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PD-L1 is an established predictive immunohistochemical biomarker of response to immune checkpoint inhibitors. At present, PD-L1 is routinely assessed on biopsy samples of advanced gastroesophageal cancer patients before initiating first-line treatment. However, PD-L1 is still a suboptimal biomarker, due to changing cut-off values and scoring systems, interobserver and interlaboratory variability.This practical illustrated review discusses the range of staining patterns of PD-L1 and the potential pitfalls and challenges that can be encountered when evaluating PD-L1, focusing on gastric and gastroesophageal adenocarcinoma (G/GEA) and esophageal squamous cell carcinoma (ESCC).

Purpose Accurate evaluation of breast cancer on bioptic samples is of fundamental importance to guide therapeutic decisions, especially in the neoadjuvant or metastatic setting. We aimed to assess concordance for oestrogen receptor (ER), progesterone receptor (PR), c-erbB2/HER2 and Ki-67. We also reviewed the current literature to evaluate our results in the context of the data available at present. Methods We included patients who underwent both biopsy and surgical resection for breast cancer at San Matteo Hospital, Pavia, Italy, between January 2014 and December 2020. ER, PR, c-erbB2, and Ki-67 immunohistochemistry concordance between biopsy and surgical specimen was evaluated. ER was further analysed to include the recently defined ER-low-positive in our analysis. Results We evaluated 923 patients. Concordance between biopsy and surgical specimen for ER, ER-low-positive, PR, c-erbB2 and Ki-67 was, respectively, 97.83, 47.8, 94.26, 68 and 86.13%. Cohen’s κ for interobserver agreement was very good for ER and good for PR, c-erbB2 and Ki-67. Concordance was especially low (37%) in the c-erbB2 1 + category. Conclusion Oestrogen and progesterone receptor status can be safely assessed on preoperative samples. The results of this study advise caution in interpreting biopsy results regarding ER-low-positive, c-erbB2/HER and Ki-67 results due to a still suboptimal concordance. The low concordance for c-erbB2 1 + cases underlines the importance of further training in this area, in the light of the future therapeutic perspectives.

Glypican-3 (GPC3) is an oncofetal protein involved in cellular signaling, strongly expressed in the placenta, absent or diminished in postnatal life, but often increased in human malignancies. Germline loss-of-function variants of GPC3 gene are associated with Simpson-Golabi-Behmel syndrome type 1 (SGBS1), a rare recessive X-linked overgrowth disease characterized by typical facial features, congenital abnormalities, and an increased risk of developing childhood cancers.A clinical suspicion of SGBS1 was postulated for a newborn with prenatal history of overgrowth and polyhydramnios, presenting with neonatal weight and length99th percentile, coarse facies, iris and retinal coloboma, supernumerary nipples, and splenomegaly. While waiting for whole-genome sequencing (WGS) results, we investigated placental GPC3 immunohistochemical expression in the proband, in three additional cases of SGBS1, and disorders commonly associated with fetal macrosomia and/or placentomegaly.WGS in the proband identified a likely pathogenic maternally inherited missense variant in GPC3: c.1645A G, (p.Ile549Val), and GPC3 immunohistochemistry demonstrated full-thickness loss of stain of the placental parenchyma. The same pattern ("null") was also present in the placentas of three additional cases of SGBS1, but not in those of unaffected controls.Immunohistochemical expression of GPC3 in the placenta is highly reproducible. Our findings showed that a "null pattern" of staining is predictive of SGBS1 and represents a valuable aid in the differential diagnosis of fetal macrosomias, allowing targeted genetic testing and earlier diagnosis.

Aims This study assessed comparative effectiveness of glargine 300 U/mL (Gla-300) versus degludec 100 U/mL (Deg-100) in insulin-naïve patients with T2D. Methods This is a retrospective, multicenter, non-inferiority study based on electronic medical records. All patients initiating Gla-300 or Deg-100 were 1:1 propensity score-matched (PSM). Linear mixed models were used to assess the changes in continuous endpoints. Incidence rates (IR) of hypoglycemia were compared using Poisson’s regression models. Results Nineteen centers provided data on 357 patients in each PSM cohort. HbA1c after 6 months (primary endpoint) decreased by − 1.70% (95%CI − 1.90; − 1.50) in Gla-300 group and − 169% (95%CI − 1.89; − 1.49) in Deg-100 group, confirming non-inferiority of Gla-300 versus Deg-100. Fasting blood glucose (BG) decreased by ~60 mg/dl in both groups; body weight remained unchanged. In both groups, the mean starting dose was 12U (0.15U/kg) and it was slightly titrated to 16U (0.20U/kg). IR (episodes per patient-months) of BG ≤70 mg/dl was 0.13 in Gla-300 group and 0.14 in Deg-100 group (p=0.87). IR of BG p=0.49). No severe hypoglycemia occurred. Conclusion Initiating Gla-300 or Deg-100 was associated with similar improvements in glycemic control, no weight gain and low hypoglycemia rates, without severe episodes during 6 months of treatment.

Objective Obesity is a growing emergency also in type 1 diabetes (T1D). Sex-differences in obesity prevalence and its clinical consequences in adult T1D subjects have been poorly investigated. The aim of this study was to investigate the prevalence of obesity and severe obesity, clinical correlates and potential sex-differences in a large cohort of T1D subjects, participating to the AMD Annals Initiative in Italy. Research design and methods The prevalence of obesity (BMI ≥30 kg/m2) and severe obesity (BMI ≥ 35 kg/m2) according to sex and age, as well as obesity-associated clinical variables, long-term diabetes complications, pharmacological treatment, process indicators and outcomes, and overall quality of care (score Q) were evaluated in 37,436 T1D subjects (45.3% women) attending 282 Italian diabetes clinics during 2019. Results Overall, the prevalence of obesity was similar in the two gender (13.0% in men and 13.9% in women; mean age 50 years), and it increased with age, affecting 1 out of 6 subjects aged >65 years. Only severe obesity (BMI >35 Kg/m2) was more prevalent among women, who showed a 45% higher risk of severe obesity, compared with men at multivariate analysis. CVD risk factors (lipid profile, glucose and blood pressure control), and the overall quality of diabetes care were worse in obese subjects, with no major sex-related differences. Also, micro- and macrovascular complications were more frequent among obese than non-obese T1D men and women. Conclusions Obesity is a frequent finding in T1D adult subjects, and it is associated with a higher burden of CVD risk factors, micro- and macrovascular complications, and a lower quality of care, with no major sex-differences. T1D women are at higher risk of severe obesity.

Inflammatory Bowel Disease (IBD) patients on biological therapy are receiving vaccines against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). However, it is unclear if IBD therapy could influence the response to this vaccine. In a case-control study, we assessed the antibody profiling after anti-SARS-CoV-2 BNT162b2 vaccine in IBD patients on biological therapy.We analyzed seroprevalence and antibody titer, after 14 weeks from the first BNT162b2 vaccine dose, in IBD patients on biological therapy and Health Care Workers (HCWs). In IBD patients, medical history and disease data were recorded.Eighty-two subjects were enrolled in this study. Among them, 40 were IBD patients on biological therapy and 42 were HCWs. All subjects developed an IgG anti-Spike antibody titer above the cut-off. IBD patients on biological therapy developed a lower antibody titer than HCWs (P0.00001). No differences were reported in patients who received at least one dose of the vaccine within a period of 7 days from the last biological drug administration, compared to all other IBD patients. A difference was found between patients who were on concomitant immunosuppressive therapy and patients on sole biological therapy (P = 0.0287). Patients with presence of any sign of disease activity (clinical, endoscopic or laboratory) showed a higher development of antibody titer compared to those in complete disease remission (P = 0,0468).Our data indicate that in IBD patients, treatment with biological therapies do not affect the seroprevalence but leads to a lower antibody titer development after anti-SARS-CoV-2 BNT162b2 vaccine.

ContextSodium glucose co-transporter-2 inhibitors exert clinically relevant cardiorenal protection. Among several mechanisms, inhibition of sodium-hydrogen exchanger-3 (NHE3) in proximal renal tubules has been proposed in rodents. Demonstration of this mechanism with the associated electrolyte and metabolic changes in humans is lacking.ObjectiveThe present proof-of-concept study was designed to explore the involvement of NHE3 in modulating the response to sodium glucose co-transporter-2 inhibitors in humans.MethodsTwenty healthy male volunteers received 2 tablets of empagliflozin 25 mg during a standardized hydration scheme; freshly voided urines and blood samples were collected at timed intervals for 8 hours. Protein expression of relevant transporters was examined in exfoliated tubular cells.ResultsUrine pH levels increased after empagliflozin (from 5.81 ± 0.5 to 6.16 ± 0.6 at 6 hours, P = .008) as did urinary output (from median, 1.7; interquartile range [IQR, 0.6; 2.5] to 2.5 [IQR, 1.7; 3.5] mL/min−1, P = .008) and glucose (from median, 0.03 [IQR, 0.02; 0.04] to 34.8 [IQR, 31.6; 40.2] %, P < .0001), and sodium fractional excretion rates (from median, 0.48 [IQR, 0.34; 0.65] to 0.71 [IQR, 0.55; 0.85] %, P = .0001), whereas plasma glucose and insulin concentrations decreased and plasma and urinary ketones increased. Nonsignificant changes in NHE3, phosphorylated NHE3, and membrane-associated protein 17 protein expression were detected in urinary exfoliated tubular cells. In a time-control study in 6 participants, neither urine pH nor plasma and urinary parameters changed.ConclusionsIn healthy young volunteers, empagliflozin acutely increases urinary pH while inducing a substrate shift toward lipid utilization and ketogenesis, without significant changes in renal NHE3 protein expression.

Purpose. The present study aims to investigate the relationship between physical activity (PA) and the development of relational empathy skills in children, taking into account weight status. Methods. Parents/guardians of primary school children were involved in filling out a questionnaire: the Empathy Questionnaire (EmQue-I13) and children were asked to complete the PAQ-C to investigate the self-reported PA levels. The weight status was assessed using a self-reported Body Mass Index (BMI). Results. 370 parents or guardians of students who attended primary school (8.53±1.61 yrs) were recruited. The total score was 2.41±0.89 for PAQ-C and 41.17±6.32 for EmQue-I13. The three domains of EmQue-I13 were: Contagion (8.16±2.67), Attention to Others’ Feelings (19.40±2.99) and Prosocial actions (13.62±3.01). Linear regression models showed that a higher PAQ-C score was positively associated with empathy-related total score p Conclusion. Our results underline the positive association between physical activity and the development of relational empathic skills.

BackgroundMultiple sclerosis (MS) is a neurodegenerative disease characterized by neuronal and synaptic loss, resulting in an imbalance of excitatory and inhibitory synaptic transmission and potentially cognitive impairment. Current methods for measuring the excitation/inhibition (E/I) ratio are mostly invasive, but recent research combining neurocomputational modeling with measurements of local field potentials has indicated that the slope with which the power spectrum of neuronal activity captured by electro- and/or magnetoencephalography rolls off, is a non-invasive biomarker of the excitation/inhibition (E/I) ratio. A steeper roll-off is associated with a stronger inhibition. This novel method can be applied to assess the E/I ratio in people with multiple sclerosis (pwMS), detect the effect of medication such as benzodiazepines, and explore its utility as a biomarker.MethodsWe recruited 44 healthy control subjects and 95 people with multiple sclerosis (pwMS) who underwent resting-state magnetoencephalographic recordings. The 1/f spectral slope of the neural power spectra was calculated for each subject and for each brain region.ResultsAs expected, the spectral slope was significantly steeper in pwMS treated with benzodiazepines compared to pwMS not receiving this medication (p = 0.01). In the sub-cohort of pwMS not treated with benzodiazepines, we observed a steeper slope in cognitively impaired pwMS compared to cognitively preserved pwMS (p = 0.01) and healthy subjects (p = 0.02). Furthermore, we observed a significant correlation between 1/f slope and verbal and spatial working memory functioning in the brain regions located in the prefrontal and parietal cortex.ConclusionsIn this study, we highlighted the value of the spectral slope, a novel non-invasive biomarker of the E/I ratio, in MS by quantifying the inhibitory effect of benzodiazepines and by putting it forward as a potential biomarker of cognitive deficits in pwMS.HighlightsAs expected, the 1/f roll-off was steeper in people with MS (pwMS) treated with benzodiazepines as compared to people with MS not treated with benzodiazepines.We performed a dynamic moving time window approach and demonstrated that this difference in 1/f roll-off between pwMS with and without benzodiazepine treatment remains stable across different segments of the recording.In the sub-cohort of people with MS not being treated with benzodiazepines, the 1/f roll-off in the prefrontal and parietal cortex significantly correlates with verbal and spatial working memory functioning.People with multiple sclerosis with cognitive impairment demonstrate a steeper 1/f slope, suggesting a decreased E/I ratio, and a stronger inhibition/weaker excitation when compared with cognitively preserved pwMS and healthy subjects.

Working memory (WM) plays a central role in cognition, prompting neuroscientists to investigate its functional and structural substrates. The WM dynamic recruits large-scale frequency-specific brain networks that unfold over a few milliseconds – this complexity challenges traditional neuroimaging analyses. In this study, we unravel the WM network dynamics in an unsupervised, data-driven way, applying the time delay embedded-hidden Markov model (TDE-HMM). We acquired MEG data from 38 healthy subjects performing an n-back working memory task. The TDE-HMM model inferred four task-specific states with each unique temporal (activation), spectral (phase-coherence connections), and spatial (power spectral density distribution) profiles. A theta frontoparietal state performs executive functions, an alpha temporo-occipital state maintains the information, and a broad-band and spatially complex state with an M300 temporal profile leads the retrieval process and motor response. The HMM states can be straightforwardly interpreted within the neuropsychological multi-component model of WM, significantly improving the comprehensive description of WM.HighlightsWorking memory recruits different frequency-specific brain networks that wax and wane at a millisecond scale.Through the time-delay embedded hidden (TDE-HMM) we are able to extract data-driven functional networks with unique spatial, spectral, and temporal profiles.We demonstrate the existence of four task-specific brain networks that can be interpreted within the well-known Baddeley’s multicomponent model of working memory.This novel WM description unveils new features that will lead to a more in-depth characterization of cognitive processes in MEG data.

IntroductionAim of the present study was to evaluate the real-world impact of once-weekly (OW) subcutaneous semaglutide on different end-points indicative of metabolic control, cardiovascular risk factors, and beta-cell function in type 2 diabetes (T2D).MethodsThis was a retrospective, observational study conducted in 5 diabetes clinics in Italy. Changes in HbA1c, fasting blood glucose (FBG), body weight, blood pressure, lipid profile, renal function, and beta-cell function (HOMA-B) during 12 months were evaluated.ResultsOverall, 594 patients (97% GLP-1RA naïve) were identified (mean age 63.9 ± 9.5 years, 58.7% men, diabetes duration 11.4 ± 8.0 years). After 6 months of treatment with OW semaglutide, HbA1c levels were reduced by 0.90%, FBG by 26 mg/dl, and body weight by 3.43 kg. Systolic blood pressure, total and LDL-cholesterol significantly improved. Benefits were sustained at 12 months. Renal safety was documented. HOMA-B increased from 40.2% to 57.8% after 6 months (pDiscussionThe study highlighted benefits of semaglutide on metabolic control, multiple CV risk factors, and renal safety in the real-world. Semaglutide seems to be an advisable option for preservation of β-cell function and early evidence suggests it might have a role in modifying insulin resistance (HOMA-IR), the pathogenetic basis of prediabetes and T2D.

The development of non-planar structures such as arrays of nanowires (NWs), poses a significant challenge for dopant concentration determination. Techniques that can be readily used for 3D structures usually lack the desired sensitivity whereas secondary ion mass spectrometry (SIMS), known for its excellent detection limits, is designed to analyze flat samples. In this work, we overcome the limitation of standard SIMS approaches. NWs are covered with photoresist forming a flat surface. For high incident angle bombardment, the sputtering process becomes self-flattening, i.e. the ions collide with the sidewalls of the exposed tips of NWs at much lower angles and sputter them significantly faster. Thus, reliable information about the dopant distribution along the height of NWs can be obtained. The SIMS analysis can be performed on an array of 1000 x 1000 nanowires with a detection limit of about 5 x 1016 atoms/cm3 and a reasonable signal-to-noise ratio of about 10 dB.

Very early onset inflammatory bowel disease (VEO-IBD) represents approximately 25% of cases of IBD-like colitis occurring during childhood and, by definition, it is characterized by an onset prior to 6 years of age. This subgroup of patients presents significant differences from IBD occurring in older children and in adults, including a more severe clinical course, a reduced responsiveness to conventional IBD therapy, and a greater proportion of cases featuring an underlying monogenic disorder. Histological findings from gastro-intestinal (GI) biopsies are characterized by an IBD-like, apoptotic or enterocolitis-like pattern, complicating the differential diagnosis with other pediatric diseases involving GI tract. Moreover, individuals with monogenic disorders may develop significant comorbidities, such as primary immunodeficiency (PID), impacting treatment options. Without an appropriate diagnosis, the clinical course of VEO-IBD has greater potential for escalated treatment regimens involving extensive surgery, more intensive medical therapies and, even more important, inadequate recognition of underlying monogenic defect that may lead to inappropriate (sometimes fatal) therapy. For these reasons, an adequate context leading to an appropriate diagnosis is imperative, calling for a close collaboration between pediatricians, pathologists, geneticists, and immunologists.

Scopo: L'intervento precoce nell'ambito della psicosi dimostra che, intervenendo immediatamente in presenza di sintomi psicotici, è possibile osservare un tasso di successo terapeutico elevato. Inoltre, questo tipo di trattamento massimizza l'efficacia degli interventi terapeutici includendo non solo la figura dello psichiatra, ma anche quella dello psicologo e di altre figure socio-sanitarie. Questo studio si propone di identificare trattamenti terapeutici e assistenziali innovativi e di indagare gli effetti di un trattamento integrato e multidimensionale a distanza di un anno su soggetti con stato mentale a rischio. Metodi: Il presente studio catamnestico ha osservato 30 giovani pazienti (suddivisi in due gruppi da 15) durante un anno di trattamento, confrontando il protocollo di cura standard con un intervento precoce specializzato, denominato Programma TR-43. Il trattamento terapeutico e i risultati sono stati valutati attraverso le consultazioni delle cartelle cliniche dei soggetti e della Scala di Valutazione Globale del Funzionamento (GAF) da parte dei clinici. Risultati: Il gruppo che ha partecipato al Programma TR-43 ha presentato un aumento del punteggio GAF statisticamente significativo. Tale gruppo ha visto una presenza più consistente di professionisti complementari allo psichiatra come lo psicologico, l'infermiere, l'assistente sociale e/o l'educatore di riferimento.Conclusioni: L'esito positivo osservato in tutto il gruppo del Programma TR-43 si basa su un'appropriata gestione del paziente. Un trattamento integrato e multidimensionale, come quello proposto, può quindi produrre risultati clinici migliori rispetto ad uno generico che coinvolga principalmente la figura dello psichiatra. Una riduzione della sua presenza, come nel caso del Programma TR-43, può permettere al paziente di sentirsi meno medicalizzato e più coinvolto nel suo percorso di cura.&nbsp

Immune-checkpoint inhibitors targeting the PD-1/PD-L1 axis have brought significant clinical benefit in many solid cancer types, including gastrointestinal malignancies. However, it has been estimated that only 20-40% of patients respond to treatment. The pattern of expression and potential predictive value of PD-L1 as an immunohistochemical biomarker has been extensively studied in gastrointestinal neoplasms. Until now, its predictive value has been demonstrated, and is currently in use only in upper gastrointestinal malignancies (gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma).In this Review, we describe the technical aspects and challenges related to PD-L1 immunohistochemical assays, the current role of PD-L1 as a biomarker in clinical practice and we outline the main studies and clinical trials analyzing the prognostic and predictive value of PD-L1 in gastrointestinal cancers.

There are few data regarding the diagnostic delay and its predisposing factors in coeliac disease (CD).To investigate the overall, the patient-dependant, and the physician-dependant diagnostic delays in CD.CD adult patients were retrospectively enroled at 19 Italian CD outpatient clinics (2011-2021). Overall, patient-dependant, and physician-dependant diagnostic delays were assessed. Extreme diagnostic, i.e., lying above the third quartile of our population, was also analysed. Multivariable regression models for factors affecting the delay were fitted.Overall, 2362 CD patients (median age at diagnosis 38 years, IQR 27-46; M:F ratio=1:3) were included. The median overall diagnostic delay was 8 months (IQR 5-14), while patient- and physician-dependant delays were 3 (IQR 2-6) and 4 (IQR 2-6) months, respectively. Previous misdiagnosis was associated with greater physician-dependant (1.076, p = 0.005) and overall (0.659, p = 0.001) diagnostic delays. Neurological symptoms (odds ratio 2.311, p = 0.005) and a previous misdiagnosis (coefficient 9.807, p = 0.000) were associated with a greater extreme physician-dependant delay. Gastrointestinal symptoms (OR 1.880, p = 0.004), neurological symptoms (OR 2.313, p = 0.042), and previous misdiagnosis (OR 4.265, p = 0.000) were associated with increased extreme overall diagnostic delay.We identified some factors that hamper CD diagnosis. A proper screening strategy for CD should be implemented.

Telemedicine is advocated as a fundamental tool in modern clinical management. However, data on the effects of telemedicine vs face-to-face consultation on clinical outcomes in type 2 diabetes (T2DM) are still uncertain. This paper describes the use of telemedicine during the 2020 COVID-19 emergency and compares volume activity and quality indicators of diabetes care between face-to-face vs telemedicine counseling in the large cohort of T2DM patients from the AMD Annals Initiative.Demographic and clinical characteristics, including laboratory parameters, rate of the screening of long-term complications, current therapies and the Q-score, a validated score that measures the overall quality of care, were compared between 364,898 patients attending face-to-face consultation and 46,424 on telemedicine, during the COVID-19 pandemic.Patients on telemedicine showed lower HbA1c levels (7.1 ± 1.2 % vs 7.3 ± 1.3 %, p 0.0001), and they were less frequently treated with metformin, GLP1-RAs and SGLT2i and more frequently with DPP4i. The telemedicine group showed reduced monitoring of the various parameters considered as process indicators, especially, eye and foot examination. The proportion of patients with a good quality of care (Q score 25) was higher among those receiving face-to-face consultation. Moreover, in the telemedicine group, all major clinical outcomes remained stable when further compared to those collected in the year 2019, when the same patients underwent a regular face-to-face consultation, suggesting that the care provided through telemedicine did not negatively affect the most important parameters.During the COVID-19 pandemic, telemedicine provided an acceptable quality of diabetes care, comparable to that of patients attending face-to-face consultation, although a less frequent screening of complications seems to have occurred in subjects consulted by telemedicine.

Pivotal trials documented glycemic benefits of fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide (iGlarLixi), with no weight gain and low hypoglycemia risk in type 2 diabetes (T2D). This study aimed at assessing effectiveness and patterns of use of iGlarLixi in a real-world setting.This was a retrospective, multicenter, study, based on electronic medical records. All patients initiating iGlarLixi from May 2018 to July 2020 were considered.Overall, 25 centers provided data on 675 patients initiating iGlarLixi with the following characteristics: age 66.4 ± 10.1 years, 54.2% men, T2D duration 15.5 ± 11.5 years, HbA1c 8.6 ± 1.4%, body mass index (BMI) 30.8 ± 5.3 kg/mIn adults with T2D, effectiveness and safety of iGlarLixi were documented in a real-world setting; appropriateness of use and adequate titration should be urgently improved so that clinical practice outcomes become more comparable to clinical trials results. Further real-world studies on the effect of iGlarLixi therapy are warranted.

Background: Enumeration of CTCs in blood samples with the CELLSEARCH® system is a prognostic biomarker in metastatic breast, prostate and colorectal cancer (full intended use documents.cellsearchctc.com). Currently, the final CTC identification is performed by human reviewers through visual assessment, which is a time-consuming procedure that could be affected by subjective interpretations. Modern Artificial Intelligence (AI) methods can provide a solution by automating the process of CTC identification, thus eliminating subjectivity and producing faster and more reproducible results. We have recently presented an automated algorithm (for research use only) based on deep learning models for cell segmentation and classification which allows the automated identification of CTCs in CELLSEARCH® fluorescent images (Ansaloni et al., EACR 2022). The purpose of this study was to assess inter-rater variability among human reviewers and to compare the AI performance against them. Methods: Blood samples derived from metastatic cancer patients were processed with CELLTRACKS® AUTOPREP®. The AI algorithm was trained on fluorescent images of 7255 CTCs and 32876 non-CTC events (training set) acquired by CELLTRACKS ANALYZER II® (CTAII) from 90 breast, 122 prostate and 54 colorectal cancer samples. 10 human reviewers, qualified for CTC image analysis, performed blind labeling of a separate dataset independently (test set: 55 samples taken from 27 breast and 28 prostate cancer). We studied inter-rater agreement and variability using Fleiss Kappa and Coefficient of Variation (CV). The labels provided by 5 experienced reviewers (average experience ≅ 15 years) were used to generate the ground truth (GT) by majority voting. The CTC detection performance of the AI was ranked against the other 5 reviewers (average experience ≅ 5 years). Results: In the test dataset, 2990 out of 9554 events were identified as CTCs by the GT review on CTAII images. In the task of classifying each event as CTC or non-CTC, the inter-rater agreement among the 10 human reviewers measured by Fleiss Kappa was 0.85. These classification results provided the number of CTCs per patient counted by each reviewer. The inter-rater variability on the CTC enumeration among the 10 reviewers was evaluated for each sample (median CV = 17.9% and interquartile range = 17.6% , excluding 27 samples with mode = 0 CTC). Measured against the GT classification, the AI performance (accuracy = 94.7%; F1 = 91.6%) was at the top of the human reviewers’ ranking (accuracy = 92.4 - 93.6 - 93.8 - 94.0 - 95.8%; F1 = 86.8 - 89.2 - 89.2 - 89.5 - 93.1%). Conclusion: The AI algorithm reached top-ranking performance in CTC identification, surpassing 4 out of 5 expert reviewers. These results show the applicability of AI to cell classification to remove human subjectivity from the review process and to maximize standardization among different research centers. Citation Format: Luca Biasiolli, Pietro Ansaloni, Nicolò Gentili, Ramona Miserendino, Chiara Rossi, Giulio Signorini, Gianni Medoro. Deep learning for circulating tumor cell (CTC) identification with the CELLSEARCH system: achieving top human-level performance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3373.

Recent advances in CMOS scaling have made circuits more and more sensitive to errors and dysfunction caused by ionizing radiation, even at ground level, requiring accurate modeling of such effects. Besides generation, transport, and collection of radiation-induced excess carriers, another phenomenon, called funneling, has to be modeled for an accurate prediction of soft errors. The funneling effect occurs when the radiation track crosses a space charge region and generates excess carriers with a density higher than the doping close to it. These carriers distort the electric field of the space charge region, deeply changing the transport mechanism, from diffusion in a field-free semiconductor to drift. The objective of this work is to include funneling as part of the generalized lumped devices model in order to obtain a complete tool for SPICE-compatible simulations of single-event effects (SEEs). The latter approach has been recently proposed to simulate radiation-induced charges in the silicon substrate and is based on the so-called generalized lumped devices that simulate charge generation, propagation, and collection using standard circuit simulators. The generalized devices are here extended to include funneling and used to simulate an alpha particle impinging on the bulk of nMOS and pMOS transistors. The results obtained are validated with TCAD numerical simulations. Finally, an static random-access memory (SRAM) struck by an alpha particle is analyzed. The model predicts that the occurrence of a soft error, i.e., flipping of memory state, may depend on whether or not there is funneling. This justifies the need for accurate modeling of funneling phenomena to predict SEEs in ICs.

Sheep meat is consumed and appreciated all over the world for its nutritional value and flavor. However, this meat is very perishable and easily subjected to the action of both spoilage and pathogenic microorganisms. For this reason, in combination with cold storage, effective preservation techniques are required. There is increasing interest in the application of natural antimicrobials, such as essential oils, extracts, spices, and by-products of the food industry. This review analyses the studies on natural antimicrobials in sheep meat and sheep meat products and gathers evidence about the encouraging results achieved on the reduction and/or elimination of spoilage and pathogenic microorganisms. The use of these natural antimicrobial alternatives might open up important perspectives for industrial application, considering that this specific meat is often traded over long distances. In fact, on the basis of scientific literature, natural antimicrobials can be considered a sustainable and affordable alternative to extend the shelf life of sheep meat and guarantee its safety, although many factors need to be further investigated, such as the sensory impact, potential toxicity, and economic aspects. For all these issues, investigated in some of the studies reviewed here, it is fundamental to obtain the antimicrobial effect with the minimum amount of effective substance to avoid sensory modifications, toxic effects, and unbearable costs. This study sets foundations for the possible direction of future studies, which will contribute to identify effective solutions for industrial applications of natural antimicrobials in the sheep meat industry.

An obturator hernia is the protrusion of an organ/tissue through the obturator canal. Fondly called ‘little old lady’s hernia’, as they typically affect elderly thin female patients [7]. They are rare and difficult to clinically diagnose [2]. Diagnosis is often delayed and presentation could vary from symptoms of bowel obstruction, and pain in the groin or medial thigh [6] to atypical presentations like in our case. We report a case of a 99-year-old female with a 3-day history of low back pain, nausea and constipation. Computerized tomography scan revealed small bowel obstruction with transition point in left obturator hernia. The obstruction was successfully relieved via surgery without the need for bowel resection. This case highlights the importance of a high index of suspicion when faced with vague symptoms. Obturator hernias carry a reasonable degree of morbidity and mortality without intervention but have good outcomes if promptly managed.

The use of dasatinib and nilotinib in the treatment of patients with chronic myeloid leukemia represents a valid therapeutic option for patients resistant or intolerant to imatinib. In this multicentre study, adherence, persistence and efficacy in real life over two years of treatment were evaluated.Adherence to treatment was calculated as the ratio between the dose received and the prescribed dose. The dose received was calculated using pharmacy refill data. The persistence with treatment was calculated as the difference between the end and the beginning of the treatment. Efficacy was assigned as Progression-Free Survival (PFS) and Events-Free Survival (EFS) and represented through the Kaplan-Meier curve.The number of patients analysed was 117, 70 treated with dasatinib and 47 with nilotinib. Adherence to treatment for dasatinib and nilotinib at two years was 0.91 and 0.82 respectively. Persistence at two years was 77% while the PFS was 92% for both drugs in the study.Adherence to the treatment calculated over two years showed a superiority of dasatinib over nilotinib. Nevertheless, the efficacy in terms of PFS and EFS is superimposable between the two drugs in the study.

Vertical junctionless gate-all-around nanowire transistors show excellent electrical performance and can be fabricated using a top-down approach in conventional CMOS process technology. Thinning of the nanowires to the desired diameter is obtained by sacrificial wet oxidation. Then, the gate oxide is grown by dry oxidation. These oxidation steps deeply affect the doping distribution in the nanowire due to dopant segregation and self-interstitial injection, especially for p-type dopants. This effect is more pronounced in 3D nanostructures with respect to bulk devices, due to geometry. Modeling the resulting doping distribution is a prerequisite for understanding the electrical properties of the devices and exploring their potential for optimization. In this work, 3D TCAD process and device simulations were performed using Synopsys Sentaurus and the results are compared with experimental data of devices fabricated at CNRS-LAAS. The impact of the implemented process and device models and their capability to predict nanowire properties and device behavior is assessed.