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Leung Li,1 Stephen L Chan,1 Frankie Mo,1 Edwin P Hui,1 Jane Koh,1 Allen KC Chan,2 Nelson LS Tang,2 Kit F Lee,3 Paul BS Lai,3 Simon CH Yu,4 Winnie Yeo1 1Department of Clinical Oncology, Prince of Wales Hospital, Faculty of Medicine, Hong Kong Cancer Institute, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR; 2Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR; 3Department of Surgery, Prince of Wales Hospital, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR; 4Department of Diagnostic and Interventional Radiology, Prince of Wales Hospital, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR Purpose: Health-related quality of life (HRQoL) is a significant prognostic factor for overall survival in hepatocellular carcinoma (HCC) patients, and this is independent of stage and liver function. Inflammation plays a significant role in HCC development and progression. It was hypothesized that the inflammatory status of HCC patients may affect their HRQoL. The relationship between HRQoL and inflammatory status was explored using indicators IL-8 level and modified inflammation-based index (mIBI, based on IL-8, C-reactive protein, and albumin). Methods: From 2007–2011, HCC patients were enrolled prospectively. Baseline HRQoL assessment utilized the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-HCC18; clinical and laboratory data were collected at diagnosis. Two summary indices, C30 and HCC18 index-scores, were calculated. Correlation analyses were performed between HRQoL and inflammatory markers. Results: In the 445 patients studied, significant correlations were found between IL-8 levels and EORTC QLQ-C30, QLQ-HCC18, C30, and HCC18 index-scores. The strongest correlated factors were those reflective of constitutional symptoms, namely QLQ-C30 “appetite loss” (with Pearson’s correlation coefficient, r=0.322, P

Ip Tim Lau,1 Ka Fai Lee,2 Wing Yee So,3 Kathryn Tan,4 Vincent Tok Fai Yeung5 1Department of Medicine, Tseung Kwan O Hospital, 2Department of Medicine and Geriatrics, Kwong Wah Hospital, 3Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, 4Department of Medicine, Queen Mary Hospital, University of Hong Kong, 5Department of Medicine and Geriatrics, Our Lady of Maryknoll Hospital, Hong Kong, China Objective: To review published clinical studies on the efficacy and safety of new insulin glargine 300 units/mL (Gla-300), a new long-acting insulin analog, for the treatment of type 1 and type 2 diabetes mellitus (T1DM, T2DM)Materials and methods: Data sources comprised primary research articles on Gla-300, including pharmacodynamic, pharmacokinetic, and clinical studies.Results: In pharmacodynamic and pharmacokinetic studies, Gla-300 showed a flatter time–action profile and longer duration of action than Gla-100. Noninferiority of Gla-300 versus Gla-100 for lowering of glycated hemoglobin was demonstrated in Phase III clinical studies covering a range of T1DM and T2DM patient populations. Over 6–12 months of follow-up, Gla-300 consistently showed comparable glycemic efficacy with less hypoglycemia vs Gla-100, even during the first 8 weeks of treatment. Although titrated insulin doses were 11%–17% higher with Gla-300 vs Gla-100, changes in body weight were similar or favored Gla-300.Conclusion: Clinical studies provide evidence that the pharmacodynamic and pharmacokinetic properties of Gla-300 may translate into clinical benefits in both T1DM and T2DM. Gla-300 may provide a new option for people initiating basal insulin, those requiring higher basal insulin doses, those with T1DM, and those who may be at increased risk for hypoglycemia, such as people with chronic kidney disease, the elderly, and those with cardiovascular comorbidities. Keywords: diabetes mellitus, long-acting insulin, insulin glargine

Objective: Gestational diabetes mellitus (GDM) is a common metabolic disorder of pregnancy. Patients with GDM are at risk for high fetal mortality and gestational complications associated with reduced immune tolerance and abnormal carbohydrate metabolism. Glycodelin-A (GdA) is an abundant decidual glycoprotein with glycosylation-dependent immunomodulatory activities. We hypothesized that aberrant carbohydrate metabolism in GDM was associated with changes in glycosylation of GdA, leading to defective immunomodulatory activities.Research Design and Methods: GdA in the amniotic fluid from women with normal (NGdA) and GDM (DGdA) pregnancies was purified by affinity chromatography. Structural analysis of protein glycosylation was preformed by lectin-binding assay and mass spectrometry. Cytotoxicity, cell death, cytokine secretion, and GdA binding of the GdA-treated lymphocytes and natural killer (NK) cells were determined. The sialidase activity in the placental tissue from normal and GDM patients was measured.Results: GDM affected the glycosylation but not the protein core of GdA. Specifically, DGdA had a lower abundance of α2-6-sialylated and high-mannose glycans and a higher abundance of glycans with Sda (NeuAcα2-3[GalNAcβ1-4]Gal) epitopes compared with NGdA. DGdA had reduced immuosuppressive activities in terms of cytotoxicity on lymphocytes, inhibitory activities on interleukin (IL)-2 secretion by lymphocytes, stimulatory activities on IL-6 secretion by NK cells, and binding to these cells. Desialylation abolished the immunomodulation and binding of NGdA. Placental sialidase activity was increased in GDM patients, which may account for the reduced sialic acid content of DGdA.Conclusions: Taken together, this study provides the first direct evidence for altered enzymatic glycosylation and impaired bioactivity of GdA in GDM patients. [ABSTRACT FROM AUTHOR]

Purpose: To compare the embolization efficacy and treatment effectiveness of transarterial ethanol ablation (TEA) versus those of chemoembolization and evaluate the correlation between embolization efficacy and treatment effectiveness of these treatments for hepatocellular carcinoma (HCC). Materials and Methods: A case-controlled study was undertaken with 30 patients in each group matched based on Child-Pugh grade, tumor characteristics, and performance status. Primary endpoints were embolization efficacy (ie, Lipiodol retention within tumor at 2 months) and treatment effectiveness as evaluated by tumor response, disease progression, progression-free survival, and overall survival. The secondary endpoint was correlation between embolization efficacy and treatment effectiveness. Results: Lipiodol retention was greater in the TEA group (89.5% +/- 10.7% vs 47.5% +/- 21.2%; P < .0001). The tumor progression rate at 1 year was higher in the chemoembolization group (five of 30 vs zero of 30; P = .0261). One- and 2-year overall survival rates were higher in the TEA group (93.3% and 80.0%, respectively, vs 73.3% and 43.3%, respectively; P = .0053). One- and 2-year extrahepatic disease progression rates were lower in the TEA group (P = .0002). There were no differences in progression-free survival and intrahepatic disease progression rates at 1 and 2 years. Patients with greater Lipiodol retention (ie, >60%) had better treatment outcomes at 1 year than those with lesser retention, with higher overall survival rates (88.9% vs 66.7%; P = .0192), lower intrahepatic disease progression rates (25.6% vs 59.4%; P = .0169), lower extrahepatic disease progression rates (0.31% vs 35.5%; P = .0047), and higher progression-free survival rates (72.1% vs 36.3%; P = .005). Conclusions: The embolization efficacy and treatment effectiveness of TEA are probably superior to those of chemoembolization for HCC. [ABSTRACT FROM AUTHOR]

Improvement in surgical outcomes of liver resection has been achieved in the past decade. Among other factors, a gradual change of technology platforms and refinement of surgical techniques have played significant roles. In this review, the various surgical approaches, operative techniques, operative instruments, and adjunctive measures as applied in liver resection are described, along with discussion of the pros and cons of each of these attributes. A brief description of laparoscopic liver resection is also included to address this important and emerging area in liver surgery. [ABSTRACT FROM AUTHOR]

Fertilization and development of mouse embryos occur in the oviduct. Accumulating data suggested that embryo - maternal communication exists in the preimplantation period, with the female reproductive tract providing the optimal microenvironment conducive to the development of embryos. Signals produced from the developing embryos not only affect their own transport in the oviduct, but the physiology and gene expression patterns of the oviduct. As a step towards understanding the action of embryos on oviductal physiology, both genomics and proteomics approaches are being used to unveil the underlying mechanism of embryo - maternal interaction at the preimplantation stage. Results from recent studies allow us to better understand the roles and the use of oviductal secretory proteins or factors that affect embryo development in vivo and in vitro. It has been shown that in vitro culture alters gene expression of the cultured embryos and may predispose the embryo to certain disease. Therefore, the interaction between gamete/embryo and oviduct in vitro and in vivo, and the long-term effects of embryo culture on foetal development warrant further investigation. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers., Methods: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m 2 ) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts., Results: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts., Conclusions/interpretation: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification., (© 2024. The Author(s).)

Restrictive federal and state immigration policies create conditions of employment exclusion that may negatively influence the health of immigrants. In particular, these policy effects are reflected in labor market and workplace experiences that determine the types of work and employment opportunities that immigrants are able to access and pursue. This study examines the relationship between both cumulative and individual measures of employment exclusion and self-rated health and psychological distress among Asian and Latino immigrants in California, and whether this relationship is modified by legal status. We used data from the Research on Immigrant Health and State Policy (RIGHTS) study (n = 2010). We used both multivariable logistic regression and linear regression models for our analyses. For cumulative models, labor market exclusion was associated with poor health (OR = 1.21, 95% CI: 1.01, 1.46). Workplace exclusion was also associated with poor self-rated health (OR = 1.45, 95% CI: 1.15, 1.82) and increased psychological distress (β = 0.69, 95% CI: 0.31, 1.07). For individual measures of employment exclusion, settling for a job - a labor market exclusion - and working in a dangerous job and experiencing wage theft - workplace exclusions - were associated with poor health and increased psychological distress. There was no evidence that the association between employment exclusions and health varied by legal status. These findings demonstrate that the combined effect of employment exclusions is detrimental to immigrant health. To improve population health, public health researchers should continue to interrogate the policy conditions at the federal, state, and local level that exclude immigrants from employment opportunities and workplace protections., Competing Interests: The authors have no competing interests to declare., (© 2024 The Authors. Published by Elsevier Ltd.)

Background: Hepatectomy is an established treatment for colorectal liver metastasis (CLM) or neuroendocrine liver metastasis. However, its role in non-colorectal non-neuroendocrine liver metastasis (NCNNLM) is controversial. This study aims to compare long-term survival outcomes after hepatectomy between NCNNLM and CLM in a population-based cohort., Methods: From 2009 to 2018, curative hepatectomy were performed in 964 patients with NCNNLM (n ​= ​133) or CLM (n ​= ​831). Propensity score (PS) matching was performed. Short-term and long-term outcomes were compared between PS-matched groups. Univariate and multivariate analyses were performed to identify prognostic factors affecting survival., Results: There were 133 patients in the NCNNLM group and 266 patients in the CLM group. The mortality (1.5 ​% vs 1.5 ​%) and morbidity (19.5 ​% vs 20.3 ​%) rates were comparable between the two groups. There was no statistically significant difference in 5-year overall (48.9 ​% vs 39.8 ​%) and recurrence-free (25.1 ​% vs 23.4 ​%) survival rates between NCNNLM and CLM groups. A high pre-operative serum bilirubin level, severe postoperative complications and multiple tumors were independent prognostic factors for poor survival., Conclusion: Hepatectomy for selected patients with NCNNLM can achieve similar long-term oncological outcomes as those with CLM. High serum bilirubin, severe postoperative complication and multiple tumors are poor prognostic factors for survival., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

This project was undertaken to develop the first set of consensus statements regarding the management of pancreatic ductal adenocarcinoma (PDAC) in Hong Kong, with the goal of providing guidance to local clinicians. A multidisciplinary panel of experts discussed issues surrounding current PDAC management and reviewed evidence gathered in the local context to propose treatment recommendations. The experts used the Delphi approach to finalise management recommendations. Consensus was defined as ≥80% acceptance among all expert panel members. Thirty-nine consensus statements were established. These statements cover all aspects of PDAC management, including diagnosis, resectability criteria, treatment modalities according to resectability, personalised management based on molecular profiling, palliative care, and supportive care. This project fulfils the need for guidance regarding PDAC management in Hong Kong. To assist clinicians with treatment decisions based on varying levels of evidence and clinical experience, treatment options are listed in several consensus statements., Competing Interests: SL Chan has served as an advisor for AstraZeneca, MSD, Eisai, and Ipsen, and has received research funding from Bayer, Eisai, Ipsen, Sirtex, and MSD. CL Chiang has served as an advisor for AstraZeneca, MSD, and Eisai, and has received research funding from Merck KGaA, AstraZeneca, and Taiho. Other authors have disclosed no conflicts of interest.

Hericium erinaceus , a consumable mushroom, has shown a potential to enhance the production of neuroprotective bioactive metabolites. Traumatic brain injury (TBI) often leads to cognitive, physical, and psychosocial impairments, resulting in neuroinflammation and the loss of cortical neurons. In this research, the effects of H. erinaceus mycelium, its derivative erinacine C, along with the underlying mechanisms, were examined in terms of oxidative stress modulation and neurological improvement in a rat model of mild traumatic brain injury (mTBI). Male Sprague-Dawley rats were administered diets containing H. erinaceus mycelium and erinacine C following experimental brain injury; these supplements were continued throughout the recovery phase. The binding activity of NF-E2-related factor 2 (Nrf2) near antioxidant genes in mixed glial cells was measured by chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR). The motor beam walking test revealed that dietary supplementation of H. erinaceus mycelium resulted in modest improvements in spatial memory while inhibiting neuron cell death and microglial activation according to brain histological examination. These findings were further corroborated by the upregulation of several antioxidant enzymes (catalase, glutathione reductase, thioredoxin reductase, and superoxide dismutase) and phospho-CAMP-response element-binding (p-CREB) levels in the mTBI model treated with H. erinaceus mycelium. Erinacine C treatment led to significantly reduced brain inflammation and normalization of mTBI-induced deficits through the modulation of the Nrf2 activation pathway and upregulated expression of numerous Nrf2-binding antioxidant genes such as catalase, thioredoxin reductase, superoxide dismutase, and brain-derived neurotrophic factor. This study demonstrates the potential of H. erinaceus mycelium and erinacine C in facilitating recovery following mTBI, including the prevention of neuronal injury and inactivation of microglia through the Nrf2-mediated antioxidant pathway in vivo.

Background: Laparoscopic liver resection (LLR) of high difficulty score is technically challenging. There is a lack of clinical evidence to support its applicability in terms of the long-term survival benefits. This study aims to compare clinical outcomes between LLR and the open liver resection of high difficulty score for hepatocellular carcinoma (HCC)., Materials and Methods: From 2010 to 2020, using Iwate criteria, 424 patients underwent liver resection of high difficulty score by the laparoscopic (n = 65) or open (n = 359) approach. Propensity score (PS) matching was performed between the two groups. Short-term and long-term outcomes were compared between PS-matched groups. Univariate and multivariate analyses were performed to identify prognostic factors affecting survival., Results: The laparoscopic group had significantly fewer severe complications (3% vs. 10.8%), and shorter median hospital stays (6 days vs. 8 days) than the open group. Meanwhile, the long-term oncological outcomes were comparable between the two groups, in terms of the tumor recurrence rate (40% vs. 46.1%), the 5-year overall survival rate (75.4% vs. 76.2%), and the 5-year recurrence-free survival rate (50.3% vs. 53.5%). The high preoperative serum alpha-fetoprotein level, multiple tumors, and severe postoperative complications were the independent poor prognostic factors associated with worse overall survival. The surgical approach (Laparoscopic vs. Open) did not influence the survival., Conclusion: LLR of high difficulty score for selected patients with HCC has better short-term outcomes than the open approach. More importantly, it can achieve similar long-term survival outcomes as the open approach., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The purpose of this study was to compare the outcomes of robotic limited liver resections (RLLR) versus laparoscopic limited liver resections (LLLR) of the posterosuperior segments., Background: Both laparoscopic and robotic liver resections have been used for tumors in the posterosuperior liver segments. However, the comparative performance and safety of both approaches have not been well examined in the existing literature., Methods: This is a post hoc analysis of a multicenter database of 5446 patients who underwent RLLR or LLLR of the posterosuperior segments (I, IVa, VII, and VIII) at 60 international centers between 2008 and 2021. Data on baseline demographics, center experience and volume, tumor features, and perioperative characteristics were collected and analyzed. Propensity score-matching (PSM) analysis (in both 1:1 and 1:2 ratios) was performed to minimize selection bias., Results: A total of 3510 cases met the study criteria, of whom 3049 underwent LLLR (87%), and 461 underwent RLLR (13%). After PSM (1:1: and 1:2), RLLR was associated with a lower open conversion rate [10 of 449 (2.2%) vs 54 of 898 (6.0%); P =0.002], less blood loss [100 mL [IQR: 50-200) days vs 150 mL (IQR: 50-350); P <0.001] and a shorter operative time (188 min (IQR: 140-270) vs 222 min (IQR: 158-300); P <0.001]. These improved perioperative outcomes associated with RLLR were similarly seen in a subset analysis of patients with cirrhosis-lower open conversion rate [1 of 136 (0.7%) vs 17 of 272 (6.2%); P =0.009], less blood loss [100 mL (IQR: 48-200) vs 160 mL (IQR: 50-400); P <0.001], and shorter operative time [190 min (IQR: 141-258) vs 230 min (IQR: 160-312); P =0.003]. Postoperative outcomes in terms of readmission, morbidity and mortality were similar between RLLR and LLLR in both the overall PSM cohort and cirrhosis patient subset., Conclusions: RLLR for the posterosuperior segments was associated with superior perioperative outcomes in terms of decreased operative time, blood loss, and open conversion rate when compared with LLLR., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The ability to integrate resources and share knowledge across organisations empowers scientists to expedite the scientific discovery process. This is especially crucial in addressing emerging global challenges that require global solutions. In this work, we develop an architecture for distributed self-driving laboratories within The World Avatar project, which seeks to create an all-encompassing digital twin based on a dynamic knowledge graph. We employ ontologies to capture data and material flows in design-make-test-analyse cycles, utilising autonomous agents as executable knowledge components to carry out the experimentation workflow. Data provenance is recorded to ensure its findability, accessibility, interoperability, and reusability. We demonstrate the practical application of our framework by linking two robots in Cambridge and Singapore for a collaborative closed-loop optimisation for a pharmaceutically-relevant aldol condensation reaction in real-time. The knowledge graph autonomously evolves toward the scientist's research goals, with the two robots effectively generating a Pareto front for cost-yield optimisation in three days., (© 2024. The Author(s).)

Objective: To compare the outcomes between robotic major hepatectomy (R-MH) and laparoscopic major hepatectomy (L-MH)., Background: Robotic techniques may overcome the limitations of laparoscopic liver resection. However, it is unknown whether R-MH is superior to L-MH., Methods: This is a post hoc analysis of a multicenter database of patients undergoing R-MH or L-MH at 59 international centers from 2008 to 2021. Data on patient demographics, center experience volume, perioperative outcomes, and tumor characteristics were collected and analyzed. Both 1:1 propensity-score matched (PSM) and coarsened-exact matched (CEM) analyses were performed to minimize selection bias between both groups., Results: A total of 4822 cases met the study criteria, of which 892 underwent R-MH and 3930 underwent L-MH. Both 1:1 PSM (841 R-MH vs. 841 L-MH) and CEM (237 R-MH vs. 356 L-MH) were performed. R-MH was associated with significantly less blood loss {PSM:200.0 [interquartile range (IQR):100.0, 450.0] vs 300.0 (IQR:150.0, 500.0) mL; P = 0.012; CEM:170.0 (IQR: 90.0, 400.0) vs 200.0 (IQR:100.0, 400.0) mL; P = 0.006}, lower rates of Pringle maneuver application (PSM: 47.1% vs 63.0%; P < 0.001; CEM: 54.0% vs 65.0%; P = 0.007) and open conversion (PSM: 5.1% vs 11.9%; P < 0.001; CEM: 5.5% vs 10.4%, P = 0.04) compared with L-MH. On subset analysis of 1273 patients with cirrhosis, R-MH was associated with a lower postoperative morbidity rate (PSM: 19.5% vs 29.9%; P = 0.02; CEM 10.4% vs 25.5%; P = 0.02) and shorter postoperative stay [PSM: 6.9 (IQR: 5.0, 9.0) days vs 8.0 (IQR: 6.0 11.3) days; P < 0.001; CEM 7.0 (IQR: 5.0, 9.0) days vs 7.0 (IQR: 6.0, 10.0) days; P = 0.047]., Conclusions: This international multicenter study demonstrated that R-MH was comparable to L-MH in safety and was associated with reduced blood loss, lower rates of Pringle maneuver application, and conversion to open surgery., Competing Interests: B.K.P.G. has received travel grants and honorariums from Johnson and Johnson, Olympus and Transmedic, the local distributor for the Da Vinci Robot. M.V.M. is a consultant for CAVA robotics LLC. J.P. reports a research grant from Intuitive Surgical Deutschland GmbH and personal fees or non-financial support from Johnson and Johnson, Medtronic, AFS Medical, Astellas, CHG Meridian, Chiesi, Falk Foundation, La Fource Group, Merck, Neovii, NOGGO, pharma-consult Peterson, and Promedicis. M. Schmelzle reports personal fees or other support outside of the submitted work from Merck, Bayer, ERBE, Amgen, Johnson and Johnson, Takeda, Olympus, Medtronic, and Intuitive. A.A.F. reports receiving speaker fees from Bayer. F.R. reports speaker fees and support outside the submitted work from Integra, Medtronic, Olympus, Corza, Sirtex, and Johnson and Johnson. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Single-cell analyses parse the brain's billions of neurons into thousands of 'cell-type' clusters residing in different brain structures 1 . Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq 2 to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use., (© 2023. The Author(s).)

The development of microglial endotoxin tolerance (ET) is a critical event in protecting neurons against excessive immune responses when microglia are administered two consecutive lipopolysaccharide (LPS) challenges. However, the intrinsic mechanisms of microglia shape ET programs and protect neurons remain unclear. This study aimed to determine whether extracellular autocrine cascades or intracellular signaling pathways are involved in ET microglia-mediated tumor necrosis factor-alpha (TNF-α) reduction and neuroprotection. Neuron-glia cultures composed of astroglia, neurons, and microglia were performed in different conditions: with or without serum or LPS-binding proteins (LBP), along with an induction approach of ET. Enzyme-linked immunosorbent assay results revealed that LPS induced TNF-α tolerance of microglia in an LBP-dependent manner. Furthermore, we determined whether the early pro-inflammatory cytokines induced by LPS might contribute to the development of microglial ET. Our data showed that the neutralization of TNF-α using an anti-TNF-α antibody had no change in the TNF-α tolerance of microglia during the ET challenge. Furthermore, pre-incubation of TNF-α, interleukin-1 beta, and prostaglandin E2 failed to induce any TNF-α tolerance in microglia after LPS treatment. Moreover, using three specific chemical inhibitors that respectively blocked the activities of the mitogen-activated protein kinases (MAPKs) namely p38, c-Jun N-terminal kinase and extracellular signal-related kinases revealed that inhibition of p38 MAPK by SB203580 disrupted the tolerated microglia-mediated TNF-α reduction and neuroprotection. In summary, our findings demonstrated that the LPS pre-treatment immediately programmed the microglial ET to prevent endotoxin-induced TNF-α production and neuronal damage through the intracellular p38 MAPK signaling pathway., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To evaluate the attachment rate of a human embryonic stem cell-derived trophoblastic spheroid onto endometrial epithelial cells in predicting the cumulative live birth rate of an in vitro fertilization (IVF) cycle., Design: A prospective observational study., Setting: University hospital and research laboratory., Patient(s): A total of 240 infertile women from 2017-2021., Intervention(s): Infertile women with regular cycles attending for IVF were recruited. An endometrial aspirate was collected from a natural cycle 1 month before IVF to determine the BAP-EB attachment rate., Main Outcome Measure(s): Cumulative live birth rates from a stimulated cycle and its derived frozen embryo transfer cycles within 6 months of ovarian stimulation were obtained., Result(s): The BAP-EB attachment rate in women who attained a cumulative live birth was similar to that in those who did not. When women were stratified by age into <35 years and ≥35 years, the BAP-EB attachment rate was significantly higher only in women aged ≥35 years having a live birth when compared with those in the same age group without a live birth. Receiver operating characteristic curve analysis of BAP-EB attachment rate in predicting cumulative live birth showed the areas under the curve of 0.559 (95% confidence interval [CI], 0.479-0.639), 0.448 (95% CI, 0.310-0.585), and 0.613 (95% CI, 0.517-0.710) for all ages, an age of <35 years, and an age of ≥35 years, respectively., Conclusion(s): The BAP-EB attachment rate offers only a very modest prediction of the cumulative live birth rate in women aged ≥35 years undergoing IVF., Clinical Trial Registration Number: NCT02713854 (https://clinicaltrials.gov/ct2/show/NCT02713854; Date of registration, March 21, 2016; date of enrollment of the first subject, August 1, 2017)., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Baveno VII criteria for predicting varices needing treatment (VNT) have not been tested in hepatocellular carcinoma (HCC) population. We evaluated Baveno VII consensus for VNT in HCC patients of different stages according to Barcelona Clinic Liver Cancer (BCLC) stages undergoing curative hepatectomy., Methods: This was a prospective cohort study of patients with HCC. Patients underwent transient elastography examination before HCC treatment and received at least one upper endoscopic examination afterwards. Patients were prospectively followed for clinical events including VNT., Results: Six hundred and seventy-three patients (83.1% male, median age 62 years) with HCC of BCLC stage 0 (10%), A (57%), B (17%) and C (15%) were recruited and followed for 47 months. The median (range) LSM was 10.5 (6.9-20.4) kPa; 74% had LSM ≤ 20 kPa and 58% had platelet count ≥150 × 10/L, respectively. VNT occurred in 51 (7.6%) patients. In patients who fulfilled Baveno VII criteria, that is, LSM ≤ 20 kPa and platelet count above 150 × 10/L, only 11 (1.6%) patients had VNT. In all BCLC stages of HCC, the proportion of patients with VNT was below 5%, which support the validity and applicability of Baveno VII criteria in all BCLC stages of HCC., Conclusions: The Baveno VII criteria are valid and applicable in HCC patients undergoing curative hepatectomy for selecting patients to undergo screening endoscopy for VNT. The validity was consistent across different BCLC stages of HCC., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)