NK-cell-elicited gasdermin-D-dependent hepatocyte pyroptosis induces neutrophil extracellular traps that facilitate HBV-related acute-on-chronic liver failure.

BACKGROUND AND AIMS: HBV infection is a major etiology of acute-on-chronic liver failure (ACLF). At present, the pattern and regulation of hepatocyte death during HBV-ACLF progression are still undefined. Evaluating the mode of cell death and its inducers will provide new insights for developing therapeutic strategies targeting cell death. In this study, we aimed to elucidate whether and how immune landscapes trigger hepatocyte death and lead to the progression of HBV-related ACLF. APPROACH AND RESULTS: We identified that pyroptosis represented the main cell death pattern in the liver of patients with HBV-related ACLF. Deficiency of MHC-I in HBV-reactivated hepatocytes activated cytotoxic NK cells, which in turn operated in a perforin/granzyme-dependent manner to trigger GSDMD/caspase-8-dependent pyroptosis of hepatocytes. Neutrophils selectively accumulated in the pyroptotic liver, and HMGB1 derived from the pyroptotic liver constituted an important factor triggering the generation of pathogenic extracellular traps in neutrophils (NETs). Clinically, elevated plasma levels of myeloperoxidase-DNA complexes were a promising prognostic biomarker for HBV-related ACLF. More importantly, targeting GSDMD pyroptosis-HMGB1 release in the liver abrogates NETs that intercept the development of HBV-related ACLF. CONCLUSIONS: Studying the mechanisms that selectively modulate GSDMD-dependent pyroptosis, as well as its immune landscapes, will provide a novel strategy for restoring the liver function of patients with HBV-related ACLF.

Dampened motivation in schizophrenia: evidence from a novel effort-based decision-making task in social scenarios.

Apathy represents a significant manifestation of negative symptoms within individuals diagnosed with schizophrenia (SCZ) and exerts a profound impact on their social relationships. However, the specific implications of this motivational deficit in social scenarios have yet to be fully elucidated. The present study aimed to examine effort-based decision-making in social scenarios and its relation to apathy symptoms in SCZ patients. We initially recruited a group of 50 healthy participants (16 males) to assess the validity of the paradigm. Subsequently, we recruited 45 individuals diagnosed with SCZ (24 males) and 49 demographically-matched healthy controls (HC, 25 males) for the main study. The Mock Job Interview Task was developed to measure effort-based decision-making in social scenarios. The proportion of hard-task choice and a range of subjective ratings were obtained to examine potential between-group differences. SCZ patients were less likely than HC to choose the hard task with strict interviewers, and this group difference was significant when the hard-task reward value was medium and high. More severe apathy symptoms were significantly correlated with an overall reduced likelihood of making a hard-task choice. When dividing the jobs into two categories based on the levels of social engagement needed, SCZ patients were less willing to expend effort to pursue a potential offer for jobs requiring higher social engagement. Our findings indicated impaired effort-based decision-making in SCZ can be generalized from the monetary/nonsocial to a more ecologically social dimension. Our findings affirm the critical role of aberrant effort allocation on negative symptoms, and may facilitate the development of targeted clinical interventions.

Functional Outcomes after Abdominal Surgery in Older Adults - How concerned are we about this?

Amidst trends of a rapidly ageing population with better surgical outcomes for geriatric patients, it is imperative to consider outcome measures beyond mortality and morbidity rates. In fact, the preservation of one's postoperative function has been cited as a key priority for older adults and is a crucial determinant of postoperative independence and survival. This review aims to examine the prevalence of perioperative function reporting amongst older surgical patients undergoing elective major abdominal surgery for cancer. We systematically reviewed studies from inception to December 2023 for studies which focused on the outcomes of older surgical patients undergoing elective major abdominal surgery for cancer. Relevant citations were screened (title, abstract and full article review) based on the inclusion and exclusion criteria. 103 studies were included, of which only 31 studies consisting of 20885 participants reported perioperative function. While the nominal number of studies which report perioperative function has been on a steady rise since 2018, the proportion of studies which do so remains low. Postoperative function is three times less likely to be reported than preoperative function, suggesting that functional recovery is not sufficiently assessed. This suggests that there is still a poor uptake of functional recovery as an outcome measure amongst surgeons, and any increase in perioperative function reporting is likely due to the increased administration of frailty assessments. These findings should urge greater efforts in quantifying and enabling functional recovery to improve the clinical outcomes and quality of care for older surgical patients.

The small-molecule drug homoharringtonine targets HSF1 to suppress pancreatic cancer progression.

Heat shock factor 1 (HSF1), an essential transcription factor for stress response, is exploited by various tumors to facilitate their initiation, progression, invasion, and migration. Amplification of HSF1 is widely regarded as an indicator in predicting cancer severity, the likelihood of treatment failure and reduced patient survival. Notably, HSF1 is markedly amplified in 40% of pancreatic cancer (PC), which typically have limited treatment options. HSF1 has been proven to be a promising therapeutic target for multiple cancers. However, a direct small molecule HSF1 inhibitor with sufficient bioactivity and reliable safety has not been developed clinically. In this study, we successfully established a high-throughput screening system utilizing luciferase reporter assay specifically designed for HSF1, which leads to the discovery of a potent small molecule inhibitor targeting HSF1. Homoharringtonine (HHT) selectively inhibited PC cell viability with high HSF1 expression and induced a markedly stronger tumor regression effect in the subcutaneous xenograft model than the comparator drug KRIBB11, known for its direct action on HSF1. Moreover, HHT shows promise in countering the resistance encountered with HSP90 inhibitors, which have been observed to increase heat shock response intensity in clinical trials. Mechanistically, HHT directly bound to HSF1, suppressing its expression and thereby inhibiting transcription of HSF1 target genes. In conclusion, our work presents a preclinical discovery and validation for HHT as a HSF1 inhibitor for PC treatment.

Differences in vascular endothelial function and serum proteome between obese people with phlegm-dampness constitution and balanced constitution.

OBJECTIVE: To evaluate the extent of vascular endothelial dysfunction and preliminary identify serum protein biomarkers associated with obese individuals at risk for cardiovascular disease (CVD). METHODS: Fifteen obese volunteers with the phlegm-dampness constitution or balanced constitution were recruited for this study respectively. The clinical baseline data was collected, and the vascular endothelial function was evaluated using the EndoPATTM. Blood samples were collected for the serum proteome analysis. The differences in the serum protein expression levels between the two groups were detected and the protein interaction network analysis, correlation analysis, receiver operating characteristic (ROC) curve analysis, and random forest model investigation were conducted. RESULTS: There were no statistical differences found in the baseline data. For vascular endothelial function, the reactive hyperemia index (RHI) of the phlegm-dampness constitution obese group was significantly lower than that of the balanced constitution obese group (1.46 ± 0.30 vs 2.82 ± 0.78, P < 0.0001), indicating vascular endothelial dysfunction. There are 66 differentially expressed serum proteins between the two groups. apolipoprotein A2 (ApoA2), angiotensin-converting enzyme 2 (ACE-2), interleukin-33 (IL-33), and forkhead box P3 (FoxP3) showed significant differences and area under curve values of their ROC curves were greater than 0.7 and correlated significantly with RHI. CONCLUSION: Vascular endothelial dysfunction was present in the phlegm-dampness constitution obese group. Thus, alterations in the expression levels of key serum proteins, including ApoA2, ACE-2, IL-33, and FoxP3 could serve as potential biomarkers in the obese population at risk of CVD.

Nickel-catalyzed γ-alkylation of cyclopropyl ketones with unactivated primary alkyl chlorides: balancing reactivity and selectivity via halide exchange.

A novel method was developed for synthesizing γ-alkyl ketones via nickel-catalyzed cross-electrophile coupling of cyclopropyl ketones and non-activated primary alkyl chlorides. High reactivity and selectivity can be achieved with sodium iodide as a crucial cocatalyst that generates a low concentration of alkyl iodide via halide exchange, thus avoiding the formation of alkyl dimers. This reaction possessed excellent regioselectivity and high step economy circumventing in situ or pregenerated organometallics.

Selection of lubricant type and concentration for orodispersible tablets.

Lubricants are essential for most tablet formulations as they assist powder flow, prevent adhesion to tableting tools and facilitate tablet ejection. Magnesium stearate (MgSt) is an effective lubricant but may compromise tablet strength and disintegratability. In the design of orodispersible tablets, tablet strength and disintegratability are critical attributes of the dosage form. Hence, this study aimed to conduct an in-depth comparative study of MgSt with alternative lubricants, namely sodium lauryl sulphate (SLS), stearic acid (SA) and hydrogenated castor oil (HCO), for their effects on the tableting process as well as tablet properties. Powder blends were prepared with lactose, sodium starch glycolate or crospovidone as the disintegrant, and a lubricant at different concentrations. Angle of repose was determined for the mixtures. Comparative evaluation was carried out based on the ejection force, tensile strength, liquid penetration and disintegratability of the tablets produced. As the lubricant concentration increased, powder flow and tablet ejection improved. The lubrication efficiency generally decreased as follows: MgSt > HCO > SA > SLS. Despite its superior lubrication efficacy, MgSt is the only lubricant of four evaluated that reduced tablet tensile strength. Tablet disintegration time was strongly determined by tensile strength and liquid penetration, which were in turn affected by the lubricant type and concentration. All the above factors should be taken into consideration when deciding the type and concentration of lubricant for an orodispersible tablet formulation.

Correction: Nickel-catalyzed γ-alkylation of cyclopropyl ketones with unactivated primary alkyl chlorides: balancing reactivity and selectivity via halide exchange.

[This corrects the article DOI: 10.1039/D4RA02616K.].

The network characteristics in schizophrenia with prominent negative symptoms: a multimodal fusion study.

Previous studies on putative neural mechanisms of negative symptoms in schizophrenia mainly used single modal imaging data, and seldom utilized schizophrenia patients with prominent negative symptoms (PNS).This study adopted the multimodal fusion method and recruited a homogeneous sample with PNS. We aimed to identify negative symptoms-related structural and functional neural correlates of schizophrenia. Structural magnetic resonance imaging (sMRI) and resting-state functional MRI (rs-fMRI) were performed in 31 schizophrenia patients with PNS and 33 demographically matched healthy controls.Compared to healthy controls, schizophrenia patients with PNS exhibited significantly altered functional activations in the default mode network (DMN) and had structural gray matter volume (GMV) alterations in the cerebello-thalamo-cortical network. Correlational analyses showed that negative symptoms severity was significantly correlated with the cerebello-thalamo-cortical structural network, but not with the DMN network in schizophrenia patients with PNS.Our findings highlight the important role of the cerebello-thalamo-cortical structural network underpinning the neuropathology of negative symptoms in schizophrenia. Future research should recruit a large sample and schizophrenia patients without PNS, and apply adjustments for multiple comparison, to verify our preliminary findings.

Range adaptive value representations in schizophrenia and major depression.

Anhedonia and amotivation are core symptoms of schizophrenia (SCZ) and major depressive disorder (MDD). Reward processing involves constructing and contrasting the representations for expected value (EV) and outcome value (OV) of a given stimulus, a phenomenon termed range adaptation. Impaired range adaptation can lead to anhedonia and amotivation. This study aimed to examine range adaptation in SCZ patients and MDD patients. Fifty SCZ, 46 MDD patients and 56 controls completed the Effort-based Pleasure Experience Task to measure EV and OV adaptation. SCZ and MDD patients showed altered range adaptation, albeit in different patterns. SCZ patients exhibited over-adaptation to OV and reduced adaptation to EV. By contrast, MDD patients exhibited diminished OV adaptation but intact EV adaptation. Both OV and EV adaptation were correlated with anhedonia and amotivation in SCZ and MDD. Taken together, our findings suggest that range adaptation is altered in both SCZ and MDD patients. Associations of OV and EV adaptation with anhedonia and amotivation were consistently found in SCZ and MDD patients. Impaired range adaptation in SCZ and MDD patients may be putative neural mechanisms and potential intervention targets for anhedonia and amotivation.

A Transdiagnostic Network Analysis of Childhood Trauma and Psychopathology.

BACKGROUND AND HYPOTHESIS: Psychiatric comorbidities suggest that symptoms overlap across different diagnoses; the transdiagnostic network approach is valuable for studying psychopathology. Childhood trauma is a common transdiagnostic risk factor for psychiatric disorders, but the complex relationship between childhood trauma and psychopathology has seldom been investigated using a large cross-sectional transdiagnostic sample. STUDY DESIGN: This study recruited 869 patients with different diagnoses, including 418 schizophrenia, 215 bipolar disorder, and 236 major depressive disorder. Participants completed psychiatric interviews and self-report questionnaires. We constructed dimension- and item-level Least Absolute Shrinkage and Selection Operator-based (LASSO) networks to explore the relationship between childhood trauma, psychopathology, and duration of illness. Moreover, we constructed directed acyclic graphs (DAGs) to tentatively clarify the potential directions of associations among these variables. Network Comparison Tests (NCTs) were conducted for different diagnostic groups and gender-stratified groups. STUDY RESULTS: The transdiagnostic LASSO networks showed that different types of childhood trauma exerted distinct impacts on various psychopathological dimensions. Emotional abuse was linked to depressive symptoms, physical abuse to excited symptoms, sexual abuse to positive and disorganized symptoms, emotional neglect to depressive symptoms and motivation and pleasure (MAP) deficits factor of negative symptoms, and physical neglect to MAP factor. The DAG findings generally concurred with the LASSO network. The NCT showed comparable networks. CONCLUSIONS: Our findings suggest that childhood trauma is significantly associated with the development of psychopathology across different diagnostic groups. The affective pathway model suggests that early identification and tailored interventions would be needed for people with a history of childhood trauma.

Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer.

Emotional distress (ED), commonly characterized by symptoms of depression and/or anxiety, is prevalent in patients with cancer. Preclinical studies suggest that ED can impair antitumor immune responses, but few clinical studies have explored its relationship with response to immune checkpoint inhibitors (ICIs). Here we report results from cohort 1 of the prospective observational STRESS-LUNG study, which investigated the association between ED and clinical efficacy of first-line treatment of ICIs in patients with advanced non-small-cell lung cancer. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. The study included 227 patients with 111 (48.9%) exhibiting ED who presented depression (Patient Health Questionnaire-9 score ≥5) and/or anxiety (Generalized Anxiety Disorder 7-item score ≥5) symptoms at baseline. On the primary endpoint analysis, patients with baseline ED exhibited a significantly shorter median progression-free survival compared with those without ED (7.9 months versus 15.5 months, hazard ratio 1.73, 95% confidence interval 1.23 to 2.43, P = 0.002). On the secondary endpoint analysis, ED was associated with lower objective response rate (46.8% versus 62.1%, odds ratio 0.54, P = 0.022), reduced 2-year overall survival rate of 46.5% versus 64.9% (hazard ratio for death 1.82, 95% confidence interval 1.12 to 2.97, P = 0.016) and detriments in quality of life. The exploratory analysis indicated that the ED group showed elevated blood cortisol levels, which was associated with adverse survival outcomes. This study suggests that there is an association between ED and worse clinical outcomes in patients with advanced non-small-cell lung cancer treated with ICIs, highlighting the potential significance of addressing ED in cancer management. ClinicalTrials.gov registration: NCT05477979 .

General limit to thermodynamic annealing performance.

Annealing has proven highly successful in finding minima in a cost landscape. Yet, depending on the landscape, systems often converge towards local minima rather than global ones. In this Letter, we analyze the conditions for which annealing is approximately successful in finite time. We connect annealing to stochastic thermodynamics to derive a general bound on the distance between the system state at the end of the annealing and the ground state of the landscape. This distance depends on the amount of state updates of the system and the accumulation of nonequilibrium energy, two protocol and energy landscape-dependent quantities which we show are in a trade-off relation. We describe how to bound the two quantities both analytically and physically. This offers a general approach to assess the performance of annealing from accessible parameters, both for simulated and physical implementations.

Bound on annealing performance from stochastic thermodynamics, with application to simulated annealing.

Annealing is the process of gradually lowering the temperature of a system to guide it towards its lowest energy states. In an accompanying paper [Y. Luo et al., Phys. Rev. E 108, L052105 (2023)10.1103/PhysRevE.108.L052105], we derived a general bound on annealing performance by connecting annealing with stochastic thermodynamics tools, including a speed limit on state transformation from entropy production. We here describe the derivation of the general bound in detail. In addition, we analyze the case of simulated annealing with Glauber dynamics in depth. We show how to bound the two case-specific quantities appearing in the bound, namely the activity, a measure of the number of microstate jumps, and the change in relative entropy between the state and the instantaneous thermal state, which is due to temperature variation. We exemplify the arguments by numerical simulations on the Sherrington-Kirkpatrick (SK) model of spin glasses.

Research progress on refractory Tourette syndrome / 中华实用儿科临床杂志

The clinical characteristics and diagnosis and treatment of refractory Tourette syndrome (TS) are gaining more academic attention.Based on the latest research, this article explores the possible mechanisms of refractory TS and reviews the progress in diagnosis and treatment of refractory TS, including strategies for combination therapy, new drug development, traditional Chinese medicine treatment, deep brain stimulation, electroconvulsive therapy, repetitive transcranial magnetic stimulation, and direct current stimulation.

Research progress in ulna impingement syndrome / 沈阳医学院学报

Ulna impingement syndrome is the main cause of wrist ulnar pain.It is caused by repeated impingement between the ulnar bone,triangular fibrocartilage complex,lunate bone and triangular bone,resulting in long-term overload of the ulnar side of wrist,affecting local blood supply and joint lubrication fluid nutrition disorders,and finally causing a series of pathological changes and clinical symptoms of joint degenerative diseases.The main clinical manifestations are pain on the ulnar side of the wrist,which gradually aggravated with repeated strong grasping activities,forearm pronation or ulnar deviation of the wrist.At present,the diagnosis of ulna impingement syndrome mainly depends on the symptoms,physical examination,imaging examination and wrist arthroscopy.Conservative treatment can be selected for ulnar impaction syndrome,but the effect is often poor.Therefore,surgery is still the main treatment.The surgical methods mainly include ulna shortening osteotomy,Wafer,Darrach and Sauvé-Kapandji,and the former two are the most commonly used.This article reviews the progress of diagnosis and treatment of ulna impingement syndrome.

Study progress on monitoring technologies and health effects of air quality in urban rail transit / 环境与职业医学

With the acceleration of urbanization, urban rail transit systems have become one of the most important modes of transportation in modern cities. Urban rail transit systems operate in enclosed or semi-enclosed environments, characterized by poor air circulation and high passenger flow. During the period of high incidence of respiratory infectious diseases in autumn and winter, air quality and pathogenic microorganism monitoring in public places have attracted much attention. This article provided a detailed introduction to air pollutants and their sources related to urban rail transit, including chemical pollutants, such as particulate matter and gaseous pollutants, and microbial aerosols. Based on identified air pollutants related to urban rail transit, this paper reviewed the research progress on air quality monitoring technologies for chemical pollution factors and microbial aerosols. Finally, a summary of the health effects of chemical pollutants and microbial aerosols was provided, along with suggestions for monitoring and improving air quality tailored to the characteristics of urban rail transit systems. Through a review of previous studies, carrying out research on air quality monitoring technologies and associated health effects related to urban rail transit is of great significance and values for air quality management, urban development, and public health.

The application value of multimodal MRI imaging in early neurological deterioration and clinical prognosis prediction of acute ischemic stroke / 中国医师杂志

Objective:To explore the application value of multimodal MRI imaging in early neurological deterioration (END) and clinical prognosis prediction of acute ischemic stroke (AIS).Methods:A total of 200 AIS patients admitted to the Chengde Central Hospital from October 2019 to October 2022 were selected as the study subjects. Based on whether END occurred within 7 days of enrollment, there were 40 cases in the occurrence group and 160 cases in the non occurrence group. The influencing factors of END occurrence in AIS patients and the predictive value of multimodal magnetic resonance imaging (MRI) parameters on END were analyzed; According to the modified Rankin (mRS) score, patients were divided into good prognosis and poor prognosis groups, and the impact of multimodal MRI imaging parameters on the risk of poor prognosis in AIS patients was analyzed.Results:There were statistically significant differences in the apparent diffusion coefficient (ADC), cerebral blood flow (CBF), and their differences before and after thrombolysis in multimodal MRI imaging parameters between the END group and the non END group, as well as in the National Institutes of Health Stroke Scale (NIHSS) score at admission, age, and time from onset to admission (all P<0.05). The difference between ADC and CBF before and after thrombolysis, time from onset to admission, NIHSS score at admission, and age were all independent influencing factors for the occurrence of END in AIS patients (all P<0.05). The area under the curve (AUC) of the combined prediction of the difference between ADC and CBF before and after thrombolysis for the occurrence of END in AIS patients was 0.924, which was higher than that predicted by a single indicator ( P<0.05). The incidence of poor prognosis in patients with END was significantly higher than that in patients without END ( P<0.05). The risk of poor prognosis in AIS patients with a difference of less than <45.83×10 -9 mm 2/s before and after ADC thrombolysis was 3.136 times higher than that in patients with ≥45.83×10 -6 mm 2/s. The risk of poor prognosis in AIS patients with a difference of less than 10.52 ml/(min·100 g) before and after ADC thrombolysis was 2.640 times higher than that in patients with ≥10.52 ml/(min·100 g). Conclusions:Multimodal MRI imaging can be used for END evaluation in AIS patients and can provide reference for clinical prognosis evaluation.

Study on policy texts in the field of medical insurance payment system in China from the perspective of policy tools / 中国卫生政策研究

Objective:To analyze the release and distribution characteristics of Chinese medical insurance payment policies,and to provide reference for future policy formulation in the field of medical insurance payment construction.Methods: Content analysis method was used to construct a two-dimensional framework of "policy goals-policy tools",and text analysis was carried out according to 63 policy documents.Results: A total of 493 policy codes were completed.From the perspective of policy goals,the policy objectives of Chinese medical insurance payment mainly focused on three aspects: improving the payment level,optimizing the medical insurance environment,and standardizing the supervision regulations.From the perspective of policy tools,environmental policy tools are the most used policy tools,followed by supply and demand tools.There is a shortage of financial input and talent training in all policy objectives,so more attention should be paid to demonstration and Category of payment.Conclusion: Our country puts forth effort to build a perfect medical insurance payment system,but should further strengthen policy content supplement,optimize the structure of policy tools,and give full play to the payment ability of medical insurance when pulling the demand of medical insurance payment and driving the supply of medical insurance payment.

Construction and application of a management process for enteral nutrition-associated diarrhea in postoperative esophageal cancer patients / 中华护理杂志

Objective To explore the application effect of enteral nutrition-related diarrhea in postoperative esophageal cancer patients.Methods Based on literature search and expert meeting,a management process for enteral nutrition-associated diarrhea in postoperative esophageal cancer patients was constructed.A convenience sampling method was used to select a total of 68 patients with enteral nutrition-related diarrhea after esophageal cancer surgery admitted to the thoracic surgery department of a tertiary A cancer hospital in Jiangsu Province.Among them,patients admitted from January 2022 to December 2022 were set as an experimental group.The experimental group was implemented the management process for enteral nutrition-associated diarrhea in postoperative esophageal cancer patients.Those admitted from January 2021 to December 2021 were set as a control group with routine nursing.Then,the time of stopping diarrhea,the King's of Stool Chart(KSC-Tr)diarrhea score,and abnormal incidence of nutrition-related indexes,electrolytes abnormalities(low sodium,low potassium,and low calcium)were compared between 2 groups.Results The time of stopping diarrhea,KSC diarrhea score after 3 days of intervention and the time to achieve target feeding volume of the experimental group were lower than those in the control group,and the difference was statistically significant(P＜0.05).There were no significant differences in hemoglobin,albumin,prealbumin after 3 days of intervention,the incidence of electrolyte abnormalities(low sodium,low potassium,and low calcium)after 3 days of intervention,and the BMI index after 7 days of intervention between 2 groups(P＞0.05).Conclusion The management process for enteral nutrition-associated diarrhea in postoperative esophageal cancer patients can reduce the time of diarrhea,improve the severity of diarrhea,and shorten the time to achieve the target feeding,but has no significant change in the incidence of electrolyte abnormalities.