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Diabetes mellitus involves both insufficient insulin secretion and dysregulation of glucagon secretion 1 . In healthy people, a fall in plasma glucose stimulates glucagon release and thereby increases counter-regulatory hepatic glucose production. This response is absent in many patients with type-1 diabetes (T1D) 2 , which predisposes to severe hypoglycaemia that may be fatal and accounts for up to 10% of the mortality in patients with T1D 3 . In rats with chemically induced or autoimmune diabetes, counter-regulatory glucagon secretion can be restored by SSTR antagonists 4-7 but both the underlying cellular mechanism and whether it can be extended to humans remain unestablished. Here, we show that glucagon secretion is not stimulated by low glucose in isolated human islets from donors with T1D, a defect recapitulated in non-obese diabetic mice with T1D. This occurs because of hypersecretion of somatostatin, leading to aberrant paracrine inhibition of glucagon secretion. Normally, K ATP channel-dependent hyperpolarization of β-cells at low glucose extends into the δ-cells through gap junctions, culminating in suppression of action potential firing and inhibition of somatostatin secretion. This 'electric brake' is lost following autoimmune destruction of the β-cells, resulting in impaired counter-regulation. This scenario accounts for the clinical observation that residual β-cell function correlates with reduced hypoglycaemia risk 8 ., (© 2024. The Author(s).)

A promising superparamagnetic nanomagnetite dipped with Gd was synthesized for possible medical applications. Its size and morphology are independent of Gd content ranging from 1 to 5%. Gadolinium (III) replaced Fe(III) in the lattice. The sizes of Gd-doped nanoparticles ranged from 5 to 50 nm and exhibited a pure magnetite mineralogical phase., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Using green techniques to convert native starches into nanoparticles is an interesting approach to producing stabilizers for Pickering emulsions, aiming at highly stable emulsions in clean label products. Nanoprecipitation was used to prepare the Pickering starch nanoparticles, while ultrasound technique has been used to modulate the size of these nanoparticles at the same time as the emulsion was developed. Thus, the main objective of this study was to evaluate the stabilizing effect of cassava starch nanoparticles (SNP) produced by the nanoprecipitation technique combined with ultrasound treatment carried out in the presence of water and oil (more hydrophobic physicochemical environment), different from previous studies that carry out the mechanical treatment only in the presence of water. The results showed that the increased ultrasound energy input could reduce particle size (117.58 to 55.75 nm) and polydispersity (0.958 to 0.547) in aqueous dispersions. Subsequently, Pickering emulsions stabilized by SNPs showed that increasing emulsification (ultrasonication) time led to smaller droplet sizes and monomodal size distribution. Despite flocculation, long-term ultrasonication (6 and 9 min) caused little variation in the droplet size after 7 days of storage. The cavitation effects favored the interaction between oil droplets through weak attraction forces and particle sharing, favoring the Pickering stabilization against droplet coalescence. Our results show the potential to use only physical modifications to obtain nanoparticles that can produce coalescence-stable emulsions that are environmentally friendly., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The benefit of catheter ablation for atrial fibrillation (AF) in patients with heart failure with preserved ejection fraction (HFpEF) remains uncertain., Objective: We performed a systematic review and meta-analysis to compare catheter ablation and medical therapy (antiarrhythmics for rhythm or rate control) in patients with AF and HFpEF., Methods: We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials. Outcomes were the composite end points of death or heart failure (HF) hospitalization, all-cause death, cardiovascular death, all-cause rehospitalization, and HF hospitalization. Statistical analysis was performed using R statistical software, version 4.3.2 (R Foundation for Statistical Computing). Heterogeneity was assessed with I 2 statistics., Results: We included 20,257 patients from 8 studies. Of those, 3 were derived from RCTs, either through post hoc analysis or subgroup analysis, and 5 were observational studies. The median follow-up ranged from 24.6 to 61.2 months. Compared with medical therapy, catheter ablation was associated with a statistically significant lower risk of death or HF hospitalization (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.47-0.83; P = .001; I 2 = 66%), all-cause death (HR 0.68; 95% CI 0.46-0.99; P = .047; I 2 = 61%), cardiovascular death (HR 0.42; 95% CI 0.21-0.84; P = .014; I 2 = 22%), and HF hospitalization (HR 0.43; 95% CI 0.23-0.82; P = .011; I 2 = 87%)., Conclusion: In this meta-analysis, catheter ablation was associated with a lower risk of all-cause death, cardiovascular death, HF hospitalization, and all-cause rehospitalization in comparison to medical therapy in patients with AF and HFpEF., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Recently, the PORT-C and LUNG-ART trials, which evaluated the role of postoperative radiation therapy (PORT), have significantly altered the treatment landscape for NSCLC pN2 patients who previously underwent surgery. In response, the Italian Association of Radiotherapy and Oncology Thoracic Oncology study group has initiated an observational multicenter trial to assess both acute and late toxicities of PORT in pN2 NSCLC patients treated with modern techniques., Methods: Data on NSCLC patients submitted to PORT after radical surgery treated between 2015 and 2020 in six Italian Centers were collected. Heart, lung, and esophageal acute and late toxicities have been retrospectively analyzed and related to radiation therapy dosimetric parameters. Furthermore, loco-regional control, distant metastasis and overall survival have been analyzed., Results: A total of 212 patients with a median age of 68 years from six different centers were included in this analysis (142 males and 70 females). Prior to undergoing PORT, 96 patients (45.8%) had a history of heart disease, 110 patients (51.9%) had hypertension, and 51 patients (24%) had COPD. Acute toxicity was observed in 147 patients (69.3%), with lung toxicity occurring in 93 patients (G1 in 70 patients, G2 in 17 patients, and G3 in 4 patients), esophageal toxicity in 114 patients (G1 in 89 patients, G2 in 23 patients, and G3 in 1 patient), and cardiac toxicity in 4 patients (G1 in 2 patients and G3 in 2 patients). Late side effects were found in 60 patients (28.3%), predominantly involving the lungs (51 patients: 32 G1, 11 G2, and 1 G3) and the esophagus (11 patients: 8 G1 and 3 G2), with no reported late cardiac side effects. Various clinical and dosimetric parameters were found to correlate with both acute and chronic toxicities. Over a median follow-up period of 54 months, 48 patients (22.6%) showed locoregional disease relapse, 106 patients (50%) developed distant metastases, and 66 patients (31.1%) died., Conclusions: RAC-TAC retrospective multicentric study showed the low toxicity of PORT when advanced technology is used. At the same time, it's noteworthy to underline that 50% of the patients develop distant recurrences in the follow up., (© 2024. The Author(s).)

Background: Choroid plexus (ChP) is the secretory epithelial structure located in brain ventricles. Choroid plexus tumors (CPTs) are rare neoplasms predominantly occurring in young patients with intensified malignancy in children. CPT treatment is hindered by insufficient knowledge of the tumor pathology and limited availability of valid models., Methods: Genomic and transcriptomic data from CPT patients were analyzed to identify the putative pathological pathway. Cellular and molecular techniques were employed to validate bioinformatic results in CPT patient samples. Pharmacologic inhibition of Wnt/β-catenin signaling was assessed in CPT cells. Cell-based assays of ChP cell lines were performed following CRISPR-Cas9-derived knockout and over-expression of Wnt/β-catenin pathway genes. 3D CPT model was generated through CRISPR-Cas9-derived knockout of APC., Results: We discovered that Wnt/β-catenin signaling is activated in human CPTs, likely as a consequence of large-scale chromosomal instability events of the CPT genomes. We demonstrated that CPT-derived cells depend on autocrine Wnt/β-catenin signaling for survival. Constitutive Wnt/β-catenin pathway activation, either through knock-out of the negative regulator APC or overexpression of the ligand WNT3A, induced tumorigenic properties in ChP 2D in vitro models. Increased activation of Wnt/β-catenin pathway in ChP organoids, through treatment with a potent GSK3β inhibitor, reduced the differentiation of mature ChP epithelia cells. Remarkably, the depletion of APC was sufficient to induce the oncogenic transformation of ChP organoids., Conclusions: Our research identifies Wnt/β-catenin signaling as a critical driver of CPT tumorigenesis and provides the first 3D in vitro model for future pathological and therapeutic studies of CPT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Chimeric antigen receptor T-cell (CAR-T) therapy has shown promise in treating hematologic malignancies, yet its potential cardiotoxic effects require thorough investigation., Objectives: We aim to conduct a systematic review and meta-analysis to examine the cardiotoxic effects of CAR-T therapy in adults with hematologic malignancies., Methods: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for studies reporting cardiovascular outcomes, such as arrhythmias, heart failure, and reduced left ventricle ejection fraction (LVEF)., Results: Our analysis of 20 studies involving 4789 patients revealed a 19.68% incidence rate of cardiovascular events, with arrhythmias (7.70%), heart failure (5.73%), and reduced LVEF (3.86%) being the most prevalent. Troponin elevation was observed in 23.61% of patients, while NT-Pro-BNP elevation was observed in 9.4. Subgroup analysis showed higher risks in patients with pre-existing conditions, such as atrial arrhythmia (OR 3.12; p < .001), hypertension (OR 1.85; p = .002), previous heart failure (OR 3.38; p = .003), and coronary artery disease (OR 2.80; p = .003)., Conclusion: Vigilant cardiovascular monitoring is crucial for patients undergoing CAR-T therapy to enhance safety and treatment efficacy.Novelty Statements., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The association between atrial fibrillation (AF) and mental health is well-documented, but the relative benefits of catheter ablation versus medical therapy on mental health and quality of life are not clearly understood. This study assesses the impact of these interventions on AF patients' mental health and quality of life., Methods: Through a systematic review of PubMed, Scopus, and Cochrane databases, randomized controlled trials (RCTs) comparing catheter ablation to medical therapy for AF were analyzed. The study focused on a range of outcomes, particularly mental health and quality of life, measured by tools including the SF-36 mental component, HADS, SF-36 physical component, and AFEQT scores, among others. Analyses were stratified by AF type (paroxysmal versus persistent) and synthesized using random or fixed-effects models to calculate mean differences (MDs) or standardized mean differences (SMDs) with 95% confidence intervals (CIs)., Results: From 24 RCTs totaling 6,353 patients (51.4% receiving catheter ablation, 71.1% male, average age 59), catheter ablation was found to significantly improve mental health (SMD 0.34; 95% CI 0.05-0.63; p = 0.02) and quality of life as indicated by PCS SF-36 (MD 2.64; 95% CI 1.06-4.26; p < 0.01) and AFEQT scores (MD 6.24; 95% CI 4.43-8.05; p < 0.01), with no significant difference in outcomes between AF subtypes., Conclusion: Catheter ablation offers significant improvements in mental health and quality of life over medical therapy for AF patients, demonstrating its efficacy across different types of AF., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Evidence from randomized studies support complete over culprit-only revascularization for patients with acute coronary artery syndrome (ACS) and multivessel coronary artery diseases (MVD). Whether these findings extend to elderly patients, however, has not been thoroughly explored., Methods: We conducted a systematic review and meta-analysis comparing clinical outcomes of elderly individuals (defined as age ≥75 years) with ACS and MVD submitted to complete vs partial-only percutaneous coronary intervention (PCI). PubMed, Embase, and Cochrane were searched. We computed pooled hazard ratios with 95% confidence intervals (CI) to preserve time time-to-event data., Results: We included 7 studies, of which 2 were RCT and 5 were multivariable adjusted cohorts, comprising a total 10 147, of whom 43.8% underwent complete revascularization. As compared with partial-only PCI, complete revascularization was associated with a lower all-cause mortality (hazard ratio 0.71; 95% CI 0.60-0.85; P < 0.01), cardiovascular mortality (hazard ratio 0.64; 95% CI 0.52-0.79; P < 0.01), and recurrent myocardial infarction (hazard ratio 0.65; 95% CI 0.50-0.85; P < 0.01). There was no significant difference between groups regarding the risk of revascularizations (hazard ratio 0.80; 95% CI 0.53-1.20; P = 0.28)., Conclusion: Among elderly patients with ACS and multivessel CAD, complete revascularization is associated with a lower risk of all-cause mortality, cardiovascular mortality, and recurrent myocardial infarction., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Conduction system pacing (CSP) has emerged as a promising alternative to biventricular pacing (BVP) in patients with heart failure with reduced ejection fraction (HFrEF) and ventricular dyssynchrony, but its benefits are uncertain. In this study, we aimed to evaluate clinical outcomes of CSP vs BVP for cardiac resynchronization in patients with HFrEF. PubMed, Scopus, and Cochrane databases were searched for randomized controlled trials comparing CSP to BVP for resynchronization therapy in patients with HFrEF. Heterogeneity was examined with I 2 statistics. A random-effects model was used for all outcomes. We included 7 randomized controlled trials with 408 patients, of whom 200 (49%) underwent CSP. Compared to BVP, CSP resulted in a significantly greater reduction in QRS duration (MD -13.34 ms; 95% confidence interval [CI] -24.32 to -2.36, P = .02; I 2 = 91%) and New York Heart Association functional class (standardized mean difference [SMD] -0.37; 95% CI -0.69 to -0.05; P = .02; I 2 = 41%), and a significant increase in left ventricular ejection fraction (mean difference [MD] 2.06%; 95% CI 0.16 to 3.97; P = .03; I 2 = 0%). No statistical difference was noted for left ventricular end-systolic volume (SMD -0.51 mL; 95% CI -1.26 to 0.24; P = .18; I 2 = 83%), lead capture threshold (MD -0.08 V; 95% CI -0.42 to 0.27; P = .66; I 2 = 66%), and procedure time (MD 5.99 minutes; 95% CI -15.91 to 27.89; P = .59; I 2 = 79%). These findings suggest that CSP may have electrocardiographic, echocardiographic, and symptomatic benefits over BVP for patients with HFrEF requiring cardiac resynchronization., Competing Interests: Disclosures The authors have no conflicts to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background/aim: Overall survival (OS)-predictive models to clinically stratify patients with stage I Non-Small Cell Lung Cancer (NSCLC) undergoing stereotactic body radiation therapy (SBRT) are still unavailable. The aim of this work was to build a predictive model of OS in this setting., Patients and Methods: Clinical variables of patients treated in three Institutions with SBRT for stage I NSCLC were retrospectively collected into a reference cohort A (107 patients) and 2 comparative cohorts B1 (32 patients) and B2 (38 patients). A predictive model was built using Cox regression (CR) and artificial neural networks (ANN) on reference cohort A and then tested on comparative cohorts., Results: Cohort B1 patients were older and with worse chronic obstructive pulmonary disease (COPD) than cohort A. Cohort B2 patients were heavier smokers but had lower Charlson Comorbidity Index (CCI). At CR analysis for cohort A, only ECOG Performance Status 0-1 and absence of previous neoplasms correlated with better OS. The model was enhanced combining ANN and CR findings. The reference cohort was divided into prognostic Group 1 (0-2 score) and Group 2 (3-9 score) to assess model's predictions on OS: grouping was close to statistical significance (p=0.081). One and 2-year OS resulted higher for Group 1, lower for Group 2. In comparative cohorts, the model successfully predicted two groups of patients with divergent OS trends: higher for Group 1 and lower for Group 2., Conclusion: The produced model is a relevant tool to clinically stratify SBRT candidates into prognostic groups, even when applied to different cohorts. ANN are a valuable resource, providing useful data to build a prognostic model that deserves to be validated prospectively., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aims/hypothesis: Diabetes mellitus is associated with impaired insulin secretion, often aggravated by oversecretion of glucagon. Therapeutic interventions should ideally correct both defects. Glucagon-like peptide 1 (GLP-1) has this capability but exactly how it exerts its glucagonostatic effect remains obscure. Following its release GLP-1 is rapidly degraded from GLP-1(7-36) to GLP-1(9-36). We hypothesised that the metabolite GLP-1(9-36) (previously believed to be biologically inactive) exerts a direct inhibitory effect on glucagon secretion and that this mechanism becomes impaired in diabetes., Methods: We used a combination of glucagon secretion measurements in mouse and human islets (including islets from donors with type 2 diabetes), total internal reflection fluorescence microscopy imaging of secretory granule dynamics, recordings of cytoplasmic Ca 2+ and measurements of protein kinase A activity, immunocytochemistry, in vivo physiology and GTP-binding protein dissociation studies to explore how GLP-1 exerts its inhibitory effect on glucagon secretion and the role of the metabolite GLP-1(9-36)., Results: GLP-1(7-36) inhibited glucagon secretion in isolated islets with an IC 50 of 2.5 pmol/l. The effect was particularly strong at low glucose concentrations. The degradation product GLP-1(9-36) shared this capacity. GLP-1(9-36) retained its glucagonostatic effects after genetic/pharmacological inactivation of the GLP-1 receptor. GLP-1(9-36) also potently inhibited glucagon secretion evoked by β-adrenergic stimulation, amino acids and membrane depolarisation. In islet alpha cells, GLP-1(9-36) led to inhibition of Ca 2+ entry via voltage-gated Ca 2+ channels sensitive to ω-agatoxin, with consequential pertussis-toxin-sensitive depletion of the docked pool of secretory granules, effects that were prevented by the glucagon receptor antagonists REMD2.59 and L-168049. The capacity of GLP-1(9-36) to inhibit glucagon secretion and reduce the number of docked granules was lost in alpha cells from human donors with type 2 diabetes. In vivo, high exogenous concentrations of GLP-1(9-36) (>100 pmol/l) resulted in a small (30%) lowering of circulating glucagon during insulin-induced hypoglycaemia. This effect was abolished by REMD2.59, which promptly increased circulating glucagon by >225% (adjusted for the change in plasma glucose) without affecting pancreatic glucagon content., Conclusions/interpretation: We conclude that the GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of glucagon secretion. We propose that the increase in circulating glucagon observed following genetic/pharmacological inactivation of glucagon signalling in mice and in people with type 2 diabetes reflects the removal of GLP-1(9-36)'s glucagonostatic action., (© 2023. The Author(s).)

Hand osteoarthritis (OA) severity can be assessed visually through radiographs using semi-quantitative grading systems. However, these grading systems are subjective and cannot distinguish minor differences. Joint space width (JSW) compensates for these disadvantages, as it quantifies the severity of OA by accurately measuring the distances between joint bones. Current methods used to assess JSW require users' interaction to identify the joints and delineate initial joint boundary, which is time-consuming. To automate this process and offer a more efficient and robust measurement for JSW, we proposed two novel methods to measure JSW: 1) The segmentation-based (SEG) method, which uses traditional computer vision techniques to calculate JSW; 2) The regression-based (REG) method, which is a deep learning approach employing a modified VGG-19 network to predict JSW. On a dataset with 3,591 hand radiographs, 10,845 DIP joints were cut as regions of interest and served as input to the SEG and REG methods. The bone masks of the ROI images generated by a U-Net model were sent as input in addition to the ROIs. The ground truth of JSW was labeled by a trained research assistant using a semi-automatic tool. Compared with the ground truth, the REG method achieved a correlation coefficient of 0.88 and mean square error (MSE) of 0.02 mm on the testing set; the SEG method achieved a correlation coefficient of 0.42 and MSE of 0.15 mm. Results show the REG method has promising performance in automatic JSW measurement and in general, Deep Learning approaches can facilitate the automatic quantification of distance features in medical images.

The present study investigated the intimate partner femicide (IPF) and intimate partner femicide-suicide (IPFS) perpetrators' individual, relational, and contextual characteristics by analyzing, within the ecological approach, femicide cases that occurred in Italy from 2010 to 2019. On the topic, to date, scant studies examined possible differences between IPF and IPFS risk factors, and no studies have analyzed these factors by adopting an ecological systems model perspective. To this aim, archival research was carried out. Of a total of 1.207 femicides, 409 were IPF, and 227 were IPFS. Perpetrators' age, level of employment, law enforcement membership, mental and/or physical illnesses, use of psychoactive substances, previous crimes, previous violent relationships, presence of children, previous violence in the couple, inability to accept the end of the relationship, quarrels and conflict, jealousy and the psychophysical illnesses of both authors and victims, as well as the use of firearms and victim's request for help were analyzed. The results underlined the existence of different risk factors contributing to the IPF perpetrators' decision to commit suicide such as perpetrators' age, law enforcement membership, and firearm availability. These findings stress the need for specific risk assessment and management strategies for IPFS perpetrators.

We performed a pilot study to evaluate the use of MRI delta texture analysis (D-TA) as a methodological item able to predict the frequency of complete pathological responses and, consequently, the outcome of patients with locally advanced rectal cancer addressed to neoadjuvant chemoradiotherapy (C-RT) and subsequently, to radical surgery. In particular, we carried out a retrospective analysis including 100 patients with locally advanced rectal adenocarcinoma who received C-RT and then radical surgery in three different oncological institutions between January 2013 and December 2019. Our experimental design was focused on the evaluation of the gross tumor volume (GTV) at baseline and after C-RT by means of MRI, which was contoured on T2, DWI, and ADC sequences. Multiple texture parameters were extracted by using a LifeX Software, while D-TA was calculated as percentage of variations in the two time points. Both univariate and multivariate analysis (logistic regression) were, therefore, carried out in order to correlate the above-mentioned TA parameters with the frequency of pathological responses in the examined patients' population focusing on the detection of complete pathological response (pCR, with no viable cancer cells: TRG 1) as main statistical endpoint. ROC curves were performed on three different datasets considering that on the 21 patients, only 21% achieved an actual pCR. In our training dataset series, pCR frequency significantly correlated with ADC GLCM-Entropy only, when univariate and binary logistic analysis were performed (AUC for pCR was 0.87). A confirmative binary logistic regression analysis was then repeated in the two remaining validation datasets (AUC for pCR was 0.92 and 0.88, respectively). Overall, these results support the hypothesis that D-TA may have a significant predictive value in detecting the occurrence of pCR in our patient series. If confirmed in prospective and multicenter trials, these results may have a critical role in the selection of patients with locally advanced rectal cancer who may benefit form radical surgery after neoadjuvant chemoradiotherapy.

Head and neck squamous cell carcinomas (HNSCC) constitute the sixth most common malignancy worldwide, with approximately 25-40% of the diagnosed patients older than 70 years. HNSCC patients are often frail and frequently have multiple comorbidities due to their unhealthy lifestyle, and evidence suggests that older patients may receive less aggressive and suboptimal treatment than younger patients with the same disease status. The aim of this review is to depict and summarize the evidence regarding the different strategies that can be used in the clinical management of elderly HNSCC patients. Key references were derived from a PubMed query. Hand searching and clinicaltrials.gov were also used. This paper contains a narrative report and a critical discussion of clinical approaches in the context of elderly HNSCC.

Aim: Head and neck squamous cell cancer (HNSCC) is the ninth most common tumor worldwide. Neck lymph node (LN) status is the major indicator of prognosis in all head and neck cancers, and the early detection of LN involvement is crucial in terms of therapy and prognosis. Diffusion-weighted imaging (DWI) is a non- invasive imaging technique used in magnetic resonance imaging (MRI) to characterize tissues based on the displacement motion of water molecules. This review aims to provide an overview of the current literature concerning quantitative diffusion imaging for LN staging in patients with HNSCC., Methods: This systematic review performed a literature search on the PubMed database (https://pubmed.ncbi.nlm.nih.gov/) for all relevant, peer-reviewed literature on the subject following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) criteria, using the keywords: DWI, MRI, head and neck, staging, lymph node., Results: After excluding reviews, meta-analyses, case reports, and bibliometric studies, 18 relevant papers out of the 567 retrieved were selected for analysis., Conclusions: DWI improves the diagnosis, treatment planning, treatment response evaluation, and overall management of patients affected by HNSCC. More robust data to clarify the role of apparent diffusion coefficient (ADC) and DWI parameters are needed to develop models for prognosis and prediction in HNSCC cancer using MRI., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2022.)

This study proposes a Geographic Information Systems-based methodology to measure accessibility to urban services from the elderly perspective to support urban planning processes. Specifically, it seeks to understand and clarify how the urban environment can influence the quality of life for older adults, mostly through pedestrian and public transport networks, locations of essential urban services, and the organisation of their resources. In light of a significant demographic change, policymakers will have to promote age-friendly urban planning approaches to guarantee equal access to services and activities. We propose a methodology to measure accessibility to healthcare provision services that considers land-use and mobility features and older adults' behavioural traits. The method belongs to the family of 2SFCA-2 steps floating catchment area-which evaluate accessibility as the combination of both supply and demand of urban services. Therefore, we have introduced innovative elements to shape actual mobility opportunities for the elderly and their travel choices. The methodology was applied to Milan's city to measure accessibility to the Health Protection Agency (ATS) services, which is responsible for healthcare assistance to the elderly dwelling in the city. The outputs show that a significant share of older people (almost 40%) suffer from poor accessibility to primary health services and that they mostly live in the city periphery. Moreover, the application to a case study has shown that the methodology could identify the critical aspects needed to aid urban planning to achieve a high quality of life for elderly people., (© The Author(s) 2022.)

Purpose: Diabetes mellitus is a common condition in the clinically obese. Bariatric surgery is one of the ways to put type 2 diabetes in remission. Recent findings propose the appetite-regulator peptide tyrosine tyrosine (PYY) as a therapeutic option for patients with type 2 diabetes. This novel gut hormone restores impaired insulin and glucagon secretion in pancreatic islets and is implicated in type 2 diabetes reversal after bariatric surgery. The current study elucidates the interactions between PYY and the NPY1R and NPY4R receptors using computational methods., Methods: Protein structure prediction, molecular docking simulation, and molecular dynamics (MD) simulation were performed to elucidate the interactions of PYY with NPY1R and NPY4R., Results: The predicted binding models of PYY-NPY receptors are in agreement with those described in the literature, although different interaction partners are presented for the C-terminal tail of PYY. Non-polar interactions are predicted to drive the formation of the protein complex. The calculated binding energies show that PYY has higher affinity for NPY4R (ΔG GBSA = -65.08 and ΔG PBSA = -87.62 kcal/mol) than for NPY1R (ΔG GBSA = -23.11 and ΔG PBSA = -50.56 kcal/mol)., Conclusions: Based on the constructed models, the binding conformations obtained from docking and MD simulation for both the PYY-NPY1R and PYY-NPY4R complexes provide a detailed map of possible interactions. The calculated binding energies show a higher affinity of PYY for NPY4R. These findings may help to understand the mechanisms behind the improvement of diabetes following bariatric surgery., (© 2021. Hellenic Endocrine Society.)

Mucopolysaccharidosis III (Sanfilippo syndromes) types A-D are rare lysosomal storage disorders characterized by heparan sulfate accumulation and neurodegeneration. Patients with MPS III present with developmental stagnation and/or regression, sleep disturbance, and behavioral abnormalities usually in the first years of life. Epilepsy may occur in a proportion of patients during the disease course. However, the progression of epilepsy and EEG changes in MPS III have not been systematically investigated. We report electroclinical features in a cohort of patients with MPS III over a follow-up period ranging from 6.5 to 22 years. Participants include 15 patients (11 females; aged 7-31 years) with MPS III A ( n = 7, 47%), MPS III B ( n = 5, 34%), MPS III C ( n = 2, 13%), and MPS III D ( n = 1, 6%). At the time of this study, 8 out of 15 patients (53%) had epilepsy. Epilepsy occurred in patients with advanced disease even in the first decade of life (mean age at onset: 12.1 ± 6.7 years). However, seizure onset may also be associated with abrupt worsening of the neurobehavioral phenotype. The main epilepsy types observed were generalized (four out of eight, 50%), followed by focal (three out of eight, 37%) and combined (two out of eight, 25%) epilepsy and status epilepticus (one out of eight, 12.5%). Seizures were generally controlled by one antiepileptic drug (AED) and most patients (seven out of eight, 87%) were still on therapy after a median follow-up period of 5 years (range: 1-9 years). A total of 66 EEGs were analyzed with a median EEG follow-up duration of 7 years (range: 6 months-14 years). Slowing of the background activity occurred in 7 (46%) patients aged 4-19 years. Epileptiform EEG abnormalities were observed in 10 patients at a mean age of 9.6 ± 2.9 years. EEG epileptiform discharges were not unavoidably linked to epilepsy. Early recognition and careful monitoring of electroclinical features in MPS III is necessary for appropriate care and for the detection of disease progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Barone, Fiumara, Gulisano, Cirnigliaro, Cocuzza, Guida, Pettinato, Greco, Elia and Rizzo.)

Background/aim: The aim of the study was to investigate boost volume definition, doses, and delivery techniques for rectal cancer dose intensification., Patients and Methods: An online survey was made on 25 items (characteristics, simulation, imaging, volumes, doses, planning and treatment)., Results: Thirty-eight radiation oncologists joined the study. Twenty-one delivered long-course radiotherapy with dose intensification. Boost volume was delineated on diagnostic magnetic resonance imaging (MRI) in 18 centres (85.7%), and computed tomography (CT) and/or positron emission tomography-CT in 9 (42.8%); 16 centres (76.2%) performed co-registration with CT-simulation. Boost dose was delivered on gross tumor volume in 10 centres (47.6%) and on clinical target volume in 11 (52.4%). The most common total dose was 54-55 Gy (71.4%), with moderate hypofractionation (85.7%). Intensity-modulated radiotherapy (IMRT) was used in all centres, with simultaneous integrated boost in 17 (80.8%) and image-guidance in 18 (85.7%)., Conclusion: A high quality of treatment using dose escalation can be inferred by widespread multidisciplinary discussion, MRI-based treatment volume delineation, and radiation delivery relying on IMRT with accurate image-guided radiation therapy protocols., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Novel coronavirus (COVID-19) is having a devastating psychological impact on patients, especially patients with cancer. This work aims to evaluate mood disorders of cancer patients undergoing radiation therapy during COVID-19 in comparison with cancer patients who underwent radiation therapy in 2019. Materials and Methods: We included all the patients undergoing radiation therapy at our department in two-time points (once a week for a month in May 2019) and during the COVID-19 outbreak (in April 2020). All the patients were asked to fulfill a validated questionnaire (STAI-Y1, State trait anxiety inventory scale), the Symptom Distress thermometer (SDT) (from 0 to 10 score), and the Beck Depression Inventory v.2 (BDI-2). We took into account the COVID-19 outbreak and also sex, age, week of radiation treatment, and disease. Results: We included 458 patients (220 males and 238 females), with a median age of 64 years. STAI-Y1 median score was 40 (mean 41,3, range 19-79), whereas the median score of SDT was five and BDI-2 median score was 11. STAI-Y1, SDT, and BDI-2 were significantly correlated with the COVID-19 outbreak ( p < 0,001 for all the tests), sex ( p : 0,016 for STAI-Y1, p < 0.001 for SDT, p :0.013 for BDI-2), week of treatment ( p : 0.012 for STAI-Y1 and p : 0.031 for SDT), and disease ( p :0.015 for STAI-Y1, p < 0.001 for SDT and p :0.020 for BDI-2). Conclusions: The prevalence of mood disorders in patients undergoing radiation therapy is higher than expected and even higher during the COVID-19 outbreak. These measurements could be useful as a baseline to start medical humanities programs to decrease these scores., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nardone, Reginelli, Vinciguerra, Correale, Calvanese, Falivene, Sangiovanni, Grassi, Di Biase, Polifrone, Caraglia, Cappabianca and Guida.)

The outbreak of the Coronavirus during the first months of 2020 completely reshaped urban lives because of the need to limit the spread of the disease and ensure essential services to the most vulnerable city users, such as elderly people. The urban population in European is ageing at unprecedented rate; at the same time, ageing is associated with increased vulnerability and dependence on medical care services. Age-friendly approaches are consequently necessary in urban planning strategies to ensure equal accessibility to essential services, not least in view of coronavirus pandemic. This article aims at defining a methodology for measuring urban accessibility to healthcare services as indicative of quality of life for the elderly within the city of Milan - affected by Covid - both in ordinary working scenarios and during the pandemic. The outputs show that entire neighbourhoods' elderly populations suffer from very poor accessibility to primary health services, especially in the city suburbs, and their condition deteriorates even more because of limited services and activities. The methodology would be effective to suggest policy recommendations to distribution of public services in urban areas and to reduce the potential effects of the Covid-19 pandemic on old people's health and quality of life., Competing Interests: The authors declare that they haveno known competingfinancialinterestsor personal relationships that could have appeared to influence the work reported in this paper., (© 2020 Elsevier Ltd. All rights reserved.)

By restoring glucose-regulated insulin secretion, glucagon-like peptide-1-based (GLP-1-based) therapies are becoming increasingly important in diabetes care. Normally, the incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) jointly maintain normal blood glucose levels by stimulation of insulin secretion in pancreatic β cells. However, the reason why only GLP-1-based drugs are effective in improving insulin secretion after presentation of diabetes has not been resolved. ATP-sensitive K+ (KATP) channels play a crucial role in coupling the systemic metabolic status to β cell electrical activity for insulin secretion. Here, we have shown that persistent membrane depolarization of β cells due to genetic (β cell-specific Kcnj11-/- mice) or pharmacological (long-term exposure to sulfonylureas) inhibition of the KATP channel led to a switch from Gs to Gq in a major amplifying pathway of insulin secretion. The switch determined the relative insulinotropic effectiveness of GLP-1 and GIP, as GLP-1 can activate both Gq and Gs, while GIP only activates Gs. The findings were corroborated in other models of persistent depolarization: a spontaneous diabetic KK-Ay mouse and nondiabetic human and mouse β cells of pancreatic islets chronically treated with high glucose. Thus, a Gs/Gq signaling switch in β cells exposed to chronic hyperglycemia underlies the differential insulinotropic potential of incretins in diabetes.

Pain management is one of the main challenges in addressing the improved care of hospitalized newborns. The administration of oral sucrose with and without non-nutritive suction has been proposed as a nonpharmacological intervention to relieve procedural pain in newborns. The effects have not yet been well characterized. The aim of this study is to investigate, using skin conductance algesimeter (SCA) pain monitor index, the effects of 24% sucrose solution on pain perception during capillary and arterial blood sampling. It is a prospective, randomized controlled study: sucrose versus placebo. Sucrose was given orally to infants who were submitted to arterial or capillary sampling. The SCA was measured during, and for 3 min before and after the intervention. Fifty-six infants were enrolled: 31 in the sucrose group and 25 in the placebo group. SCA showed that the measurement of peaks per second of pain during and 3 min after the procedures was lower in the sucrose group than the placebo group and that this difference was statistically significant ( p  < .05). In conclusion, 24% sucrose administered orally is effective in reducing pain during and after capillary and arterial sampling in newborns and can be used for the prevention and treatment of pain in the Neonatal Intensive Care Unit. Brief rationale To treat neonatal pain, a tiered approach with nonpharmacological and pharmacological method can be used.Among nonpharmacological therapies, sucrose administration is safe and effective in reducing single episodes of minor procedural pain. This study aimed to investigate, the effects of 24% sucrose solution on pain perception during capillary and arterial blood withdrawn by using an objective method: skin conductance algesimeter (SCA) pain monitor index.This randomized controlled trial in which term and/or preterm neonates (postnatal age maximum of 28 days corrected for postmenstrual age) received sucrose for procedural pain. Oral sucrose was administered directly by a disposable plastic vial. SCA was measured by means of a specific device.We demonstrated, using SCA pain monitor index, the efficacy of 24% sucrose solution on pain perception during capillary and arterial blood withdrawn. The results of this study provide an objective evidence of sucrose efficacy for the prevention and treatment of neonatal painful procedures.

Femicide is a wide-spread lethal form of violence against women. Despite its diffusion, to date, very few studies analyzed possible victims' age differences in regard to fatal risk factors for femicide. To this aim, we carried out archive research on Italian femicide cases in the last decade, by comparing prior types of violence suffered and motives for femicide, which are considered crucial fatal risk factors for femicide, across adolescent/young (15-24 years), adults (25-64 years) and older women (65-93 years). From 2010 to 2019 we found 1207 female victims. Characteristics of victims, perpetrators, and their relationship were consistent with those found by international studies and underlined that the majority of femicides were perpetrated by an intimate partner. The results regarding fatal risk factors comparisons across age groups showed the existence of significant differences regarding both types of violence suffered prior to femicide and motives for femicide. The results are discussed in terms of policy implication and intervention.

Background: Erythropoietic protoporphyria (EPP) is a rare inherited disease associated with heme metabolism, characterized by severe life-long photosensitivity and liver involvement., Objective: To provide epidemiological data of EPP in Italy., Materials & Methods: Prospective/retrospective data of EPP patients were collected by an Italian network of porphyria specialist centres (Gruppo Italiano Porfiria, GrIP) over a 20-year period (1996-2017)., Results: In total, 179 patients (79 females) with a clinical and biochemical diagnosis of EPP were assessed, revealing a prevalence of 3.15 cases per million persons and an incidence of 0.13 cases per million persons/year. Incidence significantly increased after 2009 (due to the availability of alfa-melanotide, which effectively limits skin photosensitivity). Mean age at diagnosis was 28 years, with only 22 patients (12.2%) diagnosed ≤10 years old. Gene mutations were assessed in 173 (96.6%) patients; most (164; 91.3%) were FECH mutations on one allele in association with the hypomorphic variant, c.315-48C, on the other (classic EPP), and nine (5.2%) were ALAS2 mutations (X-linked EPP). Only one case of autosomal recessive EPP was observed. Of the 42 different FECH mutations, 15 are novel, three mutations collectively accounted for 45.9% (75/164) of the mutations (c.215dupT [27.2%], c.901&#95;902delTG [11.5%] and c.67 + 5G > A [7.2%]), and frameshift mutations were prevalent (33.3%). A form of light protection was used by 109/179 (60.8%) patients, and 100 (56%) had at least one α-melanotide implant. Three cases of severe acute liver involvement, requiring OLT, were observed., Conclusion: These data define, for the first time, the clinical and molecular epidemiology of EPP in Italy.

Internal organs at risk volumes (IRV) represent the propagation of organs at risk (OARs) in 4DCT. Sixty consecutive patients that underwent 4DCT for thoracic stereotactic radiotherapy were analyzed and IRVs for heart, trachea, esophagus, bronchial tree, great vessels, and spinal cord were calculated. IRVs were then tested for the respect of dose constraints. IRVs were significantly bigger than standard OARs (p-value <0.001 for all the IRVs). IRVs that did not respect the dose constraints were, respectively, 7/60 (11.7%) for Heart IRV, 6/60 (10%) for Esophagus IRV, 11/60 (18.3%) for Trachea IRV, 16/60 (26.6%) for Bronchial Tree and 0/60 (0%) for great vessel and spinal cord IRV. In the subset of central targets, the percentage of plans that can be unacceptable taking into consideration OARs motion reaches 42%. The correlation of IRVs with clinical parameters and toxicity deserves future investigations in prospective trials., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Methods based on crash data analysis are effective in identifying intersections with a potential for safety improvement. However, it is well recognized that crash data suffer from several shortcomings and that there are clues to safety other than crash occurrence. The systemic approach is an alternative method to address safety issues. In this approach, a transportation agency is able to identify priority locations based on the presence of risk factors rather than actual crashes. To promote wider use of the systemic safety approach, this paper aims at developing and validating a procedure to rank unsignalised urban intersections for safety improvement based on the evaluation of risk factors by road safety inspections. The procedure assesses a Safety Index (SI) that measures the safety performance of unsignalised urban intersections. The SI is formulated by combining two components of risk: the exposure of road users to road hazards (Exposure) and the risk factors, which increase the probability of involvement in crashes (Risk Index). The SI is made of two elements, one related to vehicles and one to pedestrians. Twenty-three detailed safety issues and ten general safety issues are assessed to compute the vehicle Risk Index and the pedestrian Risk Index. Safety issues were selected considering that they are common issues and that effective remedial measures exist and have already proven their effectiveness. Finally, criteria for identifying and ranking safety issues were defined. The SI has two main practical applications. High risk intersections, where safety measures that can reduce crash frequency exist, can be identified and ranked by the SI. Specific safety issues, that give more contribution to unsafety, are pointed out in order to give indication about more appropriate safety measures according to the systemic safety approach. The procedure was validated with a sample of eighty-nine urban intersections located in Orange County (Florida, U.S.). For these intersections, the SI scores, the Empirical Bayes (EB) safety estimates, and the potential for improvement (PFI) were compared. The correlation between the SI scores and the EB estimates was highly significant both for vehicles (R 2  = 0.66) and pedestrians (R 2  = 0.58) as well as for the total crashes (R 2  = 0.68). The results from the Spearman's rank-correlation analysis provided further validation for the SI indicating that ranking from the SI and the EB estimates agree at the 99.9% confidence level for vehicles (ρ s  = 0.78), pedestrians (ρ s  = 0.93), and total (ρ s  = 0.93)., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)