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Ming-Ming Ma,1,* Yao-Yao Xu,2,* Li-Hua Sun,1,* Wen-Jie Cui,1 Miao Fan,3 Su Zhang,4 Lei Liu,5 Ling-Zhi Wu,6 Liu-Cheng Li7 1Department of Diagnostic Ultrasound & Echocardiography, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People’s Republic of China; 2Department of Pharmacy, The People’s Hospital of Pingyang, Wenzhou, 325400, People’s Republic of China; 3Department of Pharmacy, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, People’s Republic of China; 4Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China; 5Department of Orthopaedics, Shaoxing Hospital of Traditional Chinese Medicine, Shaoxing, 312000, People’s Republic of China; 6Department of Pharmacy, The Affiliated Hospital of Jiaxing University (The First Hospital of Jiaxing), Jiaxing, 314000, People’s Republic of China; 7Department of Pharmacy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liu-Cheng Li, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Hangzhou, 310016, People’s Republic of China, Email 3415116@zju.edu.cn Ling-Zhi Wu, The Affiliated Hospital of Jiaxing University (The First Hospital of Jiaxing), No. 1882 South Central Road, Jiaxing, 314000, People’s Republic of China, Email wulingzhi1992@163.comAbstract: Surveillance of drug safety is an important aspect in the routine medical care. Adverse events caused by real-world drug utilization has become one of the leading causes of death and an urgent issue in the field of toxicology. Cardiovascular disease is now the leading cause of fatal diseases in most countries, especially in the elderly population who often suffer from multiple diseases and need long-term multidrug therapy. Among which, statins have been widely used to lower bad cholesterol and regress coronary plaque mainly in patients with hyperlipidemia and atherosclerotic cardiovascular diseases (ASCVD). Although the real-world benefits of statins are significant, different degrees and types of adverse drug reactions (ADR) such as liver dysfunction and muscle injury, have a great impact on the original treatment regimens as well as the quality of life. This review describes the epidemiology, mechanisms, early identification and post-intervention of statin-associated liver dysfunction and muscle injury based on the updated clinical evidence. It provides systematic and comprehensive guidance and necessary supplement for the clinical safety of statin use in cardiovascular diseases.Keywords: statin, cardiovascular diseases, liver dysfunction, muscle injury, countermeasures

Hao Wu, Qing-Jie Ji, Yu-Yang Xu, Jian-Wei Zhu Department of Dermatology, Quzhou TCM Hospital at the Junction of Four Provinces Affiliated to Zhejiang Chinese Medical University, Quzhou, People’s Republic of ChinaCorrespondence: Jian-Wei Zhu, Email zjwmed@163.comAbstract: Pityriasis rosea (PR) is a common inflammatory, erythematous and scaly skin condition that usually affects individuals aged from 20 to 40 years old. The disease often exhibits a self-limiting course up to 6– 8 weeks. We report a 25-year-old female patient with a six-month history of red scaly rashes on the trunk and proximal limbs, accompanied by severe pruritus that has been remained ineffective conventional treatments. She was diagnosed as persistent pityriasis rosea. As abrocitinib has been proved to be effective for many inflammatory diseases, therefore in this case, we tried abrocitinib for the patient, and a good result had been achieved.Keywords: pityriasis rosea, abrocitinib, JAK-STAT pathway

Hong-Ping Wang,1,&ast; Yuan-Ying Xu,1,&ast; Bi-Lin Xu,1 Jun Lu,1 Juan Xia,1 Tian Shen,1 Ji Fang,1,2 Tao Lei1 1Department of Endocrinology, Putuo Hospital, Shanghai University of Traditonal Chinese Medicine, Shanghai, 200333, People’s Republic of China; 2Department of Nephrology, Putuo Hospital, Shanghai University of Traditonal Chinese Medicine, Shanghai, 200333, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Lei, Department of Endocrinology, Putuo Hospital, Shanghai University of Traditonal Chinese Medicine, No. 164 of Lanxi Road, Putuo District, Shanghai, 200333, People’s Republic of China, Tel +86 021-22233222-58142, Email leitao5899@126.com Ji Fang, Department of Nephrology, Putuo Hospital, Shanghai University of Traditonal Chinese Medicine, No. 164 of Lanxi Road, Putuo District, Shanghai, 200333, People’s Republic of China, Tel +86 021-22233222-58082, Email 13601833102@163.comObjective: To investigated the link between the distribution of abdominal fat and the concentration of serum uric acid (SUA) in individuals recently diagnosed with type 2 diabetes.Methods: Studied 364 individuals had been diagnosed with type 2 diabetes within one month, and evaluated factors such as the distribution of fat in the abdomen, indicators related to glucose and lipid metabolism. The participants’ SUA concentrations were divided into a normal control group (CG) and a hyperuricemia group (HG).Results: The HG group had elevated abdominal subcutaneous fat area (SFA), visceral fat content (VFA), body mass index (BMI), fasting blood glucose (FBG), 2-hour postprandial blood glucose (PBG), glycosylated albumin (GA), serum creatinine (SCr), triacylglycerol (TG), and lower values in glomerular filtration rate (eGFR), high-density lipoprotein cholesterol (HDL-C) when compared to the CG group (P < 0.05). Among the obese individuals, the hyperuricemia subgroup exhibited higher measurements in waistline, hipline, VFA, SFA, BMI, PBG, SCr, TG, and lower HDL-C (P < 0.05) compared to the subgroup with normal uric acid levels. In the non-obese group, the hyperuricemia subgroup showed higher VFA, SCr, and FBG levels, and lower HDL-C (P < 0.05). There was a positive correlation between VFA and serum uric acid (SUA) levels (r = 0.329, P < 0.0001). Logistic regression analysis indicated a 24% increased risk of hyperuricemia with every 10cm2 increase in abdominal VFA. Generate the Receiver Operating Characteristic (ROC) curve analysis revealed that VFA was the most effective predictor of hyperuricemia and insulin resistance (P < 0.05).Conclusion: Newly diagnosed type 2 diabetes patients exhibit a strong correlation between abdominal visceral fat and SUA concentration, the former is identified as an autonomous risk factor for hyperuricemia and an effective indicator for assessing the presence of hyperuricemia and predicting insulin resistance.Keywords: abdominal fat distribution, newly diagnosed type 2 diabetes, serum uric acid, visceral fat area

Hao Wu, Qing-Jie Ji, Yu-Yang Xu, Jian-Wei Zhu Department of Dermatology, Quzhou TCM Hospital at the Junction of Four Provinces Affiliated to Zhejiang Chinese Medical University, Quzhou, People’s Republic of ChinaCorrespondence: Jian-Wei Zhu, Email zjwmed@163.com

Chun-Fang Gao,1 Guo-Hai Zhang,1 Zhe-Hao Ye,1 Yu-Yu Xu,2 Zhao Li1 1Department of Neurosurgery, The Shengzhou Hospital of Traditional Chinese Medicine, Shengzhou, Zhejiang Province, People’s Republic of China; 2Department of Neurology, The Shengzhou Hospital of Traditional Chinese Medicine, Shengzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Guo-Hai Zhang, Department of Neurosurgery, The Shengzhou Hospital of Traditional Chinese Medicine, Shengzhou, Zhejiang Province, People’s Republic of China, Email gcf20230503@sina.comObjective: Stanniocalcin-1 (STC1) may be neuroprotective. This study aimed to evaluate the prognostic role of serum STC1 levels in intracerebral hemorrhage (ICH).Methods: This prospective observational study was assigned in two parts. In the first part, blood samples of 48 patients with ICH were acquired on admission and on days 1, 2, 3, 5, and 7 after ICH, and those of 48 controls were collected at their entry into the study. In the second part, blood samples of 141 patients with ICH were obtained upon admission. Serum STC1 levels were measured, and the National Institutes of Health Stroke Scale (NIHSS), hematoma volume, and poststroke 6-month modified Rankin Scale (mRS) scores were recorded. Dynamic changes in serum STC levels and their correlation with disease severity and prognosis were investigated.Results: Serum STC1 levels were elevated after ICH, peaked on day 1, plateaued on day 2, declined gradually afterwards, and were significantly higher than those in controls. Serum STC1 levels were independently correlated with NIHSS scores, hematoma volume, and the 6-month post-injury mRS scores. Serum STC1 levels, NIHSS scores, and hematoma volume independently predicted a poor prognosis (mRS scores of 3– 6). The model integrating serum STC1 levels, NIHSS scores, and hematoma volume was visually displayed using a nomogram and was relatively stable using the Hosmer–Lemeshow test and calibration curve analysis. Under the receiver operating characteristic curve, serum STC1 levels efficiently predicted a poor prognosis and showed similar prognostic ability to NIHSS scores and hematoma volume. The preceding model had significantly higher prognostic capability than NIHSS scores and hematoma volume alone and their combination.Conclusion: Substantial enhancement of serum STC1 levels after ICH, which is strongly correlated with severity, independently distinguished the risk of poor prognosis, assuming that serum STC1, as a prognostic parameter, may be clinically valuable in ICH.Keywords: stanniocalcin-1, intracerebral hemorrhage, prognosis, severity, biomarkers

Hao-Qi Zheng,1 Yu-Cong Ma,1 Yu-Quan Chen,2 Yan-Yue Xu,1 Yan-Lin Pang,1 Li Liu1 1Department of Pediatrics, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China; 2Institute of Medical Information/Library, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100020, People’s Republic of ChinaCorrespondence: Li Liu, Department of Pediatrics, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China, Email lli01@jlu.edu.cnPurpose: Severe mycoplasma pneumoniae (MP) pneumonia can cause bronchiolitis obliterans (BO). In order to improve the prognosis of BO, it is necessary to grasp the clinical characteristics and risk factors of BO after severe MP pneumonia and intervene as soon as possible.Patients and Methods: This study retrospectively analyzed the clinical data of 110 patients with severe MP pneumonia, and divided them into BO group (22 cases) and non-BO group (88 cases). The clinical characteristics of BO group were analyzed, and the clinical data of two groups were compared to identify the risk factors of BO.Results: At the time of diagnosis, all BO patients had symptoms of cough and wheezing, and 10 (45.45%) had decreased exercise intolerance. Lung function showed moderate to severe obstructive ventilatory dysfunction, high-resolution computed tomography (HRCT) showed mosaic perfusion patterns. Multivariate binomial regression analysis showed that higher levels of serum lactate dehydrogenase (LDH) and hypoxemia were independent risk factors for BO after severe MP pneumonia.Conclusion: Higher levels of serum LDH and hypoxemia were independent risk factors for BO after severe MP pneumonia. For patients with risk factors, clinicians should regular follow-up for early diagnosis and intervention of BO.Keywords: children, bronchiolitis obliterans, mycoplasma pneumoniae pneumonia, post-infectious bronchiolitis obliterans, risk factors

Hui-Ling Chen,1,2,&ast; Yi-Bin Zeng,3,&ast; Zheng-Yan Zhang,1,2,&ast; Chao-Yue Kong,1,2 Shi-Long Zhang,1,2 Zhan-Ming Li,1,2 Jia-Ting Huang,1,2 Ya-Yun Xu,1,2 Yu-Qin Mao,1,2 Pei-Ran Cai,1,2 Bing Han,1,2 Wu-Qing Wang,3 Li-Shun Wang1,2 1Center for Traditional Chinese Medicine and Gut Microbiota, Minhang Hospital, Fudan University, Shanghai, 201100, People’s Republic of China; 2Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201100, People’s Republic of China; 3Dermatological Department, Minhang Hospital, Fudan University, Shanghai, 201100, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li-Shun Wang; Wu-Qing WangCenter for Traditional Chinese Medicine and Gut Microbiota, Minhang Hospital, Fudan University, Shanghai, 201100, People’s Republic of ChinaTel +86 21-64923400-6244Email lishunwang@fudan.edu.cn; wuqingw2006@sina.comBackground: Psoriasis is a chronic autoinflammatory skin disease, and its aetiology remains incompletely understood. Recently, gut microbial dysbiosis is found to be tightly associated with psoriasis.Objective: We sought to reveal the causal role of gut microbiota dysbiosis in psoriasis pathogenesis and investigate the protective effect of healthy commensal bacteria against imiquimod -induced psoriasis-like skin response.Methods: By using fecal microbial transplantation (FMT), 16S rRNA gene-based taxonomic profiling and Lactobacillus supplement, we have assessed the effect of FMT from healthy individuals on psoriasis-like skin inflammation and associated immune disorders in imiquimod-induced psoriasis mice.Results: Here, by using psoriasis mice humanized with the stools from healthy donors and psoriasis patients, the imiquimod-induced psoriasis in mice with psoriasis patient stool was found to be significantly aggravated as compared to the mice with healthy donor stools. Further analysis showed fecal microbiota of healthy individuals protected against Treg/Th17 imbalance in psoriasis. Moreover, we found the gut and skin microbiome in mice receipted with gut microbiota of healthy individuals (HD) differed from those of mice receipted with gut microbiota of psoriasis patients (PSD). 16S rRNA sequencing revealed that Lactobacillus reuteri was greatly enriched in fecal and cutaneous microbiome of HD mice as compared to PSD mice. Intriguingly, supplement with Lactobacillus reuteri was sufficient to increase the expression of anti-inflammatory gene IL-10, reduce Th17 cells counts and confer resistance to imiquimod-induced inflammation on the mice with gut microbiota dysbiosis.Conclusion: Our results suggested that the gut microbiota dysbiosis is the potential causal factor for psoriasis and the gut microbiota may serve as promising therapy target for psoriasis patients.Keywords: gut microbiota, cutaneous microbiome, psoriasis, fecal microbiota transplantation, Lactobacillus reuteri, Th17

Jun-Da Li,1– 3 Le Cui,1– 3 Ying-Yang Xu,1– 3 Kai Guan1– 3 1Department of Allergy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 2Beijing Key Laboratory of Precision Medicine for Diagnosis and Treatment on Allergic Diseases, Beijing, People’s Republic of China; 3National Clinical Research Center for Dermatologic and Immunologic Disease, Beijing, People’s Republic of ChinaCorrespondence: Kai GuanDepartment of Allergy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Shuaifuyuan, Wangfujing, Beijing, 100730, People’s Republic of ChinaTel/Fax +86 10-69156346Email dr_guankai@126.comPurpose: Royal jelly and honeycomb are commonly consumed in China, and anaphylaxis caused by ingestion of royal jelly is rare. To date, there is no report of anaphylaxis after ingestion of royal jelly in China. Its cross-reactivity with honeycomb is still unclear.Case Report: A 56-year-old Chinese female experienced two episodes of anaphylaxis within 1 hour after ingestion of royal jelly within one month. After avoiding royal jelly and other bee products, no anaphylactic reaction occurred again. The skin prick test and basophil activation test showed positive reactivity to royal jelly and honeycomb. In immunoblotting and immunoblotting inhibition tests, a 60 kDa protein was recognized in royal jelly and cross-reactivity with honeycomb. The mass spectrometry data revealed that the 62kDa protein belongs to major royal jelly protein 3.Conclusion: Our data suggest that major royal jelly protein 3 of royal jelly is a main allergen that induces anaphylaxis and cross-reactivity with honeycomb. Therefore, the patient was allergic to royal jelly to avoid other bee products.Keywords: royal jelly, honeycomb, major royal jelly protein 3, anaphylaxis

Chen XG, Hua F, Wang SG, Xu YY, Yue HT, Sun J. Drug Des Devel Ther. 2018;12:2389–2402The authors have advised Figures 1 (on page 2393), Figure 3 (on page 2394), Figure 5 (on page 2395), Figure 7 and Figure 8 (on page 2396) are incorrect due to a fault in their microscope camera. The correct Figures are shown below:Read the original article

Ya-Yun Xu,1–4 Qian-Hui Xia,5 Qing-Rong Xia,1,3,4 Xu-Lai Zhang,6,7 Jun Liang1,3,4 1Department of Pharmacy, Hefei Fourth People’s Hospital, Hefei 230000, People’s Republic of China; 2CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei 230022, People’s Republic of China; 3Department of Psychopharmacology, Anhui Mental Health Center, Hefei 230000, People’s Republic of China; 4Department of Clinical Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei 230000, People’s Republic of China; 5School of Pharmacy, Wannan Medical College, Wuhu 241002, People’s Republic of China; 6Department of Geriatric Psychology, Hefei Fourth People’s Hospital, Hefei 230000, People’s Republic of China; 7Clinical School of Mental Health, Anhui Medical University, Hefei 230000, People’s Republic of ChinaCorrespondence: Jun LiangDepartment of Pharmacy, Hefei Fourth People’s Hospital, 316 Huangshan Road, Hefei 230000, People’s Republic of ChinaTel/Fax +86 551 63616022Email amhcliangj@163.comXu-Lai ZhangDepartment of Geriatric Psychology, Hefei Fourth People’s Hospital, 316 Huangshan Road, Hefei 230000, People’s Republic of ChinaTel/Fax +86 551 63616022Email Xulaizhang@ahmhcentre.comAbstract: Depression is a debilitating mental illness that affects up to 120 million people worldwide; it is currently determined based on subjective diagnostic schemes that are limited by high uncertainty. Hence, there is an urgent need to identify effective and reliable biomarkers to increase diagnostic accuracy. MicroRNAs (miRNAs) constitute a recently discovered class of non-coding RNAs that play a key role in the regulation of gene expression by modulating translation, messenger RNA (mRNA) degradation, or stability of mRNA targets. Dysregulated expression of miRNAs is being investigated as a clinical biomarker for a variety of diseases, including depression. Accumulating evidence has shown that miRNAs participate in many aspects of neural plasticity, neurogenesis, and the stress response. This is supported by more direct studies based on human postmortem brain tissue that strongly indicate that miRNAs not only play a key role in the pathogenesis of major depressive disorder, but also present potential for the development of therapeutic targets. miRNAs in the peripheral and central nervous system are being considered as potential biomarkers in the diagnosis of depression and in monitoring the therapeutic response to antidepressants, owing to their stability, tissue-specificity, and disease-specific expression. In this review, we focus on various miRNAs in tissues and fluids that could be employed as diagnostic and therapeutic biomarkers in patients with depression.Keywords: depression, microRNA, biomarker, diagnosis, therapy

Ya-Yun Xu,*,1,2 Qian-Hui Xia,*,3 Jun Liang,1,2 Yin Cao,1,2 Feng Shan,1,2 Yang Liu,1,2 Chun-Yu Yan,1,2 Qing-Rong Xia1,21Department of Pharmacy, Hefei Fourth People’s Hospital, Hefei 230000, People’s Republic of China; 2Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei 230000, People’s Republic of China; 3School of Pharmacy, Wannan Medical College, Wuhu 241002, People’s Republic of China*These authors contributed equally to this workBackground: The goal of this study was to identify the physiological factors related to the blood concentration of lithium in Chinese Han patients with bipolar disorder (BD).Materials and methods: A total of 186 Chinese Han patients with BD were assessed. Patients were recruited from the Anhui Mental Health Center. The concentrations of serum lithium were measured by a Dimension RxL Max biochemistry analyzer. Physiological factors, including body weight, body mass index (BMI), and routine laboratory parameters, were collected. Relationships between the serum lithium concentration and relevant clinical data were analyzed by Pearson correlation tests, and the independent relationships were determined by multivariate linear regression analysis.Results: Pearson correlation analysis showed that serum lithium concentrations were positively correlated with creatinine concentrations (r=0.147, P=0.046), Mg2+ concentrations (r=0.151, P=0.04), and the percentage of neutrophils (r=0.178, P=0.015) and negatively correlated with high-density lipoprotein (HDL) concentrations (r=−0.142, P=0.05), apolipoprotein A1 concentrations (r=−0.169, P=0.02), and Na+ concentrations (r=−0.148, P=0.046) in 186 patients with BD. Furthermore, multivariate linear regression analysis showed that serum lithium concentrations were negatively associated with Na+ concentrations and positively associated with the percentage of neutrophils.Conclusion: These results suggest that physiological factors, including creatinine, HDL, apolipoprotein A1, Na+, and Mg2+ concentrations and percentage of neutrophils, might be related to serum lithium concentrations and provide a basis for parameter selection of lithium population pharmacokinetics in Chinese Han patients with BD.Keywords: bipolar disorder, apolipoprotein A1, creatinine, high-density lipoprotein, neutrophil, lithium

Jianping Xiong,* Weiyu Xu,* Jin Bian, Hanchun Huang, Yi Bai, Yiyao Xu, Xin Lu, Haitao Zhao Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China *These authors contributed equally to this work Background: Aspirin has been revealed to probably decrease the risk of cholangiocarcinoma (CCC), which, nevertheless, is of controversy. To this end, a systematic review and meta-analysis was performed to investigate the above-described association. Methods: We thoroughly searched PubMed, EMBASE, and ISI Web of Science for relevant studies published prior to October 2017, followed by random-effects model for calculation of pooled ORs and corresponding 95% CIs. Additionally, subgroup and sensitivity analyses were carried out to confirm whether the outcomes were stable. Results: Nine articles, consisting of 12,535 CCC patients and 92,97,450 healthy controls, were enrolled in this study. We demonstrated a significantly decreased risk of CCC in those using aspirin, with studies being heterogeneous (OR=0.69; CI=0.43–0.94; I2=97.4%). Moreover, this relationship was detected only in case-control studies (OR=0.65; 95% CI=0.38–0.93), rather than cohort studies (OR=0.94; 95% CI=0.70–1.27). Besides, in separated analysis of intrahepatic CCC and extrahepatic CCC, aspirin was more strongly correlated with a declined risk of intrahepatic CCC (OR=0.33, 95% CI=0.26–0.39; I2=93.6%) than the risk of extrahepatic CCC (OR=0.56, 95% CI=0.41–0.73; I2=0%). Conclusion: Collectively, the aspirin administration was correlated with a significant 31% decreased risk of CCC, particularly in the intrahepatic CCC. Keywords: aspirin, cholangiocarcinoma, biliary tract neoplasms, meta-analysis

Ya-Yun Xu,1,2 Jin-Fang Ge,3 Jun Liang,1,2 Yin Cao,1,2 Feng Shan,1,2 Yang Liu,1,2 Chun-Yu Yan,1,2 Qing-Rong Xia1,2 1Department of Pharmacy, Hefei Fourth People’s Hospital, Hefei 230022, China; 2Psychopharmacology Laboratory, Anhui Mental Health Center, Hefei 230032, China; 3Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei 230032, China Background: This study aimed to determine whether plasma nesfatin-1, cortisol, and inflammatory cytokines could be used as novel noninvasive biomarkers for the diagnosis of moderate and severe depressive disorder (MSDD). Materials and methods: A total of 70 patients with MSDD and 70 healthy subjects were assessed. Patients with MSDD were selected from Hefei Fourth People’s Hospital, Anhui Mental Health Center, and subjects in the control group were selected from healthy volunteers. Hamilton Depression Rating Scale-17 (HAMD-17) was used to evaluate the two groups. ELISA was used for the measurement of plasma nesfatin-1, cortisol, IL-6, C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) levels. The diagnostic value of plasma nesfatin-1, cortisol, IL-6, CRP, and TNF-α for MSDD was assessed. Results: Compared to healthy controls, the HAMD-17 scores and average nesfatin-1, cortisol, IL-6, and CRP levels in patients with MSDD were significantly increased. Moreover, multivariate linear regression analysis showed that HAMD-17 score was positively associated with plasma nesfatin-1 and cortisol. Furthermore, the results of the receiver operating characteristic (ROC) curve analysis revealed an area under curve (AUC) of 0.985 with 94.3% sensitivity and 97.1% specificity of nesfatin-1, and an AUC of 0.957 with 91.4% sensitivity and 85.7% specificity of cortisol in discriminating patients with MSDD from healthy volunteers. A combined ROC analysis using nesfatin-1 and cortisol revealed an AUC of 0.993 with a sensitivity of 97.1% and a specificity of 98.6% in separating patients with MSDD from healthy volunteers. Conclusion: These results suggest that plasma nesfatin-1 and cortisol might be potential novel biomarkers for the diagnosis of MSDD. Keywords: C-reactive protein, cortisol, IL-6, depression, nesfatin-1, tumor necrosis factor-α

Xiao-Gang Chen,1 Fu Hua,2 Shou-Guo Wang,1 Yong-Yi Xu,1 Hai-Tao Yue,1 Jin Sun1 1Department of Orthopedics, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu 223300, People’s Republic of China; 2Department of Gynaecology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu 223300, People’s Republic of China Background: Biosynthesis of leukotriene (LT) by arachidonic acid involves 5-lipoxygenase (5-LO) as an important precursor. Here, we evaluated the role of pseudohypericin (PHP) for its postulated 5-LO inhibitory activity along with a Cys-LT receptor antagonist zafirlukast (ZFL) against inflammatory response and tissue injury in mice. Materials and methods: The spinal injury was induced by two-level laminectomy of T6 and T7 vertebrae. The inflammation was assessed by histology, inflammatory mediators by enzyme-linked immunosorbent assay, apoptosis by Annexin-V, FAS staining, terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL) assay and expression of Bax and Bcl-2 by Western blot. Effect on motor recovery of hind limbs was evaluated for 10 days postinjury. Results: The spinal injury resulted in tissue damage, apoptosis, edema, infiltration of neutrophils with increased expression of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). The spinal tissue showed elevated levels of prostaglandin E2 (PGE2), and LTB4 and increased phosphorylation of injured extracellular signal-regulated kinase-1/2 (ERK1/2). The PHP, ZFL and combination decreased inflammation, tissue injury and infiltration of neutrophils. Treatment also decreased the levels of PGE2, phosphorylation of extracellular signal-regulated kinase-1/2 (pERK 1/2), LT, TNF-α and COX-2 with a marked reduction in apoptosis and improved the motor function. Conclusion: The present study confirmed 5-LO antagonist activity of PHP and established its neuroprotective role along with ZFL. Keywords: pseudohypericin, zafirlukast, 5-lipoxygenase, Cys-LT, mice

Ya-Yun Xu,1,2 Jun Liang,1,2 Yin Cao,1,2 Feng Shan,1,2 Yang Liu,1,2 Qing-Rong Xia1,2 1Department of Pharmacy, Hefei Fourth People’s Hospital, Hefei, People’s Republic of China; 2Anhui Mental Health Center, Hefei, People’s Republic of China Abstract: Despite the increasing amount of evidence suggesting a relationship between depression and subclinical hypothyroidism (SCH), the exact mechanism underlying this relationship remains unclear. The main purpose of this study was to investigate the roles of plasma Nesfatin-1 levels and dysfunction of the hypothalamic–pituitary–adrenal (HPA) and hypothalamus–pituitary–thyroid (HPT) axes in the comorbidity of depression and SCH. Dysfunctions of the HPA and HPT axes were detected by measuring plasma corticosterone and thyroid-stimulating hormone (TSH) concentrations, respectively. Subjects in the patient group were selected from patients hospitalized at the Anhui Mental Health Center, and subjects in the control group were recruited from healthy volunteers. Healthy control subjects were matched to the patients in terms of weight and body mass index. The Hamilton Depression Rating Scale was administered to both the groups. The enzyme-linked immunosorbent assay method was used to measure plasma Nesfatin-1, corticosterone, and TSH levels. A radioimmunoassay kit was used for the measurement of the plasma-free triiodothyronine and plasma-free thyroxine. The results showed that the Hamilton Depression Rating Scale scores and average Nesfatin-1, corticosterone, and TSH levels were significantly higher in depressed patients with SCH than in the control group. Moreover, positive relationships were observed between Nesfatin-1 levels and the concentrations of corticosterone (r=0.626, P

Abstract Background: The present study investigated the enhancement efficiency between liposomes and microbubbles for insulin pulmonary absorption. Methods: Two types of phospholipid-based vesicle-liposomes and microbubbles-were prepared, and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) cytotoxicity test was used to evaluate their in vitro toxicity in A549 cells. Cellular uptake of insulin combined with liposomes or microbubbles was determined using A549 cells. With intratracheal insufflation of Sprague-Dawley rats, an insulin mixture with liposomes or microbubbles was administered to assess its potential for promoting drug pulmonary absorption. Results: Both liposomes and microbubbles had a narrow and monodispersed size distribution with average diameter of 3.1 [mu]m and 1.0 [mu]m, respectively. From the MTT cytotoxicity test, a phospholipid-based vesicle concentration of <25% (vol/vol) in the final volume was the safe dosage range that could avoid severe cytotoxic effects. The intracellular uptake amount of insulin in the insulin-microbubble mixture was significantly higher than that in the insulin-liposome mixture. The minimum reductions of the blood glucose concentration produced by insulin-microbubble and insulin-liposome mixtures were 60.8% and 35.0% of the initial glucose levels, respectively, and their bioavailabilities relative to subcutaneous injection were 48.6% and 30.8%, respectively. Conclusions: Microbubbles have much better efficiency than liposomes in the rate and extent of insulin pulmonary absorption. Microbubbles might be recommended as a potential agent for enhancing protein intrapulmonary absorption. [ABSTRACT FROM AUTHOR]

Background and Objectives: A quarter of ischemic strokes are of lacunar clinical subtype and have an underlying recent small subcortical infarct (RSSI), but their long-term outcomes remain poorly characterized. Hemosiderin deposits (HDs) have been noted in RSSIs at chronic stages and might mimic primary hemorrhage. We characterized HDs' morphology, frequency, and clinical relevance., Methods: Participants with RSSIs were identified from a prospective longitudinal study and evaluated on 3T MRI including susceptibility-weighted imaging (SWI) from stroke diagnosis to 12 months. We categorized HDs in RSSIs on SWI at all available time points into 4 types (spots, smudge, rim, cluster) and assessed their associations with demographic factors, stroke-related factors, and image markers with adjusted logistic regression., Results: HDs were observed in 43 (55.0%) of 108 participants within 3 months and 83 (76.9%) of 108 within 12 months after stroke onset. The mean time to first detection of HDs was 87 (interquartile range 53-164) days. A "rim" pattern (similar to late appearance of primary hemorrhage) occurred in at least 26.5% of RSSIs at all follow-up time points, mainly those located in the lentiform/internal capsule (50.0%) or thalamus (36.4%). Infarct volume (odds ratio [OR] 1.003, 95% CI 1.001-1.006; p = 0.004) and the total small vessel disease (SVD) score at baseline (OR 2.50, 95% CI 1.28-4.86, p = 0.007) independently predicted HDs at 12 months. HDs were positively associated with more lacunes (OR 1.60, 95% CI 1.13-2.26, p < 0.01), but not the Fazekas score, number of microbleeds, basal ganglia mineral deposit score, or clinical outcomes., Discussion: HDs occur commonly in RSSIs and may be associated with infarct volume and SVD score. Hemosiderin "rim" is common in RSSIs, urging caution to avoid mistaking ischemic RSSI for primary hemorrhage in subacute and chronic stages.

Objective: To analyze the temporal trends of the incidence rate of tuberculosis (TB) in Shaanxi Province and provide a reference for WHO to control the prevalence of TB effectively. Methods: Joinpoint regression was used to analyze the trend of the incidence rate of TB in Shaanxi Province from 2004 to 2022, and the seasonal autoregressive moving average model was used to forecast the incidence rate of TB in Shaanxi Province to 2030. Results: The incidence rate of TB in Shaanxi Province decreased from 90.896/100 000 in 2004 to 35.364/100 000 in 2022, showing a general downward trend (AAPC=-7.72%, P <0.001). From 2014 to 2019, the reduction trend slowed down (APC=-0.69%, P =0.814), of which the largest decline occurred from 2019 to 2022 (APC=-13.26%, P =0.010). The predicted incidence rate of TB in Shaanxi Province from 2020 to 2022 was higher than the reported incidence rate, with the expected incidence rate of 51.342/100 000 in 2022 and 43.468/100 000 in 2030. Conclusion: The incidence rate of TB in Shaanxi Province shows a downward trend from 2004 to 2022, but the decline has shrunk in recent years. It is predicted that the downward trend will continue to slow down by 2030.

Aims: MicroRNA-126 (miR-126), one of the most abundant microRNAs in platelets, is involved in the regulation of platelet activity and the circulating miR-126 is reduced during antiplatelet therapy. However, whether intraplatelet miR-126 plays a role in thrombosis and platelet inhibition remains unclear., Methods and Results: Here, using tissue-specific knockout mice, we reported that the deficiency of miR-126 in platelets and vascular endothelial cells significantly prevented thrombosis and prolonged bleeding time. Using chimeric mice, we identified that the lack of intraplatelet miR-126 significantly prevented thrombosis. Ex vivo experiments further demonstrated that miR-126-deficient platelets displayed impaired platelet aggregation, spreading, and secretory functions. Next, miR-126 was confirmed to target phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2) in platelet, which encodes a negative regulator of the phosphoinositide 3-kinase/protein kinase B pathway, enhancing platelet activation through activating the integrin αIIbβ3-mediated outside-in signalling. After undergoing myocardial infarction (MI), chimeric mice lacking intraplatelet miR-126 displayed reduced microvascular obstruction and prevented MI expansion in vivo. In contrast, overexpression of miR-126 by the administration of miR-126 agonist (agomiR-126) in wild-type mice aggravated microvascular obstruction and promoted MI expansion, which can be almost abolished by aspirin administration. In patients with cardiovascular diseases, antiplatelet therapies, either aspirin alone or combined with clopidogrel, decreased the level of intraplatelet miR-126. The reduction of intraplatelet miR-126 level was associated with the decrease in platelet activity., Conclusion: Our murine and human data reveal that (i) intraplatelet miR-126 contributes to platelet activity and promotes thrombus formation, and (ii) the reduction of intraplatelet miR-126 contributes to platelet inhibition during antiplatelet therapy., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Humans are often exposed to complex mixtures of multiple pollutants rather than a single pollutant. However, the combined toxic effects and the molecular mechanism of PFOS and BaP remain poorly understood. In this study, two typical environmental pollutants, perfluorooctane sulfonate acid (PFOS) and benzo [a]pyrene (BaP), were selected to investigate their combined neurotoxic effects on rat C6 glioma cells at environmentally relevant concentrations. The results showed that coexposure to low-dose PFOS and BaP induced greater toxicity (synergistic effect) than did single exposure. PFOS-BaP coexposure had stronger toxic effects on inducing oxidative stress and promoting early apoptosis. Targeted metabolomics confirmed that increased levels of the neurotransmitters 5-hydroxytryptophan, dopamine, tryptophan and serotonin disturb the phenylalanine, tyrosine and tryptophan biosynthesis pathways. Mechanistically, exposure to a low-dose PFOS-BaP binary mixture induces steroid hormone synthesis disorder through the activation of Cyp1a1 and Hsd17b8 (steroid hormone synthesis genes) and Dhcr24 and Dhcr7 (cholesterol synthesis genes). These findings are useful for comprehensively and systematically elucidating the biological safety of PFOS-BaP and its potential threats to human health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Diabetic Kidney Disease (DKD) is a complex disease associated with circadian rhythm and biological clock regulation disorders. Melatonin (MT) is considered a hormone with renal protective effects, but its mechanism of action in DKD is unclear., Methods: We used the GSE151325 dataset from the GEO database for differential gene analysis and further explored related genes and pathways through GO and KEGG analysis and PPI network analysis. Additionally, this study used a type 2 diabetes db/db mouse model and investigated the role of melatonin in DKD and its relationship with clock genes through immunohistochemistry, Western blot, real-time PCR, ELISA, chromatin immunoprecipitation (ChIP), dual-luciferase reporter technology, and liposome transfection technology to study DEC1 siRNA., Results: Bioinformatics analysis revealed the central position of clock genes such as CLOCK, DEC1, Bhlhe41, CRY1, and RORB in DKD. Their interaction with key inflammatory regulators may reveal melatonin's potential mechanism in treating diabetic kidney disease. Further experimental results showed that melatonin significantly improved the renal pathological changes in db/db mice, reduced body weight and blood sugar, regulated clock genes in renal tissue, and downregulated the TLR2/MyD88/NF-κB signaling pathway. We found that the transcription factor DEC1 can bind to the TLR2 promoter and activate its transcription, while CLOCK's effect is unclear. Liposome transfection experiments further confirmed the effect of DEC1 on the TLR2/MyD88/NF-κB signaling pathway., Conclusion: Melatonin shows significant renal protective effects by regulating clock genes and downregulating the TLR2/MyD88/NF-κB signaling pathway. The transcription factor DEC1 may become a key regulatory factor for renal inflammation and fibrosis by activating TLR2 promoter transcription. These findings provide new perspectives and directions for the potential application of melatonin in DKD treatment., (© 2024. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Purpose: The neurologic examination of patients undergoing extracorporeal membrane oxygenation (ECMO) is crucial for evaluating irreversible encephalopathy but is often obscured by sedation or neuromuscular blockade. Noninvasive neuromonitoring modalities including diffuse correlation spectroscopy and EEG measure cerebral perfusion and neuronal function, respectively. We hypothesized that encephalopathic ECMO patients with greater degree of irreversible cerebral injury demonstrate less correlation between electrographic activity and cerebral perfusion than those whose encephalopathy is attributable to medications., Methods: We performed a prospective observational study of adults undergoing ECMO who underwent simultaneous continuous EEG and diffuse correlation spectroscopy monitoring. (Alpha + beta)/delta ratio and alpha/delta Rartio derived from quantitative EEG analysis were correlated with frontal cortical blood flow index. Patients who awakened and followed commands during sedation pauses were included in group 1, whereas patients who could not follow commands for most neuromonitoring were placed in group 2. (Alpha + beta)/delta ratio-blood flow index and ADR-BFI correlations were compared between the groups., Results: Ten patients (five in each group) underwent 39 concomitant continuous EEG and diffuse correlation spectroscopy monitoring sessions. Four patients (80%) in each group received some form of analgosedation during neuromonitoring. (Alpha + beta)/delta ratio-blood flow index correlation was significantly lower in group 2 than group 1 (left: 0.05 vs. 0.52, P = 0.03; right: -0.12 vs. 0.39, P = 0.04). Group 2 ADR-BFI correlation was lower only over the right hemisphere (-0.06 vs. 0.47, P = 0.04)., Conclusions: Correlation between (alpha + beta)/delta ratio and blood flow index were decreased in encephalopathic ECMO patients compared with awake ones, regardless of the analgosedation use. The combined use of EEG and diffuse correlation spectroscopy may have utility in monitoring cerebral function in ECMO patients., Competing Interests: I. R. Khan reports grants from the National Institute of Neurologic Disorders and Stroke, National Heart, Lung, and Blood Institute, and the Department of Defense; G. Schifitto report grants from the National Institute of Neurologic Disorders and Stroke; D. R. Busch reports grants from The Hartwell Foundation, National Institute of Neurologic Disorders and Stroke, and National Institute of Biomedical Imaging and Bioengineering. D. R. Busch has patents on aspects of DCS technologies. These patents are not licensed and produce no revenue. D. R. Busch has equity interest in NFOSYS, a startup seeking to commercialize minimally invasive DCS tools, which currently has no sales and no revenue; R. Choe reports grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases; and R. K. Maddox reports grants from the National Institute on Deafness and Other Communication Disorders, all during the conduct of this study. I. Gosev received consulting and personal fees from Abbott, ABIOMED, and Zimmer Biomet Holdings, outside the scope of this work. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2023 by the American Clinical Neurophysiology Society.)

Objective: To establish the dynamic treatment strategy of Chinese medicine (CM) for metastatic colorectal cancer (mCRC) by machine learning algorithm, in order to provide a reference for the selection of CM treatment strategies for mCRC., Methods: From the outpatient cases of mCRC in the Department of Oncology at Xiyuan Hospital, China Academy of Chinese Medical Sciences, 197 cases that met the inclusion criteria were screened. According to different CM intervention strategies, the patients were divided into 3 groups: CM treatment alone, equal emphasis on Chinese and Western medicine treatment (CM combined with local treatment of tumors, oral chemotherapy, or targeted drugs), and CM assisted Western medicine treatment (CM combined with intravenous regimen of Western medicine). The survival time of patients undergoing CM intervention was taken as the final evaluation index. Factors affecting the choice of CM intervention scheme were screened as decision variables. The dynamic CM intervention and treatment strategy for mCRC was explored based on the cost-sensitive classification learning algorithm for survival (CSCLSurv). Patients' survival was estimated using the Kaplan-Meier method, and the survival time of patients who received the model-recommended treatment plan were compared with those who received actual treatment plan., Results: Using the survival time of patients undergoing CM intervention as the evaluation index, a dynamic CM intervention therapy strategy for mCRC was established based on CSCLSurv. Different CM intervention strategies for mCRC can be selected according to dynamic decision variables, such as gender, age, Eastern Cooperative Oncology Group score, tumor site, metastatic site, genotyping, and the stage of Western medicine treatment at the patient's first visit. The median survival time of patients who received the model-recommended treatment plan was 35 months, while those who receive the actual treatment plan was 26.0 months (P=0.06)., Conclusions: The dynamic treatment strategy of CM, based on CSCLSurv for mCRC, plays a certain role in providing clinical hints in CM. It can be further improved in future prospective studies with larger sample sizes., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Although Type-I photodynamic therapy has attracted increasingly growing interest due to its reduced dependence on oxygen, the design of effective Type-I photosensitizers remains a challenge. In this work, we report a design strategy for Type-I photosensitizers by the involvement of hydrogen atom transfer (HAT). As a proof of concept, a HAT-involved Type-I PS, which simultaneously generates superoxide and carbon-centered radicals under light-irradiation, was synthesized. This photosensitizer is comprised of a fluorene-substituted BODIPY unit as an electron acceptor covalently linked with a triphenylamine moiety as an electron donor. Under light-irradiation, photo-induced intramolecular electron transfer occurs to generate the BODIPY anion radical and triphenylamine cation radical. The former transfers electrons to oxygen to generate O 2 - ⋅, while the latter loses a proton to produce a benzyl carbon-centered radical which is well characterized. The resulting carbon-centered radicals efficiently oxidize NADH by HAT reaction. This photosensitizer demonstrates remarkable photocytotoxicity even under hypoxic conditions, along with outstanding in vivo antitumor efficacy in mouse models bearing HeLa tumors. This work offers a novel strategy for the design of Type-I photosensitizers by involvement of HAT., (© 2024 Wiley-VCH GmbH.)

Objective: To describe the epidemiological characteristics and trends of leukemia incidence in Qidong between 1972 and 2021, and provide guidelines for prevention and control measures and strategies. Methods: The cancer registry data was collected and analyzed on leukemia incidence during 1972-2021 in Qidong by sex, age and time. Crude incidence rate (CR), China age-standardized rate (ASRC), world age-standardized rate (ASRW), and average annual change percentage (AAPC) was calculated by Joinpoint software. Age-period-cohort (APC) model was used to analyze the influence of age, period and birth cohort on the changes in the incidence trend of leukemia patients. Results: From 1972 to 2021, there were 2 948 patients with leukemia in Qidong, accounting for 2.00% of all cancer new cases, CR of leukemia was 5.26/10 5 , ASRC was 4.34/10 5 , ASRW was 4.35/10 5 . The truncated incidence of 35-64 years old was 5.29/10 5 , the cumulative incidence rate between the ages of 0 and 74 years old was 0.40%, the cumulative risk was 0.40%. There were 1 608 male patients, the CR, ASRC, and the ASRW were 5.81/10 5 , 4.88/10 5 and 4.85/10 5 . The number of female patients were 1 340, and the CR, ASRC, and the ASRW were 4.71/10 5 , 3.86/10 5 and 3.91/10 5 , respectively. Temporal trends indicated significant upward trends in ASRC among both gender, males and females with AAPC values of 1.41% ( P ＜0.001), 1.15% ( P ＜0.001), and 1.73% ( P ＜0.001), respectively. The results of the APC model showed that the average net drift value of leukemia incidence in all age groups was 1.57% (95% CI , 1.24%-1.89%), and the highest value of local drift was 3.20% (95% CI , 1.63%-4.78%) in the 80~ years old group. The incidence of leukemia increased with age. With the passage of time, the risk of leukemia incidence increased gradually compared with the rate ratio of leukemia incidence (risk ratio [ RR ], 1.00) in 1992-1996, the RR of leukemia incidence increased from 0.70 during 1972-1976 to 1.57 during 2017-2021. The later the cohort was born, the greater the risk of leukemia incidence compared with the relative risk of leukemia incidence ( RR , 1.00) in 1952-1956 cohort, the RR of leukemia incidence increased from 0.24 in the 1892-1896 cohort to 2.73 in the 2017-2021 cohort. Conclusions: The incidence of the leukemia has presented a rising trend in the past fifty years. Leukemia incidence increased with age, and the period and cohort effects on the risk of incidence increase. Further research is needed to investigate the risk factors related to leukemia.

Background: Histone deacetylase (HDAC), a kind of protease that regulates gene expression by modifying protein acetylation levels, is usually aberrantly activated in tumors. The approved pan-HDAC inhibitors (HDACi) have exhibited clinical benefits for hematopoietic malignancies. Recently, HDACis have emerged as enhancers of antitumor immunity. However, the effect of HDACs on the tumor immune microenvironment of lung adenocarcinoma (LUAD) and the underlying mechanism is largely unknown., Methods: C57BL/6J and BALB/c nude mice with subcutaneous tumors were used for in vivo therapeutic effects and mechanistic investigations. Flow cytometry was used to measure the toxicity and exhaustion of human CD8+T cells after co-culturing with tumor cells and to determine the immunophenotype of tumor-infiltrating CD8+T cells. A series of experimental techniques, including RNA sequencing, quantitative PCR, western blot, ELISA, mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation and immunohistochemistry, were used to explore the underlying molecular mechanism., Results: The pan-HDACi vorinostat (SAHA) promoted CD8+T cell infiltration and effector function in LUAD through suppressing FGL1, a newly identified major ligand of LAG-3. Mechanistically, SAHA inhibited the activity of HDAC1, an essential deacetylase of JAK1. This increased the acetylation level of JAK1 at lysine 1109, thus promoting its proteasomal degradation and subsequently reducing STAT3-driven FGL1 transcription. The combination regimen of SAHA and anti-LAG-3 therapy was further explored in an immunocompetent LUAD mouse model. Compared with those receiving control or single agent treatments, mice receiving combination therapy exhibited a lower tumor burden and superior CD8+T-cell-killing activity., Conclusions: Our results revealed a novel mechanism by which the HDACi SAHA potentiates CD8+T-cell-mediated antitumor activity through the HDAC1/JAK1/FGL1 axis, providing a rationale for the combined use of HDACis and immunotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The crucial role of gut microbiota in shaping immunotherapy outcomes has prompted investigations into potential modulators. Here we show that oral administration of acarbose significantly increases the anti-tumour response to anti-PD-1 therapy in female tumour-bearing mice. Acarbose modulates the gut microbiota composition and tryptophan metabolism, thereby contributing to changes in chemokine expression and increased T cell infiltration within tumours. We identify CD8 + T cells as pivotal components determining the efficacy of the combined therapy. Further experiments reveal that acarbose promotes CD8 + T cell recruitment through the CXCL10-CXCR3 pathway. Faecal microbiota transplantation and gut microbiota depletion assays indicate that the effects of acarbose are dependent on the gut microbiota. Specifically, acarbose enhances the efficacy of anti-PD-1 therapy via the tryptophan catabolite indoleacetate, which promotes CXCL10 expression and thus facilitates CD8 + T cell recruitment, sensitizing tumours to anti-PD-1 therapy. The bacterial species Bifidobacterium infantis, which is enriched by acarbose, also improves response to anti-PD-1 therapy. Together, our study endorses the potential combination of acarbose and anti-PD-1 for cancer immunotherapy., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The sustainable development of sports facilities and their integration with the ecological environment are crucial in addressing global environmental challenges. This study examines the coupling coordination between sports facilities and the ecological environment in nine prefecture-level cities in Fujian Province, China, from 2013 to 2020, within the framework of China's "Dual Carbon" strategy. Using a multidisciplinary approach that integrates economics, sociology, and geography, the study employs the entropy method and coupling coordination models to analyze the temporal evolution and spatial distribution of the coupling coordination between sports facilities and the ecological environment. The findings reveal that the overall trend of coupling coordination is positive, with the degree of coordination improving over time from severe imbalance in 2013 to high-quality coordination by 2020. Economic factors, such as per capita GDP, positively influence the coupling coordination, while factors like population density and regional GDP have a negative impact. Coastal cities, such as Xiamen and Zhangzhou, demonstrate stronger regional correlations and play a critical role in improving the overall coupling level of the province. This research provides several recommendations for promoting orderly and optimal development, considering the distinct characteristics of sports facilities and the ecological environment., (© 2024. The Author(s).)

Refractory acute T-lymphoblastic leukemia (T-ALL), which is characterized by a low sensitivity to conventional induction therapy and poor prognosis, poses significant challenges during treatment. This study reported a case of refractory T-ALL patient with mutations in the JAK1, JAK3, and STAT5B genes from Nanjing University's Gulou Hospital. Following an unsuccessful course of standard VDLP regimen chemotherapy, the treatment was modified to include ruxolitinib in combination with venetoclax and azacitidine. Subsequent to this therapy, the patient achieved bone marrow minimal residual disease (MRD) negativity. Notably, pleural effusion and mediastinal mass significantly improved the post-chest cavity infusion of dexamethasone combined with etoposide at the same stage. The patient also underwent allogeneic hematopoietic stem cell transplantation upon achieving bone marrow remission and was followed up until January 2024. Ruxolitinib combined with venetoclax and azacytidine has shown promising efficacy and safety in treating refractory T-ALL harboring the JAK1, JAK3, and STAT5B mutations, providing a novel therapeutic approach for such patients.

Dermatan sulfate and chondroitin sulfate are dietary supplements that can be utilized as prophylactics against thrombus formation. Low-molecular-weight dermatan sulfate (LMWDS) is particularly advantageous due to its high absorbability. The enzymatic synthesis of low-molecular-weight dermatan sulfates (LMWDSs) using chondroitin B lyase is a sustainable and environmentally friendly approach to manufacturing. However, the industrial application of chondroitin B lyases is severely hampered by their low catalytic activity. To improve the activity, a semi-rational design strategy of engineering the substrate-binding domain of chondroitin B lyase was performed based on the structure. The binding domain was subjected to screening of critical residues for modification using multiple sequence alignments and molecular docking. A total of thirteen single-point mutants were constructed and analyzed to assess their catalytic characteristics. Out of these, S90T, N103C, H134Y, and R159K exhibited noteworthy enhancements in activity. This study also examined combinatorial mutagenesis and found that the mutant H134Y/R159K exhibited a substantially enhanced catalytic activity of 1266.74 U/mg, which was 3.21-fold that of the wild-type one. Molecular docking revealed that the enhanced activity of the mutant could be attributed to the formation of new hydrogen bonds and hydrophobic interactions with the substrate as well as neighbor residues. The highly active mutant would benefit the utilization of chondroitin B lyase in pharmaceuticals and functional foods.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, characterized by difficulties in early diagnosis, prone to distant metastasis, and high recurrence rates following surgery. Extracellular vesicles (EVs) are a class of cell-derived particles, including exosomes, characterized by a phospholipid bilayer. They serve as effective carriers for intercellular communication cargo, including proteins and nucleic acids, and are widely involved in tumor progression. They are being explored as potential tumor biomarkers and novel therapeutic avenues. We provide a brief overview of the biogenesis and characteristics of EVs to better understand their classification standards. The focus of this review is on the research progress of EV-associated proteins in the field of HCC. EV-associated proteins are involved in tumor growth and regulation in HCC, participate in intercellular communication within the tumor microenvironment (TME), and are implicated in events including angiogenesis and epithelial-mesenchymal transition (EMT) during tumor metastasis. In addition, EV-associated proteins show promising diagnostic efficacy for HCC. For the treatment of HCC, they also demonstrate significant potential including enhancing the efficacy of tumor vaccines, and as targeting cargo anchors. Facing current challenges, we propose the future directions of research in this field. Above all, research on EV-associated proteins offers the potential to enhance our comprehension of HCC and offer novel insights for developing new treatment strategies., (© 2024. The Author(s).)

This study aimed to systematically evaluate the efficacy of liraglutide in treating type 2 diabetes mellitus (T2DM) complicated with non-alcoholic fatty liver disease (NAFLD) by comparing liraglutide with placebo or other drugs (mainly insulin). The PubMed, Web of Science, and National Library of Medicine databases were systematically searched from their inception until December 1, 2023. A meta-analysis was performed using Stata 15.1 software. A total of 12 studies with 13 outcome measures were included. The meta-analysis results revealed that liraglutide significantly reduced body mass index (mean difference [MD] = -1.06, 95%CI: -1.41, -0.70, p < 0.001), triglycerides (MD = -0.35, 95%CI: -0.61, -0.09, p = 0.0009), visceral adipose tissue (MD = -21.06, 95%CI: -34.58, -7.55, p = 0.002), and subcutaneous adipose tissue (MD = -20.53, 95%CI: -29.15, -11.90, p < 0.001) levels in patients with T2DM and NAFLD. Of the 11 studies, 2 reported the occurrence of adverse reactions, which were primarily gastrointestinal. Compared with placebo and other drugs (e.g., insulin), liraglutide may improve glucose metabolism, lipid and liver function parameters, and visceral and subcutaneous fat in patients with T2DM and NAFLD, thus constituting an effective treatment for these patients.

Machine learning has been employed in recognizing protein localization at the subcellular level, which highly facilitates the protein function studies, especially for those multi-label proteins that localize in more than one organelle. However, existing works mostly study the qualitative classification of protein subcellular locations, ignoring fraction of one multi-label protein in different locations. Actually, about 50 % proteins are multi-label proteins, and the ignorance of quantitative information highly restricts the understanding of their spatial distribution and functional mechanism. One reason of the lack of quantitative study is the insufficiency of quantitative annotations. To address the data shortage problem, here we proposed a generative model, PLocGAN, which could generate cell images with conditional quantitative annotation of the fluorescence distribution. The model was a conditional generative adversarial network, in which the condition learning utilized partial label learning to overcome the lack of training labels and allowed training with only qualitative labels. Meanwhile, it used contrastive learning to enhance diversity of the generated images. We assessed the PLocGAN on four pixel-fused synthetic datasets and one real dataset, and demonstrated that the model could generate images with good fidelity and diversity, outperforming existing state-of-the-art generative methods. To verify the utility of PLocGAN in the quantitative prediction of protein subcellular locations, we replaced the training images with generated quantitative images and built prediction models, and found that they had a boosting effect on the quantitative estimation. This work demonstrates the effectiveness of deep generative models in bioimage analysis, and provides a new solution for quantitative subcellular proteomics., Competing Interests: Declaration of competing interest None Declared., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The freshness of Atlantic salmon is influenced mainly by tissue metabolism, which in turn is affected by storage time and conditions. The alterations in taste profiles and nutritional values of salmon when packaged using vacuum methods have not been fully understood, and the factors contributing to these changes require further research. In this work, the extraction method for flavor nutrients from salmon was optimized via the Plackett-Burman (PB) test. A sensitive and rapid targeted metabolomics method for the simultaneous determination of 34 nutrients was successfully established via ultra-performance liquid chromatography-triple quadrupole/linear ion trap composite mass spectrometry (UHPLC-QTRAP/MS), and various nutritional compositions during storage at 0 °C under different vacuum conditions (0 kPa or -90 kPa) for 4 and 8 days were analyzed. Results showed that storage time had a significant effect on salmon metabolism. The total amino acids decreased by 62.95% and 65.89% at 0 kPa and -90 kPa, respectively. Notably, a marked reduction in histidine after 8 days at -90 kPa may have diminished bitterness, while decreased levels of umami-tasting amino acids like glutamine and aspartic acid affected the overall flavor profile. Overall, the packaging conditions at 0 °C and 0 kPa were more suitable for the preservation of most nutrients in salmon. Pathway enrichment analysis revealed that the reduction in substances was mainly related to the alanine, aspartate, and glutamate metabolism pathways. Alanine, inosine, and histidine, whose levels changed significantly, can bind to the typical umami taste receptor TIR1/TIR3 and can be biomarkers to monitor and determine the freshness or spoilage of salmon after 4-8 days of storage. This study revealed the changes in small-molecule nutrients in salmon during storage under different packaging conditions, which provides a reference for the packaging preservation technology of fresh salmon and new ideas for the evaluation of salmon quality and determination of freshness.

The removal of mis-incorporated nucleotides by proofreading activity ensures DNA replication fidelity. Whereas the ε-exonuclease DnaQ is a well-established proofreader in the model organism Escherichia coli , it has been shown that proofreading in a majority of bacteria relies on the polymerase and histidinol phosphatase (PHP) domain of replicative polymerase, despite the presence of a DnaQ homolog that is structurally and functionally distinct from E. coli DnaQ. However, the biological functions of this type of noncanonical DnaQ remain unclear. Here, we provide independent evidence that noncanonical DnaQ functions as an additional proofreader for mycobacteria. Using the mutation accumulation assay in combination with whole-genome sequencing, we showed that depletion of DnaQ in Mycolicibacterium smegmatis leads to an increased mutation rate, resulting in AT-biased mutagenesis and increased insertions/deletions in the homopolymer tract. Our results showed that mycobacterial DnaQ binds to the β clamp and functions synergistically with the PHP domain proofreader to correct replication errors. Furthermore, the loss of dnaQ results in replication fork dysfunction, leading to attenuated growth and increased mutagenesis on subinhibitory fluoroquinolones potentially due to increased vulnerability to fork collapse. By analyzing the sequence polymorphism of dnaQ in clinical isolates of Mycobacterium tuberculosis ( Mtb ), we demonstrated that a naturally evolved DnaQ variant prevalent in Mtb lineage 4.3 may enable hypermutability and is associated with drug resistance. These results establish a coproofreading model and suggest a division of labor between DnaQ and PHP domain proofreader. This study also provides real-world evidence that a mutator-driven evolutionary pathway may exist during the adaptation of Mtb ., Competing Interests: Competing interests statement:The authors declare no competing interest.

The coronavirus disease 2019 (COVID-19) pandemic poses an enormous threat to public health worldwide. Many retrospective studies and case reports to date have shown associations between severe COVID-19 and diseases of multi-organs. However, the research on the causal mechanisms behind this phenomenon is neither extensive nor comprehensive. We conducted a proteome-wide Mendelian randomization (MR) study using summary statistics from a Genome-Wide Association Studies (GWAS) of severe COVID-19 and diseases related to seven organs: lung, spleen, liver, heart, kidney, testis, and thyroid, based on the European ancestry. The primary analytical method used is the radial inverse variance-weighted (radial IVW) method, supplemented with the inverse variance-weighted (IVW), weighted-median (WM), MR-Egger methods. Our findings have confirmed the association between severe COVID-19 and multiple organ-related diseases, such as Hypothyroidism, strict autoimmune (HTCBSA), Thyroid disorders (TD), and Graves' disease (GD). And we have also identified certain proteins that are associated with organ-related diseases, such as Superoxide Dismutase 2 (SOD2) and TEK Receptor Tyrosine Kinase (TEK), which are also considered potential drug targets. Phenotype scanning and sensitivity analyses were implemented to consolidate the results for Mendelian randomization. This study provides a compelling foundation for investigating COVID-19 caused diseases in future studies., Competing Interests: Author HP was employed by MobiDrop (Zhejiang) Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shen, Zhang, Xu, Li, Wu, Pei, Wang and Zhu.)

The synthesis of polycyclic aromatic hydrocarbon (PAH) data allows us to quantify and gain insights into the spatiotemporal dynamics of PAH contamination in marine bays. Here, a data synthesis framework was developed to understand data-driven insights into the spatiotemporal levels, compositional profiles, and potential sources of PAHs in water and sediment of marine bays. PAHs were detected in 69 bays worldwide, with contamination hotspots located in Asian bays. PAH concentrations in pre-2000 were significantly lower than those in the 2000s and post-2010, while the dominant species in water and sediment were 2-3 ring and 4-6 ring PAHs, respectively. The composition patterns of PAHs included 2-3 ring, 3-5 ring, and 4-5 ring dominant categories, but no significant distance decay relationship was found in the composition similarity due to international energy trade. Temporal dynamic patterns of concentrations included Descending-, Ascending-, and Inverted V-type, whereas over longer time spans, the pattern is more similar to the Inverted V-type owing to the reductions in emission intensity. PAHs were derived from both petrogenic and pyrolytic sources, with combustion from both coal and petroleum being the dominant source. These data-driven discoveries provide quantitative insights into the spatiotemporal patterns in the concentration and composition of PAHs, contributing to the mitigation of PAH contamination.

Nanozymes are promising antimicrobials, as they produce reactive oxygen species (ROS). However, the intrinsic lack of selectivity of ROS in distinguishing normal flora from pathogenic bacteria deprives nanozymes of the necessary selectivities of ideal antimicrobials. Herein, we exploit the physiological conditions of bacteria (high alkaline phosphatase (ALP) expression) using a novel CuO nanoparticle (NP) nanoenzyme system to initiate an ALP-activated ROS prodrug system for use in the on-demand precision killing of bacteria. The prodrug strategy involves using 2-phospho-L-ascorbic acid trisodium salt (AAP) that catalyzes the ALP in pathogenic bacteria to generate ascorbic acid (AA), which is converted by the CuO NPs, with intrinsic ascorbate oxidase- and peroxidase-like activities, to produce ROS. Notably, the prodrug system selectively kills Escherichia coli (pathogenic bacteria), with minimal influence on Staphylococcus hominis (non-pathogenic bacteria) due to their different levels of ALP expression. Compared to the CuO NPs/AA system, which generally depletes ROS during storage, CuO NPs/AAP exhibits a significantly higher stability without affecting its antibacterial activity. Furthermore, a rat model is used to indicate the applicability of the CuO NPs/AAP fibrin gel in wound disinfection in vivo with negligible side effects. This study reveals the therapeutic precision of this bifunctional tandem nanozyme platform against pathogenic bacteria in ALP-activated conditions., (© 2024. The Author(s).)

Aesthetic education, conveyed through public art courses, serves as a vital form of humanistic literacy education. It represents an effective approach to fostering innovative and creative thinking among college students. In order to effectively analyze the aesthetic education work of 46 universities, an aesthetic education index evaluation system is constructed, involving indicators including faculty strength, curriculum setting, teaching management, artistic practice, and teaching support. The secondary indicators corresponding to the five indicators are statistically analyzed, and a comprehensive evaluation analysis of the current development status of aesthetic education in 46 universities in Anhui Province is conducted by combining theoretical analysis with empirical analysis. Based on principal component analysis, an integrated evaluation model for the development of aesthetic education in universities in Anhui Province is further constructed. The model designed quantifies the influence weight of each aesthetic education index on the development of aesthetic education in Anhui Province, and forges a theoretical basis for determining the precursors of rapid development of aesthetic education in Anhui Province. Additionally, a novel approach is introduced to gauge the progression of aesthetic education within universities in Anhui Province, considering the dispersion of aesthetic education index data across the province. The comprehensive evaluation model for the development of aesthetic education in Anhui Province exhibits an overall declining trend. Hence, it is suggested to utilize the maximum value of the first derivative of the comprehensive evaluation model as an indicator of the imminent rapid development of aesthetic education in Anhui Province. On this basis, the probability equation of sustainable development of aesthetic education in Anhui Province is defined. Overall, the research results lay a theoretical foundation for the development of aesthetic education in Anhui Province., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Global patterns in soil microbiomes are driven by non-linear environmental thresholds. Fertilization is known to shape the soil microbiome of terrestrial ecosystems worldwide. Yet, whether fertilization influences global thresholds in soil microbiomes remains virtually unknown. Here, utilizing optimized machine learning models with Shapley additive explanations on a dataset of 10,907 soil samples from 24 countries, we discovered that the microbial community response to fertilization is highly dependent on environmental contexts. Furthermore, the interactions among nitrogen (N) addition, pH, and mean annual temperature contribute to non-linear patterns in soil bacterial diversity. Specifically, we observed positive responses within a soil pH range of 5.2-6.6, with the influence of higher temperature (>15°C) on bacterial diversity being positive within this pH range but reversed in more acidic or alkaline soils. Additionally, we revealed the threshold effect of soil organic carbon and total nitrogen, demonstrating how temperature and N addition amount interacted with microbial communities within specific edaphic concentration ranges. Our findings underscore how complex environmental interactions control soil bacterial diversity under fertilization., (© 2024 John Wiley & Sons Ltd.)

Wastewater discharge from wastewater treatment plants continuously pumps microplastics into rivers, yet their transport distances within these waterways remain unknown. Herein, we developed a conceptual framework by synthesizing the microplastic data from the Yangtze River Basin to evaluate its transport distances, quantifying a significant spatial dependence between large-scale wastewater discharge and riverine microplastics ( p < 0.05). The presence of microplastics at a specific sampling site could be attributed to wastewater discharge within a large-scale range spanning >1000 km upstream, encompassing a substantial portion equivalent to one-third of the Yangtze River Basin. The dominance analysis indicated that the contribution of wastewater discharge in rivers with higher discharge (>100 m 3 /s) to riverine microplastic pollution exceeded 65% within the Yangtze River Basin. The spatial dependence framework of riverine microplastics on wastewater discharge advances our prior understanding of the prevention and control of riverine microplastics by demonstrating that such pollution is not limited to nearby environmental factors.

Background: Erythrocyte dysfunction is a characteristic of diabetes mellitus (DM). However, erythrocyte-associated biomarkers do not adequately explain the high prevalence of DM. Here, we describe red blood cell distribution width to albumin ratio (RAR) as a novel inflammatory biomarker for evaluating an association with DM prevalence and prognosis of all-cause mortality., Methods: Data analyzed in this study were extracted from the National Health and Nutrition Examination Survey (NHANES) 1999-2020. A total of 40,558 participants (non-DM and DM) were enrolled in the study; RAR quartiles were calibrated at Q1 [2.02,2.82] mL/g, Q2 (2.82,3.05] mL/g, Q3 (3.05,3.38] mL/g, and Q4 (3.38,12.08] mL/g. A total of 8,482 DM patients were followed (for a median of 84 months), of whom 2,411 died and 6,071 survived. The prevalence and prognosis associated with RAR and DM were analyzed; age and sex were stratified to analyze the prevalence of RAR in DM and the sensitivity of long-term prognosis., Results: Among non-DM ( n =30,404) and DM ( n =10,154) volunteers, DM prevalence in RAR quartiles was 8.23%, 15.20%, 23.92%, and 36.39%. The multivariable odds ratio (OR) was significant for RAR regarding DM, at 1.68 (95% CI 1.42, 1.98). Considering Q1 as a foundation, the Q4 OR was 2.57 (95% CI 2.11, 3.13). The percentages of DM morbidity varied across RAR quartiles for dead ( n =2,411) and surviving ( n =6,071) DM patients. Specifically, RAR quartile mortality ratios were 20.31%, 24.24%, 22.65%, and 29.99% (P<0.0001). The multivariable hazard ratio (HR) for RAR was 1.80 (95% CI 1.57, 2.05). Considering Q1 as a foundation, the Q4 HR was 2.59 (95% CI 2.18, 3.09) after adjusting for confounding factors. Sensitivity analysis revealed the HR of male DM patients to be 2.27 (95% CI 1.95, 2.64), higher than females 1.56 (95% CI 1.31, 1.85). DM patients who were 60 years of age or younger had a higher HR of 2.08 (95% CI1.61, 2.70) as compared to those older than 60 years, who had an HR of 1.69 (95% CI 1.47, 1.94). The HR of RAR in DM patients was optimized by a restricted cubic spline (RCS) model; 3.22 was determined to be the inflection point of an inverse L-curve. DM patients with a RAR >3.22 mL/g suffered shorter survival and higher mortality as compared to those with RAR ≤3.22 mL/g. OR and HR RAR values were much higher than those of regular red blood cell distribution width., Conclusions: The predictive value of RAR is more accurate than that of RDW for projecting DM prevalence, while RAR, a DM risk factor, has long-term prognostic power for the condition. Survival time was found to be reduced as RAR increased for those aged ≤60 years among female DM patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Wang, Gao, Zhang, Zhang, Xu, Yao, Yang and Yan.)

Lung cancer is the top cause of cancer deaths globally. Advances in immune checkpoint inhibitors (ICIs) have transformed cancer treatment, but their use in lung cancer has led to more side effects. This study examined if past pulmonary tuberculosis (TB) affects ICIs' effectiveness and safety in lung cancer treatment. We reviewed lung cancer patients treated with ICIs at Beijing Chest Hospital from January 2019 to August 2022. We compared outcomes and side effects between patients with and without prior TB. Of 116 patients (40 with TB history, 76 without), prior TB didn't reduce treatment effectiveness but did increase severe side effects. Notably, older patients (≥ 65 years) faced a higher risk of severe side effects. Detailed cases of two patients with severe side effects underscored TB as a risk factor in lung cancer patients receiving ICIs, stressing the need for careful monitoring and personalized care., (Copyright © 2024 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Research on riverine microplastics has gradually increased, highlighting an area for further exploration: the lack of extensive, large-scale regional variations analysis due to methodological and spatiotemporal limitations. Herein, we constructed and applied a comprehensive framework for synthesizing and analyzing literature data on riverine microplastics to enable comparative research on the regional variations on a large scale. Research results showed that in 76 rivers primarily located in Asia, Europe, and North America, the microplastic abundance of surface water in Asian rivers was three times higher than that in Euro-America rivers, while sediment in Euro-American rivers was five times more microplastics than Asia rivers, indicating significant regional variations (p < 0.001). Additionally, based on the income levels of countries, rivers in lower-middle and upper-middle income countries had significantly (p < 0.001) higher abundance of microplastics in surface water compared to high-income countries, while the opposite was true for sediment. This phenomenon was preliminarily attributed to varying levels of urbanization across countries. Our proposed framework for synthesizing and analyzing microplastic literature data provides a holistic understanding of microplastic disparities in the environment, and can facilitate broader discussions on management and mitigation strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)