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There is a paradigm shift in the detection of phaeochromocytomas with more being identified as adrenal ‘incidentalomas’. While majority of these individuals are asymptomatic, they are nevertheless at risk of subtle cardiovascular dysfunction and phaeochromocytoma crises. Therefore, early resection of phaeochromocytomas, even if subclinical, is recommended. However, the perioperative management can be challenging as the normotension can limit the initiation and titration of alpha-blockade. We present a man in his 60s with a subclinical phaeochromocytoma, discuss the evaluation of an incidentally discovered adrenal nodule, as well as the practical considerations in the perioperative management.

Biliary tract cancers (BTCs) comprise a heterogeneous group of aggressive malignancies with unfavorable prognoses. The benefit of chemotherapy seems to have reached a bottleneck and, therefore, new effective therapeutic strategies for advanced BTCs are needed. Molecularly targeted therapies in selected patients are rapidly changing the situation. However, the low frequency of specific driver alterations in BTCs limits their wide application. Recently, immunotherapeutic approaches are also under active investigation in BTCs, but the role of immunotherapy in BTCs remains controversial.PubMed, Web of Science, and meeting resources were searched for relevant articles published from January 2017 to May 2022. The search aimed to identify current and emerging immunotherapeutic approaches for BTCs. Information on clinical trials was obtained from https://clinicaltrials.gov/ and http://www.chictr.org.cn/.Immunotherapy in BTC patients is currently under investigation, and most of the investigations focused on the application of immune checkpoint inhibitors (ICIs). However, only a subgroup of BTCs with microsatellite-instability high (MSI-H)/DNA mismatch repair-deficient (dMMR) or tumor mutational burden-high (TMB-H) benefit from monotherapy of ICIs, and limited activity was observed in the second or subsequent settings. Nevertheless, promising results come from studies of ICIs in combination with other therapeutic approaches, including chemotherapy, in advanced BTCs, with a moderate toxicity profile. Recent studies demonstrated that compared to GEMCIS alone, durvalumab plus GEMCIS significantly improved patient survival (TOPAZ-1 trial) and that ICIs-combined chemoimmunotherapy is poised to become a new frontline therapy option, regardless of TMB and MMR/MSI status. Adoptive cell therapy and peptide- or dendritic-based cancer vaccines are other immunotherapeutic options that are being studied in BTCs. Numerous biomarkers have been investigated to define their predictive role in response to ICIs, but no predictive biomarker has been validated, except MSI-H/dMMR.The role of immunotherapy in BTCs is currently under investigation and the results of ongoing studies are eagerly anticipated. Several studies have demonstrated the safety and efficacy of ICIs in combination with chemotherapy in treatment-naive patients, such as the phase III TOPAZ-1 trial, which will change the standard care of first-line chemotherapy for advanced BTCs. However, further research is needed to understand the best combination with immunotherapy and to discover more predictive biomarkers to guide clinical practice.

Cognitive dysfunction is a significant, untreated clinical need in patients with psychiatric disorders, for which preclinical studies are needed to understand the underlying mechanisms and to identify potential therapeutic targets. Early-life stress (ELS) leads to long-lasting deficits of hippocampus-dependent learning and memory in adult mice, which may be associated with the hypofunction of the brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB). In this study, we carried out eight experiments using male mice to examine the causal involvement of the BDNF-TrkB pathway in dentate gyrus (DG) and the therapeutic effects of the TrkB agonist (7,8-DHF) in ELS-induced cognitive deficits. Adopting the limited nesting and bedding material paradigm, we first demonstrated that ELS impaired spatial memory, suppressed BDNF expression and neurogenesis in the DG in adult mice. Downregulating BDNF expression (conditional BDNF knockdown) or inhibition of the TrkB receptor (using its antagonist ANA-12) in the DG mimicked the cognitive deficits of ELS. Acute upregulation of BDNF (exogenous human recombinant BDNF microinjection) levels or activation of TrkB receptor (using its agonist, 7,8-DHF) in the DG restored ELS-induced spatial memory loss. Finally, acute and subchronic systemic administration of 7,8-DHF successfully restored spatial memory loss in stressed mice. Subchronic 7,8-DHF treatment also reversed ELS-induced neurogenesis reduction. Our findings highlight BDNF-TrkB system as the molecular target of ELS-induced spatial memory deficits and provide translational evidence for the intervention at this system in the treatment of cognitive deficits in stress-related psychiatric disorders, such as major depressive disorder.

Adverse experiences in early life have long-lasting negative impacts on behavior and the brain in adulthood, one of which is sleep disturbance. As the corticotropin-releasing hormone (CRH)-corticotropin-releasing hormone receptor 1 (CRHR1) system and nucleus accumbens (NAc) play important roles in both stress responses and sleep-wake regulation, in this study we investigated whether the NAc CRH-CRHR1 system mediates early-life stress-induced abnormalities in sleep-wake behavior in adult mice. Using the limited nesting and bedding material paradigm from postnatal days 2 to 9, we found that early-life stress disrupted sleep-wake behaviors during adulthood, including increased wakefulness and decreased non-rapid eye movement (NREM) sleep time during the dark period and increased rapid eye movement (REM) sleep time during the light period. The stress-induced sleep disturbances were accompanied by dendritic atrophy in the NAc and both were largely reversed by daily systemic administration of the CRHR1 antagonist antalarmin during stress exposure. Importantly, Crh overexpression in the NAc reproduced the effects of early-life stress on sleep-wake behavior and NAc morphology, whereas NAc Crhr1 knockdown reversed these effects (including increased wakefulness and reduced NREM sleep in the dark period and NAc dendritic atrophy). Together, our findings demonstrate the negative influence of early-life stress on sleep architecture and the structural plasticity of the NAc, and highlight the critical role of the NAc CRH-CRHR1 system in modulating these negative outcomes evoked by early-life stress.

A series of liquid crystal elastomer films (the PBC series) have been synthesized by grafting liquid crystal (LC) monomer 4-allyloxybenzoic acid cholesteryl ester (MB) and crosslinking agent [1,1'-biphenyl]-4,4'-diyl bis(undec-10-enoate) (MC) onto polymethylhydrosiloxane catalyzed by hexachloroplatinic acid at 60 °C. The PBC series are cholesteric liquid crystal elastomers (LCEs). The glass transition temperatures (Tg) of the PBC series are between 23-33 °C, and the LC range is above 200 °C. The temperatures of 5% weight loss of the PBC series are above 300 °C, which shows good thermal stability. The PBC series display good orientation. PB3C3 shows a good ability of shape recovery above Tg.

The parasite Fasciola hepatica is an important zoonotic parasite. The development of an animal model of F. hepatica's life cycle is critical for studying the biological characteristics of the parasite in snails and mammals. Eggs of F. hepatica of bovine origin were cultured, and metacercariae were obtained after infection of Galba pervia snails. The life cycle system of F. hepatica was initiated in 2 different animals by orally infecting rabbits, SD rats and Kunming mice with the metacercariae. The animals' survival after infection, parasite migration in the animals and pathological damage to the liver were observed. We discovered that rabbits died due to acute suppurative hepatitis 60–69 days after infection, and eggs were found in the feces on day 63 of infection. The liver of SD rats showed punctate lesions on day 3 of infection, and further changes occurred as the infection progressed. However, liver repair was observed at week 9. SD rats survived for more than a year after infection and continued the F. hepatica life cycle. The liver lesions in Kunming mice after infection were similar but more severe than those in SD rats. Death was observed on the 31st post-infection day. We discovered that while rabbits, SD rats and Kunming mice can all be used as animal models of F. hepatica, SD rats are more suitable experimental animals in terms of tolerance and pathological response.

Major depressive disorder (MDD) is associated with functional disturbances in subcortical regions. However, little is known about how the subcortical functional network relates to depressive symptom profile and treatment outcome. In this study, we aimed to investigate associations among subcortical connectivity, clinical symptoms and antidepressant response in MDD using multivariate methods. Data for the present study were derived from the Towards Neurobiology-based Diagnosis and Treatment of Affective Disorders (TNDTAD), which is a naturalistic prospective study of mood disorders (NCT03294525). Medication-free participants with MDD (n = 135) underwent a functional magnetic resonance imaging scan at baseline and completed posttreatment clinical assessment after 8 weeks of antidepressant monotherapy. We used partial least squares (PLS) analysis to explore associations between subcortical connectivity and symptom profile. Replication was undertaken in an independent sample (n = 74). We also investigated the association between the observed subcortical connectivity pattern and treatment outcome in the discovery sample. A distinctive subcortical connectivity pattern, critically involving dorsal striatum and thalamus, was associated with negative affect. This association was partly replicated in the independent sample. Lower composite functional connectivity score (reflecting the connectivity pattern) at baseline predicted greater symptom improvement after 8 weeks of antidepressant treatment. The emphasis here on the role of dorsal striatum and thalamus consolidates prior work of subcortical connectivity in MDD. The findings provide insight into the pathogenesis of MDD, linking subcortical functional connectivity with negative affect. However, while connectivity pattern significantly predicted treatment outcome, the low odds ratio suggests that finding predictive biomarkers for depression remains an aspiration.

The prognosis of biliary tract cancer (BTC) remains unsatisfactory. This single-arm, phase II clinical trial (ChiCTR2000036652) investigated the efficacy, safety, and predictive biomarkers of sintilimab plus gemcitabine and cisplatin as the first-line treatment for patients with advanced BTCs. The primary endpoint was overall survival (OS). Secondary endpoints included toxicities, progression-free survival (PFS), and objective response rate (ORR); multi-omics biomarkers were assessed as exploratory objective. Thirty patients were enrolled and received treatment, the median OS and PFS were 15.9 months and 5.1 months, the ORR was 36.7%. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Predefined biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations or loss-of-function mutations in chromatin remodeling genes presented better tumor response and survival outcomes. Furthermore, transcriptome analysis revealed a markedly longer PFS and tumor response were associated with higher expression of a 3-gene effector T cell signature or an 18-gene inflamed T cell signature. Sintilimab plus gemcitabine and cisplatin meets pre-specified endpoints and displays acceptable safety profile, multiomics potential predictive biomarkers are identified and warrant further verification.

Additional file 2. Listof excluded studies with reasons for exclusion.

Additional file 1. Searchteims and strategies.

In this paper, the liquid crystal elastomer films (A’BG series) have been prepared by grafting polymerisation, using the 4-allyloxybenzoic acid cholesteryl ester (MB) as liquid crystal monomer, dodecane-1,12-diyl bis(undec-10-enoate) (MG) as flexible cross-linker and polymethyl hydrosiloxane (containing 35 Si-H) as the main chain. The A’BG series films are cholesteric liquid crystal elastomer films (LCEs) with a liquid crystal region above 100°C. With the crosslinker content decreasing, A’BG-2 and A’BG-3 display selective reflection in UV region and visible region, respectively. The selective reflection wavelength of A’BG-3 occurs blue shift with the temperature increasing. The glass transition temperatures (Tg) of the A’BG series films are 16.4–40.8°C and A’BG series films display shape memory properties near room temperature. The A’BG series elastomer films have a high thermal stability and the temperatures of the 5% mass loss are above 300°C. The backbone siloxane structures in the A’BG series elastomer films are highly stable, and the -COOChol group is relatively easy to decompose.

Recently, functional homotopy (FH) architecture, defined as robust functional connectivity (FC) between homotopic regions, has been frequently reported to be altered in MDD patients (MDDs) but with divergent locations.In this study, we obtained resting-state functional magnetic resonance imaging (R-fMRI) data from 1004 MDDs (mean age, 33.88 years; age range, 18-60 years) and 898 matched healthy controls (HCs) from an aggregated dataset from 20 centers in China. We focused on interhemispheric function integration in MDDs and its correlation with clinical characteristics using voxel-mirrored homotopic connectivity (VMHC) devised to inquire about FH patterns.As compared with HCs, MDDs showed decreased VMHC in visual, motor, somatosensory, limbic, angular gyrus, and cerebellum, particularly in posterior cingulate gyrus/precuneus (PCC/PCu) (false discovery rate [FDR] q 0.002, z = -7.07). Further analysis observed that the reduction in SMG and insula was more prominent with age, of which SMG reflected such age-related change in males instead of females. Besides, the reduction in MTG was found to be a male-special abnormal pattern in MDDs. VMHC alterations were markedly related to episode type and illness severity. The higher Hamilton Depression Rating Scale score, the more apparent VMHC reduction in the primary visual cortex. First-episode MDDs revealed stronger VMHC reduction in PCu relative to recurrent MDDs.We confirmed a significant VMHC reduction in MDDs in broad areas, especially in PCC/PCu. This reduction was affected by gender, age, episode type, and illness severity. These findings suggest that the depressive brain tends to disconnect information exchange across hemispheres.

Lei-Si Zhang,1,2,* Jun Wang,1,2,* Ming-Zhu Xu,1,2,* Tian-Mei Wu,1,2 Si-Man Huang,1,2 Han-Yu Cao,1,2 Ai-Ning Sun,1,2 Song-Bai Liu,3 Sheng-Li Xue1,2 1National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, People’s Republic of China; 3Suzhou Key Laboratory of Medical Biotechnology, Suzhou Vocational Health College, Suzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Song-Bai Liu, Suzhou Key Laboratory of Medical Biotechnology, Suzhou Vocational Health College, No. 28, Kehua Road, Suzhou, 215009, People’s Republic of China, Tel +86-13862145806, Email liusongbai@126.com Sheng-Li Xue, National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, No. 188, Shizi Street, Suzhou, 215006, People’s Republic of China, Tel +86-512-67781856, Email slxue@suda.edu.cnAbstract: The presence of FLT3-ITD mutation is associated with relapse and poor survival in AML patients. Venetoclax combined with hypomethylating agents (VEN+HMA) was approved for the frontline treatment of elderly or unfit AML patients, which leads to noteworthy impacts on AML management. The combination therapy is associated with encouraging efficacy in FLT3-mutated AML among both newly diagnosed unfit and relapsed/refractory patients. However, we found that two AML patients with FLT3-ITD mutation did not respond to venetoclax plus azacitidine (VEN+AZA). Given that the combined efficacy of venetoclax and the FLT3 inhibitor has been proved in pre-clinical models of FLT3+ AML, it is a scientific rationale to investigate venetoclax combined with the FLT3 inhibitor in AML patients with FLT3-ITD mutation. This is the first report of assessing the safety and response of gilteritinib (the first and only targeted second-generation FLT3 tyrosine kinase inhibitor approved by the US FDA) and venetoclax-based therapy in two AML patients with FLT3-ITD mutation unresponsive to VEN+AZA, which may bring new hope to FLT3 mutated patients who are unresponsive to VEN+HMA.Keywords: acute myeloid leukaemia, FLT3-ITD, gilteritinib, venetoclax

Purpose Positron emission tomography (PET) with the first and only tau targeting radiotracer of 18F-flortaucipir approved by FDA has been increasingly used in depicting tau pathology deposition and distribution in patients with cognitive impairment. The goal of this international consensus is to help nuclear medicine practitioners procedurally perform 18F-flortaucipir PET imaging. Method A multidisciplinary task group formed by experts from various countries discussed and approved the consensus for 18F-flortaucipir PET imaging in Alzheimer’s disease (AD), focusing on clinical scenarios, patient preparation, and administered activities, as well as image acquisition, processing, interpretation, and reporting. Conclusion This international consensus and practice guideline will help to promote the standardized use of 18F-flortaucipir PET in patients with AD. It will become an international standard for this purpose in clinical practice.

Neurotrophic factors, particularly nerve growth factor, enhance neuronal regeneration. However, the in vivo applications of nerve growth factor are largely limited by its intrinsic disadvantages, such as its short biological half-life, its contribution to pain response, and its inability to cross the blood-brain barrier. Considering that let-7 (human miRNA) targets and regulates nerve growth factor, and that let-7 is a core regulator in peripheral nerve regeneration, we evaluated the possibilities of let-7 application in nerve repair. In this study, anti-let-7a was identified as the most suitable let-7 family molecule by analyses of endogenous expression and regulatory relationship, and functional screening. Let-7a antagomir demonstrated biosafety based on the results of in vivo safety assessments and it entered into the main cell types of the sciatic nerve, including Schwann cells, fibroblasts and macrophages. Use of hydrogel effectively achieved controlled, localized, and sustained delivery of let-7a antagomir. Finally, let-7a antagomir was integrated into chitosan conduit to construct a chitosan-hydrogel scaffold tissue-engineered nerve graft, which promoted nerve regeneration and functional recovery in a rat model of sciatic nerve transection. Our study provides an experimental basis for potential in vivo application of let-7a.

Cognitive dysfunction is a significant, untreated clinical need in patients with psychiatric disorders, for which preclinical studies are needed to understand the underlying mechanisms and to identify potential therapeutic targets. Early-life stress (ELS) leads to long-lasting deficits of hippocampus-dependent learning and memory in adult mice, which may be associated with the hypofunction of the brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB). In this study, we carried out eight experiments to examine the causal involvement of the BDNF-TrkB pathway in dentate gyrus (DG) and the therapeutic effects of the TrkB agonist (7,8-DHF) in ELS-induced cognitive deficits. Adopting the limited nesting and beding material paradigm, we first demonstrated that ELS impaired spatial memory, suppressed BDNF expression and neurogenesis in DG in adult mice. Down-regulating BDNF expression (conditional BDNF knockdown) or inhibition of the TrkB receptor (using its anatognist ANA-12) in the DG mimicked the cognitive deficits of ELS. Acute up-regulation of BDNF (exogenous human recombinant BDNF microinjection) levels or activation of TrkB receptor (using its agonist, 7,8-DHF) in the DG restored ELS-induced spatial memory loss. Finally, acute and subchronic systemic administration of 7,8-DHF successfully restored spatial memory loss in stressed mice. Subchronic 7,8-DHF treatment also reversed ELS-induced neurogenesis reduction. Our findings highlight BDNF-TrkB system as the molecular target of ELS-induced spatial memory deficits and provide translational evidence for the intervention at this system in the treatment of cognitive deficits in stress-related psychiatric disorders, such as major depressive disorder.

Whether selective serotonin reuptake inhibitors (SSRIs) can improve cognitive function in depressed patients remains unclear. We aimed to explore the effect of SSRIs on cognitive function and the influencing factors in patients with major depressive disorder (MDD) with impaired cognitive function. We used a neurocognitive test battery to assess five cognitive domains, namely, attention/vigilance, learning, memory, processing speed and executive functioning, and calculated the Global Deficit Score (GDS). A GDS≥0.5 indicated overall cognitive impairment. The changes in the cognitive domains and overall cognitive function were analyzed in MDD patients with a baseline GDS≥0.5 who completed 8 weeks of SSRI treatment. We divided the patients into the cognitive remission and nonremission groups to explore the associated factors. In total, 160 patients (mean age 37.6 ± 10.8 years, 30.6% male) were included in the final analysis. The median (quartiles) of baseline GDS and HRSD17 were 1.4 (0.8, 1.9) and 19.5 (17.0, 23.0), respectively. All five cognitive domains improved after the treatment, while only 41 (25.6%) patients achieved cognitive remission. Recurrence and a higher baseline GDS were risk factors for cognitive nonremission. More aggressive interventions may be needed to promote cognitive remission in clinical practice, especially for patients with severe cognitive impairment and recurrent episodes.

Aberrant topological organization of whole-brain networks has been inconsistently reported in studies of patients with major depressive disorder (MDD), reflecting limited sample sizes. To address this issue, we utilized a big data sample of MDD patients from the REST-meta-MDD Project, including 821 MDD patients and 765 normal controls (NCs) from 16 sites. Using the Dosenbach 160 node atlas, we examined whole-brain functional networks and extracted topological features (e.g., global and local efficiency, nodal efficiency, and degree) using graph theory-based methods. Linear mixed-effect models were used for group comparisons to control for site variability; robustness of results was confirmed (e.g., multiple topological parameters, different node definitions, and several head motion control strategies were applied). We found decreased global and local efficiency in patients with MDD compared to NCs. At the nodal level, patients with MDD were characterized by decreased nodal degrees in the somatomotor network (SMN), dorsal attention network (DAN) and visual network (VN) and decreased nodal efficiency in the default mode network (DMN), SMN, DAN, and VN. These topological differences were mostly driven by recurrent MDD patients, rather than first-episode drug naive (FEDN) patients with MDD. In this highly powered multisite study, we observed disrupted topological architecture of functional brain networks in MDD, suggesting both locally and globally decreased efficiency in brain networks.

BackgroundImmune checkpoint inhibitor (ICI)-combined chemotherapy in advanced intrahepatic cholangiocarcinoma has been proved to have more efficacy in a series of clinical trials. However, whether the tumor microenvironment (TME) plays a vital role in immune-combined therapy has not been rigorously evaluated.MethodsFirstly, we assayed the immunogenic properties of GEM-based chemotherapy. Then, 12 ICC patients treated with PD-1 inhibitor (sintilimab) combined with gemcitabine and cisplatin (GemCis) from a phase 2 clinical trial (ChiCTR2000036652) were included and their immune-related gene expression profiles were analyzed using RNA from baseline tumor samples. Immune-related signature correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in an ICC cohort with 26 patients. Multiplexed immunofluorescence (mIF) and flow cytometry (FCM) analysis were performed to evaluate the immune-related molecules with therapeutic outcomes.ResultsGEM-based chemotherapy induced immunogenic cell death of cholangiocarcinoma cells, together with increased CD274 expression. In an ICC cohort, we found that upregulation of immune-checkpoint molecules and immune response-related pathways were significantly related to better clinical outcome. On the contrary, baseline immune-cell proportions in tumor tissues did not show any correlation with clinical benefit between responders and non-responders. Immune-related signature (including six genes) correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in a small ICC cohort with 26 patients.ConclusionImmune-related RNA signature predicts the outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma, which could be tested as a biomarker for immune-chemotherapy in the future.

Objectives Genome-wide analyses of antidepressant response have suggested that genes initially associated with risk for schizophrenia may also serve as promising candidates for selective serotonin reuptake inhibitor (SSRI) efficacy. Protein tyrosine phosphatase, receptor-type, zeta-1 (PTPRZ1) has previously been shown to be associated with schizophrenia, but it has not been investigated as a predictor of antidepressant efficacy. The main objective of the study was to assess whether SSRI-mediated depressive and anxiety symptom remission in Chinese patients with major depressive disorder (MDD) are associated with specific PTPRZ1 variants. Methods Two independent cohorts were investigated, the first sample (N = 344) received an SSRI (i.e. fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine, or paroxetine) for 8 weeks. The second sample (N = 160) only received escitalopram for 8 weeks. Hamilton Depression and Hamilton Anxiety Rating Scale scores at 8-weeks post-baseline in both cohorts were used to determine remission status. Five PTPRZ1 variants (rs12154537, rs6466810, rs6466808, rs6955395, and rs1918031) were genotyped in both cohorts. Results Anxiety symptom remission was robustly associated with PTPRZ1 rs12154537 (P = 0.004) and the G-G-G-G haplotype (rs12154537-rs6466810-rs6466808-rs6955395; P = 0.005) in cohort 2 but not cohort 1 (mixed SSRI use). Associations with depressive symptom remission did not survive correction for multiple testing. Conclusions These findings suggest that PTPRZ1 variants may serve as a marker of escitalopram-mediated anxiety symptom remission in MDD.

Background : Functional specialization is a feature of human brain for understanding the pathophysiology of major depressive disorder (MDD). The degree of human specialization refers to within and cross hemispheric interactions. However, most previous studies only focused on interhemispheric connectivity in MDD, and the results varied across studies. Hence, brain functional connectivity asymmetry in MDD should be further studied. Methods : Resting-state fMRI data of 753 patients with MDD and 451 healthy controls were provided by REST-meta-MDD Project. Twenty-five project contributors preprocessed their data locally with the Data Processing Assistant State fMRI software and shared final indices. The parameter of asymmetry (PAS), a novel voxel-based whole-brain quantitative measure that reflects inter- and intrahemispheric asymmetry, was reported. We also examined the effects of age, sex and clinical variables (including symptom severity, illness duration and three depressive phenotypes). Results : Compared with healthy controls, patients with MDD showed increased PAS scores (decreased hemispheric specialization) in most of the areas of default mode network, control network, attention network and some regions in the cerebellum and visual cortex. Demographic characteristics and clinical variables have significant effects on these abnormalities. Limitations : Although a large sample size could improve statistical power, future independent efforts are needed to confirm our results. Conclusions : Our results highlight the idea that many brain networks contribute to broad clinical pathophysiology of MDD, and indicate that a lateralized, efficient and economical brain information processing system is disrupted in MDD. These findings may help comprehensively clarify the pathophysiology of MDD in a new hemispheric specialization perspective.

The nucleus accumbens (NAc) is considered a hub of reward processing and a growing body of evidence has suggested its crucial role in the pathophysiology of major depressive disorder (MDD). However, inconsistent results have been reported by studies on reward network-focused resting-state functional MRI (rs-fMRI). In this study, we examined functional alterations of the NAc-based reward circuits in patients with MDD via meta- and mega-analysis. First, we performed a coordinated-based meta-analysis with a new SDM-PSI method for all up-to-date rs-fMRI studies that focused on the reward circuits of patients with MDD. Then, we tested the meta-analysis results in the REST-meta-MDD database which provided anonymous rs-fMRI data from 186 recurrent MDDs and 465 healthy controls. Decreased functional connectivity (FC) within the reward system in patients with recurrent MDD was the most robust finding in this study. We also found disrupted NAc FCs in the DMN in patients with recurrent MDD compared with healthy controls. Specifically, the combination of disrupted NAc FCs within the reward network could discriminate patients with recurrent MDD from healthy controls with an optimal accuracy of 74.7%. This study confirmed the critical role of decreased FC in the reward network in the neuropathology of MDD. Disrupted inter-network connectivity between the reward network and DMN may also have contributed to the neural mechanisms of MDD. These abnormalities have potential to serve as brain-based biomarkers for individual diagnosis to differentiate patients with recurrent MDD from healthy controls.

The parasite

Two novel lathyrane-type diterpenoids, the Euphorbia factors L2a (1) and L2b (2), and their stereoisomer Euphorbia factor L2 (3) were obtained from seeds of Euphorbia lathyris. Both Euphorbia factors L2a and L2b possess an unprecedented trans-gem-dimethylcyclopropane as structural feature. Also, the Euphorbia factor L2a is the first example of a lathyrane diterpenoid with an endocyclic 12(Z)-double bond. The structures of the molecules and their absolute configurations were elucidated by comprehensive spectroscopic analyses, Cu-Kα radiation X-ray diffraction, and comparison with calculated electronic circular dichroism (ECD) data. The Euphorbia factor L2b exhibited an inhibitory effect against U937 cell line with an IC50 value of 0.87 μM.

BACKGROUND The overall satisfaction of patients after total knee arthroplasty (TKA) is approximately 80%, and current studies have demonstrated that patients with depression may have lower patient satisfaction. The purpose of this study was to determine whether perioperative psychological intervention in patients with depression improves the clinical outcomes and patient satisfaction in patients undergoing TKA. METHODS Six hundred patients who underwent primary TKA from May 2016 to January 2018 were prospectively screened for eligibility. A preoperative psychological evaluation was conducted by a psychiatrist to evaluate each patient's psychological status. Patients who were diagnosed with depression were randomly divided into 2 groups: the intervention group (patients received psychological interventions that were administered by a psychiatrist at the first visit before surgery and from then on) and the control group (patients received routine TKA care without psychological interventions). The primary outcome was patient satisfaction at 6 months postoperatively. The secondary outcomes were patient satisfaction at 2 years postoperatively as well as the Hospital for Special Surgery (HSS) scores, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, and range of motion at 6 months and 2 years postoperatively. RESULTS Fifty-three patients with depression were identified. Fifty-one patients were enrolled in the randomized controlled trial. Two patients were lost to follow-up at 6 months after surgery. Therefore, 49 patients (25 in the intervention group and 24 in the control group) remained in the final analysis. At 6 months postoperatively, statistical differences in patient satisfaction were identified between the 2 groups (88.0% in the intervention group compared with 62.5% in the control group; odds ratio = 4.40; 95% confidence interval, 1.02 to 18.99). There was a significant improvement in the Self-Rating Depression Scale (SDS) score (the reduction rate was 51.97% in the intervention group compared with 17.35% in the control group) and the Symptom Checklist 90 Revised (SCL-90-R) subscore for depression (the reduction rate was 44.66% in the intervention group compared with 15.73% in the control group). The clinical outcomes, including the WOMAC scores, the HSS scores, and maximal range of motion, in the intervention group had improved significantly more compared with those in the control group. CONCLUSIONS Psychological interventions during the perioperative period can improve patient satisfaction in patients with depression who undergo TKA. Therefore, psychological intervention and management may be beneficial for patients with depression who are planning to undergo TKA. LEVEL OF EVIDENCE Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Background: As the fight against the COVID-19 epidemic continues, medical workers may have allostatic load. Objective: During the reopening of society, medical and nonmedical workers were compared in terms of allostatic load. Methods: An online study was performed; 3,590 Chinese subjects were analyzed. Socio-demographic variables, allostatic load, stress, abnormal illness behavior, global well-being, mental status, and social support were assessed. Results: There was no difference in allostatic load in medical workers compared to nonmedical workers (15.8 vs. 17.8%; p = 0.22). Multivariate conditional logistic regression revealed that anxiety (OR = 1.24; 95% CI 1.18–1.31; p < 0.01), depression (OR = 1.23; 95% CI 1.17–1.29; p < 0.01), somatization (OR = 1.20; 95% CI 1.14–1.25; p < 0.01), hostility (OR = 1.24; 95% CI 1.18–1.30; p < 0.01), and abnormal illness behavior (OR = 1.49; 95% CI 1.34–1.66; p < 0.01) were positively associated with allostatic load, while objective support (OR = 0.84; 95% CI 0.78–0.89; p < 0.01), subjective support (OR = 0.84; 95% CI 0.80–0.88; p < 0.01), utilization of support (OR = 0.80; 95% CI 0.72–0.88; p < 0.01), social support (OR = 0.90; 95% CI 0.87–0.93; p < 0.01), and global well-being (OR = 0.30; 95% CI 0.22–0.41; p < 0.01) were negatively associated. Conclusions: In the post-COVID-19 epidemic time, medical and nonmedical workers had similar allostatic load. Psychological distress and abnormal illness behavior were risk factors for it, while social support could relieve it.

BackgroundIncreasing evidence has suggested an association of adiponectin gene polymorphisms rs1501299, rs2241766, rs266729 and rs3774261 with risk of nonalcoholic fatty liver disease (NAFLD). This correlation has been extensively meta-analyzed for the first two polymorphisms, but not the second two.MethodsThe PubMed, EMBASE, Google Scholar, and China National Knowledge Infrastructure databases were searched for relevant literature. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.ResultsA total of 10 case-control studies on rs266729 (2,619 cases and 1,962 controls) and 3 case-control studies on rs3774261 (562 cases and 793 controls) were included. Meta-analysis showed that rs266729 was associated with significantly higher NAFLD risk based on the following five models: allelic, OR 1.72, 95% CI 1.34-2.21, P < 0.001; recessive, OR 2.35, 95% CI 1.86-2.95, P < 0.001; dominant, OR 1.84, 95% CI 1.34-2.53, P < 0.001; homozygous, OR 2.69, 95% CI 1.84-3.92, P < 0.001; and heterozygous, OR 1.72, 95% CI 1.28-2.32, P < 0.001. This association between rs266729 and NAFLD risk remained significant for all five models among studies with Asian, Chinese and Caucasian samples. The rs2241766 polymorphism was associated with significantly higher NAFLD risk according to the recessive model (OR 1.87, 95% CI 1.15-3.04, P = 0.01).ConclusionPolymorphisms rs266729 and rs3774261 in the adiponectin gene may be risk factors for NAFLD. These findings may pave the way for novel therapeutic strategies, but they should be verified in large, well-designed studies.

The effects of twelve different pre-drying and drying methods on the chemical composition in the pericarp and kernel of Amomum tsao-ko were studied. The volatile components were isolated from the samples by simultaneous distillation and extraction and analyzed by gas chromatography-mass spectrometry (GC-MS). Sixty and thirty-eight compounds were identified from pericarp and kernel, respectively, and the main constituents were oxygenated monoterpenes. These compounds were not only significantly affected by pre-drying and drying methods but also varied in content due to different tissue locations. The total volatile content of pericarp varied from 0.70 to 1.55%, with the highest obtained by microwave-dried samples (150 W) and the lowest in freeze-dried samples. The total volatile content of the kernel varied from 6.11 to 10.69%, with the highest content obtained during sun drying (SD) and the lowest content in samples treated with boiling water for 2 min. Oxygenated monoterpenes were the highest compounds in pericarp and kernel, which were also the most affected by drying methods. The highest content of oxygenated monoterpenes in the pericarp (0.77%) could be obtained by boiling water treatment for 5 min, and the highest content of oxygenated monoterpenes in the kernel (7.48%) could be obtained by SD. Additionally, the main components such as 1,8-cineole, 2-carene, (Z)-citral, nerolidol, (Z)-2-decenal, (E)-2-dodecenal, citral, (E)-2-octenal, 4-propylbenzaldehyde, and phthalan showed remarkable variations in pre-drying and drying methods.

Supplemental material, sj-pdf-1-imr-10.1177_03000605221095224 for Surgical resection of lupus nephritis with pulmonary Aspergillus infection: a case report and review of the literature by Xiaoli Pan, Yuan Yuan, Yu Tian, Jinjing Wang, Yida Li and Mei Tian in Journal of International Medical Research

In vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) is associated with an increased risk of preterm (33rd–37th gestational week) and early preterm birth (20th–32nd gestational week). The underlying general and procedure related risk factors are not well understood so far. 4328 infertile women undergoing IVF/ICSI were entered into this study. The study population was divided into three groups: (a) early preterm birth group (n = 66), (b) preterm birth group (n = 675) and (c) full-term birth group (n = 3653). Odds for preterm birth were calculated by stepwise multivariate logistic regression analysis. We identified seven independent risk factors for preterm birth and four independent risk factors for early preterm birth. Older (> 39) or younger (< 25) maternal age (OR: 1.504, 95% CI 1.108–2.042, P = 0.009; OR: 2.125, 95% CI 1.049–4.304, P = 0.036, respectively), multiple pregnancy (OR: 9.780, 95% CI 8.014–11.935, P < 0.001; OR: 8.588, 95% CI 4.866–15.157, P < 0.001, respectively), placenta previa (OR: 14.954, 95% CI 8.053–27.767, P < 0.001; OR: 16.479, 95% CI 4.381–61.976, P < 0.001, respectively), and embryo reduction (OR: 3.547, 95% CI 1.736–7.249, P = 0.001; OR: 7.145, 95% CI 1.990–25.663, P = 0.003, respectively) were associated with preterm birth and early preterm birth, whereas gestational hypertension (OR: 2.494, 95% CI 1.770–3.514, P < 0.001), elevated triglycerides (OR: 1.120, 95% CI 1.011–1.240, P = 0.030) and shorter activated partial thromboplastin time (OR: 0.967, 95% CI 0.949–0.985, P < 0.001) were associated only with preterm birth. In conclusion, preterm and early preterm birth risk factors in patients undergoing assisted IVF/ICSI are in general similar to those in natural pregnancy. The lack of some associations in the early preterm group was most likely due to the lower number of early preterm birth cases. Only embryo reduction represents an IVF/ICSI specific risk factor.

Supplemental material, sj-pdf-1-imr-10.1177_03000605221095224 for Surgical resection of lupus nephritis with pulmonary Aspergillus infection: a case report and review of the literature by Xiaoli Pan, Yuan Yuan, Yu Tian, Jinjing Wang, Yida Li and Mei Tian in Journal of International Medical Research

OBJECTIVE Studies examining coprescription and dosages of mood stabilizers (MSs) with antipsychotics for psychotic disorders are infrequent. Based on sparse extant data and clinical experience, we hypothesized that adjunctive MS use would be associated with certain demographic (e.g., younger age), clinical factors (e.g., longer illness duration), and characteristics of antipsychotic treatment (e.g., multiple or high antipsychotic doses). METHODS Within an Asian research consortium focusing on pharmaco-epidemiological factors in schizophrenia, we evaluated rates of MS coprescription, including high doses (>1000 mg/day lithium-equivalents) and clinical correlates. RESULTS Among 3557 subjects diagnosed with schizophrenia in 14 Asian countries, MSs were coprescribed with antipsychotics in 13.6% (n = 485) of the sample, with 10.9% (n = 53) on a high dose. Adjunctive MS treatment was associated (all p < 0.005) with demographic (female sex and younger age), setting (country and hospitalization), illness (longer duration, more hospitalizations, non-remission of illness, behavioral disorganization, aggression, affective symptoms, and social-occupational dysfunction), and treatment-related factors (higher antipsychotic dose, multiple antipsychotics, higher body mass index, and greater sedation). Patients given high doses of MSs had a less favorable illness course, more behavioral disorganization, poorer functioning, and higher antipsychotic doses. CONCLUSIONS Schizophrenia patients receiving adjunctive MS treatment in Asian psychiatric centers are more severely ill and less responsive to simpler treatment regimens.

Chronic stress may disrupt the normal neurodevelopmental trajectory of the adolescent brain (especially the prefrontal cortex) and contribute to the pathophysiology of stress-related mental illnesses, but the underlying molecular mechanisms remain unclear. Here, we investigated how synaptic cell adhesion molecules (e.g., nectin3) are involved in the effects of adolescent chronic stress on mouse medial prefrontal cortex (mPFC). Male C57BL/6N mice were subjected to chronic social instability stress from postnatal days 29 to 77. One week later, the mice exposed to chronic stress exhibited impaired social recognition and spatial working memory, simplified dendritic structure, and reduced spine density in the mPFC. Membrane localization of nectin3 was also altered, and was significantly correlated with behavioral performance. Furthermore, knocking down mPFC nectin3 expression by adeno-associated virus in adolescent mice reproduced the stress-induced changes in behavior and mPFC morphology. These results support the hypothesis that nectin3 is a potential mediator of the effects of adolescent chronic stress on prefrontal structural and functional abnormalities. Electronic supplementary material The online version of this article (10.1007/s12264-020-00499-2) contains supplementary material, which is available to authorized users.

This paper aims to address the problem of geometric state control of large-segment steel box girders in offshore hoisting during the construction of large-span bridges. First, the geometric state control indexes of a large-segment steel box girder are determined, such as the manufacturing parameters of the top and bottom slabs, the width of the annular joint, and the support position. Second, the geometric state equations and state transfer matrixes of large-segment steel box girders under different conditions are deduced by taking the mileage and elevation of control points as basic state variables. In application of the geometric state transfer method in the construction control of the Hong Kong-Zhuhai-Macao Bridge, the width of the annular joint and the position parameters for the support of the large-segment steel box girder are predicted precisely. Moreover, the manufacturing parameters of the top and bottom slabs of the steel box girders are calculated reliably. The measured values show that the width of the annular joint is basically the same with the difference of less than 2 mm, the eccentricity of bridge support is less than 20 mm, and the elevation error of the bridge deck is within −10 mm to +15 mm, which meets the construction accuracy. Using the geometric state transfer method, the rapid and accurate installation of the Hong Kong-Zhuhai-Macao Bridge has been realized, demonstrating that the precise control of the geometric state of a steel box girder with ectopic installation and multi-state transition can be realized by using the geometric state transfer method.

The globally invasive cotton mealybug Phenacoccus solenopsis Tinsley, has recently invaded several Chinese regions, and continues to expand its range. This mealybug is a polyphagous insect pest, with at least 200 host plants from 63 families, including cotton, food crops, fruits, ornamental plants, tobacco, and vegetables. Here, we describe the first finding of P. solenopsis in Shandong Province, and investigate the abundances of its natural enemies (predator Coccinella septempunctata L. and parasitoid Aenasius bambawalei Hayat). All three species were detected from ornamental and weed species in Linyi, Shandong, in September 2018, and were positively identified using DNA barcoding. BLAST analysis revealed significant identity (99.38–100%) between sequences of P. solenopsis obtained in this study and those published in the past. This invasive pest represents a major potential threat to agri-horticulture in Shandong, which is a key province of China for production and export of many vegetables, flowers, fruits, and other crops. This mealybug species has a wide range of potential distribution in Shandong and is easily dispersed with agricultural and horticultural transport products. Further monitoring and management strategies are required to limit the spread of this pest species.

Rice blast caused by Magnaporthe oryzae B. Couch is one of the most devastating diseases on rice. Camptothecin (CPT), which was primarily isolated from Camptotheca acuminata, is well-known for its anti-tumor activities, and is also developed as a potential biological pesticide. We previously investigated the anti-microbial activities of CPT against 11 fungi, 3 oomycetes, and 4 bacteria, and found that CPT was strongly effective against M. oryzae, indicating its potential as a lead for developing fungicide against rice blast. However, the anti-fungal effects of CPT on M. oryzae need further elucidation. In this study, the anti-fungal activities of CPT against M. oryzae were further investigated, which revealed that CPT was effective against M. oryzae both in vitro and in vivo. The transcriptome of M. oryzae was analyzed after CPT treatment, which showed that CPT had a strong inhibitory effect on 'translation' and 'carbohydrate metabolism/energy metabolism' of M. oryzae. Some physiology characteristics of M. oryzae were also assayed, which confirmed that CPT inhibited RNA synthesis, protein synthesis, and carbohydrate metabolism/energy metabolism of M. oryzae, and caused membrane damage. The molecular simulation result showed that CPT binds to the interface of DNA-topoisomerase I complex of M. oryzae. In conclusion, CPT is a promising lead for developing fungicide against rice blast. CPT may bind to DNA-topoisomerase I complex of M. oryzae, thus affecting 'translation' and 'carbohydrate metabolism/energy metabolism', leading to cell death.

Perivascular epithelioid cell (PEC) tumors are rare tumors of mesenchymal origin and can affect many anatomic regions. Although these tumors are usually benign, malignant variants exist. We document for the first time a malignant PEComa arising from the pleura of a 43-year-old Malay woman. The pathology of the tumor as well as differential diagnoses is discussed.

Neuroimaging biomarkers of treatment efficacy can be used to guide personalized treatment in major depressive disorder (MDD). Escitalopram is recommended as first‐line therapy for MDD and severe depression. An interesting hypothesis suggests that the reconfiguration of dynamic brain networks might provide important insights into antidepressant mechanisms. The present study assesses whether the spatiotemporal modulation across functional brain networks could serve as a predictor of effective antidepressant treatment with escitalopram. A total of 106 first‐episode, drug‐naïve patients and 109 healthy controls from three different multicenters underwent resting‐state functional magnetic resonance imaging. Patients were considered as responders if they had a reduction of at least 50% in Hamilton Rating Scale for Depression scores at endpoint (>2 weeks). Multilayer modularity framework was applied on the whole brain to construct features in relation to network dynamic characters that were used for multivariate pattern analysis. Linear soft‐threshold support vector machine models were used to separate responders from nonresponders. The permutation tests demonstrated the robustness of discrimination performances. The discriminative regions formed a spatially distributed pattern with anterior cingulate cortex (ACC) as the hub in the default mode subnetwork. Interestingly, a significantly larger module allegiance of ACC was also found in treatment responders compared to nonresponders, suggesting high interactivities of ACC to other regions may be beneficial for the recovery after treatment. Consistent results across multicenters confirmed that ACC could serve as a predictor of escitalopram monotherapy treatment outcome, implying strong likelihood of replication in the future.

Seedling quality is a prerequisite for successful field performance and therefore influences crop yields. Temperature and illumination are two major factors affecting seedling quality during nursery propagation. Suboptimal temperature or light of nurseries generally result in leggy or weak seedlings and great economic loss. However, production of healthy seedlings is challenging due to the lack of knowledge in systemic management of nursery environments. In this study, we have established simulation models to predict how temperature and illumination coordinately influence the growth of tomato and cabbage seedlings. Specifically, correlation between seedling quality characteristics (root-shoot ratio, G value (growth function: defined as ratio of whole plant dry weight to days of seedling), healthy indexes) and TEP (thermal effectiveness and photosynthetically active radiation) were explored to establish the models, which were validated with independent test data. Our results suggested that the curve of healthy index 1 (HI1) and TEP fitted well with high coefficient of determination (R2) in both species, indicating that the model is highly reliable. The HI1 simulation models for tomato and cabbage are HI1=0.0009e0.0308TEP–0.0015 and HI1 = 0.0003e0.0671TEP–0.0003, respectively, which can be used for predicting vigors of tomato and cabbage seedlings grown under different temperature and light conditions.

The effects of twelve different pre-drying and drying methods on the chemical composition in the pericarp and kernel of

Increasing evidence has suggested an association of adiponectin gene polymorphisms rs1501299, rs2241766, rs266729 and rs3774261 with risk of nonalcoholic fatty liver disease (NAFLD). This correlation has been extensively meta-analyzed for the first two polymorphisms, but not the second two.The PubMed, EMBASE, Google Scholar, and China National Knowledge Infrastructure databases were searched for relevant literature. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.A total of 10 case-control studies on rs266729 (2,619 cases and 1,962 controls) and 3 case-control studies on rs3774261 (562 cases and 793 controls) were included. Meta-analysis showed that rs266729 was associated with significantly higher NAFLD risk based on the following five models: allelic, OR 1.72, 95% CI 1.34-2.21,Polymorphisms rs266729 and rs3774261 in the adiponectin gene may be risk factors for NAFLD. These findings may pave the way for novel therapeutic strategies, but they should be verified in large, well-designed studies.

Lamiophlomis rotata (Benth.) Kudo (LR) is an extensively used Chinese herbal medicine. It contains a variety of chemical constituents with significant biological activities that were first recorded in the classical masterpiece of Tibetan Medicine, Somaratsa. In this review, we summarize the information regarding the traditional uses, chemical constituents, pharmacological effects, clinical applications, quality control, toxicology, and pharmacokinetics of LR. At least 223 chemical constituents have been isolated from LR, including phenylethanoid glycosides, flavonoids, iridoids, volatile oils, et al. Their various physiological activities have been demonstrated as analgesic, hemostatic, anti-inflammatory, anti-tumor, marrow-supplementing, anti-bacterial, and immunity-strengthening. The clinical applications of LR and quality control are also discussed, as well as some existing problems. This article aims to provide more comprehensive information on the chemical composition, pharmacological activity, and clinical application of LR, so as to provide a theoretical basis for the further reasonable development of LR in clinical practice and of new drugs.