[Therapeutic Plasma Exchange in a Patient with Chronic Hemodialysis and a New Diagnosis of Myasthenia Gravis].

Case ReportC.S.T. (♂, 71 years old) is a patient with multiple and severe comorbidities, undergoing thrice-weekly chronic hemodialysis since 2008 due to the progression of post-lithiasic uropathy. Over the past 2 months, the patient had been experiencing progressive ptosis of the eyelids, muscle weakness, and ultimately dysphagia and dysarthria that emerged in the last few days. Urgently admitted to the Neurology department, electromyography (EMG) was performed, leading to a diagnosis of predominant cranial myasthenia gravis (with borderline anti-acetylcholine receptor antibody serology). Prompt treatment with pyridostigmine and steroids was initiated. Considering the high risk of acute myasthenic decompensation, therapeutic plasma exchange (TPE) with centrifugation technique was promptly undertaken after femoral CVC placement. TPE sessions were alternated with hemodialysis. The patient's condition complicated after the third TPE session, with septic shock caused by Methicillin-Sensitive Staphylococcus Aureus (MSSA). The patient was transferred to the Intensive Care Unit (ICU). Due to hemodynamic instability, continuous veno-venous hemodiafiltration (CVVHDF) with citrate anticoagulation was administered for 72 hours. After resolving the septic condition, intermittent treatment with Acetate-Free Biofiltration (AFB) technique was resumed. The patient completed the remaining three TPE sessions and, once the acute condition was resolved, was transferred back to Neurology. Here, the patient continued the treatment and underwent a rehabilitation program, showing significant motor and functional recovery until discharge. Conclusions. The multidisciplinary interaction among Nephrologists, Neurologists, Anesthesiologists, and experts from the Immunohematology and Transfusion Medicine Service enabled the management and treatment of a rare condition (MG) in a high-risk chronic hemodialysis patient.

[New Mutation of CYP24A1 in a Case of Idiopathic Infantile Hypercalcemia Diagnosed in Adulthood].

Mutations in the 24-hydroxylase gene CYP24A1 have been recognized as causes of childhood idiopathic hypercalcemia (IIH), a rare disease (incidence <1:1,000,000 live births) characterized by increased vitamin D sensitivity, with symptomatic severe hypercalcemia. IIH was first described in Great Britain two years after the start of a program of vitamin D supplementation in milk for the prevention of rickets, manifesting in about 200 children with severe hypercalcemia, dehydration, growth failure, weight loss, muscle hypotonia, and nephrocalcinosis. The association between the epidemic occurrence of IIH and vitamin D administration was quickly attributed to intrinsic hypersensitivity to vitamin D, and the pathogenic mechanism was recognized in the inactivation of Cytochrome P450 family 24 subfamily A member 1 (CYP24A1), which was identified as the molecular basis of the pathology. The phenotypic spectrum of CYP24A1 mutation can be variable, manifesting predominantly with childhood onset and severe symptomatology (severe hypercalcemia, growth retardation, lethargy, muscle hypotonia, dehydration), but also with juvenile-adult onset forms with nephrolithiasis, nephrocalcinosis, and alterations in phosphocalcium homeostasis. We describe the case of a patient in whom the diagnosis of IIH was made in adulthood, presenting with finding of nephrocalcinosis in childhood, and with subsequent onset of severe hypercalcemia with hypercalciuria, hypoparathyroidism, hypervitaminosis D, and recurrent renal lithiasis. Genetic investigation revealed the presence in homozygosity of the c_428_430delAAG_p.Glu143del variant in the CYP24A1 gene with autosomal recessive transmission, a mutation not reported in the literature.

Sustainability assessment of waste and wastewater recovery for edible mushroom production through an integrated nexus. A case study in Lazio.

With a global population of eight billion people, improving the sustainability and nutritional quality of diets has become critical. Mushrooms offer a promising solution because of their nutritional value and ability to be grown from agricultural residues, in line with the circular economy. This study, therefore, focuses on assessing the environmental compatibility of Agaricus bisporus mushroom production in Italy, the world's third largest per capita consumer, by using a Life Cycle Assessment (LCA) and an integrated Water-Energy-Nitrogen-Carbon-Food (WENCF) nexus analysis. The LCA results reveal that for a functional unit of 23,000 kg of the substrate, the production process emits 2.55 × 104 kg of CO2 eq. Sensitivity analysis shows that changing input quantities can reduce environmental impacts by about 5 %. In addition, one scenario evaluates the environmental effects of recycling resources by introducing water and ammonium sulfate from scratch instead of continuous recycling, along with water purification. The study shows that sustainable food production can mitigate resource depletion, climate-altering emissions, and intersectoral competition. Using agro residues for mushroom cultivation and optimizing resource management contribute to environmental sustainability. This approach could not only improve the resilience and efficiency of the food system but could also improve the sustainability of diets. In conclusion, this study highlights the importance of adopting sustainable and circular approaches in mushroom production to address global challenges related to food sustainability.

Effect of COVID-19 pandemic on utilisation of community-based mental health care in North-East of Italy: A psychiatric case register study.

AIMS: WHO declared that mental health care should be considered one essential health service to be maintained during the coronavirus disease 2019 (COVID-19) pandemic. This study aims to describe the effect of lockdown and restrictions due to the COVID-19 pandemic in Italy on mental health services' utilisation, by considering psychiatric diagnoses and type of mental health contacts. METHODS: The study was conducted in the Verona catchment area, located in the Veneto region (northeastern Italy). For each patient, mental health contacts were grouped into: (1) outpatient care, (2) social and supportive interventions, (3) rehabilitation interventions, (4) multi-professional assessments, (5) day care. A 'difference in differences' approach was used: difference in the number of contacts between 2019 and 2020 on the weeks of lockdown and intermediate restrictions was compared with the same difference in weeks of no or reduced restrictions, and such difference was interpreted as the effect of restrictions. Both a global regression on all contacts and separate regressions for each type of service were performed and Incidence Rate Ratios (IRRs) were calculated. RESULTS: In 2020, a significant reduction in the number of patients who had mental health contacts was found, both overall and for most of the patients' characteristics considered (except for people aged 18-24 years for foreign-born population and for those with a diagnosis of schizophrenia. Moreover, in 2020 mental health contacts had a reduction of 57 096 (-33.9%) with respect to 2019; such difference remained significant across the various type of contacts considered, with rehabilitation interventions and day care showing the greatest reduction. Negative Binomial regressions displayed a statistically significant effect of lockdown, but not of intermediate restrictions, in terms of reduction in the number of contacts. The lockdown period was responsible of a 32.7% reduction (IRR 0.673; p-value <0.001) in the overall number of contacts. All type of mental health contacts showed a reduction ascribable to the lockdown, except social and supportive interventions. CONCLUSIONS: Despite the access to community mental health care during the pandemic was overall reduced, the mental health system in the Verona catchment area was able to maintain support for more vulnerable and severely ill patients, by providing continuity of care and day-by-day support through social and supportive interventions.

Classification of first-episode psychosis using cortical thickness: A large multicenter MRI study.

Machine learning classifications of first-episode psychosis (FEP) using neuroimaging have predominantly analyzed brain volumes. Some studies examined cortical thickness, but most of them have used parcellation approaches with data from single sites, which limits claims of generalizability. To address these limitations, we conducted a large-scale, multi-site analysis of cortical thickness comparing parcellations and vertex-wise approaches. By leveraging the multi-site nature of the study, we further investigated how different demographical and site-dependent variables affected predictions. Finally, we assessed relationships between predictions and clinical variables. 428 subjects (147 females, mean age 27.14) with FEP and 448 (230 females, mean age 27.06) healthy controls were enrolled in 8 centers by the ClassiFEP group. All subjects underwent a structural MRI and were clinically assessed. Cortical thickness parcellation (68 areas) and full cortical maps (20,484 vertices) were extracted. Linear Support Vector Machine was used for classification within a repeated nested cross-validation framework. Vertex-wise thickness maps outperformed parcellation-based methods with a balanced accuracy of 66.2% and an Area Under the Curve of 72%. By stratifying our sample for MRI scanner, we increased generalizability across sites. Temporal brain areas resulted as the most influential in the classification. The predictive decision scores significantly correlated with age at onset, duration of treatment, and positive symptoms. In conclusion, although far from the threshold of clinical relevance, temporal cortical thickness proved to classify between FEP subjects and healthy individuals. The assessment of site-dependent variables permitted an increase in the across-site generalizability, thus attempting to address an important machine learning limitation.

The prognostic value of the Koret CT score in dogs following traumatic brain injury.

Traumatic brain injury (TBI) is a common condition in veterinary medicine with relatively high mortality rate. Recently, a study that correlated abnormal computed tomography (CT) findings with outcome in dogs with head trauma established a prognostic scoring system termed Koret CT score (KCTS). The purpose of this study was to evaluate the accuracy of the KCTS in making short- and long-term prognosis in dogs presented within 72 h of TBI. Thirty-five dogs that were admitted to a hospital during 2010-2019 with TBI and were CT-scanned within 72 h of injury were included in the study. Retrospectively collected data included signalment, modified Glasgow Coma Scale score (MGCS), CT findings, and outcome, i.e. short-term (defined as 10 days) and long-term (6 months) survival. CT images were reviewed and the KCTS was calculated for all dogs. Association between KCTS and outcome was examined. A significant negative association was found between KCTS and both short- and long-term survival. The area under receiver operating characteristic curve for KCTS for short- and long-term survival was 0.9 and 0.87, respectively. Furthermore, the probability of survival in the short term was predicated by the KCTS in an almost linear fashion and a score of 3 points or less on the KCTS was associated with survival with 85% sensitivity and 100% specificity. These results validate the prognostic value of the KCTS in dogs with TBI and provide a complementary tool for serial clinical and neurological evaluation.

Psychological impact of COVID-19 pandemic on healthcare workers in a highly burdened area of north-east Italy.

AIMS: Healthcare workers exposed to coronavirus 2019 (COVID-19) patients could be psychologically distressed. This study aims to assess the magnitude of psychological distress and associated factors among hospital staff during the COVID-19 pandemic in a large tertiary hospital located in north-east Italy. METHODS: All healthcare and administrative staff working in the Verona University Hospital (Veneto, Italy) during the COVID-19 pandemic were asked to complete a web-based survey from 21 April to 6 May 2020. Symptoms of post-traumatic distress, anxiety and depression were assessed, respectively, using the Impact of Event Scale (IES-R), the Self-rating Anxiety Scale (SAS) and the Patient Health Questionnaire (PHQ-9). Personal socio-demographic information and job characteristics were also collected, including gender, age, living condition, having pre-existing psychological problems, occupation, length of working experience, hospital unit (ICUs and sub-intensive COVID-19 units vs. non-COVID-19 units). A multivariable logistic regression analysis was performed to identify factors associated with each of the three mental health outcomes. RESULTS: A total of 2195 healthcare workers (36.9% of the overall hospital staff) participated in the study. Of the participants, 35.7% were nurses, 24.3% other healthcare staff, 16.4% residents, 13.9% physicians and 9.7% administrative staff. Nine per cent of healthcare staff worked in ICUs, 8% in sub-intensive COVID-19 units and 7.6% in other front-line services, while the remaining staff worked in hospital units not directly engaged with COVID-19 patients. Overall, 63.2% of participants reported COVID-related traumatic experiences at work and 53.8% (95% CI 51.0%-56.6%) showed symptoms of post-traumatic distress; moreover, 50.1% (95% CI 47.9%-52.3%) showed symptoms of clinically relevant anxiety and 26.6% (95% CI 24.7%-28.5%) symptoms of at least moderate depression. Multivariable logistic regressions showed that women, nurses, healthcare workers directly engaged with COVID-19 patients and those with pre-existing psychological problems were at increased risk of psychopathological consequences of the pandemic. CONCLUSIONS: The psychological impact of the COVID-19 pandemic on healthcare staff working in a highly burdened geographical of north-east Italy is relevant and to some extent greater than that reported in China. The study provides solid grounds to elaborate and implement interventions pertaining to psychology and occupational health.

EPA guidance on the quality of mental health services: A systematic meta-review and update of recommendations focusing on care coordination.

BACKGROUND: The quality of mental health services is crucial for the effectiveness and efficiency of mental healthcare systems, symptom reduction, and quality of life improvements in persons with mental illness. In recent years, particularly care coordination (i.e., the integration of care across different providers and treatment settings) has received increased attention and has been put into practice. Thus, we focused on care coordination in this update of a previous European Psychiatric Association (EPA) guidance on the quality of mental health services. METHODS: We conducted a systematic meta-review of systematic reviews, meta-analyses, and evidence-based clinical guidelines focusing on care coordination for persons with mental illness in three literature databases. RESULTS: We identified 23 relevant documents covering the following topics: case management, integrated care, home treatment, crisis intervention services, transition from inpatient to outpatient care and vice versa, integrating general and mental healthcare, technology in care coordination and self-management, quality indicators, and economic evaluation. Based on the available evidence, we developed 15 recommendations for care coordination in European mental healthcare. CONCLUSIONS: Although evidence is limited, some concepts of care coordination seem to improve the effectiveness and efficiency of mental health services and outcomes on patient level. Further evidence is needed to better understand the advantages and disadvantages of different care coordination models.

Detection of Intraspinal Spirocerca lupi in Canine Cerebrospinal Fluid by Polymerase Chain Reaction.

Aberrant migration of Spirocerca lupi into the spinal cord is an important cause of severe progressive neurological dysfunction in dogs. Although early diagnosis is essential to prevent deterioration, ante-mortem diagnosis of this condition remains challenging. The aim of this study was to evaluate the detection of the 18S ribosomal DNA (rDNA) S. lupi gene in the cerebrospinal fluid (CSF) of presumptively-affected dogs using polymerase chain reaction (PCR). Dogs with a non-compressive spinal cord lesion, pleocytosis with presence of eosinophils in the CSF and a characteristic clinical presentation were included. CSF samples from eight dogs were available for the study, of which seven were definitively diagnosed with intraspinal spirocercosis by PCR of either the CSF samples (6/7) or tissue samples obtained at necropsy examination (3/7), or both (2/7). Of these seven positive cases, only one dog had a negative CSF PCR, indicating a sensitivity of 86% for detecting nematode DNA in the CSF of infected dogs using this PCR protocol. The nematode DNA sequences obtained from the CSF of six dogs and the spinal cord tissue of three dogs were 98-100% identical to the publicly available sequences of S. lupi, confirming the diagnosis. These findings indicate that PCR targeting the 18S rDNA of S. lupi in CSF is useful for the ante-mortem diagnosis of canine intraspinal spirocercosis.

Fertility concerns, preservation strategies and quality of life in young women with breast cancer: Baseline results from an ongoing prospective cohort study in selected European Centers.

OBJECTIVES: Most research addressing needs and concerns of young patients with breast cancer (≤40 years) is retrospective. The HOHO European protocol is a prospective multicenter cohort study of young women with newly diagnosed breast cancer, about fertility, psychosocial and quality of life concerns. Here we report the baseline data and focus on predictors of fertility concerns. MATERIALS AND METHODS: Patient surveys and medical record review were used. The baseline survey included sociodemographic, medical and treatment data as well as questions on fertility concerns and preservation strategies. Subscales from the CAncer Rehabilitation Evaluation System-Short Form (CARES-SF) were administered to measure specific quality of life aspects. Uni- and multivariable modeling were used to investigate predictors of greater fertility concern. RESULTS: Among 297 eligible respondents, 67% discussed fertility issues before starting therapy, 64% were concerned about becoming infertile after treatment, and 15% decided not to follow prescribed therapies. Fifty-four percent of women wished future children before diagnosis; of these, 71% still desired biologic children afterwards. In multivariable analysis, not having children was the only patient characteristic significantly associated with fertility concerns at diagnosis. Twenty-seven percent used fertility preservation strategies. Women who received chemotherapy reported greater physical (p = 0.021) and sexual difficulties (p = 0.039) than women who did not. Women who were married or had a partner reported less psychosocial problems than single women (p = 0.039). CONCLUSIONS: Young women with newly diagnosed breast cancer have several concerns, including, but not limited to, fertility. The HOHO European study provides valuable information to develop targeted interventions.

Predictors and moderators of burden of care and emotional distress in first-episode psychosis caregivers: results from the GET UP pragmatic cluster randomised controlled trial.

AIMS: First-episode psychosis (FEP) is a major life event and can have an adverse impact on the diagnosed individual and their families. The importance of intervening early and providing optimal treatments is widely acknowledged. In comparison to patient groups, literature is scarce on identifying treatment predictors and moderators of caregiver outcomes. This study aimed to identify pre-treatment characteristics predicting and/or moderating carer outcomes, based on data from a multi-element psychosocial intervention to FEP patients and carers (GET-UP PIANO trial). METHODS: Carer demography, type of family relationship, patient contact hours, pre-treatment carer burden, patient perceptions of parental caregiving and expressed emotion (EE) were selected, a priori, as potential predictors/moderators of carer burden and emotional distress at 9 months post treatment. Outcomes were analysed separately in mixed-effects random regression models. RESULTS: Analyses were performed on 260 carers. Only patient perceptions of early maternal criticism predicted reports of lower carer burden at follow-up. However, multiple imputation analysis failed to confirm this result. For treatment moderators: higher levels of carer burden at baseline yielded greater reductions in carer emotional distress at follow-up in the experimental group compared with treatment as usual (TAU). Higher levels of perceived EE moderated greater reductions in carer reports of tension in experimental group, compared with TAU, at follow-up. In younger caregivers (<51 years old), there were greater reductions in levels of worry during the baseline to follow-up period, within the experimental group compared with TAU. CONCLUSION: The study failed to identify significant treatment predictors of FEP carer outcomes. However, our preliminary findings suggest that optimal treatment outcomes for carers at first episode might be moderated by younger carer age, and carers reporting higher baseline levels of burden, and where patients perceive higher levels of negative effect from caregivers.

Cost-effectiveness analysis of Daclatasvir/Sofosbuvir for the treatment of the HCV patients failed after the first line with second generation of DAAs in Italy.

BACKGROUND: Daclatasvir (DCV) combinated with Sofosbuvir (SOF) has shown good efficacy and safety profile for HCV patients. The aim was to evaluate the cost-effectiveness of DCV/SOF regimen versus HCV alternative treatments for patients who failed to achieve the SVR12 after a first DAA treatment from Italian perspective (PITER cohort). METHODS: A Markov model of HCV chronically infected patients was used to develop two scenarios: 1) DCV+ SOF versus Ledipasvir (LDV)+ SOF in Genotype (Gt)1 and Gt4; 2) DCV+ SOF versus no retreatment option in Gt1, Gt3, and Gt4. The percentage of patients who failed the first line with SOF/Simeprevir/Ribavirin (RBV) or SOF/RBV and were retreated or not according to evidences from PITER cohort, were used to populate the model. HCV resources consumption and SVR rates were quantified using PITER data. Transition probabilities and utility rates were derived from the literature. The outcomes were expressed in terms of Quality adjusted life years (QALYs). Probabilistic sensitivity analysis (PSA) was performed considering a cost-effectiveness threshold of € 30,000/QALY. RESULTS: In the base-case analysis, DCV+ SOF represents a cost-effectiveness therapy with ICERs lower than the threshold. The PSA showed robust results, ICERs remain below the threshold in 94% and 99% simulations in Scenario 1 and 2, respectively.

Economic evaluation of Zepatier for the management of HCV in the Italian scenario.

BACKGROUND: Hepatitis C virus (HCV) is a major health issue worldwide. New generation of direct-active antiviral medications is an epoch-making turning point in the management of HCV infections. OBJECTIVE: Conducing a cost-effectiveness analysis comparing the combination of elbasvir/grazoprevir and sofosbuvir + pegylated interferon/ribavirin for the management of all HCV patients (even those in the initial stages of fibrosis). METHODS: A Markov model was built on the natural history of the disease to assess the efficacy of the alternatives. The outcomes are expressed in terms of quality adjusted life-years (QALYs) and result in terms of incremental cost-effectiveness ratio). RESULTS: Elbasvir/grazoprevir implies an expenditure of €21,104,253.74 with a gain of 19,287.90 QALYs and sofosbuvir + pegylated interferon/ribavirin implies an expenditure of €31,904,410.11 with a gain of 18,855.96 QALYs. Elbasvir/grazoprevir is thus a dominant strategy. CONCLUSION: Consideration should be given to the opportunity cost of not treating patients with a lower degree of fibrosis (F0-F2).

Cost-Effectiveness Analysis of Lesinurad/Allopurinol Versus Febuxostat for the Management of Gout/Hyperuricemia in Italy.

BACKGROUND: Until very recently the only therapeutic alternative for the management of patients affected by gout/hyperuricemia that did not respond to a first-line treatment based on allopurinol alone or who cannot tolerate allopurinol was febuxostat, a xanthine oxidase non-purine-selective inhibitor. Lately, however, a new therapeutic alternative has become available for the management of this pathology: lesinurad, a urate transporter inhibitor. OBJECTIVE: To objective of this study was to evaluate the cost effectiveness of lesinurad/allopurinol in comparison with febuxostat as a second-line therapeutic strategy for the management of patients affected by gout and hyperuricemia that did not respond to a first-line therapy based on allopurinol alone. METHODS: A Markov model was built based on the natural history of the pathology; patients entered the model according to their level of serum uric acid concentration and flowed across it according to their response to the therapy. The analysis was carried out considering the perspective of the Italian National Health Service on a lifetime horizon and 6-month cycles. Costs and quality-adjusted life-years (QALYs) were discounted at a 3.5% yearly rate. The results of the model were expressed in terms of incremental cost-effectiveness ratio (ICER). Both a one-way and a multi-way Monte-Carlo analysis were carried out in order to check the robustness of the results achieved. RESULTS: The ICER derived from the comparison was equal to €77.53/QALY on the lifetime horizon, as there was a higher level of costs associated with the combination as compared with febuxostat (€10,658.27 vs. €10,645.87, for a differential of €12.40) and a higher level of QALYs achieved (7.77 vs. 7.61, for a differential of 0.16). CONCLUSIONS: The lesinurad/allopurinol combination is recommended for the treatment of patients affected by gout/hyperuricemia in the Italian Health System as it appears to be cost effective and thus sustainable for the Italian healthcare sector.

Relevance of sample preparation for flow cytometry.

INTRODUCTION: Flow cytometry is a useful tool for diagnosis and minimal residual disease (MRD) study of hematological diseases. Standard sample preparation protocols are characterized by stain-lyse-wash (SLW). To prevent nonspecific bindings and achieve high sensitivity in MRD studies, lyse-wash-stain-wash (LWSW) is required. To our knowledge, no comparison between the two methods has been performed. METHODS: We compared mean fluorescence intensity (MFI), stain index, signal-to-noise ratio, and percentage of positive cells of 104 antibodies and of 13 selected antibodies tested in 10 samples simultaneously prepared with the two methods. RESULTS: MFI and percentages of positive cells obtained by the two methods did not show significant differences and showed a very high correlation. Stain index and signal-to-noise ratio presented higher values for kappa and lambda surface chains in LWSW samples and a trend of higher values for the other antibodies in SLW samples. CONCLUSIONS: We suggest to use LWSW method also at diagnosis to obtain more comparable antibody intensity expressions when samples from the same patient are processed for MRD evaluation after bulk lysis. Moreover, LWSW can prevent nonspecific bindings, shows no differences in the identification and quantitation of the populations of interest, and reduces acquisition of cell debris.

Influence of childhood trauma on diagnosis and substance use in first-episode psychosis.

BackgroundChildhood trauma has been significantly associated with first-episode psychosis, affective dysfunction and substance use.AimsTo test whether people with first-episode psychosis who had experienced childhood trauma, when compared with those who had not, showed a higher rate of affective psychosis and an increased lifetime rate of substance use.MethodThe sample comprised 345 participants with first-episode psychosis (58% male, mean age 29.8 years, s.d. = 9.7).ResultsSevere sexual abuse was significantly associated with a diagnosis of affective psychosis (χ2 = 4.9, P = 0.04) and with higher rates of lifetime use of cannabis (68% v 41%; P = 0.02) and heroin (20% v 5%; P = 0.02). Severe physical abuse was associated with increased lifetime use of heroin (15% v 5%; P = 0.03) and cocaine (32% v 17%; P = 0.05).ConclusionsPatients with first-episode psychosis exposed to childhood trauma appear to constitute a distinctive subgroup in terms of diagnosis and lifetime substance use.

A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis.

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms with variable risk of evolution into post-PV and post-ET myelofibrosis, from now on referred to as secondary myelofibrosis (SMF). No specific tools have been defined for risk stratification in SMF. To develop a prognostic model for predicting survival, we studied 685 JAK2, CALR, and MPL annotated patients with SMF. Median survival of the whole cohort was 9.3 years (95% CI: 8-not reached-NR-). Through penalized Cox regressions we identified negative predictors of survival and according to beta risk coefficients we assigned 2 points to hemoglobin level <11 g/dl, to circulating blasts ⩾3%, and to CALR-unmutated genotype, 1 point to platelet count <150 × 109/l and to constitutional symptoms, and 0.15 points to any year of age. Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) allocated SMF patients into four risk categories with different survival (P<0.0001): low (median survival NR; 133 patients), intermediate-1 (9.3 years, 95% CI: 8.1-NR; 245 patients), intermediate-2 (4.4 years, 95% CI: 3.2-7.9; 126 patients), and high risk (2 years, 95% CI: 1.7-3.9; 75 patients). Finally, we found that the MYSEC-PM represents the most appropriate tool for SMF decision-making to be used in clinical and trial settings.

Transcriptomic analyses and leukocyte telomere length measurement in subjects exposed to severe recent stressful life events.

Stressful life events occurring in adulthood have been found able to affect mood and behavior, thus increasing the vulnerability for several stress-related psychiatric disorders. However, although there is plenty of clinical data supporting an association between stressful life events in adulthood and an enhanced vulnerability for psychopathology, the underlying molecular mechanisms are still poorly investigated. Thus, in this study we performed peripheral/whole-genome transcriptomic analyses in blood samples obtained from 53 adult subjects characterized for recent stressful life events occurred within the previous 6 months. Transcriptomic data were analyzed using Partek Genomics Suite; pathway and network analyses were performed using Ingenuity Pathway Analysis and GeneMANIA Software. We found 207 genes significantly differentially expressed in adult subjects who reported recent stressful life experiences (n=21) compared with those without such experiences (n=32). Moreover, the same subjects exposed to such stressful experiences showed a reduction in leukocyte telomere length. A correlation analyses between telomere length and transcriptomic data indicated an association between the exposures to recent stressful life events and the modulation of several pathways, mainly involved in immune-inflammatory-related processes and oxidative stress, such as natural killer cell signaling, interleukin-1 (IL-1) signaling, MIF regulation of innate immunity and IL-6 signaling. Our data suggest an association between exposures to recent stressful life events in adulthood and alterations in the immune, inflammatory and oxidative stress pathways, which could be also involved in the negative effect of stressful life events on leukocyte telomere length. The modulation of these mechanisms may underlie the clinical association between the exposure to recent Stressful life events in adulthood and an enhanced vulnerability to develop psychiatric diseases in adulthood.

Economic Analysis and Budget Impact of Tenofovir and Entecavir in the First-Line Treatment of Hepatitis B Virus in Italy.

BACKGROUND: Chronic hepatitis B is a common, progressive disease, particularly when viral replication is detected. Oral antivirals can suppress viral replication and prevent or delay the development of cirrhosis and liver-related complications. The treatments of chronic hepatitis B cannot totally cure the disease but can prevent its progression to hepatocellular carcinoma, decreasing the levels of both morbidity and mortality. To date, there are several therapies indicated by the international guidelines as first-line treatments for the management of hepatitis B; two of the most effective are those based on either tenofovir or entecavir. OBJECTIVE: The aim of this study is to evaluate the cost-effectiveness of tenofovir and entecavir in the treatment of naïve patients with chronic hepatitis B. The two treatments are compared with the "no treatment" and to one another. METHODS: The cost-effectiveness analysis was conducted using a Markov model; patients entered one of the following health states: chronic hepatitis, cirrhosis (compensated or decompensated), hepatocellular carcinoma, liver transplantation or death. The analysis was carried out from the perspective of the Italian National Health Service by considering a life-time horizon with cycles lasting 1 year and with costs and QALYs (quality-adjusted life years) discounted at a rate of 3.5%. The results of the model were analysed in terms of incremental cost-effectiveness ratio (ICER). RESULTS: ICERs for tenofovir and entecavir emerging from the comparison versus "no treatment" were equal to €10,274.73 and €16,300.44 per QALY gained, respectively, on the life-time horizon. Tenofovir was dominant in the direct comparison with entecavir, indicating more QALYs and a lower consumption of resources. The Monte Carlo simulation demonstrated that in 97% (tenofovir) and in 85% (entecavir) of the scenarios performed, the cost per QALY fell below the threshold of €30,000/QALY. The budget impact analysis showed savings for tenofovir amounting to 33% compared to entecavir in the first year on treatment and to 31% in following years. CONCLUSIONS: Entecavir and tenofovir are recommended for the treatment of patients with chronic Hepatitis B in the Italian Health System. In particular, tenofovir appeared to be the more cost-effective drug for the management of chronic hepatitis B virus (HBV) infections. These results could help decision makers and clinicians to address their decision when choosing a first-line treatment for the management of people affected by chronic HBV.