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Background & Aims: Two recently developed composite models, the alpha-fetoprotein (AFP) score and Metroticket 2.0, could be used to select patients with hepatocellular carcinoma (HCC) who are candidates for liver transplantation (LT). The aim of this study was to compare the predictive performance of both models and to evaluate the net risk reclassification of post-LT recurrence between them using each model’s original thresholds. Methods: This multicenter cohort study included 2,444 adult patients who underwent LT for HCC in 47 centers from Europe and Latin America. A competing risk regression analysis estimating sub-distribution hazard ratios (SHRs) and 95% CIs for recurrence was used (Fine and Gray method). Harrell’s adapted c-statistics were estimated. The net reclassification index for recurrence was compared based on each model’s original thresholds. Results: During a median follow-up of 3.8 years, there were 310 recurrences and 496 competing events (20.3%). Both models predicted recurrence, HCC survival and survival better than Milan criteria (p

Background & Aims: Patients with hepatocellular carcinoma (HCC) are selected for liver transplantation (LT) based on pre-LT imaging ± alpha-foetoprotein (AFP) level, but discrepancies between pre-LT tumour assessment and explant are frequent. Our aim was to design an explant-based recurrence risk reassessment score to refine prediction of recurrence after LT and provide a framework to guide post-LT management. Methods: Adult patients who underwent transplantation between 2000 and 2018 for HCC in 47 centres were included. A prediction model for recurrence was developed using competing-risk regression analysis in a European training cohort (TC; n = 1,359) and tested in a Latin American validation cohort (VC; n=1,085). Results: In the TC, 76.4% of patients with HCC met the Milan criteria, and 89.9% had an AFP score of ≤2 points. The recurrence risk reassessment (R3)-AFP model was designed based on variables independently associated with recurrence in the TC (with associated weights): ≥4 nodules (sub-distribution of hazard ratio [SHR] = 1.88, 1 point), size of largest nodule (3–6 cm: SHR = 1.83, 1 point; >6 cm: SHR = 5.82, 5 points), presence of microvascular invasion (MVI; SHR = 2.69, 2 points), nuclear grade >II (SHR = 1.20, 1 point), and last pre-LT AFP value (101–1,000 ng/ml: SHR = 1.57, 1 point; >1,000 ng/ml: SHR = 2.83, 2 points). Wolber’s c-index was 0.76 (95% CI 0.72–0.80), significantly superior to an R3 model without AFP (0.75; 95% CI 0.72–0.79; p = 0.01). Four 5-year recurrence risk categories were identified: very low (score = 0; 5.5%), low (1–2 points; 15.1%), high (3–6 points; 39.1%), and very high (>6 points; 73.9%). The R3-AFP score performed well in the VC (Wolber’s c-index of 0.78; 95% CI 0.73–0.83). Conclusions: The R3 score including the last pre-LT AFP value (R3-AFP score) provides a user-friendly, standardised framework to design post-LT surveillance strategies, protocols, or adjuvant therapy trials for HCC not limited to the Milan criteria. Clinical Trials Registration: NCT03775863. Lay summary: Considering discrepancies between pre-LT tumour assessment and explant are frequent, reassessing the risk of recurrence after LT is critical to further refine the management of patients with HCC. In a large and international cohort of patients who underwent transplantation for HCC, we designed and validated the R3-AFP model based on variables independently associated with recurrence post-LT (number of nodules, size of largest nodule, presence of MVI, nuclear grade, and last pre-LT AFP value). The R3-AFP model including last available pre-LT AFP value outperformed the original R3 model only based on explant features. The final R3-AFP scoring system provides a robust framework to design post-LT surveillance strategies, protocols, or adjuvant therapy trials, irrespective of criteria used to select patients with HCC for LT.

Background & Aims: Good outcomes after liver transplantation (LT) have been reported after successfully downstaging to Milan criteria in more advanced hepatocellular carcinoma (HCC). We aimed to compare post-LT outcomes in patients receiving locoregional therapies (LRT) before LT according to Milan criteria and University of California San Francisco downstaging (UCSF-DS) protocol and ‘all-comers’. Methods: This multicentre cohort study included patients who received any LRT before LT from Europe and Latin America (2000–2018). We excluded patients with alpha-foetoprotein (AFP) above 1,000 ng/ml. Competing risk regression analysis for HCC recurrence was conducted, estimating subdistribution hazard ratios (SHRs) and corresponding 95% CIs. Results: From 2,441 LT patients, 70.1% received LRT before LT (n = 1,711). Of these, 80.6% were within Milan, 12.0% within UCSF-DS, and 7.4% all-comers. Successful downstaging was achieved in 45.2% (CI 34.8–55.8) and 38.2% (CI 25.4–52.3) of the UCSF-DS group and all-comers, respectively. The risk of recurrence was higher for all-comers (SHR 6.01 [p

Increased cortisol levels in humans are often observed in patients suffering from mood disorders. In this study human fetal brain aggregates were exposed to cortisol at 500 nM for 3 weeks, as an in-vitro model of chronic cortisol exposure. Microarray analysis on extracted mRNA using the Affymetrix U133A platform was then performed. Our results demonstrated a significant effect of cortisol on 1648 transcripts; 736 up-regulated and 912 down-regulated genes. The most differentially regulated biological categories were: RNA processing, protein metabolism, and cell growth. Within these categories we observed a down-regulation of fibroblast growth factor 2 (FGF2) (−1.5-fold) and aquaporin4 (AQP4) (−1.7-fold), alongside an up-regulation of fibroblast growth factor 9 (FGF9) (+1.7-fold) and vesicle associated membrane protein2 (VAMP2) (+1.7-fold). FGF2, FGF9, AQP4 and VAMP2 changes were confirmed at the protein level by immunohistochemistry. Alterations in FGF transcripts are in keeping with recent literature demonstrating such effects in patients with mood disorders.

With increasing growth in applications of artificial intelligence (AI) in surgery, it has become essential for surgeons to gain a foundation of knowledge to critically appraise the scientific literature, commercial claims regarding products, and regulatory and legal frameworks that govern the development and use of AI. This guide offers surgeons a framework with which to evaluate manuscripts that incorporate the use of AI. It provides a glossary of common terms, an overview of prerequisite knowledge to maximize understanding of methodology, and recommendations on how to carefully consider each element of a manuscript to assess the quality of the data on which an algorithm was trained, the appropriateness of the methodological approach, the potential for reproducibility of the experiment, and the applicability to surgical practice, including considerations on generalizability and scalability., (© 2024 Published by Elsevier Ltd.)

Background: Caregivers of people with dementia (pwD) are at risk of depression, anxiety, and burden. COVID-19 pandemic and government-imposed lockdown as a preventive measure might increase psychological symptoms in caregivers. The authors performed a study to measure the change of psychological symptoms during quarantine or self-isolation for COVID-19 in a sample of Italian caregivers of pwD, and to investigate if the resilience is associated with psychological changes in the sample., Methods: Eighty-four caregivers of pwD completed an online survey including questionnaires assessing depressive symptomatology and anxiety before and during the lockdown, caregiver burden and levels of resilience., Results: The multivariate analysis of variance revealed an effect of time (before and during the lockdown) in the whole group on depression scores; a significant interaction between time and resilience was found on anxiety scores, revealing that caregivers with high resilience showed a more significant increase of anxiety levels during lockdown than caregivers with low resilience. Moreover, the regression analysis revealed that caregiver burden was associated negatively with resilience scores, and positively with higher functional dependence., Conclusion: COVID-19 pandemic and the lockdown produced psychological consequences in caregivers of pwD, with an increase of levels of depression. Moreover, high resilience had a negative effect on anxiety levels and no effect on depressive symptomatology during the lockdown; moreover, it was associated with lower levels of caregiver burden. All caregivers, even those with high resilience levels, should be addressed to psychological interventions to reduce levels of depression, anxiety and caregiver burden., (Copyright © 2020 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: Low levels of cognitive reserve (CR), depressive symptomatology, and apathy are considered risk factors for cognitive decline. The aim of this study was to explore the relationships between these factors across the lifespan in healthy adults., Methods: This study included 429 Italian participants with no cognitive impairment, divided in three age subgroups: young adults, adults, and elderly. Participants were categorized as having low- or high CR based on the median of the Cognitive Reserve Scale, a self-rated questionnaire evaluating engagement in several leisure and social activities. Depressive symptomatology and severity of apathy were assessed by the Beck Depression Inventory - second edition (BDI-II) and the Dimensional Apathy Scale (DAS), respectively. Analysis of variance and regression served to explore the association between CR, apathy, and depression in the whole sample and in the three age subgroups., Results: The analyses of variance and regression analyses revealed that DAS was associated with I-CRS scores in all age groups, as people with high levels of lifetime CR showed a lower level of apathy, whereas no association was found between BDI-II and I-CRS scores., Conclusion: Lifetime CR is associated with levels of apathy, but not of depressive symptomatology. Low CR is strongly associated with high levels of apathy and might indicate the need for psychoeducational interventions in order to prevent development of cognitive deterioration., (Copyright © 2019 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Study Objective: To compare long-term surgical, clinical, and functional outcomes between conservative and radical surgery in patients with rectosigmoid endometriosis (RSE) and preoperative intermediate risk of segmental resection., Design: Retrospective cohort study (Canadian Task Force classification II-2)., Setting: Endometriosis tertiary level referral center, St. Orsola Academic Hospital, Bologna, Italy., Patients: Three hundred and ninety-two patients with RSE presented for complete macroscopic surgical excision between January 2004 and January 2017., Intervention: Assessment of laparoscopic bowel shaving, discoid excision, or segmental resection for the treatment of RSE., Measurements and Main Results: The 392 patients were divided into 3 groups according to surgical technique: shaving (n = 297; 75.8%), discoid excision (n = 33; 8.4%), and segmental resection (n = 62; 15.8%). Preoperative characteristics, surgical data, short- and long-term complications, and rates of proven and suspected recurrence were assessed. The segmental resection group had a higher rate of short-term complications compared with the discoid and shaving groups (17.7% vs 9.1% vs 5.4%, respectively; p = .004). The median follow-up time was 43 months (range, 12-163 months). Suspected and proven RSE recurrence rates showed no statistically significant differences among the 3 groups. There also were no significant differences concerning the rate of de novo chronic constipation and urinary retention., Conclusion: To date, there is no consensus regarding the choice between radical (segmental resection) or conservative (shaving, discoid excision) surgical management for RSE, particularly for patients with preoperative intermediate risk of bowel segmental resection (the gray zone). Our data suggest that conservative surgery is preferred over radical surgery in patients with RSE in the gray zone risk category, resulting in similar suspected and proven RSE recurrence rates and associated with fewer short-term complications., (Copyright © 2018. Published by Elsevier Inc.)

Study Objective: Despite the enormous impact of lateral parametrial endometriosis (LPE), only a few studies have evaluated its diagnosis, prevalence, and clinical features. Our aim was to estimate the intraoperative prevalence of LPE in patients affected by deep infiltrating endometriosis (DIE) and to analyses clinical and surgical data associated with LPE., Design: Retrospective cohort study (Canadian Task Force classification II-2)., Setting: Endometriosis tertiary level referral center, Sant'Orsola Academic Hospital, Bologna, Italy., Patients: We included 1360 consecutive women submitted to surgery for DIE between 2007 and 2017. Patients were divided into 2 groups according to the presence (study group, n = 231) or absence (control group, n = 1129) of LPE., Intervention: We retrospectively compared data records on the demographic features, preoperative data, and surgical outcomes of the 2 groups., Measurements and Main Results: The intraoperative prevalence of LPE was 17%. Preoperatively, LPE patients complained of having a more severe intensity of dysmenorrhea (p <.001), more frequent voiding symptoms (p <.001), and more constipation (p = .02). At surgery, significant correlations were found with rectovaginal septum, vaginal, rectal, and ureteral involvement (p <.001). LPE patients intraoperatively presented a concomitant posterior nodule with a larger transverse diameter (p <.001). The operation time and hospital stay were longer for patients with LPE. Postoperatively, the LPE group needed self-catheterization more often than the control group at discharge (p <.001) and at the 1-month follow-up evaluation (p = .001)., Conclusions: LPE is a condition that reflects a more severe manifestation of endometriosis, requiring more aggressive surgery., (Copyright © 2018. Published by Elsevier Inc.)

Background: Controversy exists regarding the relevance of Center of Excellence accreditation to bariatric surgery outcomes. The objective of this study was to evaluate the impact of national hospital accreditation on perioperative and long-term outcomes following bariatric surgery., Methods: Retrospective, longitudinal study using 2004-2010 data from the New York Statewide Planning and Research Cooperative longitudinal administrative database (n = 47,342). Multivariable logistic regression analyzed outcomes following laparoscopic bariatric surgery. Accredited hospitals and accreditation year were identified from the Centers for Medicaid and Medicare website. Outcomes were analyzed with and without temporal correlation to accreditation year.>30-day mortality was determined from social security death records., Results: Risk of perioperative morbidity OR 1.4 (range 1.2-1.6, P<.001), mortality OR 2.6 (range 1.3-5.4, P = .01) and all-cause long-term mortality OR 1.4 (range 1.2-1.7, P = .0002) were significantly increased in unaccredited versus accredited hospitals on univariate analysis. In accredited hospitals, significant changes in payor and patient mix, operation, perioperative, and long-term outcomes were demonstrated following accreditation. A significant decrease in operations performed on black patients, Hispanic patients, and Medicare patients was also identified. Controlling for patient demographics, co-morbidity, insurance, and operative procedure, multivariable logistic regression demonstrated accreditation as independently associated with fewer major complications versus unaccredited hospitals OR 0.72 (range .63-.83, P<.001) and within the same hospital following accreditation OR .86 (range 0.77-0.96, P = .01). Following multiple cox proportional hazard model analysis, long-term mortality differences were not significant., Conclusion: In New York State, bariatric hospital accreditation improved patient outcomes as compared to unaccredited hospitals and within the same hospital compared to preaccreditation. Significant changes were identified for some underserved at-risk populations. Measures to ensure equitable health care for at-risk populations following institutional accreditation are imperative., (Copyright © 2015 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors have shown some promise in MYC-driven malignancies such as Burkitt's lymphoma (BL), we show that BRD4 inhibitors lead to robust BRD4 protein accumulation, which may account for their limited suppression of MYC expression, modest antiproliferative activity, and lack of apoptotic induction. To address these limitations we designed ARV-825, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 in all BL cell lines tested. Consequently, ARV-825 more effectively suppresses c-MYC levels and downstream signaling than small-molecule BRD4 inhibitors, resulting in more effective cell proliferation inhibition and apoptosis induction in BL. Our findings provide strong evidence that cereblon-based PROTACs provide a better and more efficient strategy in targeting BRD4 than traditional small-molecule inhibitors., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Hepatic artery (HA) rupture after liver transplantation is a rare complication with high mortality. This study aimed to review the different managements of HA rupture and their results. From 1997 to 2007, data from six transplant centers were reviewed. Of 2649 recipients, 17 (0.64%) presented with HA rupture 29 days (2-92) after transplantation. Initial management was HA ligation in 10 patients, reanastomosis in three, aorto-hepatic grafting in two and percutaneous arterial embolization in one. One patient died before any treatment could be initiated. Concomitant biliary leak was present in seven patients and could be subsequently treated by percutaneous and/or endoscopic approaches in four patients. Early mortality was not observed in patients with HA ligation and occurred in 83% of patients receiving any other treatment. After a median follow-up of 70 months, 10 patients died (4 after retransplantation), and 7 patients were alive without retransplantation (including 6 with HA ligation). HA ligation was associated with better 3-year survival (80% vs. 14%; p=0.002). Despite its potential consequences on the biliary tract, HA ligation should be considered as a reasonable option in the initial management for HA rupture after liver transplantation. Unexpectedly, retransplantation was not always necessary after HA ligation in this series., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The diagnosis of vascular dementia (VaD) remains a controversial issue in many aspects and concepts. These nosologic problems are caused both by the methods, insufficient to ascertain the diagnosis, as well as by the weak consistency of the clinical concept of VaD itself. One of the most intriguing issues on VaD, and in particular on post-stroke dementia (PSD), is related to the time of development of cognitive decline. In clinical practice, the 3-month time threshold is usually chosen to enable resolution of a possible acute post-stroke delirium, and to obtain a more reliable cognitive assessment with a complete regression of acute neuropsychological stroke-related deficits. Another relevant issue is the possibility to predict which patient will develop PSD. In this regard, recent data indicate an overlap between Alzheimer's disease (AD) and PSD, which seems to share risk factors and neuropathology. In most population samples these two disorders appear together, and the consensus is growing that a degenerative component has a more important role in determining PSD onset shortly after stroke than previously recognized. Therefore, anamnestic data have a fundamental role in this prognostic approach.

Background: Lower eyelid entropion is an eyelid malposition characterized by inward rotation of the eyelid margin associated with potentially significant discomfort and, occasionally, keratopathy. In this study we evaluated and compared the efficacy of two surgical techniques of retractor plication for involutional lower lid entropion repair., Methods: Sixty-two consecutive patients (62 eyes) with involutional lower lid entropion were included. Of the 62, 34 underwent the Jones retractor plication technique, and 28 underwent a modification of this technique that simplifies the procedure. We evaluated horizontal lid laxity, medial canthal tendon laxity and lower lid excursion before and after surgery, and determined the rate of entropion recurrence in the two groups. All measures were obtained before and 1 month, 6 months, 1 year, 2 years, 3 years and 4 years after surgery., Results: Preoperatively, there was no statistically significant difference between the two groups in any of the measures studied. Postoperatively, the mean amount of horizontal lid laxity was significantly less in the modified technique group than in the Jones technique group (6.86 mm [standard deviation (SD) 0.41 mm] vs. 7.30 mm [SD 0.64 mm]) (p < 0.05). Similarly, the mean amount of medial canthal tendon laxity in the resting position was significantly less in the modified technique group than in the Jones technique group (1.90 mm [SD 0.56 mm] vs. 1.25 mm [SD 0.43 mm]) (p < 0.05). The rate of entropion recurrence was significantly lower in the modified technique group (7.1%) than in the Jones technique group (14.7%) (p < 0.05)., Interpretation: The modified retractor plication technique showed encouraging results in terms of successful and long-lasting lower lid entropion repair.