41.2% vs 25.2%) than those without AF. The adjusted cause-specific hazard ratio for 90-day mortality by AF was 1.38 (95% CI, 0.95-1.99). CONCLUSIONS: In ICU patients, AF occurred in one of six and was associated with different conditions. AF was associated with worse outcomes while not statistically significantly associated with 90-day mortality in the adjusted analyses. We observed variations in the diagnostic and management strategies for AF.

A 5.3 pJ/Spike CMOS Neural Array Employing Time-Modulated Axon-Sharing and Background Mismatch Calibration Techniques.

Inspired by the human brain, spiking neuron networks are promising to realize energy-efficient and low-latency neuromorphic computing. However, even state-of-the-art silicon neurons are orders of magnitude worse than biological neurons in terms of area and power consumption due to the limitations. Moreover, limited routing in typical CMOS processes is another challenge for realizing the fully-parallel high-throughput synapse connections compared to biological synapses. This paper presents an SNN circuit that utilizes resource-sharing techniques to address the two challenges. Firstly, a comparator sharing neuron circuit with a background calibration technique is proposed to shrink the size of a single neuron without performance degradation. Secondly, a time-modulated axon-sharing synapse system is proposed to realize a fully-parallel connection with limited hardware overhead. To validate the proposed approaches, a CMOS neuron array is designed and fabricated under a 55-nm process. It consists of 48 LIF neurons with 3125 neurons/mm 2 area density, power consumption of 5.3 pJ/spike, and equivalent 2304 fully parallel synapses providing a unit throughput of 5500 events/s/neuron. It proves the proposed approaches are promising to realize a high-throughput high-efficiency SNN with CMOS technology.

4-Octyl itaconate attenuates glycemic deterioration by regulating macrophage polarization in mouse models of type 1 diabetes.

BACKGROUND: Pancreatic beta cell dysfunction and activated macrophage infiltration are early features in type 1 diabetes pathogenesis. A tricarboxylic acid cycle metabolite that can strongly activate NF-E2-related factor 2 (Nrf2) in macrophages, itaconate is important in a series of inflammatory-associated diseases via anti-inflammatory and antioxidant properties. However, its role in type 1 diabetes is unclear. We used 4-octyl itaconate (OI), the cell-permeable itaconate derivate, to explore its preventative and therapeutic effects in mouse models of type 1 diabetes and the potential mechanism of macrophage phenotype reprogramming. METHODS: The mouse models of streptozotocin (STZ)-induced type 1 diabetes and spontaneous autoimmune diabetes were used to evaluate the preventative and therapeutic effects of OI, which were performed by measuring blood glucose, insulin level, pro- and anti-inflammatory cytokine secretion, histopathology examination, flow cytometry, and islet proteomics. The protective effect and mechanism of OI were examined via peritoneal macrophages isolated from STZ-induced diabetic mice and co-cultured MIN6 cells with OI-pre-treated inflammatory macrophages in vitro. Moreover, the inflammatory status of peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients was evaluated after OI treatment. RESULTS: OI ameliorated glycemic deterioration, increased systemic insulin level, and improved glucose metabolism in STZ-induced diabetic mice and non-obese diabetic (NOD) mice. OI intervention significantly restored the islet insulitis and beta cell function. OI did not alter the macrophage count but significantly downregulated the proportion of M1 macrophages. Additionally, OI significantly inhibited MAPK activation in macrophages to attenuate the macrophage inflammatory response, eventually improving beta cell dysfunction in vitro. Furthermore, we detected higher IL-1ß production upon lipopolysaccharide stimulation in the PBMCs from type 1 diabetes patients, which was attenuated by OI treatment. CONCLUSIONS: These results provided the first evidence to date that OI can prevent the progression of glycemic deterioration, excessive inflammation, and beta cell dysfunction predominantly mediated by restricting macrophage M1 polarization in mouse models of type 1 diabetes.

Novel tryptanthrin derivatives with benzenesulfonamide substituents: Design, synthesis, and anti-inflammatory evaluation.

Herein, two series of tryptanthrin derivatives with benzenesulfonamide substituents were designed and synthesized to discover novel anti-inflammatory agents. The anti-inflammatory activities of all derivatives were screened by evaluating their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells. Among them, compound 8j exhibited the best NO inhibitory activity (IC50 = 1.25 ± 0.21 µM), with no obvious toxicity. Further evaluation showed that 8j could also significantly reduce the levels of pro-inflammatory cytokines interleukin-1ß (IL-1ß, IC50 = 8.48 ± 0.23 µM) and tumor necrosis factor-α (TNF-α, IC50 = 11.53 ± 0.35 µM) and downregulate the LPS-induced expression of iNOS and COX-2. Reverse docking of 8j suggested p38α as the molecular target, which is a well-known crucial player in the p38 MAPK signaling pathway that controls the transcription of pro-inflammatory mediators. Cellular thermal shift assay showed that 8j efficiently stabilized p38α in LPS-treated RAW264.7 cells. Western blot showed that inflammatory response was inhibited by 8j through inhibiting the phosphorylation of p38α and MK2 in the p38 MAPK signaling pathway. Finally, In vivo studies showed that 8j could significantly ameliorate the degree of foot swelling and knee joint pathology in adjuvant-induced arthritis (AIA) rats and reduce levels of TNF-α and IL-1ß in serum, achieving the effect of protecting synovial tissue and ameliorating arthritis. These findings suggested that 8j may be a promising compound for further development of anti-inflammatory agents.

Subject-wise model generalization through pooling and patching for regression: Application on non-invasive systolic blood pressure estimation.

BACKGROUND: Subject-wise modeling using machine learning is useful in many applications requiring low error and complexity, such as wearable medical devices. However, regression accuracy depends highly on the data available to train the model and the model's generalization ability. Adversely, the prediction error may increase severely if unknown data patterns test the model; such a model is known to be overfitted. In medicine-related applications, such as Non-Invasive Blood Pressure (NIBP) estimation, the high error renders the estimation model useless and dangerous. METHODS: This paper presents a novel algorithm to handle overfitting by editing the training data to achieve generalization for subject-wise models. The pooling and patching (PaP) algorithms use a relatively short record segment of a subject as a Key-Segment (KS) to search through a larger dataset for similar subjects. Then samples taken from the matched subjects' pool records are used to patch the original subject's KS. Due to the significance of systolic blood pressure (SBP) and the complexity of its variability, non-invasive estimation of SBP from electrocardiography (ECG) and photoplethysmography (PPG) is introduced as an application to assess the algorithm. The study was performed on 2051 subjects with a wide range of age, height, weight, length, and health status. The subjects' records were taken from a large public dataset, VitalDB, which is acquired from subjects undergoing different surgeries. Finally, all the results are obtained without using other model generalization techniques. RESULTS: The generalization effect of the proposed algorithm, PaP, significantly outperformed cross-validation, which is widely used in regression model generalization. Moreover, the testing results show that a KS of 200 to 2000 samples is sufficient for providing high accuracy for much longer testing data of about 12000 to 24000 samples long, which is less than %10 of the record length on average. Furthermore, compared to other works based on the same dataset, PaP provides a significantly lower mean error of -0.75 ± 5.51 mmHg, with a small training data portion of 15% over 2051 subjects.

Dynamic blood presepsin levels are associated with severity and outcome of acute pancreatitis: A prospective cohort study.

BACKGROUND: Acute pancreatitis (AP) is an inflammatory disorder of the pancreas with an unpredictable course of illness. A major challenge of AP is the early identification of patients at high-risk for organ failure and death. However, scoring systems are complicated and time consuming, and the predictive values for the clinical course are vague. AIM: To determine whether the dynamic changes in presepsin levels can be used to evaluate the severity of disease and outcome of AP. METHODS: In this multicentric cohort study, 133 patients with AP were included. Clinical severity was dynamically evaluated using the 2012 revised Atlanta Classification. Blood presepsin levels were measured at days 1, 3, 5 and 7 after admission by chemiluminescent enzyme immunoassay. RESULTS: The median concentration of presepsin increased and the clearance rate of presepsin decreased with disease severity and organ failure in AP patients. The presepsin levels on days 3, 5 and 7 were independent predictors of moderately severe and severe AP with time-specific area under the curve (AUC) values of 0.827, 0.848 and 0.867, respectively. The presepsin levels positively correlated with bedside index of severity in AP, Ranson, acute physiology and chronic health evaluation II, computed tomography severity index and Marshall scores. Presepsin levels on days 3, 5 and 7 were independent predictors of 28-d mortality of AP patients with AUC values of 0.781, 0.846 and 0.843, respectively. CONCLUSION: Blood presepsin levels within 7 d of admission were associated with and may be useful to dynamically predict the severity of disease course and 28-d mortality in AP patients.