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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).)

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).)

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.)

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.)

Metastatic dissemination of colorectal cancer (CRC), the third most common cancer type, is responsible for CRC deaths. Understanding the transition of lymph node metastasis (LNM) from Stage II to Stage III is beneficial in the prognosis and intervention of CRC. In this study, a quantitative proteomic survey was conducted to investigate the LNM-associated proteins and evaluate the clinicopathological characteristics of these target proteins in CRC. By using the LC-MS/MS iTRAQ technology, we analysed the proteomic changes between LMN II and LMN III. Fresh tumours from the CRC specimens consisting of 12 node-negative (Stage II) and 12 node-positive (Stage III) cases were analysed by LC-MS/MS iTRAQ proteome analysis. Subsequently, tissue microarray with immunohistochemistry staining was conducted to access the clinicopathological characteristics of these proteins in 116 paraffin-embedded CRC samples, each for non-LNM and LNM CRC. To study the effects of the differentially expressed proteins on the potential mechanism, Boyden chamber assay, flow cytometry and shRNA-based assessments were conducted to examine the role of the epithelial-mesenchymal transition (EMT) and the invasiveness of CRC cells and others in vivo xenograft mouse model experiments. Forty-eight proteins were found differentially expressed between non-LNM and LNM CRC tissues. Protein abundances of chromogranin-A (CHGA) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) were observed in node-positive CRC (p < 0.05). Knockdown of CHGA and UCHL1 significantly regulate cancer behaviours of HCT-116, including inhibition of cell migration, invasiveness, cell cycle G1/S arrest and reactive oxygen species (ROS) generation. Mechanistically, the CHGA and UCHL1 inactivation displayed decreased levels of UCH-L1, chromogranin A, β-catenin, cyclin E, twist-1/2, vimentin, MMP-9, N-cadherin and PCNA through the activation of the Rho-GTPase/AKT/NFκB pathways. Histone modification of H3K4 trimethylation of CHGA and UCHL1 promoter were increased to activate their transcription through the signalling transduction such as Rho-GTPase, AKT and NFκB pathways. Our results indicated that UCHL1 and chromogranin A are novel regulators in CRC lymph node metastasis to potentially provide new insights into the mechanism of CRC progression and serve as biomarkers for CRC diagnosis at the metastatic stage., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objective: In this study we aim to unravel genetic determinants of coronary heart disease (CHD) in type 2 diabetes (T2D) and explore their applications., Research Design and Methods: We performed a two-stage genome-wide association study for CHD in Chinese patients with T2D (3,596 case and 8,898 control subjects), followed by replications in European patients with T2D (764 case and 4,276 control subjects) and general populations (n = 51,442-547,261). Each identified variant was examined for its association with a wide range of phenotypes and its interactions with glycemic, blood pressure (BP), and lipid controls in incident cardiovascular diseases., Results: We identified a novel variant (rs10171703) for CHD (odds ratio 1.21 [95% CI 1.13-1.30]; P = 2.4 × 10-8) and BP (β ± SE 0.130 ± 0.017; P = 4.1 × 10-14) at PDE1A in Chinese T2D patients but found only a modest association with CHD in general populations. This variant modulated the effects of BP goal attainment (130/80 mmHg) on CHD (Pinteraction = 0.0155) and myocardial infarction (MI) (Pinteraction = 5.1 × 10-4). Patients with CC genotype of rs10171703 had >40% reduction in either cardiovascular events in response to BP control (2.9 × 10-8 < P < 3.6 × 10-5), those with CT genotype had no difference (0.0726 < P < 0.2614), and those with TT genotype had a threefold increase in MI risk (P = 6.7 × 10-3)., Conclusions: We discovered a novel CHD- and BP-related variant at PDE1A that interacted with BP goal attainment with divergent effects on CHD risk in Chinese patients with T2D. Incorporating this information may facilitate individualized treatment strategies for precision care in diabetes, only when our findings are validated., (© 2023 by the American Diabetes Association.)

Background: Left lateral sectionectomy (LLS) is one of the most commonly performed minimally invasive liver resections. While laparoscopic (L)-LLS is a well-established technique, over traditional open resection, it remains controversial if robotic (R)-LLS provides any advantages of L-LLS., Methods: A post hoc analysis of 997 patients from 21 international centres undergoing L-LLS or R-LLS from 2006 to 2020 was conducted. A total of 886 cases (214 R-LLS, 672 L-LLS) met study criteria. 1:1 and 1:2 propensity score matched (PSM) comparison was performed between R-LLS & L-LLS. Further subset analysis by Iwate difficulty was also performed. Outcomes measured include operating time, blood loss, open conversion, readmission rates, morbidity and mortality., Results: Comparison between R-LLS and L-LLS after PSM 1:2 demonstrated statistically significantly lower open conversion rate in R-LLS than L-LLS (0.6% versus 5%, p = 0.009) and median blood loss was also statistically significantly lower in R-LLS at 50 (80) versus 100 (170) in L-LLS (p = 0.011) after PSM 1:1 although there was no difference in the blood transfusion rate. Pringle manoeuvre was also found to be used more frequently in R-LLS, with 53(24.8%) cases versus to 84(12.5%) L-LLS cases (p < 0.001). There was no significant difference in the other key perioperative outcomes such as operating time, length of stay, postoperative morbidity, major morbidity and 90-day mortality between both groups., Conclusion: R-LLS was associated with similar key perioperative outcomes compared to L-LLS. It was also associated with significantly lower blood loss and open conversion rates compared to L-LLS., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Delayed bone defect repairs lead to severe health and socioeconomic impacts on patients. Hence, there are increasing demands for medical interventions to promote bone defect healing. Recombinant proteins such as BMP-2 have been recognized as one of the powerful osteogenic substances that promote mesenchymal stem cells (MSCs) to osteoblast differentiation and are widely applied clinically for bone defect repairs. However, recent reports show that BMP-2 treatment has been associated with clinical adverse side effects such as ectopic bone formation, osteolysis and stimulation of inflammation. Here, we have identified one new osteogenic protein, named 'HKUOT-S2' protein, from Dioscorea opposita Thunb . Using the bone defect model, we have shown that the HKUOT-S2 protein can accelerate bone defect repair by activating the mTOR signaling axis of MSCs-derived osteoblasts and increasing osteoblastic biomineralization. The HKUOT-S2 protein can also modulate the transcriptomic changes of macrophages, stem cells, and osteoblasts, thereby enhancing the crosstalk between the polarized macrophages and MSCs-osteoblast differentiation to facilitate osteogenesis. Furthermore, this protein had no toxic effects in vivo . We have also identified HKUOT-S2 peptide sequence TKSSLPGQTK as a functional osteogenic unit that can promote osteoblast differentiation in vitro . The HKUOT-S2 protein with robust osteogenic activity could be a potential alternative osteoanabolic agent for promoting osteogenesis and bone defect repairs. We believe that the HKUOT-S2 protein may potentially be applied clinically as a new class of osteogenic agent for bone defect healing., Competing Interests: The authors declare that they have no conflicts of interest., (© 2023 The Authors.)

Primary Sjögren syndrome (pSS) is a systemic autoimmune inflammatory disease. Up to now, the role of regulatory T cells (Tregs) and their subgroups in pSS is still in controversial. In this study we tried to elucidate the roles of Tregs and its subgroups in pSS. Total 43 pSS patients and 23 health persons as control were enrolled in this study. We grouped the pSS patients according to the anti-SSa/SSb and the EULAR Sjögren's syndrome disease activity index (ESSDAI). Among the 43 pSS patients, 14 patients were followed after treatment. The percentage of rTregs (resting Treg cells) among Tregs was increased in the pSS group, and decreased after treatment. In the high disease activity subpopulation (ESSDAI ≥ 5), the percentage of rTregs among Tregs decreased after treatment. On the contrary, the percentage of aTregs (activated Treg cells) increased after treatment. It was in an inverse correlation between the percentage of aTreg and rTreg in pSS patients. The Tregs are co-cultured with responder T cells. Tregs from pSS patients showed poorer proliferation inhibitory function. Our results show that the percentages of Tregs and their subgroups altered in pSS patients. The percentage of aTreg and the percentage of rTreg have an inverse correlation in pSS patients. Compared to the control group, the percentage of rTregs among Tregs was increased in the pSS patients and decreased after the treatment. Our study also showed that The Tregs from pSS patients may have poorer inhibitory functions., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Successful placentation requires delicate communication between the endometrium and trophoblasts. The invasion and integration of trophoblasts into the endometrium during early pregnancy are crucial to placentation. Dysregulation of these functions is associated with various pregnancy complications, such as miscarriage and preeclampsia. The endometrial microenvironment has an important influence on trophoblast cell functions. The precise effect of the endometrial gland secretome on trophoblast functions remains uncertain. We hypothesized that the hormonal environment regulates the miRNA profile and secretome of the human endometrial gland, which subsequently modulates trophoblast functions during early pregnancy. Human endometrial tissues were obtained from endometrial biopsies with written consent. Endometrial organoids were established in matrix gel under defined culture conditions. They were treated with hormones mimicking the environment of the proliferative phase (Estrogen, E2), secretory phase (E2+Progesterone, P4), and early pregnancy (E2+P4+Human Chorionic Gonadotropin, hCG). miRNA-seq was performed on the treated organoids. Organoid secretions were also collected for mass spectrometric analysis. The viability and invasion/migration of the trophoblasts after treatment with the organoid secretome were determined by cytotoxicity assay and transwell assay, respectively. Endometrial organoids with the ability to respond to sex steroid hormones were successfully developed from human endometrial glands. By establishing the first secretome profiles and miRNA atlas of these endometrial organoids to the hormonal changes followed by trophoblast functional assays, we demonstrated that sex steroid hormones modulate aquaporin (AQP)1/9 and S100A9 secretions through miR-3194 activation in endometrial epithelial cells, which in turn enhanced trophoblast migration and invasion during early pregnancy. By using a human endometrial organoid model, we demonstrated for the first time that the hormonal regulation of the endometrial gland secretome is crucial to regulating the functions of human trophoblasts during early pregnancy. The study provides the basis for understanding the regulation of early placental development in humans., Competing Interests: Conflict of interests 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Antrodin C, a maleimide derivative compound isolated from the ethanol extract of the mycelium of Antrodia cinnamomea , is an endemic fungus of Taiwan and a potential chemoprotective agent. However, the molecular mechanisms underlying the mode of action of antrodin C on cancer cells, especially in human colorectal cancer (CRC), remain unclear., Methods: The cell death and ROS of the antrodin-C-treated HCT-116 cells were measured by annexin V-FITC/propidium iodide staining, DCFDA, and Fluo-3 fluorescence staining assays. Moreover, signaling molecules regulating TNFα cell death pathways and ROS/AKT/ERK/P38 pathways were also detected in cells treated with antrodin C by Western blotting and chromatin immunoprecipitation. The effects of antrodin C were determined in HCT-116 cell xenograft animal models in terms of tumor volumes and histopathological evaluation., Results: Treatment with antrodin C triggered the activation of extrinsic apoptosis pathways (TNFα, Bax, caspase-3, and -9), and also suppressed the expression of anti-apoptotic molecules Bcl-2 in HCT-116 cells in a time-dependent manner. Antrodin C also decreased cell proliferation and growth through the inactivation of cyclin D1/cyclin for the arrest of the cell cycle at the G1 phase. The activation of the ROS/AKT/ERK/P38 pathways was involved in antrodin-C-induced transcriptional activation, which implicates the role of the histone H3K9K14ac (Acetyl Lys9/Lys14) of the TNFα promoters. Immunohistochemical analyses revealed that antrodin C treatment significantly induced TNFα levels, whereas it decreased the levels of PCNA, cyclin D1, cyclin E, and MMP-9 in an in vivo xenograft mouse model. Thus, antrodin C induces cell apoptosis via the activation of the ROS/AKT/ERK/P38 signaling modules, indicating a new mechanism for antrodin C to treat CRC in vitro and in vivo.

Purpose: To compare the peri-operative and long-term survival outcomes of minimally invasive liver resection (MILR) (robotic or laparoscopic) with open liver resection (OLR) in patients with hepatocellular carcinoma (HCC)., Methods: Data of patients who underwent liver resection for HCC were reviewed from a prospectively collected database. Outcomes of MILR were compared with those of OLR. A propensity score matching analysis with a ratio of 1:1 was performed to minimise the potential bias in clinical pathological factors., Results: From January 2003 to December 2017, a total of 705 patients underwent liver resection for HCC. Amongst them, 112 patients received MILR and 593 patients received OLR. After propensity score matching, there were 112 patients in each of the MILR and OLR groups. Patients were matched by age, sex, hepatitis status, presence of cirrhosis, platelet count, albumin level, bilirubin level, alkaline phosphatase (ALP) level, alanine transferase (ALT) level, creatinine level, tumour differentiation, tumour size, tumour number, presence of tumour rupture, presence of vascular invasion, extent of liver resection (minor/major) and difficulty score. The 1-, 3- and 5-year overall survival rates were 94.4%, 90.4% and 82.3% in the MILR group vs 95.4%, 80.5% and 71.8% in the open group (p = 0.240). The 1-, 3- and 5-year disease-free survival rates were 81.0%, 63.1% and 55.8% in the MILR group vs 79.1%, 58.1% and 45.7 in the open group (p = 0.449). The MILR group demonstrated significantly less blood loss (p < 0.001), less blood transfusion (p = 0.004), lower post-operative complications (p < 0.001) and shorter hospital stay (p < 0.001) when compared with the OLR group., Conclusions: Our data shows MILR yielded superior post-operative outcomes to OLR, with comparable survival outcomes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The supposed adverse effect of involved resection margin during pancreaticoduodenectomy (PD) for periampullary carcinoma or pancreatic head carcinoma (CaP) on long-term oncological outcomes is still inconclusive., Methods: This is a retrospective study on periampullary carcinoma undergoing PD. Patients with R0 (margin clear) resection were compared to patients with R1 (microscopically directly involved margin) resection. Patients with gross involved margin (R2 resection) were excluded. Long-term oncological outcomes measured included incidence and site of recurrent disease, overall survival (OS) and disease-free survival (DFS). A subgroup analysis was made on patients with CaP., Results: Between January 2003 and December 2019, 203 PD were identified for present study. The incidence of R1 resection was common (12% in periampullary carcinoma and 20% in CaP). In periampullary carcinoma, R1 resection had greater proportion of CaP, lesser proportion of carcinoma of ampulla (CaA), more perineural invasion, more lymph node (LN) metastasis. R1 group had a shorter OS and DFS, but no difference in the incidence and site of recurrent disease. In the subgroup of CaP (91 patients), R1 group did not differ from R0 group except for more LN metastasis. There was no difference in incidence and site of recurrent disease, OS and DFS. On multivariable analysis, R1 resection was not an independent factor for OS and DFS for periampullary carcinoma or for CaP only., Conclusion: Involved resection margin was not uncommon. It was not associated with higher incidence of recurrent disease including local recurrence, and was not an independent prognosticator for OS and DFS., (© 2022. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

We generate bandwidth limited 10 µJ pulses of 92 fs pulse width using an adaptive fiber Bragg grating stretcher (FBG) in conjunction with a Lyot filter. The temperature controlled FBG is used to optimize the group delay, whereas the Lyot filter counteracts gain narrowing in the amplifier chain. Soliton compression in a hollow core fiber (HCF) allows for access to the few-cycle pulse regime. Adaptive control further enables the generation of nontrivial pulse shapes.

In Brief: Implantation failure can occur even after the transfer of good-quality embryos. This study showed that the migration of human endometrial stromal cells towards embryonic trophoblasts is higher in women with live births in the first in vitro fertilization cycle than those with repeated implantation failure, suggesting that the chemotactic response of stroma cells is associated with successful pregnancy., Abstract: The success rate of in vitro fertilization (IVF) remains limited in some women despite transfers of good-quality embryos in repeated attempts. There is no reliable tool for assessing endometrial receptivity. This study aimed to assess the interaction between decidualized human primary endometrial stromal cells (1°-EnSC) and human embryonic stem cell-derived trophoblastic spheroids (BAP-EB) and to compare the invasion ability of decidualized 1°-EnSC towards BAP-EB between women attaining live birth in the first IVF cycle and those with repeated implantation failure (RIF). The invasion of the decidualized human endometrial cell line (T-HESC) and 1°-EnSC towards BAP-EB was studied. Real-time quantitative PCR and immunocytochemistry were employed to determine the expression of decidualization markers at mRNA and protein levels, respectively. Trophoblast-like BAP-EB-96h, instead of early trophectoderm (TE)-like BAP-EB-48h, facilitated the invasion ability of decidualized T-HESC and decidualized 1°-EnSC. Human chorionic gonadotropin at supra-physiological levels promoted the invasiveness of decidualized 1°-EnSC. The extent of BAP-EB-96h-induced invasion was significantly stronger in decidualized 1°-EnSC from women who had a live birth in the first IVF cycle when compared to those with RIF. While no difference was found in the expression of decidualization markers, PRL and IGFBP1 among two groups of women, significantly lower HLA-B was detected in the non-decidualized and decidualized 1°-EnSC from women with RIF. Collectively, the findings suggested that the invasion of decidualized 1°-EnSC towards trophoblast-like BAP-EB-96h was higher in women who had a live birth in the first IVF cycle than those with RIF.

Background: Hepatocellular carcinoma is the sixth most common malignancy in the world. Major hepatectomy (resection of greater than or equal to three liver segments) is needed if a tumour is large or close to major blood vessels. Despite low mortality, open major hepatectomy is associated with high rates of tumour recurrence that limits survival. Laparoscopic major hepatectomy has been proposed as an alternative approach with potential oncological benefits. This study compares laparoscopic major hepatectomy with open major hepatectomy for hepatocellular carcinoma in a randomized trial., Methods: The Asia-Pacific multicentre randomized trial of laparoscopic versus open major hepatectomy for hepatocellular carcinoma (AP-LAPO trial) is an open-labelled multicentre randomized trial to be conducted in five centres in the Asia-Pacific region. The study will test the hypothesis that laparoscopic major hepatectomy for hepatocellular carcinoma is associated with less tumour recurrence and better survival compared with open major hepatectomy; the primary outcome being 2-year recurrence-free survival. Secondary outcomes include hospital mortality, postoperative complications according to the Clavien-Dindo classification, time to functional recovery, quality of life, long-term survival, and postoperative serum surgical stress-related cytokines., Results and Conclusion: The AP-LAPO trial will determine whether laparoscopic major hepatectomy offers oncological benefits to patients with hepatocellular carcinoma compared with open major hepatectomy., Registration Number: NCT04852211 (http://www.clinicaltrials.gov) registered on 21 April 2021., Protocol Version: AP-LAPO trial version 01 (1 December 2021)., (© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd.)

Objective: High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility., Research Design and Methods: HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value., Results: Over median (IQR) 5.2 (5.0-5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate < 0.05). Very large HDL-P were positively associated with all-cause mortality [1.75 (1.19, 2.58)]. Small HDL-P improved prediction of mortality [C-statistic 0.034 (0.013, 0.055), IDI 0.052 (0.014, 0.103), categorical NRI 0.156 (0.006, 0.252), and continuous NRI 0.571 (0.246, 0.851)] and CVD [IDI 0.017 (0.003, 0.038) and continuous NRI 0.282 (0.088, 0.486)] over the RECODe model., Conclusion: Small HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D., (© 2022. The Author(s).)

The decidualization of endometrial stromal cells (ESCs) is an essential process facilitating embryo implantation. However, the roles of non-decidualized and decidualized ESCs in regulating the microenvironment of a receptive endometrium remain unclear. We investigated single-cell transcriptomic changes in the uterus of a CD-1 mouse model at the post-implantation stage. The implantation and inter-implantation sites of the uteruses of pregnant mice at 4.5 and 5.5 days post-coitum were dissected for single-cell RNA sequencing. We identified eight cell types: epithelial cells, stromal cells, endothelial cells, mesothelial cells, lymphocytes, myocytes, myeloids, and pericytes. The ESC transcriptome suggests that the four ESC subtypes are involved in the extracellular remodeling during implantation. The trajectory plot of ESC subtypes indicates embryo implantation that involves a differentiation pathway from undifferentiated ESCs (ESC 1) to decidualized ESCs (DEC ESCs), with distinct signaling pathways between the ESC subtypes. Furthermore, the ligand-receptor analysis suggests that ESCs communicate with epithelial cells and immune cells through nectin and ICAM signaling. Collectively, both decidualized and non-decidualized ESCs may regulate the endometrial microenvironment for optimal endometrial receptivity and immune tolerance. This study provides insights on the molecular and cellular characteristics of mouse ESCs in modulating the epithelial and lymphocyte functions during early embryo implantation.

After fertilization, the zygote undergoes cell division. Up to the 8-cell stage, the blastomeres of mouse preimplantation embryos are morphologically identical. The first cell differentiation starts in the morula leading to the formation of trophectoderm cells and inner cell mass cells of the blastocyst. The regulation of the differentiation event and the formation of blastocysts are not fully known. Lethal-7 (let-7) is a family of evolutionarily conserved microRNAs. Here, we showed that the expression of let-7a and let-7g decreased drastically from the 1-cell stage to the 2-cell stage, remained low up to the 8-cell stage and slightly increased after the morula stage of mouse embryos. The expression of let-7 in the inner cell mass was higher than that in the trophectoderm. Forced expression of let-7a in embryos at the 1-cell and 4-cell stage inhibited blastocyst formation and downregulated the expression of CDX2 but maintained that of OCT4 in the trophectoderm. Forced expression of other let-7 isoforms exhibited similar inhibitory action on blastulation. On the other hand, inhibition of let-7a at the 4-cell stage and the 8-cell stage enhanced blastocyst formation. Co-injection of green fluorescent protein (GFP) mRNA (lineage tracer) with either precursor of let-7a (pre-let-7a) or scramble control into one blastomere of 2-cell embryos showed that ~75% of the resulting blastocysts possessed GFP+ cells in their inner cell mass only. The biased development towards the inner cell mass with forced expression of let-7 was reproduced in 2-cell chimeric embryos consisting of one wildtype blastomere and one GFP mRNA-injected blastomere from another 2-cell embryo carrying a doxycycline-inducible let-7g gene. Bioinformatics analysis indicated that Tead4 was a potential target of let-7. Let-7 bound to the 3'UTR of Tead4 and let-7 forced expression downregulated the expression of Tead4 in mouse blastocysts. Co-injection of Tead4 mRNA partially nullified the modulatory roles of let-7a in the inner cell mass cell fate. In conclusion, a high level of let-7 at the 2-cell stage favored the formation of the inner cell mass, whereas a low level of let-7 at the 4-cell to 8-cell stage enhanced blastocyst formation. Tead4 mediated the action of let-7 on the inner cell mass cell-fate determination., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We report herein a novel mechanism, unraveled by proteomics and validated by in vitro and in vivo studies, of the aberrant aging-associated upregulation of ovarian transferrin and ferritin in rat ovaries. The ovarian mass and serum estradiol titer plummeted while the ovarian labile ferrous iron and total iron levels escalated with age in rats. Oxidative stress markers, such as nitrite/nitrate, 3-nitrotyrosine, and 4-hydroxy-2-nonenal, accumulated in the aging ovaries due to an aberrant upregulation of the ovarian transferrin, ferritin light/heavy chains, and iron regulatory protein 2(IRP2)-mediated transferrin receptor 1 (TfR1). Ferritin inhibited estradiol biosynthesis in ovarian granulosa cells in vitro via the upregulation of a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and p65/p50-induced oxidative and inflammatory factor inducible nitric oxide synthase (iNOS). An in vivo study demonstrated how the age-associated activation of NF-κB induced the upregulation of iNOS and the tumor necrosis factor α (TNFα). The downregulation of the keap1-mediated nuclear factor erythroid 2-related factor 2 (Nrf2), that induced a decrease in glutathione peroxidase 4 (GPX4), was observed. The aberrant transferrin and ferritin upregulation triggered an iron accumulation via the upregulation of an IRP2-induced TfR1. This culminates in NF-κB-iNOS-mediated ovarian oxi-inflamm-aging and serum estradiol decrement in naturally aging rats. The iron accumulation and the effect on ferroptosis-related proteins including the GPX4, TfR1, Nrf2, Keap1, and ferritin heavy chain, as in testicular ferroptosis, indicated the triggering of ferroptosis. In young rats, an intraovarian injection of an adenovirus, which expressed iron regulatory proteins, upregulated the ovarian NF-κB/iNOS and downregulated the GPX4. These novel findings have contributed to a prompt translational research on the ovarian aging-associated iron metabolism and aging-associated ovarian diseases.

Objective: To review studies evaluating clinically implemented image-guided cochlear implant programing (IGCIP) and to determine its effect on cochlear implant (CI) performance., Data Sources: PubMed, EMBASE, and Google Scholar were searched for English language publications from inception to August 1, 2021., Study Selection: Included studies prospectively compared intraindividual CI performance between an image-guided experimental map and a patient's preferred traditional map. Non-English studies, cadaveric studies, and studies where imaging did not directly inform programming were excluded., Data Extraction: Seven studies were identified for review, and five reported comparable components of audiological testing and follow-up times appropriate for meta-analysis. Demographic, speech, spectral modulation, pitch accuracy, and quality-of-life survey data were collected. Aggregate data were used when individual data were unavailable., Data Synthesis: Audiological test outcomes were evaluated as standardized mean change (95% confidence interval) using random-effects meta-analysis with raw score standardization. Improvements in speech and quality-of-life measures using the IGCIP map demonstrated nominal effect sizes: consonant-nucleus-consonant words, 0.15 (-0.12 to 0.42); AzBio quiet, 0.09 (-0.05 to 0.22); AzBio +10 dB signal-noise ratio, 0.14 (-0.01 to 0.30); Bamford-Kowel-Bench sentence in noise, -0.11 (-0.35 to 0.12); Abbreviated Profile of Hearing Aid Benefit, -0.14 (-0.28 to 0.00); and Speech Spatial and Qualities of Hearing Scale, 0.13 (-0.02 to 0.28). Nevertheless, 79% of patients allowed to keep their IGCIP map opted for continued use after the investigational period., Conclusion: IGCIP has potential to precisely guide CI programming. Nominal effect sizes for objective outcome measures fail to reflect subjective benefits fully given discordance with the percentage of patients who prefer to maintain their IGCIP map., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2022, Otology & Neurotology, Inc.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters cells via receptor angiotensin-converting enzyme 2 (ACE2) and co-receptor transmembrane serine protease 2 (TMPRSS2). However, patients with SARS-CoV-2 infection receiving ACE1 inhibitors had higher ACE2 expression and were prone to poorer prognostic outcomes. Until now, information on the expression of ACE1, ACE2, and TMPRSS2 in human endometrial tissues, and the effects of ACE inhibitors on embryo implantation are limited. We found human endometria expressed ACE1, ACE2, and TMPRSS2 transcripts and proteins. Lower ACE1, but higher ACE2 transcripts were found at the secretory than in the proliferative endometria. ACE1 proteins were weakly expressed in endometrial epithelial and stromal cells, whereas ACE2 and TMPRSS2 proteins were highly expressed in luminal and glandular epithelial cells. However, ACE1 and TMPRSS4 were highly expressed in receptive human endometrial epithelial (Ishikawa and RL95-2) cells, but not in non-receptive AN3CA and HEC1-B cells. Treatment of human endometrial epithelial cells with ACE1 (Captopril, Enalaprilat, and Zofenopril) or ACE2 (DX600) inhibitors did not significantly alter the expression of ACE1, ACE2 and TMPRSS2 transcripts and spheroid (blastocyst surrogate) attachment onto Ishikawa cells in vitro. Taken together, our data suggest that higher ACE2 expression was found in mid-secretory endometrium and the use of ACE inhibitors did not alter endometrial receptivity for embryo implantation., (Copyright © 2022 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

Background: Collision tumors are rare clinical entities that two heterogeneous neoplasms are concurrently adjacent to each other at the same location. The association of a squamous cell carcinoma and a malignant adnexal tumor is even infrequent., Case Presentation: The case of a 79-year-old woman having a slow-growing and painless tumor on the left lower eyelid was presented. The lesion, about 15 mm in diameter, was nodular, irregular, and yellow-discolored. Histopathologic and immunohistochemical findings disclosed concurrence of sebaceous carcinoma as well as squamous cell carcinoma in one specimen. Wide excision of the tumor with frozen section control and eyelid reconstruction were performed. Oncologic survey revealed no other lesion. At 6-month follow-up, no evidence of recurrence or metastasis was presented., Conclusion: Collision tumor composed of sebaceous carcinoma and squamous cell carcinoma in eyelid may be the first case described in the literature. For increasing accuracy of diagnosis and management, a thorough clinical examination and detailed histopathologic analysis, along with multidisciplinary discussion, are prerequisites.

Chronic otitis media (COM) has been considered as a localized disease, and its systemic impact is poorly understood. Whether COM-induced inflammation could be associated with systemic bone loss and hip fracture is unknown at present. Our study tried to determine the risk of hip fracture among COM patients. We selected the comparison individuals without the COM coding and paired the controls with COM patients by gender, age, and comorbidities (including osteoporosis) by about a one-to-two ratio. Our study showed that the incidence of hip fracture was 4.48 and 3.92 per 1000 person-years for comparison and COM cohorts respectively. The cumulative incidence of hip fracture is higher in the COM cohort (p < 0.001). After adjustment for gender, age, and comorbidities, the COM patients had a 1.11-fold (aHR = 1.11; 95% CI = 1.05−1.17) risk of hip fracture than the control subjects. Among COM patients, a history of hearing loss is associated with higher (aHR = 1.21; 95% CI = 1.20−1.42) fracture risk. Our study showed that COM patients, especially those with hearing loss, are susceptible to a higher risk for hip fracture.

Perception of threats is essential for survival. Previous findings suggest that parallel pathways independently relay innate threat signals from different sensory modalities to multiple brain areas, such as the midbrain and hypothalamus, for immediate avoidance. Yet little is known about whether and how multi-sensory innate threat cues are integrated and conveyed from each sensory modality to the amygdala, a critical brain area for threat perception and learning. Here, we report that neurons expressing calcitonin gene-related peptide (CGRP) in the parvocellular subparafascicular nucleus in the thalamus and external lateral parabrachial nucleus in the brainstem respond to multi-sensory threat cues from various sensory modalities and relay negative valence to the lateral and central amygdala, respectively. Both CGRP populations and their amygdala projections are required for multi-sensory threat perception and aversive memory formation. The identification of unified innate threat pathways may provide insights into developing therapeutic candidates for innate fear-related disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing DKD phenotype. We compared the risks of adverse outcomes among patients with this phenotype compared with other DKD phenotypes., Study Design: Multicenter prospective cohort study., Settings & Participants: 19,025 Chinese adults with type 2 diabetes enrolled in the Hong Kong Diabetes Biobank., Exposures: DKD phenotypes defined by baseline estimated glomerular filtration rate (eGFR) and albuminuria: no DKD (no decreased eGFR or albuminuria), albuminuria without decreased eGFR, decreased eGFR without albuminuria, and albuminuria with decreased eGFR., Outcomes: All-cause mortality, cardiovascular disease (CVD) events, hospitalization for heart failure (HF), and chronic kidney disease (CKD) progression (incident kidney failure or sustained eGFR reduction ≥40%)., Analytical Approach: Multivariable Cox proportional or cause-specific hazards models to estimate the relative risks of death, CVD, hospitalization for HF, and CKD progression. Multiple imputation was used for missing covariates., Results: Mean participant age was 61.1 years, 58.3% were male, and mean diabetes duration was 11.1 years. During 54,260 person-years of follow-up, 438 deaths, 1,076 CVD events, 298 hospitalizations for HF, and 1,161 episodes of CKD progression occurred. Compared with the no-DKD subgroup, the subgroup with decreased eGFR without albuminuria had higher risks of all-cause mortality (hazard ratio [HR], 1.59 [95% CI, 1.04-2.44]), hospitalization for HF (HR, 3.08 [95% CI, 1.82-5.21]), and CKD progression (HR, 2.37 [95% CI, 1.63-3.43]), but the risk of CVD was not significantly greater (HR, 1.14 [95% CI, 0.88-1.48]). The risks of death, CVD, hospitalization for HF, and CKD progression were higher in the setting of albuminuria with or without decreased eGFR. A sensitivity analysis that excluded participants with baseline eGFR <30 mL/min/1.73 m 2 yielded similar findings., Limitations: Potential misclassification because of drug use., Conclusions: Nonalbuminuric DKD was associated with higher risks of hospitalization for HF and of CKD progression than no DKD, regardless of baseline eGFR., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aims: A combination of fluorescence two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time of flight mass spectrometry approach was used to search for potential markers for prognosis and intervention of colorectal cancer (CRC) at different stages of lymph node metastasis (LMN). This quantitative proteomic survey aimed to investigate the LNM-associated proteins and evaluate the clinicopathological characteristics of these target proteins in CRC from stage I to stage IV., Methods: Sixteen CRC cases were categorized into paired non-LNM and LNM groups, and two-dimensional difference gel electrophoresis and MS proteome analysis were performed. Differential protein expression between non-LNM and LNM CRC was further validated in a tissue microarray, including 40 paraffin-embedded samples by immunohistochemistry staining. Moreover, a Boyden chamber assay, flow cytometry, and shRNA were used to examine the epithelial-mesenchymal transition and mechanism invasiveness of the differentially expressed proteins in DLD-1 cells and in vivo xenograft mouse model., Results: Eighteen differentially expressed proteins were found between non-LNM and LNM CRC tissues. Among them, protein levels of Gelsolin (GSN) and peroxiredoxin 4 (PRDX4) were abundant in node-positive CRC. Downregulation of GSN and PRDX4 markedly suppressed migration and invasiveness and also induced cell cycle G1/S arrest in DLD-1. Mechanistically, the EGFR/RhoA/PKCα/ERK pathways are critical for transcriptional activation of histone modification of H3 lysine 4 trimethylation (H3K4me3) of GSN and PRDX4 promoters, resulting in upregulation of GSN, PRDX4, Twist-1/2, cyclinD1, proliferating cell-nuclear antigen, β-catenin, N-cadherin, and matrix metalloprotein-9., Conclusions: GSN and PRDX4 are novel regulators in CRC lymph node metastasis to potentially provide new insights into the mechanism of CRC progression and serve as a biomarker for CRC diagnosis at the metastatic stage.

Background: Robotic distal pancreatectomy has been accepted to be safe and effective for pancreatic tail lesion. Whether spleen preservation by preserving the splenic vessels with robot assistance is feasible and beneficial remains controversial. Here we would like to compare the operative outcomes of robotic distal pancreatectomy and splenectomy (DPS) with robotic spleen preserving distal pancreatectomy by means of splenic vessel preservation (SVP)., Methods: Between March 2011 and September 2019, 56 consecutive patients undergoing robotic distal pancreatectomy were identified, with 28 patients in each group. Patient demographics, histopathology findings and operative outcomes were prospectively collected and compared between the two groups. A subgroup analysis was made after excluding malignant and pancreatic lesions >6 cm in the DPS group., Results: The two groups had similar conversion rate, blood loss, morbidity and pancreatic fistula rate. There was no operative mortality. The SVP group had shorter median operative time (245 vs 303.5 min, P = 0.019) and shorter median hospital stay (5 vs 6 days, P = 0.019) than the DPS group. However, all malignant lesions occurred in the DPS group and lesion size in DPS group was significantly larger. After matching, there were 28 SVP and 15 DPS. The histopathology findings and lesion size became comparable. The SVP group still had shorter operative time (245 vs 290 min, P = 0.022) and shorter hospital stay (5 vs 7 days, P = 0.014) than the DPS group., Conclusion: Apart from avoiding risk of overwhelming postsplenectomy sepsis, robotic SVP had additional advantage of shorter operative time and shorter hospital stay than robotic DPS., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Current contraceptive methods interfere with folliculogenesis, fertilization, and embryo implantation by physical or hormonal approaches. Although hormonal contraceptive pills are effective in regulating egg formation, they are less effective in preventing embryo implantation. To explore the use of non-hormonal compounds that suppress embryo implantation, we established a high-throughput spheroid-endometrial epithelial cell co-culture assay to screen the Library of Pharmacologically Active Compounds (LOPAC) for compounds that affect trophoblastic spheroid (blastocyst surrogate) attachment onto endometrial epithelial Ishikawa cells. We identified 174 out of 1280 LOPAC that significantly suppressed BeWo spheroid attachment onto endometrial Ishikawa cells. Among the top 20 compounds, we found the one with the lowest cytotoxicity in Ishikawa cells, P11B5, which was later identified as Nemadipine-A. Nemadipine-A at 10 µM also suppressed BeWo spheroid attachment onto endometrial epithelial RL95-2 cells and primary human endometrial epithelial cells (hEECs) isolated from LH +7/8-day endometrial biopsies. Mice at 1.5 days post coitum (dpc) treated with a transcervical injection of 100 µg/kg Nemadipine-A or 500 µg/kg PRI-724 (control, Wnt-inhibitor), but not 10 µg/kg Nemadipine-A, suppressed embryo implantation compared with controls. The transcript expressions of endometrial receptivity markers, integrin αV ( ITGAV ) and mucin 1 ( MUC1 ), but not β-catenin ( CTNNB1 ), were significantly decreased at 2.5 dpc in the uterus of treated mice compared with controls. The reduction of embryo implantation by Nemadipine-A was likely mediated through suppressing endometrial receptivity molecules ITGAV and MUC1 . Nemadipine-A is a potential novel non-hormonal compound for contraception.

Importance: Laparoscopic and robotic techniques have both been well adopted as safe options in selected patients undergoing hepatectomy. However, it is unknown whether either approach is superior, especially for major hepatectomy such as right hepatectomy or extended right hepatectomy (RH/ERH)., Objective: To compare the outcomes of robotic vs laparoscopic RH/ERH., Design, Setting, and Participants: In this case-control study, propensity score matching analysis was performed to minimize selection bias. Patients undergoing robotic or laparoscopic RH/EHR at 29 international centers from 2008 to 2020 were included., Interventions: Robotic vs laparoscopic RH/ERH., Main Outcomes and Measures: Data on patient demographics, tumor characteristics, and short-term perioperative outcomes were collected and analyzed., Results: Of 989 individuals who met study criteria, 220 underwent robotic and 769 underwent laparoscopic surgery. The median (IQR) age in the robotic RH/ERH group was 61.00 (51.86-69.00) years and in the laparoscopic RH/ERH group was 62.00 (52.03-70.00) years. Propensity score matching resulted in 220 matched pairs for further analysis. Patients' demographics and tumor characteristics were comparable in the matched cohorts. Robotic RH/ERH was associated with a lower open conversion rate (19 of 220 [8.6%] vs 39 of 220 [17.1%]; P = .01) and a shorter postoperative hospital stay (median [IQR], 7.0 [5.0-10.0] days; mean [SD], 9.11 [7.52] days vs median [IQR], 7.0 [5.75-10.0] days; mean [SD], 9.94 [8.99] days; P = .048). On subset analysis of cases performed between 2015 and 2020 after a center's learning curve (50 cases), robotic RH/ERH was associated with a shorter postoperative hospital stay (median [IQR], 6.0 [5.0-9.0] days vs 7.0 [6.0-9.75] days; P = .04) with a similar conversion rate (12 of 220 [7.6%] vs 17 of 220 [10.8%]; P = .46)., Conclusion and Relevance: Robotic RH/ERH was associated with a lower open conversion rate and shorter postoperative hospital stay compared with laparoscopic RH/ERH. The difference in open conversion rate was associated with a significant decrease for laparoscopic but not robotic RH/ERH after a center had mounted the learning curve. Use of robotic platform may help to overcome the initial challenges of minimally invasive RH/ERH.

The present study investigated the relationship between internal locus of control and the perceived impact of Instagram fitspiration images on the self with media literacy as the mediating role in this relationship. This study also examined the importance of body mass index (BMI) as a moderating factor in the mediated model, where higher BMIs could weaken the relationship between internal locus of control and the perceived effect of fitspiration images mediated through media literacy. A sample of 321 Malaysian university students who were fitspiration viewers filled out a self-report questionnaire assessing internal locus of control, media literacy, perceived effect of fitspiration images on self, body satisfaction and BMI. The data analysis was performed using SPSS PROCESS macro. Results show that internal locus of control is negatively associated with the perceived impact of fitspiration images on self, mediated by media literacy. However, BMI moderates the mediated relationship such that the negative relationship between internal locus of control and the perceived effect of fitspiration images through media literacy does not exert an effect on those with high BMI. These results accentuate the value of incorporating a potential mediator and moderator into the direct relationship between internal locus of control and perceived effect of media ideals on self to provide an enhanced understanding of this process and offer practical insights about the protective role of media literacy and negative effects of high BMI.

We tested whether social signal processing in more traditional, head-restrained contexts is representative of the putative natural analog-social communication-by comparing responses to vocalizations within individual neurons in marmoset prefrontal cortex (PFC) across a series of behavioral contexts ranging from traditional to naturalistic. Although vocalization-responsive neurons were evident in all contexts, cross-context consistency was notably limited. A response to these social signals when subjects were head-restrained was not predictive of a comparable neural response to the identical vocalizations during natural communication. This pattern was evident both within individual neurons and at a population level, as PFC activity could be reliably decoded for the behavioral context in which vocalizations were heard. These results suggest that neural representations of social signals in primate PFC are not static but highly flexible and likely reflect how nuances of the dynamic behavioral contexts affect the perception of these signals and what they communicate., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)