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Hyponatremia is the most common electrolyte abnormality observed in clinical practice and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is diagnosed in nearly 40% of the hospitalized hyponatremic patients. We present a case report of herpes zoster infection causing a severe hyponatremia/hypokalemia. This rare association between SIADH and varicella-zoster virus infection is described in only few case in the literature. In our case report, the associated hypokalemia was not related to the use of diuretics but, probably, dependent on the frank serum hyposmolality able to induce an aldosterone release. [ABSTRACT FROM AUTHOR]

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is considered the prevalent cause of hyponatremia in hospitalized patients. Neuroleptic malign syndrome (NMS) is an idiosyncratic drug reaction showing fever, dysautonomia and rigidity with increased levels of Creatinine-phosphokinase (CPK) dependent on leakage of muscle contents into the circulation and defined as rhabdomyolysis. Although different diagnostic criteria for NMS have been established, it should be recognized that atypical presentations occur, particularly during treatment with atypical antipsychotics. We here present a case report of a psychiatric patient affected by a SIADH complicated with NMS/rhabdomyolysis, induced by second-generation (atypical) antipsychotic drugs in combination with carbamazepine and promazine. [ABSTRACT FROM AUTHOR]

Background: Patient and public involvement and engagement (PPIE) is integral to health research. Reporting of PPIE methods and impact is becoming increasingly common in health research. However, reporting on PPIE in studies using large, routinely collected electronic health record data sets is less common. Anecdotal evidence suggests that involvement in this research context is more challenging and offers fewer opportunities for meaningful influence on the research process., Objectives: This paper reports the involvement approach for a Clinical Practice Research Datalink (CPRD) study and critically reflects on the process and impact of involving young people, parents and carers in research using this UK primary care electronic health record data set., Methods: The CHOOSE study investigated mental health diagnoses of children and young people (1-24 years) during the COVID-19 pandemic using the CPRD. The study was informed by a Lived Experience Advisory Panel (LEAP) which consisted of 13 members including 8 young people (13-25 years) with lived experience of mental health difficulties and 5 parents/carers, with involvement activities facilitated by project partners, mental health research charity, The McPin R Foundation. We reflect on this process in this manuscript., Results: Key benefits of involving people with lived experience in this research included making sense of and contextualising findings and ensuring that they were focused on making a difference to young people's lives. Challenges included the fixed nature of the CPRD data, which did not capture all the information people with lived experience perceived to be important. Researchers expressed limited time for PPIE activities although that was compensated by McPin colleagues who organised and facilitated online meetings, and supported the young people, parents and carers during and between meetings., Conclusions: This paper describes an approach to patient and public involvement in an electronic health record database study. Working collaboratively with young people, carers and other stakeholders requires sufficient time and adequate resources. We also highlight the importance of appropriate training and support and being transparent about the limitations of PPIE involvement., Patient or Public Contribution: Three members of the CHOOSE LEAP have been involved in conceptualising and writing this paper., (© 2024 The Author(s). Health Expectations published by John Wiley & Sons Ltd.)

Introduction: We report the case of a 76-year-old male who was hospitalized with severe dehydration, pain in the hepatic region, and weakness in the limbs., Methodology: A contrast-enhanced abdomen CT and a contrast-enhanced ultrasound identified a large liver abscess. The patient underwent percutaneous drainage of the abscess., Results: The culture examination, analyzed by multiplex polymerase chain reaction test, showed the presence of Klebsiella oxytoca. The laboratory report identified a resistance mechanism involving a plasmid-mediated SHV-1 extended-spectrum-beta-lactamase (ESBL)., Conclusions: K. oxytoca is a Gram-negative bacterium and is potentially associated with a large variety of infections. The association between the liver abscess by K. oxytoca and rhabdomyolysis had not yet been described in the literature., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Valentina Apuzzi, Marta Sodano, Rita Irace, Daniela Caterina Amoruso, Antonio Cozzolino, Alberto Enrico Maraolo, Vincenzo Bassi.)

Celiac Disease (CD) is a T-cell mediated disorder caused by immune response to gluten, although the mechanisms underlying CD progression are still elusive. We analyzed immune cell composition, plasma cytokines, and gliadin-specific T-cell responses in patients with positive serology and normal intestinal mucosa (potential-CD) or villous atrophy (acute-CD), and after gluten-free diet (GFD). We found: an inflammatory signature and the presence of circulating gliadin-specific IFN-γ + T cells in CD patients regardless of mucosal damage; an increased frequency of IL-10-secreting dendritic cells (DC-10) in the gut and of circulating gliadin-specific IL-10-secreting T cells in potential-CD; IL-10 inhibition increased IFN-γ secretion by gliadin-specific intestinal T cells from acute- and potential-CD. On GFD, inflammatory cytokines normalized, while IL-10-producing T cells accumulated in the gut. We show that IL-10-producing cells are fundamental in controlling pathological T-cell responses to gluten: DC-10 protect the intestinal mucosa from damage and represent a marker of potential-CD., (Copyright © 2023. Published by Elsevier Inc.)

Based on a growing body of evidence that a dysregulated innate immune response mediated by monocytes/macrophages plays a key role in the pathogenesis of COVID-19, a clinical trial was conducted to investigate the therapeutic potential and safety of oral macrophage activating factor (MAF) plus standard of care (SoC) in the treatment of hospitalized patients with COVID-19 pneumonia. Ninety-seven hospitalized patients with confirmed COVID-19 pneumonia were treated with oral MAF and a vitamin D3 supplement, in combination with SoC, in a single-arm, open label, multicentre, phase II clinical trial. The primary outcome measure was a reduction in an intensive care unit transfer rate below 13% after MAF administration. At the end of the study, an additional propensity score matching (PSM) analysis was performed to compare the MAF group with a control group treated with SoC alone. Out of 97 patients treated with MAF, none needed care in the ICU and/or intubation with mechanical ventilation or died during hospitalization. Oxygen therapy was discontinued after a median of nine days of MAF treatment. The median length of viral shedding and hospital stay was 14 days and 18 days, respectively. After PSM, statistically significant differences were found in all of the in-hospital outcomes between the two groups. No mild to serious adverse events were recorded during the study. Notwithstanding the limitations of a single-arm study, which prevented definitive conclusions, a 21-day course of MAF treatment plus SoC was found to be safe and promising in the treatment of hospitalized adult patients with COVID-19 pneumonia. Further research will be needed to confirm these preliminary findings., Competing Interests: Declaration of Competing Interest On the behalf of all the authors in paper, I, Dr Lucrezia Spadera, the Submitting Author hereby declares that All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declares: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Tolerogenic dendritic cells play a critical role in promoting antigen-specific tolerance via dampening of T cell responses, induction of pathogenic T cell exhaustion and antigen-specific regulatory T cells. Here we efficiently generate tolerogenic dendritic cells by genetic engineering of monocytes with lentiviral vectors co-encoding for immunodominant antigen-derived peptides and IL-10. These transduced dendritic cells (designated DC IL-10/Ag ) secrete IL-10 and efficiently downregulate antigen-specific CD4 + and CD8 + T cell responses from healthy subjects and celiac disease patients in vitro. In addition, DC IL-10/Ag induce antigen-specific CD49b + LAG-3 + T cells, which display the T regulatory type 1 (Tr1) cell gene signature. Administration of DC IL-10/Ag resulted in the induction of antigen-specific Tr1 cells in chimeric transplanted mice and the prevention of type 1 diabetes in pre-clinical disease models. Subsequent transfer of these antigen-specific T cells completely prevented type 1 diabetes development. Collectively these data indicate that DC IL-10/Ag represent a platform to induce stable antigen-specific tolerance to control T-cell mediated diseases., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aim of the Work: Cardiovascular diseases represent the main cause of death in Italy. Early recognition of pathological electrocardiographic (ECG) trace is an important skill for nurses. The theoretical knowledge and the practical skills on the recognition of pathological ECG trace of trained nursing students were compared with those of emergency nurses., Methods: The study involved 35 nursing students and 41 nurses from the emergency room, emergency medicine and ambulance service. Students were previously trained through a theoretical and practical ECG course. The data were collected using  two questionnaires aimed at evaluating in the two groups the ability to recognize electrocardiographic signs. The tools were uploaded to an online platform and remotely administered., Results: Both the students and the nurses showed a satisfactory theoretical knowledge of the ECG trace, with a statistically significant difference in favor of the nurses. Regarding practical skills, both groups showed difficulty in recognizing pathological electrocardiographic signs, particularly blockages and acute coronary syndromes., Conclusions: Nursing students' knowledge of ECG did not differ much from that of nurses. Training through simulation probably played a key role in improving the skill of ECG evaluation among students. More theoretical and practical courses on ECG should be recommended in Nursing Programme.

Anemia is frequently associated with older age and comorbidities. Also, anemia is a frequent finding in patients hospitalized for Coronavirus infectious disease 2019 (COVID-19), where it has been associated with poor outcomes. Management of anemia is thus crucial in this setting. We present the case of an elderly woman with chronic iron deficiency anemia and multiple comorbidities, hospitalized for COVID-19, whose iron deficiency was successfully treated with ferric carboxymaltose. Hemoglobin and iron stores were replenished, and transferrin saturation increased to average values. Ferric carboxymaltose was well tolerated, and there were no safety concerns. The patient recovered from COVID-19 was discharged 25 days after admission., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Bassi et al.)

Dendritic cells (DCs) dictate the outcomes of tissue-specific immune responses. In the context of autoimmune diseases, DCs instruct T cells to respond to antigens (Ags), including self-Ags, leading to organ damage, or to becoming regulatory T cells (Tregs) promoting and perpetuating immune tolerance. DCs can acquire tolerogenic properties in vitro and in vivo in response to several stimuli, a feature that opens the possibility to generate or to target DCs to restore tolerance in autoimmune settings. We present an overview of the different subsets of human DCs and of the regulatory mechanisms associated with tolerogenic (tol)DC functions. We review the role of DCs in the induction of tissue-specific autoimmunity and the current approaches exploiting tolDC-based therapies or targeting DCs in vivo for the treatment of autoimmune diseases. Finally, we discuss limitations and propose future investigations for improving the knowledge on tolDCs for future clinical assessment to revert and prevent autoimmunity. The continuous expansion of tolDC research areas will lead to improving the understanding of the role that DCs play in the development and treatment of autoimmunity.

Aim: Vaginal paraurethral leiomyomas are uncommon benign tumors of the female genitourinary tract. We report a case of anterior vaginal paraurethral leiomyoma. Furthermore, we performed a systematic review of the literature to provide information that can help the physicians in the diagnosis and management of women with this rare pathology., Methods: A case of anterior vaginal paraurethral leiomyoma in 53-year-old, primiparous, caucasian woman with history of pelvic pressure, vaginal bulging and overactive bladder symptoms, was described. Furthermore, a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement was performed between January 1, 2000 to Dec 30, 2019. Only articles that reported cases of vaginal or paraurethral leiomyoma (b) case series and case reports with literature review were included., Results: we screened a total 2281 records; 70 articles published from 2000 to 2019 were included., Conclusion: Vaginal paraurethral leiomyoma is a rare benign tumor of the vagina with a wide spectrum of symptoms and good prognosis. The recurrence and transformation into malignant condition are rare. Histopathological examination is the gold standard for diagnosis, but MRI and US can be help to define the size and localization of the tumor. Management requires surgical vaginal excision in the majority of cases; however, abdominal approach could be considered when it is large and located high in the vagina., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Introduction Thiazide and loop-diuretics are among the most widely used drugs in the therapy of hypertension and chronic heart failure. Furthermore, hyponatremia is the most prevalent electrolyte imbalance affecting up to 25-30% of hospitalized patients while syndrome of inappropriate antidiuresis (SIAD) is involving approximately 35% of hyponatraemic inpatients. Clinical and laboratoristic algorithms support the differential diagnosis of hypotonic hyponatremia in actual guidelines of SIAD, but a potential bias is represented by the misleading clinical assessment of the extracellular volume status in diuretic-treated patients where the necessity of withdrawal of the therapy is mandatory. We investigated the role of fractional uric acid and potassium excretion (FEUA and FEK) in the differential diagnosis of hypotonic hyponatremia in SIAD and diuretic-treated patients. Methods Thirty-six SIAD, 30 thiazide-induced hyponatremia (TIH), and 32 diuretic-induced hyponatremia (DIH) patients were investigated calculating FEUA and FEK values in receiver operating characteristic (ROC) curve analysis to improve the diagnostic approach of hypotonic hyponatremia. Results The combination of the two investigated markers showed different significative results generating patterns useful to discriminate among the three different hyponatremic groups. Conclusion The fractional uric acid and potassium excretion could be considered as new markers in the diagnostic approach of hyponatremic diuretic-treated patients where classical algorithms could fail., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Bassi et al.)

Background: use of fibrin sealants following pelvic, paraaortic, and inguinal lymphadenectomy may reduce lymphatic morbidity. The aim of this meta-analysis is to evaluate if this finding applies to the axillary lymphadenectomy., Methods: randomized trials evaluating the efficacy of fibrin sealants in reducing axillary lymphatic complications were included. Lymphocele, drainage output, surgical-site complications, and hospital stay were considered as outcomes., Results: twenty-three randomized studies, including patients undergoing axillary lymphadenectomy for breast cancer, melanoma, and Hodgkin's disease, were included. Fibrin sealants did not affect axillary lymphocele incidence nor the surgical site complications. Drainage output, days with drainage, and hospital stay were reduced when fibrin sealants were applied ( p < 0.0001, p < 0.005, p = 0.008)., Conclusion: fibrin sealants after axillary dissection reduce the total axillary drainage output, the duration of drainage, and the hospital stay. No effects on the incidence of postoperative lymphocele and surgical site complications rate are found.

The use of CuO nanoparticles (NPs) has increased greatly and their potential effects on human health need to be investigated. Differentiated Caco-2 cells were treated from the apical (Ap) and the basolateral (Bl) compartment with different concentrations (0, 10, 50 and 100 μg/mL) of commercial or sonochemically synthesized (sono) CuO NPs. Sono NPs were prepared in ethanol (CuOe) or in water (CuOw), obtaining CuO NPs differing in size and shape. The effects on the Caco-2 cell barrier were assessed via transepithelial electrical resistance (TEER) evaluation just before and after 1, 2 and 24 hours of exposure and through the analysis of cytokine release and biomarkers of oxidative damage to proteins after 24 hours. Sono CuOe and CuOw NPs induced a TEER decrease with a dose-dependent pattern after Bl exposure. Conversely, TEER values were not affected by the Ap exposure to commercial CuO NPs and, concerning the Bl exposure, only the lowest concentration tested (10 μg/mL) caused a TEER decrease after 24 hours of exposure. An increased release of interleukin-8 was induced by sono CuO NPs after the Ap exposure to 100 μg/mL and by sono and commercial CuO after the Bl exposure to all the concentrations. No effects of commercial and sono CuO NPs on interleukin-6 (with the only exception of 100 μg/mL Bl commercial CuO) and tumor necrosis factor-α release were observed. Ap treatment with commercial and CuOw NPs was able to induce significant alterations on specific biomarkers of protein oxidative damage (protein sulfhydryl group oxidation and protein carbonylation)., (© 2020 John Wiley & Sons, Ltd.)

Objectives: Our goal was to assess the postoperative 90-day hospital costs of patients with prolonged air leak (PAL) including costs incurred after discharge from the initial index hospitalization., Methods: We performed a retrospective analysis of 982 patients undergoing lobectomy (898) or segmentectomy (78) (April 2014-August 2018). A total of 167 operations were open, 780 were video-assisted thoracoscopic surgery and 28 were robotic. A PAL was defined as an air leak >5 days. The 90-day postoperative costs included all fixed and variable costs incurred during the 90 days following surgery. The postoperative costs of patients with and without PAL were compared. The independent association of PAL with postoperative 90-day costs was tested after adjustment for patient-related factors and other complications by a multivariable regression analysis., Results: PAL occurred in 261 patients (27%). Their postoperative stay was 4 days longer than that of those without PAL (9.6 vs 5.7; P < 0.0001). Compared to patients without PAL, those with PAL had 27% higher index postoperative costs [7354€, standard deviation (SD) 7646 vs 5759€, SD 7183, P < 0.0001] and 40% higher 90-day postoperative costs (18 340€, SD 23 312 vs 13 102€, SD 10 264; P < 0.0001). The relative postoperative costs (the difference between 90-day and index postoperative costs) were 50% higher in PAL patients compared to non-PAL patients (P < 0.0001) and accounted for 60% of the total 90-day costs. Multivariable regression analysis showed that PAL remained an independent factor associated with 90-day costs (P < 0.0001) along with the occurrence of other cardiopulmonary complications (P < 0.0001), male gender (P = 0.018), low carbon monoxide lung diffusion capacity (P = 0.043) and thoracotomy approach (P = 0.022)., Conclusions: PAL is associated not only with increased index hospitalization costs but also with increased costs after discharge. Evaluation of the cost-effectiveness of measures to prevent air leaks should also include post-discharge costs., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

A 24-year-old obese Caucasian male, without relevant anamnesis, who was admitted to the ER presented with abdominal pain, nausea and vomiting, hyperglycemia, and diabetic ketoacidosis (DKA). The diagnosis of acute pancreatitis (AP) was supported by increased serum levels of triglycerides and lipase associated with abdominal CT scans. The patient was treated for five days with IV regular insulin, hydration, electrolytes replacement, and statin/fibrate therapy with clinical improvement. Some 10% hemoglobin A1c value, normal C-peptide level and negative glutamic acid decarboxylase (GAD-65), and islet cell autoantibodies suggested the diagnosis of a new-onset type 2 diabetes mellitus (DM) presenting with an uncommon triad of DKA and hypertriglyceridemia (HTG)-induced AP. Anamnestic history suggested that DKA was dependent on sugar-sweetened soft drinks abuse (soft drink ketosis), a clinical association more frequent in Asian than in Western patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Vitelli et al.)

Hyponatraemia is the most common electrolyte imbalance found in hospital population and worldwide thiazide and loop-diuretics are among the most widely used drugs. Syndrome of inappropriate antidiuresis diagnosis (SIAD) is complicated in the presence of diuretic therapy due to the misleading clinical assessment of the extracellular volume status, and in order to make SIAD diagnosis it is often necessary to withdraw diuretic therapy. Our study aimed to investigate the diagnostic role of these alternative markers of volume status, serum uric acid (sUA) and fractional excretion of uric acid (FEUA), in hyponatraemic patients treated with different diuretic drugs. Eighty-nine patients were enrolled with the diagnosis of SIAD, diuretic-induced hyponatremia (DIH, treated with furosemide and potassium canrenoate) or thiazide-induced hyponatremia (TIH, treated with hydrochlorothiazide, metolazone or indapamide) and investigated with receiver operating characteristic analysis and a sensitivity test. Our results show that FEUA discriminated better than sUA between SIAD and DIH patients (area under curve 0.96, <0.001 vs. 0.88, <0.001) while it was a poor marker to discriminate between SIAD and TIH (0.65, NS vs. 0.67, NS). In conclusions, FEUA is an excellent marker to discriminate SIAD vs. sodium depleted patients treated with furosemide and/or potassium canrenoate while the diuretic withdrawal, beyond obtaining a serum Na normalization, is still mandatory for differential diagnosis of sodium depleted patients affected by thiazide-induced hyponatraemia., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Bassi et al.)

Sardinia (Italy), with its wide range of habitats and high degree of endemism, is an important area for plant-based drug discovery studies. In this work, the antitumor activity of 35 samples from Sardinian plants was evaluated on human osteosarcoma cells U2OS. The results showed that five plants were strongly antiproliferative: Arbutus unedo (AuL), Cynara cardunculus (CyaA), Centaurea calcitrapa (CcA), Smilax aspera (SaA), and Tanacetum audibertii (TaA), the latter endemic to Sardinia and Corsica. Thus, their ability to induce cell cycle arrest and apoptosis was tested. All extracts determined cell cycle block in G2/M phase. Nevertheless, the p53 expression levels were increased only by TaA. The effector caspases were activated mainly by CycA, TaA, and CcA, while AuL and SaA did not induce apoptosis. The antiproliferative effects were also tested on human umbilical vein endothelial cells (HUVEC). Except for AuL, all the extracts were able to reduce significantly cell population, suggesting a potential antiangiogenic activity. The phytochemical composition was first explored by 1 H NMR profiling, followed by further purifications to confirm the structure of the most abundant metabolites, such as phenolic compounds and sesquiterpene lactones, which might play a role in the measured bioactivity.

Not much is known about disease prevalence, treatment outcomes, trained manpower, programs, and patients' awareness of diseases from South Asia, compared with the Western world. While other aspects are improving, the quantitative evaluation of awareness of diseases is lagging. Compared with other diseases, the situation for mental health disorders and addiction is worse. While no single study can fully quantify all aspects of awareness, a good starting point is to understand if increasing the number of mental health facilities is beneficial by understanding people's perception toward the likelihood of contracting various diseases, their preferred approach to treatment, and their perception of whether there are enough current facilities. We surveyed over 8000 families across several states of India and asked if they would treat a particular problem at home, visit a local healer, seek religious council, or go to a modern hospital for treatment. Our questions also included non-medical options to assess how likely people are to avoid trained medical help. We also asked people about their perceived likelihood of a family member ever suffering from (1) diarrhea, (2) high fever, (3) alcoholism, and (4) schizophrenia and other mental health problems. We reversed the order of diseases in our questions for a fraction of the population to evaluate the effect of order of questioning. Finally, we asked, if people feel they have enough local healers, religious places, general hospitals, de-addiction centers, and mental health facilities. Despite the taboo around mental health, many people claimed that their family members were unlikely to contract mental health or addiction problems, people recognized the severe paucity of mental health facilities and de-addiction centers. This raises hope for improving the mental health situation in India. We also found a significant relation between education levels and choices people make, underscoring the positive role education has in improving mental health., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: The study aimed to assess the total cost (TC) and relative cost (RC) of 90-day postoperative care at the hospital after anatomic lung resection., Methods: Six hundred and forty lung resections (April 2014-September 2016) were performed at a single centre (547 lobectomies, 55 pneumonectomies and 38 segmentectomies). TC was calculated up to 90 days from the date of surgery and included the postoperative cost of the index hospitalization and the costs of hospital or emergency department readmissions, clinic appointments, medications and radiology post-discharge up to 90 days from the operation. RC was calculated as the difference between the TC and the postoperative cost of the index hospitalization. Bivariate comparisons were performed by using the Mann-Whitney test. Multivariable regression analysis was used to identify the factors associated with TC., Results: Median TC was €12 389.5 [interquartile range (IQR) 8455-23 043] for pneumonectomy, €9192.1 (IQR 6897-17 274) for open lobectomy, €7932.5 (IQR 5806-12 697) for video-assisted thoracoscopic surgery (VATS) lobectomy and €6609.9 (IQR 5215-13 907) for VATS segmentectomy. Median RCs were €4461.4 (IQR 1240-11 828) for pneumonectomy, €3326.8 (IQR 1626-8271) for open lobectomy, €2729.3 (IQR 1348-6312) for VATS lobectomy and €2771.5 (IQR 1229-9705) for segmentectomy. RC accounted for 36% of the TC for pneumonectomy, 36% for open lobectomy, 34% for VATS lobectomy and 42% for segmentectomy. Generalized linear models showed that age (P = 0.024), carbon monoxide lung diffusion capacity (P = 0.030) and body mass index (P = 0.015) were inversely associated with TC, whereas male gender (P = 0.054) was associated with increased cost., Conclusions: Cost-saving measures should be implemented to target not just the in-hospital but also the post-discharge period, particularly in patients with risk factors associated with increased cost., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: The objective of this study was to verify whether the European Society of Thoracic Surgeons prolonged air leak risk score for video-assisted thoracoscopic lobectomy was associated with incremental postoperative costs., Methods: We retrospectively analyzed 353 patients subjected to video-assisted thoracoscopic lobectomy or segmentectomy (April 2014 to March 2016). Postoperative costs were obtained from the hospital Finance Department. Patients were grouped in different classes of risk according to their prolonged air leak risk score. To verify the independent association of the prolonged air leak risk score with postoperative costs, we performed a stepwise multivariable regression analysis in which the dependent variable was postoperative cost., Results: Prolonged air leak developed in 56 patients (15.9%). Their length of stay was 3 days longer compared with those without prolonged air leak (8.3 vs 5.4, P < .0001). Their postoperative cost was higher than that of patients without prolonged air leak: $5939.8 versus $4381.7 (P = .001). After grouping the patients according to their prolonged air leak risk score, prolonged air leak incidence was 12.3% in class A, 13.7% in class B, 28.8% in class C, and 22.2% in class D (P = .020). The average postoperative cost was $4031.0 in class A, $4498.2 in class B, $6146.6 in class C, and $6809.3 in class D (analysis of variance test, P < .001). Multivariable regression analysis showed that being in classes C and D of PAL score (P = .001) and the presence of cardiopulmonary complications (P < .0001) were the only independent factors significantly associated with postoperative costs., Conclusions: We financially validated the European Society of Thoracic Surgeons prolonged air leak risk score for video-assisted thoracoscopic lobectomies, which appears useful in selecting those patients in whom the application of additional intraoperative interventions to avoid prolonged air leak may be more cost-effective., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

It has been hypothesized that gluten-dependent production of anti-tissue-transglutaminase 2 (anti-TG2) antibodies may occur only at an intestinal level. We have investigated intestinal production of anti-TG2 antibodies in 136 patients with normal serum levels of anti-TG2 antibodies and normal duodenal mucosa. Intestinal deposits of anti-TG2 antibodies were evaluated by immunofluorescence and anti-TG2 antibodies released in organ culture supernatants measured by ELISA. Intestinal antibody libraries were obtained from 10 subjects. Immunohistochemistry for CD25⁺, CD3⁺, and TCR-γδ⁺ was assessed in subjects with positive ( n = 32) and negative ( n = 31) intestinal anti-TG2 antibodies. Globally 33/136 (24%) seronegative patients produced anti-TG2 autoantibodies at an intestinal level. Antibody libraries analysis confirmed the anti-TG2 antibodies mucosal production in all ( n = 8) positive subjects. Lamina propria CD25⁺ cell count was significantly ( p < 0.05) higher in patients with intestinal anti-TG2. Moreover, 13/32 (41%) of them showed high TCR-γδ⁺/CD3⁺ ratios. Intestinal anti-TG2 antibody production does not show absolute specificity for CD. It is seen more often in association with inflamed mucosa. Further investigations are necessary to prove the possible role of dietary gluten.

In the recent years, the incidence of inflammatory bowel disease (IBD) has dramatically increased in young subjects, however, the pathogenesis of paediatric IBD is poorly investigated. In this study we aimed to evaluate the cytokine pattern and the phenotype of cytokine producing cells in the intestinal mucosa of paediatric patients affected by Crohn's disease (CD) or ulcerative colitis (UC) and of non-IBD healthy controls (HC). Cytokine (IL-15, TNF-α, INF-γ) production was analyzed at basal condition and after mitogen stimulation either intracellularly by flow cytometry or in intestinal cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). A higher frequency of enterocytes (EpCam+ cells) was observed in UC patients compared to CD or HC. An expansion of enterocytes producing IL-15 and TNF-α were found in IBD patients compared to HC. A marked expression of IL-15 in the intestinal epithelium of IBD patients was further confirmed by immunohistochemistry. Myeloid dendritic (CD11c+) cells producing TNF-α and INF-γ were increased in IBD biopsies. Unexpectedly, only after a strong mitogen stimulus, as phytohaemagglutinin, the frequency of CD3+ cells producing IFN-γ was increased in IBD compared to control intestinal mucosa. Interestingly, functional studies performed on organ cultures of intestinal biopsies with neutralizing anti-IL-15 monoclonal antibody showed a marked reduction of mononuclear cell activation, proliferation of crypt enterocytes, as well as a reduction of TNF-α release in organ culture supernatants. In conclusion, we found that in the gut mucosa of IBD children both enterocytes and dendritic cells produce proinflammatory cytokines. The over-expression of IL-15 by enterocytes in IBD intestine and the reduced IBD inflammation by IL-15 blockage suggests that this cytokine could be a therapeutic target in IBD.

Background: The objective of this study was to verify the association between the thoracic mortality and morbidity (TMM) classification system and hospital costs after lung resection., Methods: Consecutive patients (n = 503) submitted to anatomic lung resections were analyzed (April 1, 2014, to March 31, 2016). TMM system was used to grade the severity of complications. Postoperative costs were retrieved from the financial department using an electronic patient-level information system., Results: Two hundred seventy-two patients (54%) did not experience any complication. The distribution of postoperative complications in the remaining patients according to the TMM classification system was as follows: 57 (25%) grade I, 108 (47%) grade II, 29 (12%) grade III, 17 (7%) grade IV, and 20 (9%) grade V. The average postoperative cost of the uncomplicated patients was $3,560 (95% confidence interval [CI]: $3,440 to $3,680). The average postoperative costs of the patients with complications increased along with the grade of the TMM system; it was $4,548 (95% CI: $4,134 to $4,962) for grade I, $4,909 (95% CI: $4,537 to $5,281) for grade II, $6,392 (95% CI: $5,303 to $7,483) for grade III, and $14,547 (95% CI: $6,334 to $22,760) for grade IV. The average postoperative cost for the patients who eventually died was $17,695 (95% CI: $11,246 to $24,144). Linear regression analysis showed that a prolonged length of hospital stay (p < 0.0001) and an unplanned admission to the intensive care unit (p < 0.0001) were significantly associated with postoperative costs in patients with major complications., Conclusions: The severity of complications graded by the TMM system was associated with increasing postoperative costs. This instrument may be used to adjust lung resection reimbursement tariffs., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: To detect factors associated with costs of anatomic lung resection without major complications., Methods: Two hundred and fifty consecutive patients submitted to anatomic lung resection (185 by VATS) in 1 fiscal year (1 April 2014–31 March 2015) were included. Thoracic Morbidity and Mortality (TMM) system was used to grade the severity of complications. Two hundred and ten patients who did not develop major complications (TMM < 3) were analysed. Postoperative costs were retrieved from the Financial Department through a Patient Level Information and Costing System. Multivariable regression and bootstrap analyses were used to test the association of several baseline patient characteristics with costs and obtain an aggregate scoring system to estimate postoperative costs., Results: Among the 210 patients, 117 (56%) did not develop any complication and 93 (44%) had minor complications. Their average postoperative cost was 4040€, significantly lower than the one observed in patients with major complications (13 156€, P < 0.0001). Multivariable regression revealed that open thoracotomy (P = 0.01), carbon monoxide lung diffusion capacity (DLCO) < 60% (P = 0.001) and coronary artery disease (CAD) (P = 0.009) were associated with postoperative costs. Open thoracotomy would increase the cost by 648€, DLCO < 60% by 935€ and CAD by 1043€. If all three factors were present, they would cause an increase of postoperative costs from 3592€ to 6219€., Conclusion: We were able to identify clinical factors associated with postoperative costs in patients without major complications. Recognizing groups of increased cost may lead to specific process analyses aimed at optimising their pathways of care and ultimately saving money. Moreover, these findings may help administrators to tailor future individualized lung resection reimbursement tariffs based on patient characteristics., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Everolimus, an oral mTOR (mammalian target of rapamycin) inhibitor, is currently approved for the treatment of progressive pancreatic neuroendocrine tumors (NETs). Although promising, only scattered data, often from nondedicated studies, are available for extrapancreatic NETs., Patients and Methods: A systematic review of the published data was performed concerning the use of everolimus in extrapancreatic NET, with the aim of summarizing the current knowledge on its efficacy and tolerability. Moreover, the usefulness of everolimus was evaluated according to the different sites of the primary., Results: The present study included 22 different publications, including 874 patients and 456 extrapancreatic NETs treated with everolimus. Nine different primary sites of extrapancreatic NETs were found. The median progression-free survival ranged from 12.0 to 29.9 months. The median time to progression was not reached in a phase II prospective study, and the interval to progression ranged from 12 to 36 months in 5 clinical cases. Objective responses were observed in 7 prospective studies, 2 retrospective studies, and 2 case reports. Stabilization of the disease was obtained in a high rate of patients, ranging from 67.4% to 100%. The toxicity of everolimus in extrapancreatic NETs is consistent with the known safety profile of the drug. Most adverse events were either grade 1 or 2 and easy manageable with a dose reduction or temporary interruption and only rarely requiring discontinuation., Conclusion: Treatment with everolimus in patients with extrapancreatic NETs appears to be a promising strategy that is safe and well tolerated. The use of this emerging opportunity needs to be validated with clinical trials specifically designed on this topic., Implications for Practice: The present study reviewed all the available published data concerning the use of everolimus in 456 extrapancreatic neuroendocrine tumors (NETs) and summarized the current knowledge on the efficacy and safety of this drug, not yet approved except for pancreatic NETs. The progression-free survival rates and some objective responses seem promising and support the extension of the use of this drug. The site-by-site analysis seems to suggest that some subtypes of NETs, such as colorectal, could be more sensitive to everolimus than other primary NETs. No severe adverse events were usually reported and discontinuation was rarely required; thus, everolimus should be considered a valid therapeutic option for extrapancreatic NETs., (©AlphaMed Press.)

HLA genes represent the main risk factor in autoimmune disorders. In celiac disease (CD), the great majority of patients carry the HLA DQA1*05 and DQB1*02 alleles, both of which encode the DQ2.5 molecule. The formation of complexes between DQ2.5 and gluten peptides on antigen-presenting cells (APCs) is necessary to activate pathogenic CD4(+) T lymphocytes. It is widely accepted that the DQ2.5 genes establish the different intensities of anti-gluten immunity, depending whether they are in a homozygous or a heterozygous configuration. Here, we demonstrated that HLA DQA1*05 and DQB1*02 gene expression is much higher than expression of non-CD-associated genes. This influences the protein levels and causes a comparable cell surface exposure of DQ2.5 heterodimers between DQ2.5 homozygous and heterozygous celiac patients. As a consequence, the magnitude of the anti-gluten CD4(+) T cell response is strictly dependent on the antigen dose and not on the DQ2.5 gene configuration of APCs. Furthermore, our findings support the concept that the expression of DQ2.5 genes is an important risk factor in celiac disease. The preferential expression of DQ2.5 alleles provides a new functional explanation of why these genes are so frequently associated with celiac disease and with other autoimmune disorders., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aim: To investigate the correlation between autoimmune thyroid diseases (ATDs) and the prevalence of Cag-A positive strains of Helicobacter pylori (H. pylori) in stool samples., Methods: Authors investigated 112 consecutive Caucasian patients (48 females and 4 males with Graves' disease and 54 females and 6 males with Hashimoto's thyroiditis HT), at their first diagnosis of ATDs. Authors tested for H. pylori in stool samples using an amplified enzyme immunoassay and Cag-A in serum samples using an enzyme-linked immunoassay method (ELISA). The results were analyzed using the two-sided Fisher's exact test and the respective odds ratio (OR) was calculated., Results: A marked correlation was found between the presence of H. pylori (P ≤ 0.0001, OR 6.3) and, in particular, Cag-A positive strains (P ≤ 0.005, OR 5.3) in Graves' disease, but not in Hashimoto's thyroiditis, where authors found only a correlation with Cag-A strains (P ≤ 0.005, OR 8.73) but not when H. pylori was present., Conclusion: The marked correlation between H. pylori and Cag-A, found in ATDs, could be dependent on the different expression of adhesion molecules in the gastric mucosa.

Background: Viral and bacterial antigens have been suspected to be able to mimic the antigenic profile of the thyroid cell membrane and to play an important role in the onset of the autoimmune diseases, such as Graves' disease and Hashimoto thyroiditis. The Helicobacter pylori infection is worldwide diffused and is present in the developed countries up to 50% of the population. The presence of the cytotoxin-associated gene A antigens identifies the most virulent strains of the bacterium. Previous studies have demonstrated the possible correlation between the Helicobacter pylori and Hashimoto's thyroiditis but these results are controversial., Aims: We studied the prevalence rate of this bacterium in the Graves' disease and two selected subgroups such as the hyperthyroid patients, at the first time of diagnosis, and the euthyroid methimazole-treated patients., Materials and Methods: We analyzed Helicobacter pylori in fresh stool samples with an enzyme immunoassay method and the presence of cytotoxin-associated gene A antigens with a serological test., Results: Our results show that a significative increased rate of prevalence is present in Graves' patients, when the disease is ongoing, with an overall prevalence of the strains expressing the cytotoxin-associated gene A antigens compared to the control group., Conclusions: The association between the Helicobacter pylori and Graves' disease suggests a possible role of this bacterium in the onset and/or the maintenance of the disease., (© 2010 Blackwell Publishing Ltd.)

The expression of the beta 1 family of integrins was studied in normal thyroid tissue cultures and monolayer cell cultures. The expression of the various subunits was measured by flow cytofluorometry with specific monoclonal antibodies and by Northern analysis. In monolayer cell cultures but not in tissue cultures, the expression of the alpha 3 subunit on the cell membrane progressively increased soon after plating, reaching a 30-fold higher intensity. The alpha 2 subunit, not detectable in native follicular cells, was expressed de novo and reached a remarkable high level. Up-regulation of alpha 2 and alpha 3 in monolayer cell cultures was serum-independent and preceded the expression of proliferating cell nuclear antigen, [3H]thymidine incorporation, and cell replication. Northern analysis demonstrated an increased level of beta 1 integrin mRNA. The increase of alpha 2 and alpha 3 was readily reversible since the expression of these molecules returned to a lower level when cultures reached a high cell density. Down-regulation did not occur until cell cultures were confluent. When cells from high cell density and low integrin expression were harvested and sparsely seeded in culture, up-regulation of integrins was observed again, while rapid reaggregation of isolated cells inhibited this phenomenon. Altogether these data suggest that cell-to-cell contact may regulate the expression of beta 1 integrins in thyroid primary cultures.

The expression of intercellular adhesion molecule-1 (ICAM-1) in tumoral tissues may promote their interaction with the immune system and cytotoxic effect on tumoral cells. This observation led to the investigation of ICAM-1 expression and modulation in different tumoral cell systems in vitro. Recently, retinoic acid-responsive elements have been found in the 5'-regulatory region of the human ICAM-1 gene. In the present study, we investigated, by flow cytometry, the effect of retinoic acid on the surface expression of ICAM-1 in human thyroid carcinoma cell lines. Two papillary (NPA and TPC-1), one follicular (WRO), one anaplastic (ARO) and one immortalized fetal (TAD-2) cell line have been studied. All of them produced constitutively ICAM-1; its surface expression and specific messenger ribonucleic acid (mRNA) levels were increased significantly by retinoic acid in all except the WRO cell line. ICAM-1 hyperexpression by retinoic acid was time dependent, reversible, and dependent on mRNA and protein synthesis. Furthermore, cytokines, such as interferon-gamma and tumor necrosis factor-alpha, both individually and, to a greater extent, in combination with retinoic acid, increased ICAM-1 surface expression and its mRNA levels. In conclusion, retinoic acid is able to induce ICAM-1 up-regulation via mRNA accumulation in human thyroid carcinoma cell lines.

The expression and cell-membrane distribution of the beta 1 family of integrins (very-late-activation antigens, VLA) were investigated in benign and malignant human thyroid tumors. We compared tissue samples of normal glands, nodular goiters, adenomas and carcinomas. We also examined 3 thyroid-carcinoma cell lines cultured in vitro. The expression of subunits of the beta 1 family of integrins was assessed by flow cytometry and specific antibodies in dispersed single-cell suspensions and by immunofluorescence on frozen tissue sections. In contrast to the heterogeneity of the expression of beta 1 integrins observed in other tumors, thyroid neoplastic lesions showed a remarkably constant VLA profile. In all tumors, benign as well as malignant, and in carcinoma cell lines, all sub-units of beta 1 integrins were expressed at high levels. While sub-units alpha 1, alpha 3, alpha 5, alpha 6 and occasionally alpha 2 were also present in a cell sub-set of normal glands and nodular goiters, expression of alpha 4 was restricted to neoplastic lesions; this integrin can be therefore considered an antigen associated with thyroid tumors. It has been reported that in normal glands and in nodular goiters, the expression of beta 1 integrins is restricted to the basal-cell membrane. Immunofluorescence on tissue sections showed instead that, in adenomas and carcinomas, the polarized distribution of these integrins on the cell membrane is lost.

To assess the expression of the very late antigens family of the integrin superfamily in normal and diseased thyroid glands, tissue specimens were digested to a single cell suspension and analyzed by flow cytometry with antibodies against the common beta 1 chain and the six alpha chains known to be associated to beta 1. In multinodular goiters, two cell populations were recognized. The thyroglobulin containing follicular cell population, represented the majority of cells; a minor population was composed of leukocytes. In normal glands, more than 97% of follicular cells expressed the beta 1 chain, associated with high levels of alpha 3 and very low levels of alpha 1, alpha 5, and alpha 6. The remaining cells (< 3%) expressed the beta 1 chain with a 10-fold higher intensity, associated with relatively high levels of alpha 1, alpha 5, and alpha 6, in addition to alpha 3. This small subset was much more represented in multinodular goiters, where it ranged from 10-60% of the total follicular cell population. Immunofluorescence on tissue sections showed that very late antigens were mostly located on the basal cell membrane and that in multinodular goiters cells expressing the alpha 1, alpha 5, and alpha 6 chains occurred in clusters.