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Background: Enrollment of Medicare beneficiaries in medicare advantage (MA) plans has been steadily increasing. Prior research has shown differences in healthcare access and outcomes based on Medicare enrollment status. This study sought to compare utilization of minimally invasive colorectal cancer (CRC) surgery and postoperative outcomes between MA and Fee-for-Service (FFS) beneficiaries. Methods: A retrospective cohort study of beneficiaries  ≥ 65.5 years of age enrolled in FFS and MA plans was performed of patients undergoing a CRC resection from 2016 to 2019. The primary outcome was operative approach, defined as minimally invasive (laparoscopic) or open. Secondary outcomes included robotic assistance, hospital length-of-stay, mortality, discharge disposition, and hospital readmission. Using balancing weights, we performed a tapered analysis to examine outcomes with adjustment for potential confounders. Results: MA beneficiaries were less likely to have lymph node (12.9 vs 14.4%, p< 0.001) or distant metastases (15.5% vs 17.0%, p< 0.001), and less likely to receive chemotherapy (6.2% vs 6.7%, p< 0.001), compared to FFS beneficiaries. MA beneficiaries had a higher risk-adjusted likelihood of undergoing laparoscopic CRC resection (OR 1.12 (1.10–1.15), p< 0.001), and similar rates of robotic assistance (OR 1.00 (0.97–1.03), p= 0.912), compared to FFS beneficiaries. There were no differences in risk-adjusted length-of-stay (βcoefficient 0.03 (− 0.05–0.10), p= 0.461) or mortality at 30-60-and 90-days (OR 0.99 (0.95–1.04), p= 0.787; OR 1.00 (0.96–1.04), p= 0.815; OR 0.98 (0.95–1.02), p= 0.380). MA beneficiaries had a lower likelihood of non-routine disposition (OR 0.77 (0.75–0.78), p< 0.001) and readmission at 30-60-and 90-days (OR 0.76 (0.73–0.80), p< 0.001; OR 0.78 (0.75–0.81), p< 0.001; OR 0.79 (0.76–0.81), p< 0.001). Conclusions: MA beneficiaries had less advanced disease at the time of CRC resection and a greater likelihood of undergoing a laparoscopic procedure. MA enrollment is associated with improved health outcomes for elderly beneficiaries undergoing operative treatment for CRC.

Since there is no current international consensus on the optimal approach for pain management in acute pancreatitis (AP), analgesic practices may vary across different healthcare settings. This study explored global disparities in analgesic use, in particular opioids, during admission and at discharge in hospitalised AP patients. This was a post hoc analysis of the prospective PAINAP database, which included all admissions for AP between April and June 2022 with a 1‐month follow‐up. Demographic details, analgesic use, and clinical outcomes were recorded during admission and at discharge. Odds ratios (ORs) for opioid use during admission and at discharge were identified using multivariable regression analyses. Amongst the 1864 patients (52% males, median age 56 (interquartile range, 41–71)) across three different continents, simple analgesics were predominantly used as the primary analgesic (70%). Opioid use during admission was lowest in European centres (67%). Admission in Asian (OR, 2.53 (95% confidence interval (CI), 1.59–4.04), p< 0.001), and Australian (OR, 5.81 (95% CI, 3.19–10.56), p< 0.001) centres was associated with opioid administration during admission compared with European centres. Increased pain severity, longer pre‐admission pain duration, organ failure, and longer length of admission increased opioid use during admission. At discharge, Asian (OR, 2.01 (95% CI, 1.40–2.88), p< 0.001) and Australian (OR, 1.91 (95% CI, 1.28–2.85), p= 0.002) centres were associated with opioid prescription compared with European centres. Increased pain severity, longer pre‐admission pain duration, acute necrotic collections, and walled‐off necrosis also increased the likelihood of opioid prescription at discharge. There are substantial intercontinental differences in opioid use for AP pain. Accordingly, there is a need for international guidelines on pain management in AP.

Forecasting methods are important decision support tools in geo-distributed sensor networks. However, challenges such as the multivariate nature of data, the existence of multiple nodes, and the presence of spatio-temporal autocorrelation increase the complexity of the task. Existing forecasting methods are unable to address these challenges in a combined manner, resulting in a suboptimal model accuracy. In this article, we propose GAP-LSTM, a novel geo-distributed forecasting method that leverages the synergic interaction of graph convolution, attention-based long short-term memory (LSTM), 2-D-convolution, and latent memory states to effectively exploit spatio-temporal autocorrelation in multivariate data generated by multiple nodes, resulting in improved modeling capabilities. Our extensive evaluation, involving real-world datasets on traffic, energy, and pollution domains, showcases the ability of our method to outperform state-of-the-art forecasting methods. An ablation study confirms that all method components provide a positive contribution to the accuracy of the extracted forecasts. The method also provides an interpretable visualization that complements forecasts with additional insights for domain experts.

Background: Gaming can serve as an educational tool to allow trainees to practice surgical decision-making in a low-stakes environment. LapBot is a novel free interactive mobile game application that uses artificial intelligence (AI) to provide players with feedback on safe dissection during laparoscopic cholecystectomy (LC). This study aims to provide validity evidence for this mobile game. Methods: Trainees and surgeons participated by downloading and playing LapBot on their smartphone. Players were presented with intraoperative LC scenes and required to locate their preferred location of dissection of the hepatocystic triangle. They received immediate accuracy scores and personalized feedback using an AI algorithm (“GoNoGoNet”) that identifies safe/dangerous zones of dissection. Player scores were assessed globally and across training experience using non-parametric ANOVA. Three-month questionnaires were administered to assess the educational value of LapBot. Results: A total of 903 participants from 64 countries played LapBot. As game difficulty increased, average scores (p&lt; 0.0001) and confidence levels (p&lt; 0.0001) decreased significantly. Scores were significantly positively correlated with players’ case volume (p= 0.0002) and training level (p= 0.0003). Most agreed that LapBot should be incorporated as an adjunct into training programs (64.1%), as it improved their ability to reflect critically on feedback they receive during LC (47.5%) or while watching others perform LC (57.5%). Conclusions: Serious games, such as LapBot, can be effective educational tools for deliberate practice and surgical coaching by promoting learner engagement and experiential learning. Our study demonstrates that players’ scores were correlated to their level of expertise, and that after playing the game, most players perceived a significant educational value.

Background: Paraesophageal hernia repairs (PEHRs) have high rates of radiographic recurrence, with some patients requiring repeat operation. This study characterizes patients who underwent PEHR to identify the factors associated with postoperative symptom improvement and radiographic recurrence. We furthermore use propensity score matching to compare patients undergoing initial and reoperative PEHR to identify the factors predictive of recurrence or need for reoperation. Methods: After IRB approval, patients who underwent PEHR at a tertiary care center between January 2018 and December 2022 were identified. Patient characteristics, preoperative imaging, operative findings, and postoperative outcomes were recorded. A computational generalization of inverse propensity score weight was then used to construct populations of initial and redo PEHR patients with similar covariate distributions. Results: A total of 244 patients underwent PEHR (78.7% female, mean age 65.4 ± 12.3 years). Most repairs were performed with crural closure (81.4%) and fundoplication (71.7%) with 14.2% utilizing mesh. Postoperatively, 76.5% of patients had subjective symptom improvement and of 157 patients with postoperative imaging, 52.9% had evidence of radiographic recurrence at a mean follow-up of 10.4 ± 13.6 months. Only 4.9% of patients required a redo operation. Hernia type, crural closure, fundoplication, and mesh usage were not predictors of radiographic recurrence or symptom improvement (P> 0.05). Propensity weight score analysis of 50 redo PEHRs compared to a matched cohort of 194 initial operations revealed lower rates of postoperative symptom improvement (P&lt; 0.05) but no differences in need for revision, complication rates, ED visits, or readmissions. Conclusions: Most PEHR patients have symptomatic improvement with minimal complications and reoperations despite frequent radiographic recurrence. Hernia type, crural closure, fundoplication, and mesh usage were not significantly associated with recurrence or symptom improvement. Compared to initial PEHR, reoperative PEHRs had lower rates of symptom improvement but similar rates of recurrence, complications, and need for reoperation.

Cannabidiol (CBD), one of the main Cannabis sativabioactive compounds, is utilized in the treatment of major epileptic syndromes. Its efficacy can be attributed to a multimodal mechanism of action that includes, as potential targets, several types of ion channels. In the brain, CBD reduces the firing frequency in rat hippocampal neurons, partly prolonging the duration of action potentials, suggesting a potential blockade of voltage-operated K+channels. We postulate that this effect might involve the inhibition of the large-conductance voltage- and Ca2+-operated K+channel (BK channel), which plays a role in the neuronal action potential’s repolarization. Thus, we assessed the impact of CBD on the BK channel activity, heterologously expressed in HEK293 cells. Our findings, using the patch-clamp technique, revealed that CBD inhibits BK channel currents in a concentration-dependent manner with an IC50of 280 nM. The inhibition is through a direct interaction, reducing both the unitary conductance and voltage-dependent activation of the channel. Additionally, the cannabinoid significantly delays channel activation kinetics, indicating stabilization of the closed state. These effects could explain the changes induced by CBD in action potential shape and duration, and they may contribute to the observed anticonvulsant activity of this cannabinoid.

AbstractTo present evidence of the validity and reliability of the Brief MTL-BR Battery, a screening tool for language assessment for people with aphasia (PWA). The sample consisted of 138 participants, including 96 neurologically healthy adults and 42 individuals with aphasia. Construct validity was investigated through convergent validity. To examine convergent validity, correlations between the Brief MTL-BR and the Montreal Toulouse Language Assessment Battery - MTL-BR tasks were used. Criterion validity was determined using Holm-Bonferroni to compare people with aphasia and healthy adults. Reliability was determined through inter-rater (Interclass Correlation Coefficients), the test-retest method (Interclass Correlation Coefficients), and internal consistency (Cronbach’s Alpha). The Brief MTL-BR demonstrated satisfactory construct validity, with correlation coefficients ranging from substantial to very strong (0.553 to 0.862). The assessment of criterion validity demonstrated significant differences between neurologically healthy adults and people with aphasia on all tasks examined. Reliability assessments revealed excellent inter-rater agreement (0.972 to 1). All tasks in the Brief MTL-BR Battery displayed Cronbach’s alpha values above 0.88. Significant correlations between tasks and retest scores were identified ranging from good to excellent (0.752 to 0.967). The present findings support the reliability and validity of the Brief MTL-BR Battery.

Purpose: Hadrons, i.e. particles that are heavier than electrons, are playing an increasingly important role in radiation oncology. Due to the high investment costs for the necessary infrastructure, this option is only available in specialized centers. Methods: This article describes some of the physical properties that make hadrons attractive for external beam radiation therapy (EBRT), but also some of the challenges that need to be considered. Results: The importance of linear energy transfer for biological effects is discussed. Conclusions: In addition to the use of charged particles, the importance of neutrons for radiotherapy is also highlighted, in particular the properties of boron neutron capture therapy (BNCT), which open up completely new possibilities for the further development of EBRT.

Context: Cushing syndrome (CS) is associated with different hematological abnormalities. Nevertheless, conflicting data about erythropoiesis in CS have been reported. Furthermore, it is unclear whether CS sex and subtype-specific alterations in red blood cells (RBC) parameters are present. Objective: To investigate sex and subtype-specific changes in RBC in patients with CS at initial diagnosis and after remission. Design: Retrospective, monocentric study including 210 patients with CS (women, n = 162) matched 1:1 for sex and age to patients with pituitary microadenomas or adrenal incidentalomas (both hormonally inactive). RBC parameters were evaluated at initial diagnosis and after remission. Results: Women with CS had higher hematocrit (median 42.2 vs39.7%), hemoglobin (14.1 vs13.4 g/dl) and mean corpuscular volume (MCV) (91.2 vs87.9 fl) compared to the controls (all p&lt; 0.0001). Women with Cushing disease (CD) showed higher hematocrit, RBC and hemoglobin levels than those with ectopic Cushing (ECS) (all p&lt; 0.005). Men with CS had lower hematocrit (42.9 vs44.7%), RBC count (4.8 vs5.1n*106/µl) and hemoglobin (14.2 vs15.4 g/dl), but higher MCV (90.8 vs87.5 fl) than controls (all p&lt; 0.05). In men with CS, no subtype-specific differences were identified. Three months after remission hemoglobin decreased in both sexes. Conclusion: CS is characterized by sexual and subtype-specific differences in RBC parameters. Compared to controls, women with CS showed higher hematocrit/hemoglobin levels, whereas men had lower hematocrit/hemoglobin, which further decreased directly after remission. Therefore, anemia should be considered as complication of CS in men. In women, differences in RBC parameters may help to differentiate CD from ECS.

Objective: We aimed at defining the most effective routine immunoassay- or liquid chromatography-tandem mass spectrometry (LC–MS/MS)-determined steroid biomarkers for identifying non-classic adrenal hyperplasia due to 21-hydroxylase deficiency (21-NCAH) in a PCOS-like population before genotyping. Methods: Seventy PCOS-like patients in reproductive age with immunoassay-determined follicular 17OH-progesterone (17OHP) ≥ 2.00 ng/mL underwent CYP21A2gene analysis and 1–24ACTH test. Serum steroids were measured by immunoassays at baseline and 60 min after ACTH stimulation; basal steroid profile was measured by LC–MS/MS. Results: Genotyping revealed 23 21-NCAH, 15 single allele heterozygous CYP21A2mutations (21-HTZ) and 32 PCOS patients displaying similar clinical and metabolic features. Immunoassays revealed higher baseline 17OHP and testosterone, and after ACTH stimulation, higher 17OHP (17OHP60) and lower cortisol, whereas LC–MS/MS revealed higher 17OHP (17OHPLC-MS/MS), progesterone and 21-deoxycortisol and lower corticosterone in 21-NCAH compared with both 21-HTZ and PCOS patients. Steroid thresholds best discriminating 21-NCAH from 21-HTZ and PCOS were estimated, and their diagnostic accuracy in identifying 21-NCAH from PCOS was established by ROC analysis. The highest accuracy was observed for 21-deoxycortisol ≥ 0.087 ng/mL, showing 100% sensitivity, while the combination of 17OHPLC-MS/MS≥ 1.79 ng/mL and corticosterone ≤ 8.76 ng/mL, as well as the combination of ACTH-stimulated 17OHP ≥ 6.77 ng/mL and cortisol ≤ 240 ng/mL by immunoassay, showed 100% specificity. Conclusions: LC–MS/MS measurement of basal follicular 21-deoxycortisol, 17OHP and corticosterone seems the most convenient method for diagnosing 21-NCAH in a population of PCOS with a positive first level screening, providing high accuracy and reducing the need for ACTH stimulation test.

In this study, we present the preliminary imaging results obtained with a gamma module called BeNEdiCTE, specifically designed for boron neutron capture therapy (BNCT). The primary objective of the BNCT-SPECT system is to quantitatively assess and pinpoint the 10B contribution to the dose administered to a patient during BNCT treatment by detecting the 478-keV gamma rays emitted from the 10B(n, $\alpha $ )7Li reactions. Starting from a feasibility study of a collimator suitable for a BNCT-SPECT system, we end up presenting the first images obtained by reconstructing vials containing boron powder thanks to the aid of an artificial neural network (ANN). However, the extremely high-intensity neutron flux of $10{^{{9}}}$ n/cm2/s and the presence of mixed radiation fields in the irradiation room pose significant challenges to this task. To overcome these challenges, the implementation of an appropriate collimator becomes essential. Thanks to Monte Carlo simulations, we designed a lead pinhole collimator, with a twofold focus on enhancing spatial resolution (achieving <1 cm) and maximizing geometric efficiency (GE) (attaining $\gt 10{^{-}6 }$ ).

DNA double-strand breaks (DSBs) contribute to genome instability, a key feature of cancer. DSBs are mainly repaired by homologous recombination (HR) and non-homologous end-joining (NHEJ). We investigated the role of an isoform of the multifunctional cyclin-dependent kinase 9, CDK9-55, in DNA repair, by generating CDK9-55-knockout HeLa clones (through CRISPR-Cas9), which showed potential HR dysfunction. A phosphoproteomic screening in these clones treated with camptothecin revealed that CDC23 (cell division cycle 23), a component of the E3-ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome), is a new substrate of CDK9-55, with S588 being its putative phosphorylation site. Mutated non-phosphorylatable CDC23(S588A) affected the repair pathway choice by impairing HR and favouring error-prone NHEJ. This CDK9 role should be considered when designing CDK-inhibitor-based cancer therapies.

Dealing with acute cholecystitis in high-risk, critically ill, and unfit-for-surgery patients is frequent during daily practice and requires complex management. Several procedures exist to postpone and/or prevent surgical intervention in those patients who temporarily or definitively cannot undergo surgery. After a systematic review of the literature, an expert panel from the Italian Society of Emergency Surgery and Trauma (SICUT) discussed the different issues and statements in subsequent rounds. The final version of the statements was discussed during the annual meeting in Rome (September 2022). The present paper presents the definitive conclusions of the discussion. Fifteen statements based on the literature evidence were provided. The statements gave precise indications regarding the decisional process and the management of patients who cannot temporarily or definitively undergo cholecystectomy for acute cholecystitis. Acute cholecystitis management in high-risk, critically ill, and unfit-for-surgery patients should be multidisciplinary. The different gallbladder drainage methods must be tailored according to each patient and based on the expertise of the hospital. Percutaneous gallbladder drainage is recommended as the first choice as a bridge to surgery or in severely physiologically deranged patients. Endoscopic gallbladder drainage (cholecystoduodenostomy and cholecystogastrostomy) is suggested as a second-line alternative especially as a definitive procedure for those patients not amenable to surgical management. Trans-papillary gallbladder drainage is the last option to be reserved only to those unfit for other techniques. Delayed laparoscopic cholecystectomy in patients with percutaneous gallbladder drainage is suggested in all those patients recovering from the conditions that previously discouraged surgical intervention after at least 6 weeks from the gallbladder drainage.

Introduction:TNFα-inducible matrix metalloproteinases play a critical role in the process of airway remodeling in respiratory inflammatory disease including asthma. The cationic host defense peptide LL-37 is elevated in the lungs during airway inflammation. However, the impact of LL-37 on TNFα-driven processes is not well understood. Here, we examined the effect of LL-37 on TNFα-mediated responses in human bronchial epithelial cells (HBECs). Methods:We used a slow off-rate modified aptamer-based proteomics approach to define the HBEC proteome altered in response to TNFα. Abundance of selected protein candidates and signaling intermediates was examined using immunoassays, ELISA and Western blots, and mRNA abundance was examined by qRT-PCR. Results:Proteomics analysis revealed that 124 proteins were significantly altered, 12 proteins were enhanced by ≥2-fold compared to unstimulated cells, in response to TNFα. MMP9 was the topmost increased protein in response to TNFα, enhanced by ∼10-fold, and MMP13 was increased by ∼3-fold, compared to unstimulated cells. Furthermore, we demonstrated that LL-37 significantly suppressed TNFα-mediated MMP9 and MMP13 in HBEC. Mechanistic data revealed that TNFα-mediated MMP9 and MMP13 production is controlled by SRC kinase and that LL-37 enhances related upstream negative regulators, namely, phospho-AKT (T308) and TNFα-mediated TNFAIP3 or A20. Conclusions:The findings of this study suggest that LL-37 may play a role in intervening in the process of airway remodeling in chronic inflammatory respiratory disease such as asthma.

Background: Surgery generates a vast amount of data from each procedure. Particularly video data provides significant value for surgical research, clinical outcome assessment, quality control, and education. The data lifecycle is influenced by various factors, including data structure, acquisition, storage, and sharing; data use and exploration, and finally data governance, which encompasses all ethical and legal regulations associated with the data. There is a universal need among stakeholders in surgical data science to establish standardized frameworks that address all aspects of this lifecycle to ensure data quality and purpose. Methods: Working groups were formed, among 48 representatives from academia and industry, including clinicians, computer scientists and industry representatives. These working groups focused on: Data Use, Data Structure, Data Exploration, and Data Governance. After working group and panel discussions, a modified Delphi process was conducted. Results: The resulting Delphi consensus provides conceptualized and structured recommendations for each domain related to surgical video data. We identified the key stakeholders within the data lifecycle and formulated comprehensive, easily understandable, and widely applicable guidelines for data utilization. Standardization of data structure should encompass format and quality, data sources, documentation, metadata, and account for biases within the data. To foster scientific data exploration, datasets should reflect diversity and remain adaptable to future applications. Data governance must be transparent to all stakeholders, addressing legal and ethical considerations surrounding the data. Conclusion: This consensus presents essential recommendations around the generation of standardized and diverse surgical video databanks, accounting for multiple stakeholders involved in data generation and use throughout its lifecycle. Following the SAGES annotation framework, we lay the foundation for standardization of data use, structure, and exploration. A detailed exploration of requirements for adequate data governance will follow.

The most frequent genetic alteration of familial isolated growth hormone producing pituitary neuroendocrine tumors is a germline mutation of the aryl hydrocarbon receptor-interacting protein (AIP)gene. Various AIPmutations are already known; however, an AIPmutation in exon 6 (c.811_812del; p.Arg271Glyfs*16) has not been reported yet. Here, we report a German family with two identical twins who were both affected by acromegaly and carried the above-mentioned novel AIPmutation. The father was found to be an unaffected carrier, while the paternal aunt most likely suffered from acromegaly as well and died from metastatic colorectal cancer. Apart from reporting a novel AIPmutation, this study does not only highlight the different clinical and histological features of the AIPmutated growth hormone producing pituitary neuroendocrine tumors but also confirms the poor responsiveness of dopamine agonists in AIPmutated acromegaly. Furthermore, it highlights the increased mortality risk of comorbidities typically associated with acromegaly.

Background: Communication is key to success in bariatric surgery. This study aims to understand how outcomes after bariatric surgery differ between patients with a non-English primary language and those with English as their primary language. Methods: This retrospective, observational cohort study of bariatric surgery patients age ≥ 18 years utilized the Michigan, Maryland, and New Jersey State Inpatient Databases and State Ambulatory Surgery and Services Databases, 2016 to 2018. Patients were classified by primary spoken language: English and non-English. Primary outcome was complications. Secondary outcomes included length of stay (LOS) and cost, with cost calculated using cost-to-charge ratios provided by Healthcare Cost and Utilization Project and reported in 2019 United States dollars. Multivariable regression models (logistic, Poisson, and quantile) were used to examine associations between primary language and outcomes. Given the uneven distribution of race by primary language, interaction terms were used to examine conditional effects of race. Results: Among 69,749 bariatric surgery patients, 2811 (4.2%) spoke a non-English primary language. Covariates, notably race distribution, and unadjusted outcomes differed significantly by primary language. However, after adjustment, non-English primary language was not associated with significantly increased odds of complications (odds ratio 1.24, p= 0.389), significantly different LOS (− 0.02 days, p= 0.677), nor significantly different mean healthcare costs (− $265, p= 0.309). There were no significant conditional effects of race seen among outcomes. Conclusions: Though non-English primary language was associated with a significantly different distribution of observable characteristics (including race, income quartile, and insurance type), after adjustment, non-English primary language was not associated with significant differential risk of adverse outcomes after bariatric surgery, and there were no significant conditional effects of race. As such, this study suggests that disparities in bariatric surgery by primary spoken language more likely related to access to care, or the pre- and post-hospital care continuum, rather than index hospitalization after surgery. Graphical abstract:

Olive cultivars present unique chemical properties due to the different ripening conditions and the dielectric factor of the extracted extra virgin olive oil (EVOO) is one of the most acceptable parameters for their evaluation. This study aims at discriminating olive oil samples using their chemical and dielectric properties. Three cultivars of olives: Oily, Yellowand Fishemi, at three ripening stages of unripe, semi-ripe and ripe, harvested using two different machines were tested. The quality characteristics of olive oil include the value of acidity, peroxide, sterol compounds, fatty acid composition and total phenol of the extracted olive oil were measured. The EVOO’s dielectric parameters were measured using a laboratory developed low-frequency device. The measures were done in the range from 0.1 to 10 MHz. The obtained parameters consisted of gain and phase shift voltages that were analyzed by principal component analysis, linear discriminant analysis, decision trees, support vector machine and artificial neural network. Out-of sample validation indicated the artificial neural network had the best performance with correlation coefficient of 0.9479, mean absolute error of 4.762 and root mean square error of 6.6652.The results revealed that the sensor measure followed by a machine learning approach have potential for the industrial application for discriminating the EVOO on the basis of the cultivar and ripening stage of the processed olive.

IMPORTANCE: The lack of family-friendly policies continues to contribute to the underrepresentation and attrition of surgical trainees. Women in surgery face unique challenges in balancing surgical education with personal and family needs. OBSERVATIONS: The Association of Women Surgeons is committed to supporting surgical families and developing equitable family-friendly guidelines. Herein we detail recommendations for adequate paid parental leave, access to childcare, breastfeeding support, and insurance coverage of fertility preservation and assisted reproductive technology. CONCLUSIONS AND RELEVANCE: The specific recommendations outlined in this document form the basis of a comprehensive initiative for supporting surgical families.

Background: The incidence of neuroendocrine neoplasm (NEN) and related carcinoid syndrome (CaS) has increased markedly in recent decades, and women appear to be more at risk than men. As per other tumors, gender may be relevant in influencing the clinical and prognostic characteristics of NEN-associated CS. However, specific data on carcinoid syndrome (CaS) are still lacking. Purpose: To evaluate gender differences in clinical presentation and outcome of CaS. Methods: Retrospective analysis of 144 CaS patients from 20 Italian high-volume centers was conducted. Clinical presentation, tumor characteristics, therapies, and outcomes (progression-free survival, PFS, overall survival, OS) were correlated to gender. Results: Ninety (62.5%) CaS patients were male. There was no gender difference in the site of primary tumor, tumor grade and clinical stage, as well as in treatments. Men were more frequently smokers (37.2%) and alcohol drinkers (17.8%) than women (9.5%, p= 0.002, and 3.7%, p= 0.004, respectively). Concerning clinical presentation, women showed higher median number of symptoms (p= 0.0007), more frequent abdominal pain, tachycardia, and psychiatric disorders than men (53.3% vs 70.4%, p= 0.044; 6.7% vs 31.5%, p= 0.001; 50.9% vs. 26.7%, p= 0.003, respectively). Lymph node metastases at diagnosis were more frequent in men than in women (80% vs 64.8%; p= 0.04), but no differences in terms of PFS (p= 0.51) and OS (p= 0.64) were found between gender. Conclusions: In this Italian cohort, CaS was slightly more frequent in males than females. Gender-related differences emerged in the clinical presentation of CaS, as well as gender-specific risk factors for CaS development. A gender-driven clinical management of these patients should be advisable.

La presenza di metastasi ossee è sempre stata considerata un evento raro e tardivo nella storia naturale delle neoplasie neuroendocrine (NEN), con un’incidenza variabile tra il 4 e il 12%, fino ad arrivare al 20% nelle NEN avanzate. L’avvento clinico delle tecniche di imaging come la PET/CT con peptidi coniugati con Gallio-68 ha aumentato in modo sostanziale la frequenza di diagnosi delle metastasi ossee nei pazienti con NEN, consentendone una caratterizzazione più precoce. Le metastasi ossee sono associate a una peggiore prognosi nelle NEN e, se non adeguatamente trattate, si associano allo sviluppo di eventi scheletrici, quali dolore osseo, fratture patologiche, sindromi midollari e ipercalcemia, impattando negativamente anche sulla qualità della vita. Tuttavia, la gestione delle metastasi ossee delle NEN è attualmente guidata da un’evidenza limitata. Farmaci ad azione sull’osso, come acido zoledronico o denosumab, insieme all’eventuale radioterapia a fasci esterni, in associazione con terapie sistemiche, tra cui su tutte la terapia radiorecettoriale (PRRT), rappresentano i trattamenti cardini delle metastasi ossee nelle NEN.

•Hydroxytyrosol preserves wine from oxidation after 6 months of bottle storage.•No statistical change in hydroxytyrosol after 12 months of bottle storage.•Wine with the highest hydroxytyrosol levels was preferred after 6 months.•Complexation of copper by HT also occurs in wine.

•Direct ridership models are very useful tools to evaluate alternative routes for the expansion of a LRT.•Direct demand ride models coupled with transfer models are particularly useful to assess the performance of a LRT network operating in articulation with other modes of transport.•Direct ridership models, complemented with indirect (transfers) demand models, can produce very satisfactory results in terms of goodness-of-fit across an entire LRT network.•The understanding and awareness of the limitations of OLS models in transport planning are key factors to increase the quality standards of applied research and professional practice.

ABSTRACTMitochondria are key tumor drivers, but their suitability as a therapeutic target is unknown. Here, we report on the preclinical characterization of Gamitrinib (GA mitochondrial matrix inhibitor), a first-in-class anticancer agent that couples the Heat Shock Protein-90 (Hsp90) inhibitor 17-allylamino-geldanamycin (17-AAG) to the mitochondrial-targeting moiety, triphenylphosphonium. Formulated as a stable (≥24 weeks at −20°C) injectable suspension produced by microfluidization (<200 nm particle size), Gamitrinib (>99.5% purity) is heavily bound to plasma proteins (>99%), has intrinsic clearance from liver microsomes of 3.30 mL/min/g and minimally penetrates a Caco-2 intestinal monolayer. Compared to 17-AAG, Gamitrinib has slower clearance (85.6 ± 5.8 mL/min/kg), longer t1/2(12.2 ± 1.55 h), mean AUC0-tof 783.1 ± 71.3 h∙ng/mL, and unique metabolism without generation of 17-AG. Concentrations of Gamitrinib that trigger tumor cell killing (IC50 ~1-4 µM) do not affect cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8 or ion channel conductance (Nav1.5, Kv4.3/KChIP2, Cav1.2, Kv1.5, KCNQ1/mink, HCN4, Kir2). Twice weekly IV administration of Gamitrinib to Sprague-Dawley rats or beagle dogs for up to 36 d is feasible. At dose levels of up to 5 (rats)- and 12 (dogs)-fold higher than therapeutically effective doses in mice (10 mg/kg), Gamitrinib treatment is unremarkable in dogs with no alterations in clinical-chemistry parameters, heart function, or tissue histology, and causes occasional inflammation at the infusion site and mild elevation of serum urea nitrogen in rats (≥10 mg/kg/dose). Therefore, targeting mitochondria for cancer therapy is feasible and well tolerated. A publicly funded, first-in-human phase I clinical trial of Gamitrinib in patients with advanced cancer is ongoing (ClinicalTrials.gov NCT04827810)

ABSTRACTThe αVβ6 integrin, an epithelial-specific cell surface receptor absent in normal prostate and expressed during prostate cancer (PrCa) progression, is a therapeutic target in many cancers. Here, we report that transcript levels of ITGB6(encoding the β6 integrin subunit) are significantly increased in metastatic castrate-resistant androgen receptor-negative prostate tumors compared to androgen receptor-positive prostate tumors. In addition, the αVβ6 integrin protein levels are significantly elevated in androgen receptor-negative PrCa patient derived xenografts (PDXs) compared to androgen receptor-positive PDXs. In vitro, the androgen receptor-negative PrCa cells express high levels of the αVβ6 integrin compared to androgen receptor-positive PrCa cells. Additionally, expression of androgen receptor (wild type or variant 7) in androgen receptor-negative PrCa cells downregulates the expression of the β6 but not αV subunit compared to control cells. We demonstrate an efficient strategy to therapeutically target the αVβ6 integrin during PrCa progression by using short interfering RNA (siRNA) loaded into PrCa cell-derived small extracellular vesicles (sEVs). We first demonstrate that fluorescently-labeled siRNAs can be efficiently loaded into PrCa cell-derived sEVs by electroporation. By confocal microscopy, we show efficient internalization of these siRNA-loaded sEVs into PrCa cells. We show that sEV-mediated delivery of ITGB6-targeting siRNAs into PC3 cells specifically downregulates expression of the β6 subunit. Furthermore, treatment with sEVs encapsulating ITGB6siRNA significantly reduces cell adhesion and migration of PrCa cells on an αVβ6-specific substrate, LAP-TGFβ1. Our results demonstrate an approach for specific targeting of the αVβ6 integrin in PrCa cells using sEVs encapsulating ITGB6-specific siRNAs.

Objective:A troublesome implication of the COVID-19 pandemic has been an increased incidence of antimicrobial resistance. Implementation of containment measures, surveillance and monitoring of multiresistant microorganisms and/or alert organisms (MDROs_AL) should be strengthened. Here, we present the results of our observational study in which the isolation trend of MDROs_AL was compared over several quarters before and during the SARS-CoV-2 pandemic (2019-2020).Results:Although in our hospital the number of hospital admissions decreased significantly during the SARS-CoV-2 pandemic (due to the conversion of our hospital to a COVID hospital), the incidence rate of MDRO_AL infection increased from 18.0–34.6. (incidence rate) Among the MDROs_AL, A. baumannii, carbapenem-resistant enterobacteria, staphylococci/streptococci-MLSB, intermediate/glycopeptide-resistant coagulase-negative staphylococci and vancomycin-resistant enterococci were the most represented.

Background: Prostate cancer is the second most commonly diagnosed cancer in men. The diagnostic accuracy in prostate cancer can be increased by employing a preliminary multiparametric MRI followed by a fusion-targeted biopsy.Methods: To compare the diagnostic accuracy of fusion-targeted biopsy with the standard systematic biopsy in prostate cancer patients, we enrolled 139 patients on which we performed 139 prostate biopsies consisting of three targeted samples followed by 12 regular systematic samples. Based on histology, we analyzed the diagnostic performance of the two methods.Results: Both methods were equally good at detecting clinically significant cancer (83.3%, 50/60), while systematic biopsy detected more clinically insignificant cancers. However, the best diagnostic performance is obtained by combining the two methods.Conclusion: The two methods are best seen as synergistic, and the addition of fusion biopsy can be used to detect more clinically significant prostate cancers than systematic biopsy alone.

abstract:Scholars tend to focus on Bishop's sense of place, travel writing, and geographical feelings, yet few scholars examine her role as a literary cartographer. This article explores Bishop's literary cartography considering her obsession with mapping and exploration. But Bishop also carefully revises the mapmaker's task to define possibilities for imaginative reversals of cartographic practices. We concentrate on the imaginative logic motivating her implicit contrast between "The Map" and "A Map."

Dissolved oxygen (DO) is a critically important ecological variable, and the prevalence of marine hypoxia is expected to increase due to the combined effects of ocean warming and eutrophication. Thermal stress can co‐occur with hypoxia, especially in tropical systems, and can exacerbate its effects. We examine the physical processes that are important in regulating hypoxia and temperature inversions in Bahía Almirante, a semi‐enclosed tropical embayment on the Caribbean coast of Panama. A 10‐yr record of observations at 7 locations within Bahía Almirante reveals seasonal temperature inversions and hypoxia at depth that often co‐occur. These features are more severe and persistent in the back bay, though they occur throughout Bahía Almirante. DO reductions correspond to periods with high freshwater input, including direct precipitation, resulting in strong salinity stratification that isolates bottom waters, allowing biological oxygen demand to draw down DO. Evidence indicates that lateral advection can contribute to reoxygenation events, and the relationship between near bottom DO and bottom salinities in the mid bay and back bay is consistent with deep‐water renewal as the mechanism for bottom water ventilation. These hypoxia and temperature inversion events impact the biological communities of Bahía Almirante, and the physical dynamics that regulate these coincident and persistent stressors for marine organisms are likely present in other shallow, tropical estuaries.

Ranchers are continuously searching for suitable tools to rapidly and inexpensively assess the characteristics of donkey milk and because spectroscopic models are useful to assess the composition of many foods, an attempt to further improve the prediction performance of donkey milk protein, lactose and dry-matter content has been made using three widely used spectroscopic models by adding some interaction terms, namely product, ratio, sum and difference of absorbances for each couple of wavelengths. Principal component regression using product terms showed an improvement in prediction error achieving 1.8%, 1.7% and 0.9% for protein, lactose and dry-matter content respectively. Furthermore, the added ratio terms showed a very great improvement in the predictive overall performance achieving 0.3%, 0.4% and 0.2%. A coefficient has been found relating the widely used RPD, a standard index of prediction performance, to the new proposed “range of confident prediction error percent” being a more understandable parameter to assess the goodness of the prediction model.

Despite the growing numbers of individuals who identify as transgender, this population continues to face worse mental health outcomes compared with the general population. Transgender individuals attempt suicide at a rate that is almost 9 times that of the general population. Few studies have reported on the positive effect of gender-affirming hormone therapy on mental health outcomes in transgender individuals. It is likely that this effect is due in part to the physiological responses that occur as a result of hormone therapy that mitigate incongruencies between one’s gender identity and assigned sex. To our knowledge, only limited studies have shown a connection between gender-affirming hormone therapy, its effect on the brain’s structure, and long-term effects that this may have on mental health outcomes. The authors propose that, in addition to the physiological responses that occur as a direct result of hormone therapy and the validation that results from receiving gender-affirming medical care, mental health outcomes in transgender individuals may also improve due to the role that hormone therapy plays in altering the brain’s structure, possibly shaping the brain to become more like that of the gender with which an individual identifies. In this article, the authors review the current literature on the effects that gender-affirming hormone therapy has on mental health outcomes and anatomic structures of the brain in transgender individuals.

The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing).

Small extracellular vesicles (sEV) contribute to the crosstalk between tumor cells and stroma, but the underlying signals are elusive. Here, we show that sEV generated by breast cancer cells in hypoxic (sEVHYP), but not normoxic (sEVNORM) conditions activate NFκB in recipient normal mammary epithelial cells. This increases the production and release of inflammatory cytokines, promotes mitochondrial dynamics leading to heightened cell motility and disrupts 3D mammary acini architecture with aberrant cell proliferation, reduced apoptosis and EMT. Mechanistically, Integrin-Linked Kinase packaged in sEVHYPvia HIF1α is sufficient to activate NFκB in the normal mammary epithelium, in vivo. Therefore, sEVHYPactivation of NFκB drives multiple oncogenic steps of inflammation, mitochondrial dynamics, and mammary gland morphogenesis in a breast cancer microenvironment.

Introduction: Achalasia is a debilitating primary esophageal motility disorder. Heller myotomy (HM) is a first-line therapy for the treatment of achalasia patients who have failed other modalities. Other indications for HM include diverticulum, diffuse esophageal spasm, and esophageal strictures. However, long-term outcomes of HM are unclear. This study aims to assess incidence of reintervention, either endoscopically or through minimally invasive or resectional procedures, in patients who underwent HM in New York State. Methods: The Statewide Planning and Research Cooperative System (SPARCS) administrative longitudinal database identified 1817 adult patients who underwent HM between 2000 and 2008 for achalasia, esophageal diverticulum, diffuse esophageal spasm, and esophageal strictures, based on ICD-9 and CPT codes. Through the use of unique identifiers, patients requiring reintervention were tracked up to 2016 (for at least 8 years follow-up). Primary outcome was incidence of subsequent procedures following HM. Secondary outcomes were time to reintervention and risk factors for reintervention. Results: Of the 1817 patients who underwent HM, 320 (17.6%) required subsequent intervention. Of the 320 patients, 234 (73.1%) underwent endoscopic reinterventions, 54 (16.9%) underwent minimally invasive procedures, and 32 (10%) underwent resectional procedures as their initial revisional intervention. Of the 234 patients who underwent endoscopic reintervention as their initial revisional procedure, only 40 (16.8%) required subsequent surgical procedures. Over a mean follow-up of 7.0 years, the mean time to a subsequent procedure was 4.3 ± 3.74 years. Reintervention rates after 10 years following HM for achalasia, diverticulum ,and other indication were 24.4%, 12.6%, and 37%, respectively. Conclusion: The majority of HM reinterventions were managed solely by endoscopic procedures (60.6%). Heller myotomy remains an excellent procedure to prevent surgical reintervention for achalasia and diverticulum. Graphic Abstract:

Purpose: Data regarding vitamin D status in patients affected by gastroenteropancreatic (GEP) neuroendocrine tumor (NET) are limited and often showing contrasting results. The aim of the study was to evaluate the incidence of vitamin D deficiency (&lt;20 ng/mL) in GEP-NET patients and compare the 25-hydroxyvitamin D (25(OH)D) levels with clinicopathological parameters and clinical outcome. Methods: A retrospective cross-sectional study including 75 low grade (G1-G2) GEP-NETs and 123 healthy controls matched for age, sex, and body mass index, was performed. Results: GEP-NET patients had significantly lower 25(OH)D levels compared to controls (17.9 ± 7.8 vs 24.2 ± 7.7 ng/mL, p&lt; 0.0001). Ileal NETs were associated to lower 25(OH)D levels compared to other primary tumor sites (p= 0.049) and small bowel resection posed a significant increased risk of severe vitamin D deficiency (OR = 2.81, 95% CI = 1.25–3.37, p= 0.018). No correlation with somatostatin analogs treatment was found. 25(OH)D levels were significantly lower in G2 compared to G1 GEP-NETs (15.6 ± 7.8 vs 19.9 ± 7.4 ng/mL, p= 0.016) and in patients with progressive disease (12.6 ± 5.7 ng/mL) compared to those with stable disease (mean 21.5 ± 8.2 ng/mL, p= 0.001) or tumor free after surgery (19.6 ± 7.3 ng/mL, p= 0.002). Patients with vitamin D deficiency and insufficiency had shorter progression-free survival compared to those with sufficiency (p= 0.014), whereas no correlation was found with disease-specific survival. Conclusions: Vitamin D deficiency is highly prevalent among GEP-NETs and could be associated with high tumor grade and disease progression. Therefore, the monitoring of 25(OH)D levels is relevant in these patients and vitamin D supplementation should be considered in the management of GEP-NET patients with vitamin D deficiency or insufficiency.

Celleriite, □(Mn22+Al)Al6(Si6O18)(BO3)3(OH)3(OH),$\square \,\left( \text{Mn}_{2}^{2+}\text{Al} \right)\text{A}{{\text{l}}_{6}}\left( \text{S}{{\text{i}}_{6}}{{\text{O}}_{18}} \right){{\left( \text{B}{{\text{O}}_{3}} \right)}_{3}}{{(\text{OH})}_{3}}(\text{OH}),$is a new mineral of the tourmaline supergroup. It was discovered in the Rosina pegmatite, San Piero in Campo, Elba Island, Italy (holotype specimen), and in the Pikárec pegmatite, western Moravia, Czech Republic (co-type specimen). Celleriite in hand specimen is violet to gray-blue (holotype) and dark brownish-green (co-type) with a vitreous luster, conchoidal fracture, and white streak. Celleriite has a Mohs hardness of ~7 and a calculated density of 3.13 and 3.14 g/cm3for holotype and its co-type, respectively. In plane-polarized light in thin section, celleriite is pleochroic (O = pale violet and E = light gray-blue in holotype; O = pale green and E = colorless in co-type) and uniaxial negative. Celleriite has trigonal symmetry: space group R3m, Z= 3, a= 15.9518(4) and 15.9332(3) Å, c= 7.1579(2) and 7.13086(15) Å, V= 1577.38(9) and 1567.76(6) Å3for holotype and co-type, respectively (data from single-crystal X‑ray diffraction). The crystal structure of the holotype specimen was refined to R1 = 2.89% using 1696 unique reflections collected with MoKα X‑ray intensity data. Structural, chemical, and spectroscopic analyses resulted in the formulas: x(□0.58Na0.42)∑1.00Y(Mn1.392+Fe0.162+Mg0.01Al1.14Fe0.013.0Li0.28T0.01)Σ3.00ZAl6[T(Si5.99Al0.01)Σ6.00O18](BO3)3(OH)3w[(OH)0.65F0.03O0.32]Σ1.00(forholotype)$\begin{align}& \,\,\,\,{{\,}^{\text{x}}}{{\left( {{\square }_{0.58}}\text{N}{{\text{a}}_{0.42}} \right)}_{\sum 1.00}}\text{Y}{{\left( \text{Mn}_{1.39}^{2+}\text{Fe}_{0.16}^{2+}\text{M}{{\text{g}}_{0.01}}\text{A}{{\text{l}}_{1.14}}\text{Fe}_{0.01}^{3.0}\text{L}{{\text{i}}_{0.28}}~{{\text{T}}_{0.01}} \right)}_{\Sigma 3.00}}^{\text{Z}}\text{A}{{\text{l}}_{6}}\left[ {{~}^{\text{T}}}{{\left( \text{S}{{\text{i}}_{5.99}}\text{A}{{\text{l}}_{0.01}} \right)}_{\Sigma 6.00}}{{\text{O}}_{18}} \right]{{\left( \text{B}{{\text{O}}_{3}} \right)}_{3}}{{(\text{OH})}_{3}} \\ & ^{\text{w}}{{\left[ {{(\text{OH})}_{0.65}}~{{\text{F}}_{0.03}}{{\text{O}}_{0.32}} \right]}_{\Sigma 1.00}}\,\text{(for}\,\text{holotype)} \\ \end{align}$andX(□0.51Na0.49)Σ1.00Y(Mn0.902+Fe0502+Al1.36Fe0043+Li0.17Zn0.04)Σ3.00ZAl6[T(Si5.75B0.25)Σ6.00O18](BO3)3(OH)3w[(OH)0.35F0.17O0.48]∑1.00(forco-type)$\begin{align}& \,\,\,\,\,{{\,}^{\text{X}}}{{\left( {{\square }_{0.51}}\text{N}{{\text{a}}_{0.49}} \right)}_{\Sigma 1.00}}^{\text{Y}}{{\left( \text{Mn}_{0.90}^{2+}\text{Fe}_{050}^{2+}\text{A}{{\text{l}}_{1.36}}\text{Fe}_{004}^{3+}\text{L}{{\text{i}}_{0.17}}\text{Z}{{\text{n}}_{0.04}} \right)}_{\Sigma 3.00}}^{\text{Z}}\text{A}{{\text{l}}_{6}}\left[ ^{\text{T}}{{\left( \text{S}{{\text{i}}_{5.75}}~{{\text{B}}_{0.25}} \right)}_{\Sigma 6.00}}{{\text{O}}_{18}} \right]{{\left( \text{B}{{\text{O}}_{3}} \right)}_{3}}{{(\text{OH})}_{3}} \\ & ^{\text{w}}{{\left[ {{(\text{OH})}_{0.35}}~{{\text{F}}_{0.17}}{{\text{O}}_{0.48}} \right]}_{\sum 1.00}}\text{(for}\,\text{co-type)} \\ \end{align}$

FGF/FGFR signaling regulates embryogenesis, angiogenesis, tissue homeostasis and wound repair by modulating proliferation, differentiation, survival, migration and metabolism of target cells. Understandably, compelling evidence for deregulated FGF signaling in the development and progression of different types of tumors continue to emerge and FGFR inhibitors arise as potential targeted therapeutic agents, particularly in tumors harboring aberrant FGFR signaling. There is first evidence of a dual role of the FGF/FGFR system in both organogenesis and tumorigenesis, of which this review aims to provide an overview. FGF-1 and FGF-2 are expressed in the adrenal cortex and are the most powerful mitogens for adrenocortical cells. Physiologically, they are involved in development and maintenance of the adrenal gland and bind to a family of four tyrosine kinase receptors, among which FGFR1 and FGFR4 are the most strongly expressed in the adrenal cortex. The repeatedly proven overexpression of these two FGFRs also in adrenocortical cancer is thus likely a sign of their participation in proliferation and vascularization, though the exact downstream mechanisms are not yet elucidated. Thus, FGFRs potentially offer novel therapeutic targets also for adrenocortical carcinoma, a type of cancer resistant to conventional antimitotic agents.