[Development of green pesticides from traditional Chinese medicines based on artificial intelligence and compatibility of traditional Chinese medicines].

The food security of China as a big agricultural country is attracting increasing attention. With the progress in the traditional Chinese medicine industry, Chinese medicinal materials and their preparations have been gradually developed as agents for disease prevention and with antimicrobial and insecticidal functions in agriculture. Promoting pesticide innovation by interdisciplinary integration has become the trend in pesticide research globally. Considering the increasingly important roles of green pesticides from traditional Chinese medicines and artificial intelligence in pest target prediction, this paper proposed an innovative green control strategy in line with the concepts of ecological sustainable development and food security protection. CiteSpace was used for visual analysis of the publications. The results showed that artificial intelligence had been extensively applied in the pesticide field in recent years. This paper explores the application and development of biopesticides for the first time, with focus on the plant-derived pesticides. The thought of traditional Chinese medicine compatibility can be employed to creat a new promosing field: pesticides from traditional Chinese medicine. Moreover, artificial intelligence can be employed to build the formulation system of pesticides from traditional Chinese medicines and the target prediction system of diseases and pests. This study provides new ideas for the future development and market application of biopesticides, aiming to provide more healthy and safe agricultural products for human beings, promote the innovation and development of green pesticides in China, and protect the sustainable development of the environment and ecosystem. This may be the research hotspot and competition point for the green development of the pesticide industry chain in the future.

Xianlian Jiedu Decoction alleviates colorectal cancer by regulating metabolic profiles, intestinal microbiota and metabolites.

BACKGROUND: Xianlian Jiedu Decoction (XLJDD) has been used for the treatment of colorectal cancer (CRC) for several decades because of the prominent efficacy of the prescription. Despite the clear clinical efficacy of XLJDD, the anti-CRC mechanism of action is still unclear. PURPOSE: The inhibitory effect and mechanism of XLJDD on CRC were investigated in the azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mice. METHODS: The AOM/DSS-induced mice model was adopted to evaluate the efficacy after administering the different doses of XLJDD. The therapeutic effects of XLJDD in treating AOM/DSS-induced CRC were investigated through histopathology, immunofluorescence and ELISA analysis methods. In addition, metabolomics profile and 16S rRNA analysis were used to explore the effective mechanisms of XLJDD on CRC. RESULTS: The results stated that the XLJDD reduced the number of tumor growth on the inner wall of the colon and the colorectal weight/length ratio, and suppressed the disease activity index (DAI) score, meanwhile XLJDD also increased body weight, colorectal length, and overall survival rate. The treatment of XLJDD also exhibited the ability to lower the level of inflammatory cytokines in serum and reduce the expression levels of ß-catenin, COX-2, and iNOS protein in colorectal tissue. The findings suggested that XLJDD has anti-inflammatory properties and may provide relief for those suffering from inflammation-related conditions. Mechanistically, XLJDD improved gut microbiota dysbiosis and associated metabolic levels of short chain fatty acids (SCFAs), sphingolipid, and glycerophospholipid. This was achieved by reducing the abundance of Turicibacter, Clostridium_sensu_stricto_1, and the levels of sphinganine, LPCs, and PCs. Additionally, XLJDD increased the abundance of Enterorhabdus and Alistipes probiotics, as well as the content of butyric acid and isovaleric acid. CONCLUSION: The data presented in this article demonstrated that XLJDD can effectively inhibit the occurrence of colon inner wall tumors by reducing the level of inflammation and alleviating intestinal microbial flora imbalance and metabolic disorders. It provides a scientific basis for clinical prevention and treatment of CRC.

[Predictive Value of Peripheral Blood Biomarkers in the Treatment of 
Lung Cancer Patients with Anti PD-1 Immunotherapy].

BACKGROUND: The application of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibodies has greatly improved the clinical outcomes of lung cancer patients. Here, we retrospectively analyzed the efficacy of PD-1 antibody therapy in locally advanced non-surgical or metastatic lung cancer patients, and preliminarily explored the correlation between peripheral blood biomarkers and clinical responses. METHODS: We conducted a single center study that included 61 IIIA-IV lung cancer patients who received PD-1 antibody treatment from March 2020 to December 2021, and collected the medical record data on PD-1 antibody first-line or second-line treatment. The levels of multiple Th1 and Th2 cytokines in the patient's peripheral blood serum, as well as the phenotype of peripheral blood T cells, were detected and analyzed. RESULTS: All the patients completed at least 2 cycles of PD-1 monoclonal antibody treatment. Among them, 42 patients (68.9%) achieved partial response (PR); 7 patients (11.5%) had stable disease (SD); and 12 patients (19.7%) had progressive disease (PD). The levels of peripheral blood interferon gamma (IFN-γ) (P=0.023), tumor necrosis factor α (TNF-α) (P=0.007) and interleukin 5 (IL-5) (P=0.002) before treatment were higher in patients of the disease control rate (DCR) (PR+SD) group than in the PD group. In addition, the decrease in absolute peripheral blood lymphocyte count after PD-1 antibody treatment was associated with disease progression (P=0.023). Moreover, the levels of IL-5 (P=0.0027) and IL-10 (P=0.0208) in the blood serum after immunotherapy were significantly increased compared to baseline. CONCLUSIONS: Peripheral blood serum IFN-γ, TNF-α and IL-5 in lung cancer patients have certain roles in predicting the clinical efficacy of anti-PD-1 therapy. The decrease in absolute peripheral blood lymphocyte count in lung cancer patients is related to disease progression, but large-scale prospective studies are needed to further elucidate the value of these biomarkers.

Predictive value of peripheral blood biomarkers in patients with non-small-cell lung cancer responding to anti-PD-1-based treatment.

BACKGROUND: The introduction of the anti-PD-1 antibody has greatly improved the clinical outcomes of patients with non-small cell lung cancer (NSCLC). In this study, we retrospectively analyzed the efficacy of PD-1 antibody-based therapy in patients with locally advanced inoperable or metastatic NSCLC and reported an association between peripheral blood biomarkers and clinical response in these patients. METHODS: This single-center study included medical record data of patients with NSCLC treated with the PD-1 antibody as a first-line or subsequent line of treatment, either as monotherapy or in combination with chemotherapy. The patients were enrolled from 2020 to 2022. We dynamically evaluated multiple Th1 and Th2 cytokines in the blood serum and analyzed the phenotype of T cells from the peripheral blood to explore the correlation between cytokine levels, T cell phenotypes, and clinical response. RESULTS: A total of 88 patients with stage IIIA-IV NSCLC were enrolled, out of which 60 (68.18%) achieved a partial response (PR), 13 (14.77%) had stable disease (SD), and 15 (17.05%) experienced disease progression (PD). The disease control rate was 82.95%. Our results suggested a significant reduction (P = 0.002, P < 0.005) in lymphocyte absolute counts after treatment in patients with PD. Higher levels of IFN-γ (P = 0.023, P < 0.05), TNF-α (P = 0.00098, P < 0.005), IL-4 (P = 0.0031, P < 0.005), IL-5 (P = 0.0015, P < 0.005), and IL-10 (P = 0.036, P < 0.05) were detected in the peripheral blood before treatment in the PR group compared to the PD group. Moreover, patients with high levels of IL-5, IL-13, IL-4, IL-6, IFN-γ, and TNF-α (> 10 ng/mL) had superior progression-free survival compared to those with low levels (< 10 ng/mL). Furthermore, PD-1 expression on CD8+ T cells was higher in patients who showed a PR than in those who did not show a response (SD + PD; P = 0.042, P < 0.05). CONCLUSIONS: The findings of this study imply that the decrease in absolute blood lymphocyte counts after treatment is correlated with disease progression. Serum cytokine levels may predict the effectiveness and survival rates of anti-PD-1 blockade therapy in patients with NSCLC. In addition, PD-1 expression on CD8+ T cells was positively associated with better clinical response. Our findings highlight the potential of peripheral blood biomarkers to predict the effectiveness of PD-1-targeted treatments in patients with NSCLC. Larger prospective studies are warranted to further clarify the value of these biomarkers.

Assessment of the glymphatic function in children with attention-deficit/hyperactivity disorder.

OBJECTIVES: Whether the alternation of the glymphatic system exists in neurodevelopmental disease still remains unclear. In this study, we investigated structural and functional changes in the glymphatic system in the treatment-naïve attention-deficit/hyperactivity disorder (ADHD) children by quantitatively measuring the Virchow-Robin spaces (VRS) volume and diffusion tensor image-analysis along the perivascular space (DTI-ALPS). METHODS: Forty-seven pediatric ADHD patients and 52 age- and gender-matched typically developing (TD) children were recruited in this prospective study. The VRS volume was calculated using a semi-automated approach in axial T2-weighted images. Diffusivities along the x-, y-, and z-axes in the projection, association, and subcortical neural fiber areas were measured. The ALPS index, a ratio that accentuated water diffusion along the perivascular space, was calculated. The Mann-Whitney U test was used to compare the quantitative parameters; Pearson's correlation was used to analyze the correlation with clinical symptoms. RESULTS: The cerebral VRS volume (mean, 15.514 mL vs. 11.702 mL) and the VRS volume ratio in the ADHD group were larger than those in the TD group (all p < 0.001). The diffusivity along the x-axis in association fiber area and ALPS index were significantly smaller in the ADHD group vs. TD group (mean, 1.40 vs.1.59, p < 0.05 after false discovery rate adjustment). Besides, the ALPS index was related to inattention symptoms of ADHD (r = - 0.323, p < 0.05). CONCLUSIONS: Our study suggests that the glymphatic system alternation may participate in the pathogenesis of ADHD, which may be a new research direction for exploring the mechanisms of psycho-behavioral developmental disorders. Moreover, the VRS volume and ALPS index could be used as the metrics for diagnosing ADHD. CLINICAL RELEVANCE STATEMENT: Considering the potential relevance of the glymphatic system for exploring the mechanisms of attention deficit/hyperactivity, the Virchow-Robin spaces volume and the analysis along the perivascular space index could be used as additional metrics for diagnosing the disorder. KEY POINTS: • Increased Virchow-Robin space volume and decreased analysis along the perivascular space index were found in the treatment-naïve attention-deficit/hyperactivity disorder children. • The results of this study indicate that the glymphatic system alternation may have a valuable role in the pathogenesis of attention-deficit/hyperactivity disorder. • The analysis along the perivascular space index is correlated with inattention symptoms of attention-deficit/hyperactivity disorder children.

Salvianolic acid B and tanshinone IIA synergistically improve early diabetic nephropathy through regulating PI3K/Akt/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic nephropathy (DN) is one of the most common and serious complications of diabetes, which lacks effective treatment. Salviae Miltiorrhizae Radix Et Rhizoma is one of the key compatible traditional Chinese medicine in the prescription for the treatment of DN. Salvianolic acid B and tanshinone IIA are two monomer active components with high content and clear structure in Salvia miltiorrhiza, which can effectively improve early (DN), respectively. AIM OF THE STUDY: To evaluate the compatible effect of salvianolic acid B and tanshinone IIA on early DN rats and elucidate the mechanism. METHODS: Early DN rats were induced by streptozotocin combined with high glucose and high fat diet, and intervened by salvianolic acid B, tanshinone IIA and their combinations. The pathological sections of kidney, liver and biochemical indexes were analyzed. Network pharmacology method was used to predict the possible mechanism. The mechanisms were elucidated by metabolomics, Elisa, and Western blot. RESULTS: Given our analysis, salvianolic acid B and tanshinone IIA can synergistically regulate 24 h UTP, Urea and Scr and improve kidney damage in early DN rats. The metabolic abnormalities of early DN rats were improved by regulating the biosynthesis of saturated fatty acids, glycerol phospholipid metabolism, steroid biosynthesis, alanine, and arachidonic acid. Salvianolic acid B combined with tanshinone IIA at a mass ratio of 13.4:1 can significantly reduce kidney inflammation, up-regulate p-PI3K/PI3K and p-Akt/Akt and down-regulate p-NF-κB/NF-κB, which better than the single-used group and can be reversed by PI3K inhibitor LY294002. CONCLUSION: Salvianolic acid B and tanshinone IIA can synergistically improve glucose and lipid disorders, liver and kidney damage, and resist kidney inflammation in early DN rats, and the mechanism may be related to regulating PI3K/Akt/NF-κB signaling pathway.

Recent advances in neoantigen vaccines for treating non-small cell lung cancer.

The breakthrough of programmed cell death protein 1 (PD-1) blockade therapy has changed the clinical treatment of non-small cell lung cancer (NSCLC) in the past few years. The success of PD-1 blockade therapy has been attributed to high tumor mutation burden and high immunogenicity of lung cancer cells. To further improve the efficacy of NSCLC immunotherapy and overcome the resistance of lung cancer cells to immune checkpoint blockade, new approaches that enhance the active immune response, such as neoantigen vaccines and cellular-based therapies, are urgently required. Neoantigens are considered ideal targets for cancer immunotherapy because of their high immunogenicity and specificity. In this mini review, we first discuss the current advances in neoantigen vaccines for treating cancers and then review the results of preclinical studies and early-phase human clinical trials of neoantigen-based therapies for NSCLC. Finally, we focus on the identification of neoantigens in patients with NSCLC and review the candidate mutations reported by recent studies and our investigations. The review concludes that, in addition to immune checkpoint blockade, approaches targeting neoantigens are promising for improving the efficacy of NSCLC immunotherapy.

Pathology of MRI and second-look ultrasound detected multifocal breast cancer.

INTRODUCTION: Targeted second-look ultrasound (US) is often performed following MRI of the breast to determine if an MRI-detected lesion is visible on US and thus amenable to US-guided biopsy. This study aimed to assess the pathology of lesions detected and biopsied on the second-look US. In particular, for multifocal cancers, whether the pathology of additional lesions detected by second-look US is different to the index lesion. METHODS: Multicentre single-institution retrospective study of 300 consecutive cases of second-look US biopsies from August 2017 to April 2022 was performed, with their histopathology and imaging characteristics recorded. For multifocal cancers, Wilcoxon Signed Ranks Tests were used to compare differences between the index and additional lesions in the histopathology category (i.e., high-risk benign, precursor or malignant) and BRE grade. RESULTS: 69 multifocal cancers were detected. For the purposes of this study, additional lesions were considered more invasive if they were of a higher histopathological category or BRE grade, or demonstrated lymphovascular invasion when the primary lesion did not. 15/69 additional lesions were not seen on the initial mammogram/tomography or ultrasound, seen on subsequent MRI and second look US, and were less invasive than the index lesion. 3/69 additional lesions were more invasive than their index lesions. Wilcoxon Signed Ranks test showed additional lesions were of either similar or lesser invasiveness compared to index lesions (z= -3.207, p = 0.001) in the histopathological category, and the same or lower BRE grade (z= -2.972, p = 0.003). CONCLUSION: In multifocal breast cancers, additional lesions detected on MRI and second-look US have the same or less invasive histopathology compared to the index lesion.

Blueprint to hepatitis B elimination in China: A modelling analysis of clinical strategies.

Background & Aims: Globally, one-third of individuals infected with HBV live in China. Eliminating HBV in China would therefore be paramount in achieving the World Health Organization's (WHO's) targets of viral hepatitis elimination as a worldwide public health threat. Methods: We constructed a dynamic HBV transmission model in China, structured by age and sex. We calibrated the model by HBsAg prevalence, acute HBV incidence, and nationally reported HBV-related cancer mortality. We investigated seven intervention scenarios (A-G) based on assumptions in diagnostic, linkage-to-care, and treatment coverages in achieving the WHO's HBV elimination goals. Results: With the status quo, HBsAg prevalence among children 1-4 years would reduce to 0.09% (95% CI 0.09-0.10%) by 2025; acute HBV incidence would drop to <2/100,000 person-years by 2024, achieving the elimination target of 90% incidence reduction. Nonetheless, China would not achieve a 65% reduction target in HBV-related mortality until 2059 with 9.98 (95% CI 9.27-10.70) million HBV-related deaths occurred by 2100. If China achieves 90% diagnostic and 80% treatment coverages (scenario E), HBV elimination would be achieved 8 years earlier, potentially saving 1.98 (95% CI 1.83-2.12) million lives. With more effective therapies for HBV control in preventing cirrhosis and hepatocellular carcinoma, elimination targets could be achieved in 2048 (scenario F) and 2038 (scenario G), additionally saving 3.59 (95% CI 3.37-3.82) and 5.19 (95% CI 4.83-5.55) million lives, respectively. Conclusions: Eliminating HBV will require interventional strategies to improve diagnostic, linkage-to-care, and treatment coverages. Developing novel therapies will be crucial in further reducing HBV-related mortality and removing HBV as a public health threat. Impact and Implications: This study explores the key developments and optimal intervention strategies needed to achieve WHO hepatitis B elimination targets by 2030 in China. It highlights that China can realise the HBV elimination targets in the incidence by 2025, and by upscaling diagnostic, linkage-to-care, and treatment coverages, up to 2 million lives could potentially be saved from HBV-related deaths.

Shared-care models are highly effective and cost-effective for managing chronic hepatitis B in China: reinterpreting the primary care and specialty divide.

Background: We evaluate the impact and cost-effectiveness of shared primary-specialty chronic hepatitis B (CHB) care models in China. Methods: We constructed a decision-tree Markov model to simulate hepatitis B virus (HBV) disease progression in a cohort of 100,000 CHB individuals aged ≥18 years over their lifetime (aged 80). We evaluated the population impacts and cost-effectiveness in three scenarios: (1) status quo; (2) shared-care model with HBV testing and routine CHB follow-ups in primary care and antiviral treatment initiation in specialty care; and (3) shared-care model with HBV testing, treatment initiation and routine CHB follow-up in primary care and treatment for predetermined conditions in specialty care. We evaluated from a healthcare provider's perspective with 3% discounting rate and a willingness-to-pay (WTP) threshold of 1-time China's GDP. Findings: Compared with status quo, scenario 2 would result in an incremental cost of US$5.79-132.43m but a net gain of 328-16,993 quality-adjusted life years (QALYs) and prevention of 39-1935 HBV-related deaths over cohort's lifetime. Scenario 2 was not cost-effective with a WTP of 1-time GDP per capita, but became cost-effective when treatment initiation rate increased to 70%. In contrast, compared with status quo, secnario 3 would save US$144.59-192.93m in investment and achieve a net gain of 23,814-30,476 QALYs and prevention of 3074-3802 HBV-related deaths. Improving HBV antiviral treatment initiation among eligible CHB individuals substantially improved the cost-effectiveness of the shared-care models. Interpretation: Shared-care models with HBV testing, follow up and referring of predetermined conditions to specialty care at an appropriate time, especially antiviral treatment initiation in primary care, are highly effective and cost-effective in China. Funding: National Natural Science Foundation of China.

Testing the generalizability of cfDNA fragmentomic features across different studies for cancer early detection.

cfDNA fragmentomic features have been used in cancer detection models; however, the generalizability of the models needs to be tested. We proposed a type of cfDNA fragmentomic feature named chromosomal arm-level fragment size distribution (ARM-FSD), evaluated and compared its performance and generalizability for lung cancer and pan-cancer detection with existing cfDNA fragmentomic features (as reference) by using cohorts from different institutions. The ARM-FSD lung cancer model outperformed the reference model by ∼10% when being tested by two external cohorts (AUC: 0.97 vs. 0.86; 0.87 vs. 0.76). For pan-cancer detection, the performance of the ARM-FSD based model is consistently higher than the reference (AUC: 0.88 vs. 0.75, 0.98 vs. 0.63) in a pan-cancer and a lung cancer external validation cohort, indicating that ARM-FSD model produces stable performance across multiple cohorts. Our study reveals ARM-FSD based models have a higher generalizability, and highlights the necessity of cross-study validation for predictive model development.

Radiological analysis of maxillary artery relationships to key bony landmarks in maxillofacial surgery.

The maxillary artery (MA) is a key structure at risk of injury in numerous oral and maxillofacial surgical (OMS) procedures. Knowledge of safe distances from this vessel to surgically familiar bony landmarks could improve patient safety and prevent catastrophic haemorrhage. Distances between the MA and bony landmarks on the maxilla and mandible were measured using CT angiograms on 100 patients (200 facial halves). The vertical height of the pterygomaxillary junction (PMJ) was mean (SD) measurement of 16 (3) mm. The MA enters the pterygomaxillary fissure (PMF) a mean (SD) distance of 29 (3) mm from the most inferior point of the PMJ. The mean (SD) shortest distance between the MA and medial surface of the mandible was 2 (2) mm (with the vessel directly contacting the mandible in 17% of cases). The branchpoint (bifurcation of the superficial temporal artery (STA) and MA) was directly in contact with the mandible in 5% of cases. The mean (SD) distances between this bifurcation point and the medial pole of the condyle were 20 (5) mm and 22 (5) mm, respectively. A horizontal plane through the sigmoid notch perpendicular to the posterior border of the mandible is a good approximation of the trajectory of the MA. The branchpoint is usually within 5 mm of this line and inferior in 70% of cases. Surgeons should take note that both the branchpoint and the MA contact the surface of the mandible in a significant number of cases.

Fatigue and Quality of Life Among Patients with Diabetes and Non-diabetes Receiving Primary Percutaneous Coronary Interventions.

PURPOSE: Few studies have examined the effect of diabetes mellitus (DM) on patients with coronary artery disease. The relationships between quality of life (QoL), risk factors, and DM of patients receiving percutaneous coronary interventions (PCIs) are poorly understood. We investigated the influence of DM on fatigue and QoL over time among patients receiving PCIs. METHODS: An observational cohort study with a longitudinal, repeated-measures design was used to investigate fatigue and QoL among 161 Taiwanese patients with coronary artery disease with/without DM who received primary PCIs between February and December 2018. Participants provided demographic information and their Dutch Exertion Fatigue Scale and the 12-Item Short-Form Health Survey scores before the PCI and two weeks, three months, and six months post-discharge. RESULTS: Seventy-seven PCI patients were in the DM group (47.8%; mean age = 67.7 [SD = 10.4] years). The mean scores of fatigue, physical component scale (PCS), and mental component scale (MCS) were 7.88 (SD = 6.74), 40.74 (SD = 10.05), and 49.44 (SD = 10.57), respectively. DM did not affect the magnitude of change in fatigue or QoL over time. Patients with DM perceived similar fatigue as those without DM before PCI and two weeks, three and six months post-discharge. Patients with DM perceived lower psychological QoL than those without DM two weeks post-discharge. Compared to pre-surgery scores, patients without DM perceived lower fatigue at two weeks, three months, and six months post-discharge, and higher physical QoL at three- and six-months post-discharge. CONCLUSIONS: Compared with DM patients, patients without DM had higher pre-intervention QoL and better psychological QoL two weeks post-discharge, and DM did not influence fatigue or QoL of patients receiving PCIs over six months. DM may affect patients in the long term; therefore, nurses should educate patients to regularly take medication, maintain proper habits, notice comorbidities, and follow rehabilitation regimes after PCIs to improve prognosis.

Glymphatic system dysfunction in pediatric acute lymphoblastic leukemia without clinically diagnosed central nervous system infiltration: a novel DTI-ALPS method.

BACKGROUND AND OBJECTIVE: Central nervous system (CNS) infiltration commonly occurs in children with acute lymphoblastic leukemia (ALL). Nevertheless, CNS infiltration is rarely detected at the initial diagnosis. The glymphatic system, which regulates cerebrospinal fluid (CSF) and interstitial fluid transport, is considered one of the possible routes of CNS infiltration by leukemia cells. In this study, we used diffusion tensor image analysis along the perivascular space (DTI-ALPS) method to investigate glymphatic system function and obtained CSF volume using synthetic magnetic resonance imaging (SyMRI) in pediatric ALL without clinically diagnosed CNS infiltration. MATERIALS AND METHODS: Twenty-nine ALL and 29 typically developing (TD) children were prospectively recruited (age 4-16 years) in the present study. Group differences in brain volumetric parameters, brain water diffusivities, and the ALPS index were evaluated after controlling for age, gender, and handedness. Furthermore, significant group-different parameters were correlated with clinical information using partial correlations analysis. RESULTS: Lower Dxassoc and ALPS index, and increased CSF volume were found in pediatric ALL (all pFDR-corrected < 0.05). Moreover, the ALPS index was negatively associated with the risk classification (r = - 0.59, pFDR-corrected = 0.04) in pediatric ALL. CONCLUSIONS: Dysfunction of the glymphatic system and accumulation of CSF were presented in pediatric ALL without clinically diagnosed CNS infiltration. These novel findings suggested that the glymphatic system might be essential in the early-stage process of ALL CNS infiltration, which provides a new direction for exploring underlying mechanisms and early detection of pediatric ALL CNS infiltration. KEY POINTS: • Lower Dxassoc and ALPS index, and increased CSF volume were found in pediatric ALL (all pFDR-corrected < 0.05). • The ALPS index was negatively associated with the risk classification (r = -0.59, pFDR-corrected = 0.04) in pediatric ALL. • Dysfunction of the glymphatic system and accumulation of CSF were presented in pediatric ALL without clinically diagnosed CNS infiltration, which suggested that the ALPS index and CSF volume might be promising imaging markers for early detection of pediatric ALL CNS infiltration.

Associations among Health Status, Occupation, and Occupational Injuries or Diseases: A Multi-Level Analysis.

PURPOSE: The present study used a hierarchical generalized linear model to explore the effects of physical and mental health and occupational categories on occupational injuries and diseases. METHODS: The data were obtained from the Registry for Beneficiaries of the 2002-2013 National Health Insurance Research Database. The benefit categories involved adults with occupational injuries and diseases. Six major occupational categories and 28 subcategories were used. The main analysis methods were binary logistic regression (BLR) and hierarchical generalized linear model (HGLM). RESULTS: After adjustment for relevant factors, the three major occupation subcategories most likely to develop occupational injuries and diseases were Subcategory 12 "employees with fixed employers" of Category 1 "civil servants, employees in public or private schools, laborers, and self-employed workers"; Subcategory 2 "employees in private organizations" of Category 1; and "sangha and religionists" of Category 6 "other citizens." Conditions such as mental disorders and obesity increased the risk of occupational injuries and diseases. CONCLUSION: A portion of the occupational categories had a higher risk of occupational injuries and diseases. Physical and mental health issues were significantly correlated with occupational injuries and diseases. To the authors' knowledge, this is the first study to use HGLM to analyze differences in occupational categories in Taiwan.

Leukemic cells resist lysosomal inhibition through the mitochondria-dependent reduction of intracellular pH and oxidants.

Acidic lysosomes are indispensable for cancer development and linked to chemotherapy resistance. Chloroquine (CQ) and functional analogues have been considered as a potential solution to overcome the cancer progression and chemoresistance by inhibiting the lysosome-mediated autophagy and multidrug exocytosis. However, their anti-cancer efficacy in most clinical trials demonstrated modest improvement. In this study, we investigated the detailed mechanisms underlying the acquired resistance of K562 leukemic cells to CQ treatment. In response to 5-80 µM CQ, the lumen pH of endosomal-lysosomal system immediately increased and gradually reached dynamic equilibrium within 24 h. Leukemic cells produced more acidic organelles to tolerate 5-10 µM CQ. CQ (20-80 µM) concentration-dependently triggered cytosolic pH (pHi) rise, G0/G1 arrest, mitochondrial depolarization/fragmentation, and necrotic/apoptotic cell death. Oxidant induction by CQ was responsible for the mitochondria-dependent cytotoxicity and partial pHi elevation. Cells that survived the CQ cytotoxicity were accompanied with increased mitochondria. Under the 80 µM CQ challenge, co-treatment with the inhibitor of F0 part of mitochondrial H+-ATP synthase, oligomycin (40 nM), prevented the elevation of oxidants as well as pHi, and attenuated stresses on mitochondria, cell survival, and cell proliferation. Besides, oligomycin-treated cells obviously displayed the lysosomal peripheralization and plasma membrane blebbing, suggesting that these cells were in process of lysosomal exocytosis and microvesicle release. Enhanced motion of these secretory processes allowed the cells to exclude CQ and repair necrotic injury. Together, the oxidant production and the proton dynamic interconnection among lysosomes, mitochondria, and cytosol are crucial for leukemic susceptibility to lysosomotropic chemotherapeutics.

Disparities in the medical expenditures of patients with cancer and concomitant mental disorder: analyzing the effects of diagnosis sequence order.

BACKGROUND: Cancer is the leading cause of death in Taiwan. Medical expenditures related to cancer accounted for 44.8% of all major illness insurance claims in Taiwan. Prior research has indicated that the dual presence of cancer and mental disorder in patients led to increased medical burden. Furthermore, patients with cancer and concomitant mental disorder could incur as much as 50% more annual costs than those without. Although previous studies have investigated the utilization of patients with both diseases, the effects of morbidity sequence order on patient costs are, however, uncertain. This study explored medical expenditures linked with the comorbidity of cancer and mental disorder, with a focus on the impact of diagnosis sequence order. METHODS: This population-based retrospective matched cohort study retrieved patients with cancer and mental disorder (aged ≥ 20 years) from the Ministry of Health and Welfare Data Science Center 2005-2015 database. 321,045 patients were divided based on having one or both diseases, as well as on the sequence of mental disorder and cancer diagnosis. Study subjects were paired with comparison counterparts free of both diseases using Propensity Score Matching at a 1:1 ratio. Annual Cost per Patient Linear Model (with a log-link function and gamma distribution) was used to assess the average annual cost, covarying for socio-demographic and clinical factors. Binomial Logistic Regression was used to evaluate factors associated with the risk of high-utilization. RESULTS: The "Cancer only" group had higher adjusted mean annual costs (NT$126,198), more than 5-times that of the reference group (e^ß: 5.45, p < 0.001). However, after exclusion of patients with non-cancer and inclusion of diagnosis sequence order for patients with cancer and concomitant mental disorder, the post-cancer mental disorder group had the highest expenditures at over 13% higher than those diagnosed with only cancer on per capita basis (e^ß: 1.13, p < 0.001), whereas patients with cancer and any pre-existing mental disorder incurred lower expenditures than those with only cancer. The diagnosis of post-cancer mental disorder was significantly associated with high-utilization (OR = 1.24; 95% CI: 1.047-1.469). Other covariates associated with high-utilizer status included female sex, middle to old age, and late stage cancer. CONCLUSION: Presence of mental disorder prior to cancer had a diminishing effect on medical utilization in patients, possibly indicating low medical compliance or adherence in patients with mental disorder on initial treatments after cancer diagnosis. Patients with post-cancer mental disorder had the highest average annual cost. Similar results were found in the odds of reaching high-utilizer status. The follow-up of cancer treatment for patients with pre-existing mental disorders warrants more emphasis in an attempt to effectively allocate medical resources.

Targeted liver ultrasound performed by an expert is the pivotal imaging examination for low phospholipid-associated cholelithiasis.

OBJECTIVES: Low phospholipid-associatedcholelithiasis (LPAC) is a clinical syndrome that can be associated with variants in the adenosinetriphosphate-binding cassette subfamily B, member 4 (ABCB4) transporter gene, in a proportion of patients. The diagnosis of LPAC is defined by clinical as well as imaging criteria of intrahepatic hyperechoic foci or microlithiasis and biliary sludge on ultrasound. The aim of the study was to assess the role of imaging in investigating patients presenting with clinical features suggesting a diagnosis of LPAC. METHODS: Imaging findings in 51 patients with clinical LPAC were retrospectively reviewed. Most patients had been referred with difficult-to-manage biliary pain postcholecystectomy and some with intrahepatic dilated ducts and stones. The diagnosis of LPAC was made on clinical features. RESULTS: The patients were young with symptom onset at median age 24 years and were mainly female (75%). Ultrasound was performed by an expert in 48/51 and magnetic resonance cholangiopancreatography (MRCP) in 47/51 patients. Targeted liver ultrasound found small hyperechoic foci with comet tail artifacts or posterior acoustic shadowing typical of LPAC in 30/48 (63%) of examinations. However, ultrasound examinations performed before referral for investigation did not report these findings. Intrahepatic duct dilatation was seen in 26/51 (51%) of cases. MRCP did not reliably detect microlithiasis. CONCLUSIONS: Targeted liver ultrasound performed by an expert aware of the possible diagnosis is the pivotal investigation for patients with clinical features suggesting LPAC. The findings in ultrasound performed before referral suggest LPAC is under-recognized and under-diagnosed.