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Background. Life-saving technologies have completely changed the normal conception of medical treatments. Left Ventricular Assist Devices (LVAD) can prolong survival for patients who are not candidates for heart transplantation. In order to analyze the pre-implantation phase, which involves a shared-decision making process before activation of the device, attention should be paid to the criterion of "proportionality" in order to properly assess the risks and benefits of implantation. Aim. The aim of our analysis is to provide an useful tool for the assessment of LVAD proportionality during the physicians' decision making. Methods. The method of the "four boxes", developed by Jonsen et al, was chosen to analyze the notion of proportionality and the other main ethical issues regarding LVAD activation in adult patients. Results. Medical issues are not the sole factors, which influence the choice of implantation by patients. Indeed, patient preferences, his/her quality of life, and contextual features should be taken into consideration when proposing LVADs: these factors are as important as clinical issues where outcomes are concerned. Conclusion. In order to assess the proportionality of such a device, we present, discuss and examine, in the framework of the pre-implant phase, the content of each topic treated by the "four boxes method", that is, an essential tool for the assessment of the proportionality of the treatment for LVAD candidates. [ABSTRACT FROM AUTHOR]

Motivated by a recent work performed at Australian National University by S. Kalkal et al. [Phys. Rev. C 93, 044605 (2016)] on breakup and its time scale, where it was shown that the prompt (or near-target) breakup of 6,7Li is almost negligible and consequently the near-barrier complete fusion cross section induced by these weakly bound Li isotopes on light targets should not be suppressed by the breakup, as it is for heavier targets, we estimated the contributions of complete and incomplete fusion in the measured total fusions for several light systems available in the literature. The chosen systems were those for which the fusion cross sections had been measured using the γ-ray spectroscopy method and all evaporation channel cross sections were reported. For the estimation, we used, apart from the data, the predictions of the evaporation code cascade. The results show that, indeed, the complete fusion suppression is negligible for such systems at energies slightly above the barrier, in agreement with the above-mentioned recent measurements of breakup time scales. [ABSTRACT FROM AUTHOR]

Introduction: Artificial tear substitutes are key elements in the first-line treatment of dry eye disease (DED). We hypothesized that GlicoPro ® , a new multimolecular complex based on proteins, sulfured and unsulfured glycosaminoglycans and opiorphin, was able to significantly improve the effect of hydroxypropyl-methylcellulose (HPMC) eyedrops in treating DED., Methods: We performed an in vitro experiment and a clinical study, comparing an HPMC + GlicoPro ® -based to an HPMC-based ophthalmic formulation (similar kinematic viscosity and comparable HPMC concentration). An in vitro dry eye model was established by inducing hyperosmolarity in the base medium of human corneal epithelial cells HCE-2. After treatment with ophthalmic formulations, the expression levels of inflammatory cytokines and enzymes (IL-20, IL-1β, TNF-α, IL-6, IL-8, MMP-9, and MCP-1) was measured by real-time polymerase chain reaction. Moreover, we performed a single-blind randomized 1:1 clinical trial, aimed to compare the efficacy of the two formulations instilled four times per day (QID), in treating mild-to-moderate DED. Symptoms (Ocular Surface Disease Index and Symptom Assessment iN Dry Eye), clinical signs, and ocular surface imaging data were assessed at baseline and after 1 and 3 months of treatment., Results: In vitro experiment: under hyperosmotic conditions, corneal epithelial cells upregulated the expression of inflammatory cytokines IL-20, IL-1β, TNF-α, IL-6, and IL-8. Treatment with HPMC + GlicoPro ® significantly decreased the expression of all inflammatory markers tested, including cytokines, MMP-9, and MCP-1 (P < 0.05)., Clinical Study: the HPMC + GlicoPro ® formulation showed a significantly higher effect in improving symptoms (overall treatment effect: P < 0.001), tear film stability, and markers of inflammation on corneal confocal microscopy (P < 0.01)., Conclusions: Both in vitro and clinical data provided evidence supporting the role of GlicoPro ® in improving the effect of HPMC in DED treatment., Clinical Trial Registration: NCT06726525., Competing Interests: Declarations. Conflict of Interest: Edoardo Villani has received honoraria from AbbVie, Alcon, Diadema, FB Vision, Fidia, Essilor Luxottica, NTC, Santen, Sifi, Thea, Unifarco, Visufarma for contributing to advisory boards, educational events, and/or expert panels. Pasquale Aragona has received honoraria from AbbVie, Alcon, Bausch and Lomb, DMG, FB Vision, Fidia, Medivis, Santen, Sifi, Sun Pharma, Thea for contributing to advisory boards, educational events, and/or expert panels. Giuseppe Campagna, Valentina Gentili, Elisa Imelde Postorino, Paola Genovese, Paola Palino, Gloria Maini, Alice Carbucicchio, Eleonora Ferioli, Paolo Nucci, and Roberta Rizzo declare that they have no competing interests. Ethical Approval: The clinical study was approved by Intercompany Ethics Committee of Messina (Italy), protocol number: Prot. 20–22, and was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. All subjects included provided informed consent to participate in the study., (© 2025. The Author(s).)

Dedifferentiated endometrioid adenocarcinoma is characterised by the coexistence of an undifferentiated carcinoma and a low-grade endometrioid adenocarcinoma. The low-grade component in this subtype of endometrial carcinoma is Grade 1 or 2 according to the Federation of Gynaecology and Obstetrics (FIGO) grading system. The coexistence of low-grade endometrial carcinoma and solid undifferentiated carcinoma can cause diagnostic problems on histological examination. In fact, this combination can often be mistaken for a more common Grade 2 or Grade 3 endometrial carcinoma. Therefore, this subtype of uterine carcinoma can often go under-recognised. An accurate diagnosis of dedifferentiated endometrial carcinoma is mandatory because of its poorer prognosis compared to Grade 3 endometrial carcinoma, with a solid undifferentiated component that can amount to as much as 20% of the entire tumour. The aim of this review is to provide clinical, immunohistochemical, and molecular data to aid with making an accurate histological diagnosis and to establish whether there are any findings which could have an impact on the prognosis or therapeutic implications of this rare and aggressive uterine neoplasm.

Background: Early colorectal cancer (ECC) is defined as T1NXM0 colorectal cancer (CRC). Although a non-negligible number of T1-CRCs presents metastatic lymph-nodes, local excision is increasingly proposed as alternative to radical resection. Several criteria have been suggested to identify low-risk T1-CRC, but recommendations on this topic are still heterogeneous. This study aims to identify criteria associated with N+ T1-CRC, to select patients to undergo (or not) local excision., Methods: A retrospective analysis of demographic, clinical, and histology criteria of 122 consecutive T1-CRC patients undergoing radical resection at Parma University Hospital between 2000 and 2018 has been performed., Results: Lymph-node metastasis (LNM) was observed in 15/122 patients (12.3%). No LNM was observed among well-differentiated (G1) tumors (0/37), while 10/65 (15.4%) G2 cases as well as 5/20 (25%) G3 patients presented LNM. G1 was associated with absence of LNM (p = 0.013). After excluding G1 patients, the rate of N + T1-CRC was 17.6% (15/85). LNM was observed in 4/8 (50%) patients with lymphovascular invasion (LVI) and in 11/77 (14.2%) without LVI. LVI resulted being associated with LNM (p < 0.042). LNM was reported in 28.3% of cases with a tumor infiltration >4.25 mm (13/46), compared to 5.1% in cases with an infiltration ≤4.25 mm (2/39) (p = 0.012). In Cox regression analysis, the higher hazard ratio (HR) was reported for the LVI + and infiltration >4.25 mm (HR 24.849)., Conclusions: In patients with ECC (pT1NXM0), good differentiation (G1), absence of lymphovascular invasion (LVI-), and tumor radial infiltration ≤4.25 mm may allow performing local resection and avoiding radical surgery., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mesothelin (MSLN) is a protein expressed in the mesothelial cell lining of the pleura, peritoneum, and pericardium; its biological functions in normal cells are still unknown. Experimental studies using knockout mice have suggested that this molecule does not play an important role in development and reproduction. In contrast, it has been observed that this molecule is produced in abnormal amounts in several malignant neoplasms, such as mesotheliomas and pancreatic adenocarcinomas. Many molecular studies have also demonstrated that mesothelin is overexpressed in HSOCs. Here, we discuss the current knowledge of mesothelin and focus on its role in clinical and pathological diagnoses, as well as its impact on the prognosis of HSOC. Moreover, regarding the binding of MSLN to the ovarian cancer antigen CA125, which has been demonstrated in many studies, we also report on signal transduction pathways that may play an important role in the spread and neoplastic progression of this lethal neoplasm. Given that mesothelin is overexpressed in many solid tumours and has antigenic properties, this molecule could be considered an antigenic target for the treatment of many malignancies. Consequently, we also review the literature to report on mesothelin-targeting therapies for HSOC that have been recently investigated in many clinical studies.

Background: The choice of the specific modality and treatment duration of renal replacement therapy (RRT) to adopt in metformin-associated lactic acidosis (MALA) is still debated. We aimed to verify if sustained low-efficiency dialysis (SLED) is a rational choice in patients with MALA and acute kidney injury (AKI)., Methods: We collected serial serum metformin measurements, clinical parameters, and outcome data in ten consecutive patients (mean age 77 years [range 58-88], 5 males) admitted to our renal intensive care unit for suspected MALA associated with AKI and hemodynamic instability. Patients underwent a 16-h SLED session performed with either conventional dialysis machines or machines for continuous RRT (CRRT). A 2-compartment open-infusion pharmacokinetic model with first-order elimination was fitted to each subject's serum concentration-time data to model post-SLED rebound and predict the need for further treatments., Results: Two patients died within 24 h after SLED start. Three patients needed one further dialysis session. Surviving patients (n = 8) were dialysis-free at discharge. Metformin levels were in the toxic range at baseline (median [range] 32.5 mg/l [13.6-75.6]) and decreased rapidly by the end of SLED (8.1 mg/l [4.5-15.8], p < 0.001 vs. baseline), without differences according to the dialysis machine used (p = 0.84). We observed a slight 4-h post-SLED rebound (9.7 mg/l [3.5-22.0]), which could be predicted by our pharmacokinetic model. Accordingly, we predicted that the majority of patients would need one additional dialysis session performed the following day to restore safe metformin levels., Conclusions: A 16-h SLED session, performed with either conventional dialysis machines or CRRT machines, allows effective metformin removal in patients with MALA and AKI. However, due to possible post-SLED rebound in serum metformin levels, one additional dialysis treatment is required the following day in the majority of patients.

Background: Life-saving technologies have completely changed the normal conception of medical treatments. Left Ventricular Assist Devices (LVAD) can prolong survival for patients who are not candidates for heart transplantation. In order to analyze the pre-implantation phase, which involves a shared-decision making process before activation of the device, attention should be paid to the criterion of "proportionality" in order to properly assess the risks and benefits of implantation., Aim: The aim of our analysis is to provide an useful tool for the assessment of LVAD proportionality during the physicians' decision making., Methods: The method of the "four boxes", developed by Jonsen et al, was chosen to analyze the notion of proportionality and the other main ethical issues regarding LVAD activation in adult patients., Results: Medical issues are not the sole factors, which influence the choice of implantation by patients. Indeed, patient preferences, his/her quality of life, and contextual features should be taken into consideration when proposing LVADs: these factors are as important as clinical issues where outcomes are concerned., Conclusions: In order to assess the proportionality of such a device, we present, discuss and examine, in the framework of the pre-implant phase, the content of each topic treated by the "four boxes method", that is, an essential tool for the assessment of the proportionality of the treatment for LVAD candidates.

Objective: Since its birth in 1895, radiology has been used to study ancient mummies. The purpose of this article is to present paleoradiological investigations conducted on several medieval human remains in Varese province. Anthropological (generic identification) and paleopathological analyses were carried out with the support of diagnostic imaging (X-ray and CT scans)., Materials and Methods: Human remains were discovered during excavations of medieval archaeological sites in northwest Lombardy. Classical physical anthropological methods were used for the macroscopic identification of the human remains. X-ray and CT scans were performed on the same scanner (16-layer Hitachi Eclos 16 X-ray equipment). Results Radiological analysis permitted investigating (1) the sex, (2) age of death, (3) type of trauma, (4) therapeutic interventions and (5) osteomas in ancient human remains. In particular, X-ray and CT examinations showed dimorphic facial traits on the mummified skull, and the same radiological approaches allowed determining the age at death from a mummified lower limb. CT analyses allow investigating different types of traumatic lesions in skulls and postcranial skeleton portions and reconstructing the gait and functional outcomes of a fractured femur. Moreover, one case of possible Gardner’s syndrome (GS) was postulated from observing multiple osteomas in an ancient skull., Conclusion: Among the medical tests available to the clinician, radiology is the most appropriate first-line procedure for a diagnostic approach to ancient human remains because it can be performed without causing any significant damage to the specimen.

Severe acute respiratory syndrome (SARS) is a systemic disease characterized by both lung pathology and widespread extrapulmonary virus dissemination causing multiple organ injuries. In this regard, renal dysfunction is an ominous sign in patients with SARS. Indeed, clusters of SARS coronavirus (SARS-CoV) particles have been detected in the cytoplasm of renal tubular epithelial cells in postmortem studies, explaining the presence of infectious virus in the urine of SARS patients. In order to investigate the potential SARS-CoV kidney tropism, we have evaluated the susceptibility of human renal cells of tubular and glomerular origin to in vitro SARS-CoV infection. Immortalized cultures of differentiated proximal tubular epithelial cells (PTEC), glomerular mesangial cells (MC), and glomerular epithelial cells (podocytes) were found to express the SARS-CoV receptor angiotensin-converting enzyme 2 on their surface. Productive infection, however, occurred only in PTEC but not in glomerular cells. A transient infection with poor virus production was observed in MC, whereas podocytes were not permissive to SARS-CoV infection. In contrast to the cytopathic infection of the Vero E6 cell line, SARS-CoV did not cause overt cytopathic effects in PTEC or MC. Of interest, PTEC, but not MC, maintained stable levels of SARS-CoV production in serial subcultures, suggesting a persistent state of infection. In this regard, a SARS-CoV variant with increased replication capacity in PTEC was selected after four serial subculture passages. This SARS-CoV variant acquired a single nonconservative amino acid change from glutamic acid (E) to alanine (A) at position 11 in the viral membrane (M) protein. The E11A point mutation was sufficient for enhanced SARS-CoV replication and persistence in PTEC when introduced in a SARS-CoV recombinant infectious clone. These findings indicate that human PTEC may represent a site of SARS-CoV productive and persistent replication favoring the emergence of viral variants with increased replication capacity, at least in these kidney cells.

Enteroviruses, such as the coxsackievirus (CV) group, have been linked to the induction of inflammatory and autoimmune diseases. Virus tropism and tissue access are modulated by endothelial cells. To examine the susceptibility of microvascular endothelial cells (MECs) derived from pancreatic islets to infection with CV group B (CVB), purified cultured human islet MECs were infected with CVB-4 strain, and the immunological phenotype of the infected cells was analyzed. CVB-4 persistently infected the islet MECs, which expressed the CV receptors human coxsackievirus and adenovirus receptor (HCAR) and decay accelerating factor (DAF) and maintained EC characteristics, without overt cytopathic effects. CVB-4 infection transiently up-regulated expression of the adhesion molecules ICAM-1 and VCAM-1 and increased production of the proinflammatory cytokines IL-1beta and IL-6, and chemokines IL-8 and lymphotactin, as well as IFN-alpha. Mononuclear cell adhesion to CVB infected monolayers was increased, compared to uninfected monolayers. Moreover, infection up-regulated the viral receptors HCAR and DAF and coreceptor alpha(v)beta3 integrin on islet MECs, while down-regulating expression of HCAR on human aortic endothelial cells, indicating potential tissue-specific influence on the pathological outcome of infection. These results provide evidence that islet MECs are natural targets and reservoirs for persistent CVB infection resulting in acute endothelial cell activation by virus, which may contribute to selective recruitment of subsets of leukocytes during inflammatory immune responses, such as insulitis in type 1 diabetes.