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Background: Seasonal influenza has a significant impact on public health, generating substantial direct healthcare costs, production losses and fiscal effects. Understanding these consequences is crucial to effective decision-making and the development of preventive strategies. This study aimed to evaluate the economic and the fiscal impact of implementing an incremental strategy for seasonal influenza prevention using the cell-based quadrivalent influenza vaccine (QIVc) among healthcare workers (HCWs) in Italy., Methods: To estimate the economic impact of implementing this strategy, we performed a cost analysis that considered direct healthcare costs, productivity losses and fiscal impact. The analysis considered a 3-year time horizon. A deterministic sensitivity analysis was also conducted., Results: Assuming a vaccination coverage rate of 30% among HCWs, the analysis considered a total of 203 018 vaccinated subjects. On analysing the overall differential impact (including direct costs, indirect costs and fiscal impact), implementing QIVc vaccination as a preventative measure against influenza among HCWs in Italy would yield societal resource savings of €23 638.78 in the first year, €47 277.56 in the second year, and €70 916.35 in the third year, resulting in total resource savings of €141 832.69., Conclusions: The study demonstrated that implementing the incremental use of QIVc as part of a preventive strategy for seasonal influenza among HCWs in Italy could yield positive economic outcomes, especially in terms of indirect costs and fiscal impact. The resources saved could be utilized to fund further public health interventions. Policy-makers should consider these findings when making decisions regarding influenza prevention strategies targeting HCWs., (© 2024. The Author(s).)

Background: About 30% of Prostate cancer (PCa) patients progress to metastatic PCa that remains largely incurable. This evidence underlines the need for the development of innovative therapies. In this direction, the potential research focus might be on long non-coding RNAs (lncRNAs) like H19, which serve critical biological functions and show significant dysregulation in cancer. Previously, we showed a transcriptional down-regulation of H19 under combined pro-tumoral estrogen and hypoxia treatment in PCa cells that, in turn, induced both E-cadherin and β4 integrin expression. H19, indeed, acts as transcriptional repressor of cell adhesion molecules affecting the PCa metastatic properties. Here, we investigated the role of H19/cell adhesion molecules circuitry on in vivo PCa experimental tumor growth and metastatic dissemination models., Methods: H19 was silenced in luciferase-positive PC-3 and 22Rv1 cells and in vitro effect was evaluated by gene expression, proliferation and invasion assays before and after treatment with the histone lysine demethylase inhibitor, GSK-J4. In vivo tumor growth and metastasis dissemination, in the presence or absence of GSK-J4, were analyzed in two models of human tumor in immunodeficient mice by in vivo bioluminescent imaging and immunohistochemistry (IHC) on explanted tissues. Organotypic Slice Cultures (OSCs) from fresh PCa-explant were used as ex vivo model to test GSK-J4 effects., Results: H19 silencing in both PC-3 and 22Rv1 cells increased: i) E-cadherin and β4 integrin expression as well as proliferation and invasion, ii) in vivo tumor growth, and iii) metastasis formation at bone, lung, and liver. Of note, treatment with GSK-J4 reduced lesions. In parallel, GSK-J4 efficiently induced cell death in PCa-derived OSCs., Conclusions: Our findings underscore the potential of the H19/cell adhesion molecules circuitry as a targeted approach in PCa treatment. Modulating this interaction has proven effective in inhibiting tumor growth and metastasis, presenting a logical foundation for targeted therapy., (© 2024. The Author(s).)

Background: Long-term outcomes of patients treated with helmet noninvasive ventilation (NIV) are unknown: safety concerns regarding the risk of patient self-inflicted lung injury and delayed intubation exist when NIV is applied in hypoxemic patients. We assessed the 6-month outcome of patients who received helmet NIV or high-flow nasal oxygen for COVID-19 hypoxemic respiratory failure., Methods: In this prespecified analysis of a randomized trial of helmet NIV versus high-flow nasal oxygen (HENIVOT), clinical status, physical performance (6-min-walking-test and 30-s chair stand test), respiratory function and quality of life (EuroQoL five dimensions five levels questionnaire, EuroQoL VAS, SF36 and Post-Traumatic Stress Disorder Checklist for the DSM) were evaluated 6 months after the enrollment., Results: Among 80 patients who were alive, 71 (89%) completed the follow-up: 35 had received helmet NIV, 36 high-flow oxygen. There was no inter-group difference in any item concerning vital signs (N = 4), physical performance (N = 18), respiratory function (N = 27), quality of life (N = 21) and laboratory tests (N = 15). Arthralgia was significantly lower in the helmet group (16% vs. 55%, p = 0.002). Fifty-two percent of patients in helmet group vs. 63% of patients in high-flow group had diffusing capacity of the lungs for carbon monoxide < 80% of predicted (p = 0.44); 13% vs. 22% had forced vital capacity < 80% of predicted (p = 0.51). Both groups reported similar degree of pain (p = 0.81) and anxiety (p = 0.81) at the EQ-5D-5L test; the EQ-VAS score was similar in the two groups (p = 0.27). Compared to patients who successfully avoided invasive mechanical ventilation (54/71, 76%), intubated patients (17/71, 24%) had significantly worse pulmonary function (median diffusing capacity of the lungs for carbon monoxide 66% [Interquartile range: 47-77] of predicted vs. 80% [71-88], p = 0.005) and decreased quality of life (EQ-VAS: 70 [53-70] vs. 80 [70-83], p = 0.01)., Conclusions: In patients with COVID-19 hypoxemic respiratory failure, treatment with helmet NIV or high-flow oxygen yielded similar quality of life and functional outcome at 6 months. The need for invasive mechanical ventilation was associated with worse outcomes. These data indicate that helmet NIV, as applied in the HENIVOT trial, can be safely used in hypoxemic patients. Trial registration Registered on clinicaltrials.gov NCT04502576 on August 6, 2020., (© 2023. The Author(s).)

Background: During the COVID-19 pandemic, migrants arriving in host countries irregularly have not infrequently been perceived as increasing the COVID-19 burden. Italy is a transit and destination country for migrants who cross the Central Mediterranean route and, during the pandemic, all migrants who landed on Italian shores were COVID-19 tested and quarantined. Our study aimed to investigate the impact of the SARS-CoV-2 infection among migrants who landed on the Italian coasts by analyzing both incidence and health outcomes., Methods: A retrospective observational study has been designed. The population of interest was represented by 70,512 migrants (91% male, 99% <60 years old) who landed in Italy between January 2021 and 2022. SARS-CoV-2 incidence rate per 1,000 (with 95%CI) in migrants and the resident population in Italy of the corresponding age group was computed. The incidence rate ratio (IRR) was used to compare the incidence rates in migrants and the resident population., Results: 2,861 migrants out of those landed in Italy during the observation period tested positive, with an incidence rate of 40.6 (39.1-42.1) cases per 1,000. During the same period, 177.6 (177.5-177.8) cases per 1,000 were reported in the resident population, with an IRR of 0.23 (0.22-0.24). 89.7% of cases were male and 54.6% belonged to the 20-29 age group. 99% of cases reported no symptoms, no relevant comorbidities were reported and no cases were hospitalized., Conclusions: Our study found a low rate of SARS-CoV-2 infection in migrants reaching Italy by sea with an incidence rate that is roughly a quarter of that of the resident population. Thus, irregular migrants who arrived in Italy during the observation period did not increase the COVID-19 burden. Further studies are needed to investigate possible reasons for the low incidence observed in this population., (© 2023. The Author(s).)

Background: Pediatric anesthesia care in the Magnetic Resonance Imaging is a challenge for clinicians. The recent debate about the role of anesthetic agent on neural development, encouraged an evaluation of their actual activity in this environment. In this active call survey, the authors sought to delineate the Italian situation regarding national centers, staff involved, monitoring tools available and sedation techniques., Methods: A complete sample of all national centers performing almost a pediatric discharge in the 2014 was obtained from Health Ministry registers. All Institutions were contacted for a prospective phone investigation and a three-section survey was fill out with the Physician in charge. A descriptive and exploratory analyzes about the organization setting of the Centers were performed., Results: Among 876 Institution screened, only 106 (37%) met minimal criteria for inclusion. Children are managed by anesthesiologists in the 95% of cases, while neonates in the 54%. A dedicated nurse is present in 74% of centers. While a pulse oximetry is present in 100% of centers, the rate of prevalence of other monitoring is lower. A specific MRI-compatible ventilator is available in the 95% of Centers, but many tools are not equally homogenously distributed. Pharmacological approach is preferred in pediatric age (98%), but its use for newborns is reduced to 43%., Conclusions: We found significant heterogeneity in the daily clinical practice of sedation in MRI. Our results could be a starting point to evaluate the further evolution of approach to children and neonates in magnetic resonance setting., Trial Registration: ClinicalTrials.gov identifier: NCT04775641., (© 2022. The Author(s).)

Background: In acute respiratory distress syndrome (ARDS), response to positive end-expiratory pressure (PEEP) is variable according to different degrees of lung recruitability. The search for a tool to individualize PEEP based on patients' individual response is warranted. End-expiratory lung volume (EELV) assessment by nitrogen washing-washout aids bedside estimation of PEEP-induced alveolar recruitment and may therefore help titrate PEEP on patient's individual recruitability. We designed a randomized trial to test whether an individualized PEEP setting protocol driven by EELV measurement may improve a composite clinical outcome in patients with moderate-to-severe ARDS (IPERPEEP trial)., Methods: IPERPEEP is an open-label, multicenter, randomized trial that will be conducted in 10 intensive care units in Italy and will enroll 132 ARDS patients showing PaO 2 /FiO 2 ratio ≤ 150 mmHg within 24 h from endotracheal intubation while on mechanical ventilation with PEEP 5 cmH 2 O. To standardize lung volumes at study initiation, all patients will undergo mechanical ventilation with tidal volume of 6 ml/kg of predicted body weight and PEEP set to obtain a plateau pressure within 28 and 30 cmH 2 O for 30 min (EXPRESS PEEP). Afterwards, a 5-step decremental PEEP trial will be conducted (EXPRESS PEEP to PEEP 5 cmH 2 O), and EELV will be measured at each step. Recruitment-to-inflation ratio will be calculated for each PEEP range from EELV difference. Patients will be then randomized to receive mechanical ventilation with PEEP set according to the optimal recruitment observed in the PEEP trial (IPERPEEP arm) trial or to achieve a plateau pressure of 28-30 cmH 2 O (control arm, EXPRESS strategy). In both groups, tidal volume size, use of prone positioning and neuromuscular blocking agents, and weaning from PEEP and from mechanical ventilation will be standardized. The primary endpoint of the study is a composite clinical outcome incorporating in-ICU mortality, 60-day ventilator-free days, and serum interleukin-6 concentration over the course of the initial 72 h of treatment., Discussion: The IPERPEEP study is a randomized trial powered to elucidate whether an individualized PEEP setting protocol based on bedside assessment of lung recruitability can improve a composite clinical outcome during moderate-to-severe ARDS., Trial Registration: ClinicalTrials.gov NCT04012073 . Registered 9 July 2019., (© 2022. The Author(s).)

Background: To be able to provide high-quality palliative care, there need to be a number of organizational structures available in the nursing homes. It is unclear to what extent such structures are actually present in nursing homes in Europe. We aim to examine structural indicators for quality of palliative care in nursing homes in Europe and to evaluate the differences in terms of availability of and access to palliative care, infrastructure for residents and families, multidisciplinary meetings and quality improvement initiatives., Methods: A PACE cross-sectional study (2015) of nursing homes in Belgium, England, Finland, Italy, the Netherlands and Poland. Nursing homes (N = 322) were selected in each country via proportional stratified random sampling. Nursing home administrators (N = 305) filled in structured questionnaires on nursing home characteristics. Organization of palliative care was measured using 13 of the previously defined IMPACT structural indicators for quality of palliative care covering four domains: availability of and access to palliative care, infrastructure for residents and families, multidisciplinary meetings and quality improvement initiatives. We calculated structural indicator scores for each country and computed differences in indicator scores between the six countries. Pearson's Chi-square test was used to compute the p-value of each difference., Results: The availability of specialist palliative care teams in nursing homes was limited (6.1-48.7%). In Finland, Poland and Italy, specialist advice was also less often available (35.6-46.9%). Up to 49% of the nursing homes did not provide a dedicated contact person who maintained regular contact with the resident and relatives. The 24/7 availability of opioids for all nursing home residents was low in Poland (37.5%)., Conclusions: This study found a large heterogeneity between countries in the organization of palliative care in nursing homes, although a common challenge is ensuring sufficient structural access to specialist palliative care services. Policymakers and health and palliative care organizations can use these structural indicators to identify areas for improvement in the organization of palliative care., (© 2021. The Author(s).)

Background: Frailty is increasingly reported among older adults with cardiovascular diseases and it has been demonstrated to increase negative health outcomes and mortality. To date, no systematic review of the evidence is available regarding the association between frailty and ischemic heart disease (IHD). We performed a systematic review of literature and a meta-analysis to assess the association between frailty and IHD., Methods: We selected all the studies that provided information on the association between frailty and IHD, regardless of the study setting, study design, or definition of IHD and frailty. PubMed, Web of Science and Embase were searched for relevant papers. Studies that adopted the Fried definition for frailty were included in the meta-analyses. For each measure of interest (proportions and estimates of associations), a meta-analysis was performed if at least three studies used the same definition of frailty. Pooled estimates were obtained through random effect models and Mantel-Haenszel weighting., Results: Thirty-seven studies were included. Of these, 22 adopted the Fried criteria to define frailty and provided estimates of prevalence and therefore they were included in meta-analyses. The pooled prevalence of IHD in frail individuals was 17% (95% Confidence Interval [95%CI] 11-23%) and the pooled prevalence of frailty in individuals with IHD was 19% (95% CI 15-24%). The prevalence of frailty among IHD patients ranged from 4 to 61%. Insufficient data were found to assess longitudinal association between frailty and IHD., Conclusions: Frailty is quite common in older persons with IHD. The identification of frailty among older adults with IHD should be considered relevant to provide individualized strategies of cardiovascular prevention and care. Further research should specifically explore the association between frailty and IHD and investigate the potential common biological ground.

Background: Accountable care has profoundly changed the organizational models adopted by health care organizations and, consequently, the skill set required for doctor-managers who have become middle managers and must deal with the operational management of their units. The aim of this study was to identify the psychological microfoundations (i.e., traits) of physicians' managerial attitude. Specifically, we analysed the roles played by narcissism, specialization choices and identification with the organization., Methods: We collected primary data on a population of ward unit heads in the Italian National Health Service. A logistic regression model predicting the levels of managerial attitude was employed., Results: The results indicate that high levels of narcissism and identification with the organization are related to higher managerial attitude (instead of clinical attitude). Additionally, we found that physicians with a technique-oriented specialization present a higher probability of manifesting managerial attitude (in comparison to clinical attitude)., Conclusions: Hospital managers can benefit from the use of these findings by developing a strategic approach to human resource management that allows them to identify, train and select the right mix of technical knowledge and managerial skills for middle-management roles.

Background: The gut microbiota (GM) has been proposed as one of the main determinants of colorectal surgery complications and theorized as the "missing factor" that could explain still poorly understood complications. Herein, we investigate this theory and report the current evidence on the role of the GM in colorectal surgery., Methods: We first present the findings associating the role of the GM with the physiological response to surgery. Second, the change in GM composition during and after surgery and its association with colorectal surgery complications (ileus, adhesions, surgical-site infections, anastomotic leak, and diversion colitis) are reviewed. Finally, we present the findings linking GM science to the application of the enhanced recovery after surgery (ERAS) protocol, for the use of oral antibiotics with mechanical bowel preparation and for the administration of probiotics/synbiotics., Results: According to preclinical and translational evidence, the GM is capable of influencing colorectal surgery outcomes. Clinical evidence supports the application of an ERAS protocol and the preoperative administration of multistrain probiotics/synbiotics. GM manipulation with oral antibiotics with mechanical bowel preparation still has uncertain benefits in right-sided colic resection but is very promising for left-sided colic resection., Conclusions: The GM may be a determinant of colorectal surgery outcomes. There is an emerging need to implement translational research on the topic. Future clinical studies should clarify the composition of preoperative and postoperative GM and the impact of the GM on different colorectal surgery complications and should assess the validity of GM-targeted measures in effectively reducing complications for all colorectal surgery locations.

Background: In critically ill patients continuous EEG (cEEG) is recommended in several conditions. Recently, a new wireless EEG headset (CerebAir®,Nihon-Kohden) is available. It has 8 electrodes, and its positioning seems to be easier than conventional systems. Aim of this study was to evaluate the feasibility of this device for cEEG monitoring, if positioned by ICU physician., Methods: Neurological patients were divided in two groups according with the admission to Neuro-ICU (Study-group:20 patients) or General-ICU (Control-group:20 patients). In Study group, cEEG was recorded by CerebAir® assembled by an ICU physician, while in Control group a simplified 8-electrodes-EEG recording positioned by an EEG technician was performed., Results: Time for electrodes applying was shorter in Study-group than in Control-group: 6.2 ± 1.1' vs 10.4 ± 2.3'; p < 0.0001. Thirty five interventions were necessary to correct artifacts in Study-group and 11 in Control-group. EEG abnormalities with or without epileptic meaning were respectively 7(35%) and 7(35%) in Study-group, and 5(25%) and 9(45%) in Control-group;p > 0.05. In Study-group, cEEG was interrupted for risk of skin lesions in 4 cases after 52 ± 4 h. cEEG was obtained without EEG technician in all cases in Study-group; quality of EEG was similar., Conclusions: Although several limitations should be considered, this simplified EEG system could be feasible even if EEG technician was not present. It was faster to position if compared with standard techniques, and can be used for continuous EEG monitoring. It could be very useful as part of diagnostic process in an emergency setting.

Background: Patients' increasing needs and expectations require an overall assessment of hospital performance. Several international agencies have defined performance indicators sets but there exists no unanimous classification. The Impact HTA Horizon2020 Project wants to address this aspect, developing a toolkit of key indicators to measure hospital performance. The aim of this review is to identify and classify the dimensions of hospital performance indicators in order to develop a common language and identify a shared evidence-based way to frame and address performance assessment., Methods: Following the PRISMA statement, PubMed, Cochrane Library and Web of Science databases were queried to perform an umbrella review. Reviews focusing on hospital settings, published January 2000-June 2019 were considered. The quality of the studies selected was assessed using the AMSTAR2 tool., Results: Six reviews ranging 2002-2014 were included. The following dimensions were described in at least half of the studies: 6 studies classified efficiency (55 indicators analyzed); 5 studies classified effectiveness (13 indicators), patient centeredness (10 indicators) and safety (8 indicators); 3 studies responsive governance (2 indicators), staff orientation (10 indicators) and timeliness (4 indicators). Three reviews did not specify the indicators related to the dimensions listed, and one article gave a complete definition of the meaning of each dimension and of the related indicators., Conclusions: The research shows emphasis of the importance of patient centeredness, effectiveness, efficiency, and safety dimensions. Especially, greater attention is given to the dimensions of effectiveness and efficiency. Assessing the overall quality of clinical pathways is key in guaranteeing a truly effective and efficient system but, to date, there still exists a lack of awareness and proactivity in terms of measuring performance of nodes within networks. The effort of classifying and systematizing performance measurement techniques across hospitals is essential at the organizational, regional/national and possibly international levels to deliver top quality care to patients.

The introduction of monoclonal antibodies (mAbs) against calcitonin-gene related peptide (CGRP) or CGRP receptors in the treatment of migraine raised concerns on the possible risks associated to the long-term inhibition of CGRP physiological functions. In this proof-of-concept study, we have measured the circulating levels of CGRP in 7 patients with high-frequency episodic migraine receiving the anti-CGRP receptor mAb erenumab for at least 6 months, to test the hypothesis that long-term blockade of CGRP receptors induces an increase in systemic CGRP levels via a classical up-regulation mechanism.Plasma CGRP levels were measured by a validated radioimmunoassay at baseline, and after 1 and 6 months of treatment with erenumab, 70 mg given sc every 4 weeks.We found (data expressed as the means ± SD): 38.34 ± 30.74 pg CGRP/ml of plasma at baseline, 38.19 ± 29.23 pg/ml after 1 month and 53.89 ± 28.03 pg/ml after 6 months of treatment. Thus, the average increase in plasma CGRP levels after 6 months of treatment was about + 40% compared to both baseline and 1-month treatments; such difference was not statistically significant because of high SD values in all groups.These preliminary findings need to be confirmed in larger, sufficiently powered experiments.

Background: Neurally adjusted ventilatory assist (NAVA) is an innovative mode for assisted ventilation that improves patient-ventilator interaction in children. The aim of this study was to assess the effects of patient-ventilator interaction comparing NAVA with pressure support ventilation (PSV) in patients difficult to wean from mechanical ventilation after moderate pediatric acute respiratory distress syndrome (PARDS)., Methods: In this physiological crossover study, 12 patients admitted in the Pediatric Intensive Care Unit (PICU) with moderate PARDS failing up to 3 spontaneous breathing trials in less than 7 days, were enrolled. Patients underwent three study conditions lasting 1 h each: PSV1, NAVA and PSV2., Results: The Asynchrony Index (AI) was significantly reduced during the NAVA trial compared to both the PSV1 and PSV2 trials (p = 0.001). During the NAVA trial, the inspiratory and expiratory trigger delays were significantly shorter compared to those obtained during PSV1 and PSV2 trials (Delay trinsp p < 0.001, Delay trexp p = 0.013). These results explain the significantly longer Time sync observed during the NAVA trial (p < 0.001). In terms of gas exchanges, PaO 2 value significantly improved in the NAVA trial with respect to the PSV trials (p < 0.02). The PaO 2 /FiO 2 ratio showed a significant improvement during the NAVA trial compared to both the PSV1 and PSV2 trials (p = 0.004)., Conclusions: In this specific PICU population, presenting difficulty in weaning after PARDS, NAVA was associated with a reduction of the AI and a significant improvement in oxygenation compared to PSV mode., Trial Registration: ClinicalTrial.gov Identifier: NCT04360590 "Retrospectively registered".

Background: Equine amniotic mesenchymal stromal cells (AMSCs) and their conditioned medium (CM) were evaluated for their ability to inhibit in vitro proliferation of peripheral blood mononuclear cells (PBMCs) with and without priming. Additionally, AMSC immunogenicity was assessed by expression of MHCI and MHCII and their ability to counteract the in vitro inflammatory process., Methods: Horse PBMC proliferation was induced with phytohemagglutinin. AMSC priming was performed with 10 ng/ml of TNF-α, 100 ng/ml of IFN-γ, and a combination of 5 ng/ml of TNF-α and 50 ng/ml of IFN-γ. The CM generated from naïve unprimed and primed AMSCs was also tested to evaluate its effects on equine endometrial cells in an in vitro inflammatory model induced by LPS. Immunogenicity marker expression (MHCI and II) was evaluated by qRT-PCR and by flow cytometry., Results: Priming does not increase MHCI and II expression. Furthermore, the inhibition of PBMC proliferation was comparable between naïve and conditioned cells, with the exception of AMSCs primed with both TNF-α and IFN-γ that had a reduced capacity to inhibit T cell proliferation. However, AMSC viability was lower after priming than under other experimental conditions. CM from naïve and primed AMSCs strongly inhibited PBMC proliferation and counteracted the inflammatory process, rescuing about 65% of endometrial cells treated by LPS., Conclusion: AMSCs and their CM have a strong capacity to inhibit PBMC proliferation, and priming is not necessary to improve their immunosuppressive activity or reactivity in an inflammatory in vitro model.

Background: Stroke units provide patients with a multiparametric monitoring of vital functions, while no instruments are actually available for a continuous monitoring of patients motor performance. Our aim was to develop an actigraphic index able both to identify the paretic limb and continuously monitor the motor performance of stroke patients in the stroke unit environment., Methods: Twenty consecutive acute stroke patients (mean age 69.2 years SD 10.1, 8 males and 12 females) and 17 bed-restrained patients (mean age 70.5 years SD 7.3, 7 males and 10 females) hospitalized for orthopedic diseases of the lower limbs, but not experiencing neurological symptoms, were enrolled. This last group represented our control group. The motor activity of arms was recorded for 24 h using two programmable actigraphic systems showing off as wrist-worn watches. The firmware segmented the acquisition in epochs of 1 minute and for each epoch calculates two motor activity indices: MA e1 (Epoch-related Motor Activity index) and MA e2 (Epoch-related Motor Activity index 2). MA e1 is defined as the standard deviation of the acceleration module and MA e2 as the module of the standard deviation of acceleration components. To describe the 24 h motor performance of each limb, we calculated the mean value of MA e1 and MA e2 (respectively MA 1&#95;24h and MA 2&#95;24h ). Then we obtained two Asymmetry Rate Indices: AR 1&#95;24h and AR 2&#95;24h to show the motor activity prevalence. AR 1&#95;24h refers to the asymmetry index between the values of MA e1 of both arms and AR 2&#95;24h to MA e2 values. The stroke patients were clinically evaluated by NIHSS at the beginning (NIHSS T0 ) and at the end (NIHSS T1 ) of the 24 h actigraphic recordings., Results: Both MA 1&#95;24h and MA 2&#95;24h indices were smaller in the paretic than in the unaffected arm (respectively p = 0.004 and p = 0.004). AR 2&#95;24h showed a better capability (95% of paretic arms correctly identified, Phi Coefficient: 0.903) to discriminate the laterality of the clinical deficit than AR 1&#95;24h (85% of paretic arms correctly identified, Phi Coefficient: 0,698). We also found that AR 1&#95;24h did not differ between the two groups of patients while AR 2&#95;24h was greater in stroke patients than in controls and positively correlated with NIHSS total scores (r: 0.714, p < 0.001 for NIHSS, IC95%: 0.42-0.90) and with the sub-score relative to the paretic upper limb (r: 0.812, p < 0.001, IC95%: 0.62-0.96)., Conclusions: Our data show that actigraphic monitoring of upper limbs can detect the laterality of the motor deficit and measure the clinical severity. These findings suggest that the above described actigraphic system could implement the existing multiparametric monitoring in stroke units.

Background: By 2030, 30% of the European population will be aged 60 or over and those aged 80 and above will be the fastest growing cohort. An increasing number of people will die at an advanced age with multiple chronic diseases. In Europe at present, between 12 and 38% of the oldest people die in a long-term care facility. The lack of nationally representative empirical data, either demographic or clinical, about people who die in long-term care facilities makes appropriate policy responses more difficult. Additionally, there is a lack of comparable cross-country data; the opportunity to compare and contrast data internationally would allow for a better understanding of both common issues and country-specific challenges and could help generate hypotheses about different options regarding policy, health care organization and provision. The objectives of this study are to describe the demographic, facility stay and clinical characteristics of residents dying in long-term care facilities and the differences between countries., Methods: Epidemiological study (2015) in a proportionally stratified random sample of 322 facilities in Belgium, Finland, Italy, the Netherlands, Poland and England. The final sample included 1384 deceased residents. The sampled facilities received a letter introducing the project and asking for voluntary participation. Facility manager, nursing staff member and treating physician completed structured questionnaires for all deaths in the preceding 3 months., Results: Of 1384 residents the average age at death ranged from 81 (Poland) to 87 (Belgium, England) (p < 0.001) and length of stay from 6 months (Poland, Italy) to 2 years (Belgium) (p < 0.05); 47% (the Netherlands) to 74% (Italy) had more than two morbidities and 60% (England) to 83% (Finland) dementia, with a significant difference between countries (p < 0.001). Italy and Poland had the highest percentages with poor functional and cognitive status 1 month before death (BANS-S score of 21.8 and 21.9 respectively). Clinical complications occurred often during the final month (51.9% England, 66.4% Finland and Poland)., Conclusions: The population dying in long-term care facilities is complex, displaying multiple diseases with cognitive and functional impairment and high levels of dementia. We recommend future policy should include integration of high-quality palliative and dementia care.

Background: Type-2 diabetes mellitus is one of the major risk factors of atherosclerosis, particularly in peripheral artery disease (PAD). Several studies have documented a correlation between omentin-1 serum levels, atherosclerosis, and cardiovascular diseases. However, a clear link between circulating omentin-1 and PAD in diabetic patients has yet to be established. The aim of this study was to investigate the potential role of omentin-1 in PAD in type-2 diabetic patients., Methods: In this cross-sectional study, we analyzed omentin-1 serum levels by ELISA in 600 type-2 diabetic patients with (n = 300) and without (n = 300) PAD at Fontaine's stage II, III, or IV., Results: We found that omentin-1 serum levels were significantly lower in diabetic patients with PAD than in diabetic controls (29.46 vs 49.24 ng/mL, P < 0.001) and that the levels gradually decreased in proportion to disease severity (P < 0.05). The association between omentin-1 levels and PAD remained significant after adjusting for major risk factors in a multivariate analysis., Conclusions: Our results suggest that omentin-1 is reduced in type 2 diabetic patients with PAD and that omentin-1 levels are related to disease severity.

Background: Sortilin is a 95-kDa protein which has recently been linked to circulating cholesterol concentration and lifetime risk of developing significant atherosclerotic disease. Sortilin is found inside different cell types and circulating in blood. Higher circulating sortilin concentration has been found in patients with coronary atherosclerosis compared to control subjects. Sortilin concentration is influenced by statin therapy., Methods: We enrolled statin-naïve subjects with type 2 diabetes mellitus and we performed a cross-sectional study to evaluate the association between sortilin levels and the presence of clinically significant lower limb peripheral artery disease (PAD) in a population of statin-free diabetic subjects., Results: Out of the 154 patients enrolled in our study, 80 patients were free from PAD, while 74 had clinically significant PAD. Sortilin concentration was significantly higher in the latter group compared to the former (1.61 ± 0.54 ng/mL versus 0.67 ± 0.30 ng/mL, P < 0.01) and there was a trend toward increased sortilin levels as disease severity increased. The association of sortilin levels with PAD remained after adjusting for major risk factors in a multivariate analysis., Conclusions: We showed that sortilin is significantly and independently associated with the presence of lower limb PAD in a statin-free diabetic population and it may be a promising marker for clinically significant atherosclerosis of the lower limbs. Further studies are needed to confirm this finding and to evaluate its clinical usefulness.

Microglia, unique myeloid cells residing in the brain parenchyma, represent the first line of immune defense within the central nervous system. In addition to their immune functions, microglial cells play an important role in other cerebral processes, including the regulation of synaptic architecture and neurogenesis. Chronic microglial activation is regarded as detrimental, and it is considered a pathogenic mechanism common to several neurological disorders. Microglial activation and function have been extensively studied in rodent experimental models, whereas the characterization of human cells has been limited due to the restricted availability of primary sources of human microglia. To overcome this problem, human immortalized microglial cell lines have been developed. The human microglial clone 3 cell line, HMC3, was established in 1995, through SV40-dependent immortalization of human embryonic microglial cells. It has been recently authenticated by the American Type Culture Collection (ATCC®) and distributed under the name of HMC3 (ATCC®CRL-3304). The HMC3 cells have been used in six research studies, two of which also indicated by ATCC® as reference articles. However, a more accurate literature revision suggests that clone 3 was initially distributed under the name of CHME3. In this regard, several studies have been published, thus contributing to a more extensive characterization of this cell line. Remarkably, the same cell line has been used in different laboratories with other denominations, i.e., CHME-5 cells and C13-NJ cells. In view of the fact that "being now authenticated by ATCC®" may imply a wider distribution of the cells, we aimed at reviewing data obtained with the human microglia cell line clone 3, making the readers aware of this complicated nomenclature. In addition, we also included original data, generated in our laboratory with the HMC3 (ATCC®CRL-3304) cells, providing information on the current state of the culture together with supplementary details on the culturing procedures to obtain and maintain viable cells.

Background: Primary heart sarcomas are exceedingly rare tumors. Among primary cardiac sarcomas, synovial sarcoma is one of the rarest, involving cardiac cavities or pericardium., Case Presentation: Two cases of synovial sarcoma are presented with the clinical course and therapy. Both cases were treated with surgery and chemo/radiotherapy. Interestingly, one of the patient, a 52-year-old male with an intracardiac synovial sarcoma, undergone a SynCardia total artificial heart implantation, but died for multiple pulmonary metastases waiting for transplantation., Conclusion: Complete surgical resection of cardiac synovial sarcoma is the gold standard of therapy, though rarely possible. Although guidelines for the treatment are not well established, due to limited number of cases reported, chemotherapy and radiotherapy are frequently administered and seem to prolong mean patient's survival. Cardiac transplantation could be considered in selected cases.

Background: In an era of a growing economic pressure for all health systems, the interest for "disinvestment" in healthcare increased. In this context, evidence based approaches such as Health Technology Assessment (HTA) are needed both to invest and to disinvest in health technologies. In order to investigate the extent of application of HTA in this field, methodological projects/frameworks, case studies, dissemination initiatives on disinvestment released by HTA agencies and organizations located in Europe were searched., Methods: In July 2015, the websites of HTA agencies and organizations belonging to the European network for HTA (EUnetHTA) and the International Network of Agencies for HTA (INAHTA) were accessed and searched through the use of the term "disinvestment". Retrieved deliverables were considered eligible if they reported methodological projects/frameworks, case studies and dissemination initiatives focused on disinvestment in healthcare., Results: 62 HTA agencies/organizations were accessed and eight methodological projects/frameworks, one case study and one dissemination initiative were found starting from 2007. With respect to methodological projects/frameworks, two were delivered in Austria, one in Italy, two in Spain and three in U.K. As for the case study and the dissemination initiative, both came from U.K. The majority of deliverables were aimed at making an overview of existing disinvestment approaches and at identifying challenges in their introduction., Conclusions: Today, in a healthcare context characterized by resource scarcity and increasing service demand, "disinvestment" from low-value services and reinvestment in high-value ones is a key strategy that may be supported by HTA. The lack of evaluation of technologies in use, in particular at the end of their lifecycle, may be due to the scant availability of frameworks and guidelines for identification and assessment of obsolete technologies that was shown by our work. Although several projects were carried out in different countries, most remain constrained to the field of research. Disinvestment is a relatively new concept in HTA that could pose challenges also from a methodological point of view. To tackle these challenges, it is necessary to construct experiences at international level with the aim to develop new methodological approaches to produce and grow evidence on disinvestment policies and practices.

Objective: Regular physical activity (PA) reduces the risk of disease and premature death. Knowing factors associated with PA might help reducing the disease and economic burden caused by low activity. Studies suggest that socio-cultural factors may affect PA, but systematic overviews of findings across the life course are scarce. This umbrella systematic literature review (SLR) summarizes and evaluates available evidence on socio-cultural determinants of PA in children, adolescents, and adults., Methods: This manuscript was drafted following the recommendations of the 'Preferred Reporting Items for Systematic reviews and Meta-Analyses' (PRISMA) checklist. The MEDLINE, Web of Science, Scopus, and SPORTDiscus databases were searched for SLRs and meta-analyses (MAs) on observational studies published in English that assessed PA determinants between January 2004 and April 2016. The methodological quality was assessed and relevant information on socio-cultural determinants and any associations with PA was extracted. The available evidence was evaluated based on the importance of potential determinants and the strength of the evidence., Results: Twenty SLRs and three MAs encompassing 657 eligible primary studies investigated potential socio-cultural PA determinants, with predominantly moderate methodological quality. Twenty-nine potential PA determinants were identified that were primarily assessed in children and adolescents and investigated the micro-environmental home/household level. We found probable evidence that receiving encouragement from significant others and having a companion for PA were associated with higher PA in children and adolescents, and that parental marital status (living with partner) and experiencing parental modeling were not associated with PA in children. Evidence for the other potential determinants was limited, suggestive, or non-conclusive. In adults, quantitative and conclusive data were scarce., Conclusions: A substantial number of SLRs and MAs investigating potential socio-cultural determinants of PA were identified. Our data suggest that receiving social support from significant others may increase PA levels in children and adolescents, whereas parental marital status is not a determinant in children. Evidence for other potential determinants was limited. This was mainly due to inconsistencies in results on potential socio-cultural determinants of PA across reviews and studies., Trial Registrations: This umbrella SLR was recorded on PROSPERO (Record ID: CRD42015010616 ).

Background: Endometriosis is a chronic gynecological inflammatory disease characterized by the presence of functional endometrial glands and stroma outside of the uterine cavity. It affects 7-10% of women of reproductive age and up to 50% of women with infertility. The current gold standard for the diagnosis combines laparoscopic evaluation and biopsy of the visualized lesions. However, laparoscopy requires general anesthesia and developed surgical skills and it has a high procedural cost. In addition, it is associated with the risk, although rare, of potential intraoperative or postoperative complications. To date, several noninvasive biomarkers have been proposed; however, no definite diagnostic biomarker is yet available. The aim of this study was to characterize the CM proteome in patients with endometriosis using high resolution mass spectrometry-based proteomics, implemented by bioinformatic tools for quantitative analysis, in order to investigate the pathophysiological mechanisms of endometriosis., Methods: Cervical mucus samples were collected from patients affected by endometriosis and fertile controls. An aliquot of the soluble acidic fraction of each cervical mucus sample, corresponding to 0.5 mg of total protein, was left to digest with sequencing grade modified porcine trypsin. The peptides were analyzed by LC-MS/MS on a high resolution Orbitrap Elite mass spectrometer and data were evaluated using bioinformatic tools., Results: We aimed at the first total profiling of the cervical mucus proteome in endometriosis. From the list of identified proteins, we detected a number of differentially expressed proteins, including some functionally significant proteins. Six proteins were quantitatively increased in endometriosis, almost all being involved in the inflammatory pattern. Nine proteins were quantitatively reduced in endometriosis, including some proteins related with local innate immunity (CRISP-3 and Pglyrp1) and protection against oxidative stress (HSPB1). Fifteen proteins were not detected in endometriosis samples including certain proteins involved in antimicrobial activity (SLURP1 and KLK13) and related to seminal plasma liquefaction and male fertility (KLK13)., Conclusions: This is the first application of high resolution mass spectrometry-based proteomics aimed in detecting an array of proteins in CM to be proposed for the noninvasive diagnosis of endometriosis. This chronic disease presents in CM an inflammatory protein pattern.

Background: Dystroglycan (DG) is an adhesion receptor complex composed of two non-covalently associated subunits, transcribed from a single gene. The extracellular α-DG is highly and heterogeneously glycosylated and binds with high affinity to laminins, and the transmembrane β-DG binds intracellular dystrophin. Multiple cellular functions have been proposed for DG, notwithstanding that its role in skeletal muscle appears central as demonstrated by both primary and secondary severe muscular dystrophic phenotypes collectively known as dystroglycanopathies. We recently analysed the molecular phylogeny of the DG core protein and identified the α/β interface, transmembrane and cytoplasmic domains of β-DG as the most conserved region. It was also identified that the IG2&#95;MAT&#95;NU region has been independently duplicated in multiple lineages., Results: To understand the evolution of dystroglycan in more depth, we investigated dystroglycan gene structure in 35 species representative of the phyla in which dystroglycan has been identified (i.e., all metazoan phyla except Ctenophora). The gene structure of three exons and two introns is remarkably conserved. However, additional lineage-specific introns were identified, which interrupt the coding sequence at distinct points, were identified in multiple metazoan groups, most prominently in ecdysozoans., Conclusions: A coding DNA sequence (CDS) intron that interrupts the encoding of the IG1 domain is universally conserved and this intron is longer in gnathostomes (jawed vertebrates) than in other metazoans. Lineage-specific gain of additional introns has occurred notably in ecdysozoans, where multiple introns interrupt the large 3' exon. More limited intron gain has also occurred in placozoa, cnidarians, urochordates and the DG paralogues of lamprey and teleost fish.

Background: A large proportion of European children, adults and older adults do not engage in sufficient physical activity (PA). Understanding individual and contextual factors associated with PA behaviours is essential for the identification and implementation of effective preventative environments, policies, and programmes that can promote an active lifestyle across life course and can potentially improve health. The current paper intends to provide 1) a multi-disciplinary, Pan-European and life course view of key determinants of PA behaviours and 2) a proposal of how these factors may cluster., Methods: After gathering a list of 183 potential PA behaviours-associated factors and a consensus meeting to unify/consolidate terminology, a concept mapping software was used to collate European experts' views of 106 identified factors for youth (<19 years), adults (19-64 years), and older adults (≥65 years). The analysis evaluated common trends in the clustering of factors and the ratings of the distinct factors' expected modifiability and population-level impact on PA behaviours across the life course. Priority for research was also assessed for each cluster., Results: The concept mapping resulted in six distinct clusters, broadly merged in two themes: 1) the 'Person', which included clusters 'Intra-Personal Context and Wellbeing' and 'Family and Social Economic Status' (42 % of all factors) and 2) the 'Society', which included the remaining four clusters 'Policy and Provision', 'Cultural Context and Media', 'Social Support and Modelling', and 'Supportive Environment' (58 % of all factors). Overall, 25 factors were rated as the most impactful on PA behaviours across the life course and being the most modifiable. They were mostly situated in the 'Intra-Personal Context and Wellbeing' cluster. Furthermore, 16 of them were rated as top priority for research., Conclusions: The current framework provides a preliminary overview of factors which may account for PA behaviour across the life course and are most relevant to the European community. These insights could potentially be a foundation for future Pan-European research on how these factors might interact with each other, and assist policy makers to identify appropriate interventions to maximize PA behaviours and thus the health of European citizens.

Background: The interRAI-Home Care (interRAI-HC) instrument is commonly used in routine care to assess care and service needs, resource utilisation and health outcomes of community dwelling home care clients. Potentially, the interRAI-HC can also be used to calculate societal costs in economic evaluations. The purpose of this study was to assess the convergent validity of the interRAI-HC instrument in comparison with the RUD Lite instrument for the calculation of societal costs among care-dependent community dwelling older adults., Methods: A within-subject design was used. Participants were 65 years and older and received professional community care in five countries. The RUD Lite was administered by trained (research) nurses or self-reports within 4 weeks after the interRAI-HC assessment. Agreement between the interRAI-HC and RUD Lite estimates was assessed using Spearman's correlation coefficients. We hypothesised that there was strong correlation (Spearman's ρ > 0.5) between resource utilisation estimates, costs of care estimates and total societal cost estimates derived from both instruments., Results: Strong correlation was found between RUD Lite and interRAI-HC resource utilisation assessments for eight out of ten resource utilisation items. Total societal costs according to the RUD Lite were statistically significantly lower than according to the interRAI-HC (mean difference €-804, 95 % CI -1340; -269). The correlation between the instruments for total societal costs and all six cost categories was strong., Conclusions: The interRAI-HC has good convergent validity as compared with the RUD-Lite instrument to estimate societal cost of resource utilisation in community dwelling older adults. Since interRAI-HC assessments are part of routine care in many community care organisations and countries already, this finding may increase the feasibility of performing economic evaluations among community dwelling older adults.

Background: To assess both qualitatively and quantitatively the impact of Public Reporting (PR) on clinical outcomes, we carried out a systematic review of published studies on this topic., Methods: Pubmed, Web of Science and SCOPUS databases were searched to identify studies published from 1991 to 2014 that investigated the relationship between PR and clinical outcomes. Studies were considered eligible if they investigated the relationship between PR and clinical outcomes and comprehensively described the PR mechanism and the study design adopted. Among the clinical outcomes identified, meta-analysis was performed for overall mortality rate which quantitative data were exhaustively reported in a sufficient number of studies. Two reviewers conducted all data extraction independently and disagreements were resolved through discussion. The same reviewers evaluated also the quality of the studies using a GRADE approach., Results: Twenty-seven studies were included. Mainly, the effect of PR on clinical outcomes was positive. Meta-analysis regarding overall mortality included, in a context of high heterogeneity, 10 studies with a total of 1,840,401 experimental events and 3,670,446 control events and resulted in a RR of 0.85 (95 % CI, 0.79-0.92)., Conclusions: The introduction of PR programs at different levels of the healthcare sector is a challenging but rewarding public health strategy. Existing research covering different clinical outcomes supports the idea that PR could, in fact, stimulate providers to improve healthcare quality.

Background: Neonatal blueberry muffin lesions are rare cutaneous eruptions, presenting as transient, non-blanching, red-violaceous papules, mostly localized in the trunk, head and neck, attributable to a marked dermal hematopoietic activity. Congenital infections of the TORCH complex (toxoplasmosis, other, rubella, cytomegalovirus and herpes) and hematological disorders have been classically associated with this neonatal dermatological manifestation. We report for the first time an unusual presentation of blueberry muffin lesions in a neonate born from a mother affected by severe anemia during pregnancy., Case Presentation: A male, white Caucasian, neonate showed a cutaneous rash at birth, suggestive of "blueberry muffin"-like lesions. These cutaneous lesions were associated with marked elevation of the circulating nucleated red blood cells, and with ultrasound findings of peculiar brain ischemic porencephalic lesions. The clinical features of spontaneous disappearance and the association with marked erythroblastosis strongly suggest that these dermatological findings may be the consequence of an extramedullary hematopoiesis unexpectedly evoked by the intrauterine chronic exposure to hypoxia caused by severe maternal anemia., Conclusions: In conclusion, fetal hypoxia secondary to severe maternal anemia may play a causative and unreported role in the development of neonatal blueberry muffin lesions.

Background: Fragile X syndrome (FXS) is caused by CGG expansion over 200 repeats at the 5' UTR of the FMR1 gene and subsequent DNA methylation of both the expanded sequence and the CpGs of the promoter region. This epigenetic change causes transcriptional silencing of the gene. We have previously demonstrated that 5-aza-2-deoxycytidine (5-azadC) treatment of FXS lymphoblastoid cell lines reactivates the FMR1 gene, concomitant with CpG sites demethylation, increased acetylation of histones H3 and H4 and methylation of lysine 4 on histone 3., Results: In order to check the specificity of the 5-azadC-induced DNA demethylation, now we performed bisulphite sequencing of the entire methylation boundary upstream the FMR1 promoter region, which is preserved in control wild-type cells. We did not observe any modification of the methylation boundary after treatment. Furthermore, methylation analysis by MS-MLPA of PWS/AS and BWS/SRS loci demonstrated that 5-azadC treatment has no demethylating effect on these regions. Genome-wide methylation analysis through Infinium 450K (Illumina) showed no significant enrichment of specific GO terms in differentially methylated regions after 5-azadC treatment. We also observed that reactivation of FMR1 transcription lasts up to a month after a 7-day treatment and that maximum levels of transcription are reached at 10-15 days after last administration of 5-azadC., Conclusions: Taken together, these data demonstrate that the demethylating effect of 5-azadC on genomic DNA is not random, but rather restricted to specific regions, if not exclusively to the FMR1 promoter. Moreover, we showed that 5-azadC has a long-lasting reactivating effect on the mutant FMR1 gene.

Background: Modern healthcare is characterized by high complexity due to the proliferation of specialties, professional roles, and priorities within organizations. To perform clinical interventions, knowledge distributed across units, directorates and individuals needs to be integrated. Formal and/or informal mechanisms may be used to coordinate knowledge and tasks within organizations. Although the literature has recently considered the role of physicians' professional networks in the diffusion of knowledge, several concerns remain about the mechanisms through which these networks emerge within healthcare organizations. The aim of the present paper is to explore the impact of institutional and professional homophilies on the formation of interphysician professional networks., Methods: We collected data on a community of around 300 physicians working at a local health authority within the Italian National Health Service. We employed multiple regression quadratic assignment procedures to explore the extent to which institutional and professional homophilies influence the formation of interphysician networks., Results: We found that both institutional and professional homophilies matter in explaining interphysician networks. Physicians who had similar fields of interest or belonged to the same organizational structure were more likely to establish professional relationships. In addition, professional homophily was more relevant than institutional affiliation in explaining collaborative ties., Conclusions: Our findings have organizational implications and provide useful information for managers who are responsible for undertaking organizational restructuring. Healthcare executives and administrators may want to consider the structure of advice networks while adopting new organizational structures.

Background: Mathematical or statistical tools are capable to provide a valid help to improve surveillance systems for healthcare and non-healthcare-associated bacterial infections. The aim of this work is to evaluate the time-varying auto-adaptive (TVA) algorithm-based use of clinical microbiology laboratory database to forecast medically important drug-resistant bacterial infections., Methods: Using TVA algorithm, six distinct time series were modelled, each one representing the number of episodes per single 'ESKAPE' (E nterococcus faecium, S taphylococcus aureus, K lebsiella pneumoniae, A cinetobacter baumannii, P seudomonas aeruginosa and E nterobacter species) infecting pathogen, that had occurred monthly between 2002 and 2011 calendar years at the Università Cattolica del Sacro Cuore general hospital., Results: Monthly moving averaged numbers of observed and forecasted ESKAPE infectious episodes were found to show a complete overlapping of their respective smoothed time series curves. Overall good forecast accuracy was observed, with percentages ranging from 82.14% for E. faecium infections to 90.36% for S. aureus infections., Conclusions: Our approach may regularly provide physicians with forecasted bacterial infection rates to alert them about the spread of antibiotic-resistant bacterial species, especially when clinical microbiological results of patients' specimens are delayed.

Background: Increased activation of mammalian target of rapamycin (mTOR) is observed in numerous human cancers. Recent studies on the glioma kinome have identified several deregulated pathways that converge and activate mTOR. The available evidence on the role of microglia in CNS cancers would suggest a dual role, a tumoricidal role and -on the contrary- a role favoring tumor growth., Methods: In the present paper, we have compared the effects of μM concentrations of rapamycin (RAPA) and its analog, RAD001 (RAD), on activated microglia; the latter was obtained by exposing cells to conditioned medium harvested either from inflammatory activated glioma cells (LI-CM) or from glioma cells kept under basal conditions (C-CM)., Results: Here we show that the inhibition of mTOR polarizes glioma-activated microglial cells towards the M1 phenotype, with cytotoxic activities, preventing the induction of the M2 status that promotes tumor growth. In fact RAPA and RAD significantly increased iNOS expression and activity, while on the same time significantly reducing IL-10 gene expression induced by C-CM, thus suggesting that the drugs prevent the acquisition of a M2 phenotype in response to glioma factors promoting a classic M1 activation. Similar results were obtained using the conditioned media obtained after glioma stimulation with LPS-IFNγ (LI-CM), which was found to induce a mixture of M1 and M2a/b polarization phenotypes. In these conditions, the inhibition of mTOR led to a significant up-regulation of iNOS, and in parallel to the down-regulation of both ARG and IL-10 gene expression., Conclusions: These data suggest that mTOR inhibition may prevent glioma induced M2 polarization of microglial cells and increase their cytotoxic potential, possibly resulting in antitumor actions.

Background: To determine whether the functional effects of oral supplementation with Saffron, a natural compound that proved to be neuroprotective in early age-related macular degeneration, are influenced by complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) risk genotypes., Methods: Thirty-three early AMD patients, screened for CFH (rs1061170) and ARMS2 (rs10490924) polymorphisms and receiving Saffron oral supplementation (20 mg/day) over an average period of treatment of 11 months (range, 6-12), were longitudinally evaluated by clinical examination and focal electroretinogram (fERG)-derived macular (18°) flicker sensitivity estimate. fERG amplitude and macular sensitivity, the reciprocal value of the estimated fERG amplitude threshold, were the main outcome measures., Results: After three months of supplementation, mean fERG amplitude and fERG sensitivity improved significantly when compared to baseline values (p < 0.01). These changes were stable throughout the follow-up period. No significant differences in clinical and fERG improvements were observed across different CFH or ARMS2 genotypes., Conclusions: The present results indicate that the functional effect of Saffron supplementation in individual AMD patients is not related to the major risk genotypes of disease.

Background: We examined the methodological quality of guidelines on syndromes conferring genetic susceptibility to breast cancer., Methods: PubMed, EMBASE, and Google were searched for guidelines published up to October 2010. All guidelines in English were included. The Appraisal of Guidelines, Research and Evaluation (AGREE) instrument was used to assess the quality of the guidelines, and their reported evidence base was evaluated., Results: Thirteen guidelines were deemed eligible: seven had been developed by independent associations, and the other six had national/state endorsements. Four guidelines performed satisfactorily, achieving a score of greater than 50% in all six AGREE domains. Mean ± SD standardized scores for the six AGREE domains were: 90 ± 9% for 'scope and purpose', 51 ± 18% for 'stakeholder involvement', 55 ± 27% for 'rigour of development', 80 ± 11% for 'clarity and presentation', 37 ± 32% for 'applicability', and 47 ± 38% for 'editorial independence'. Ten of the thirteen guidelines were found to be based on research evidence., Conclusions: Given the ethical implications and the high costs of genetic testing for hereditary breast cancer, guidelines on this topic should provide clear and evidence-based recommendations. Our analysis shows that there is scope for improving many aspects of the methodological quality of current guidelines. The AGREE instrument is a useful tool, and could be used profitably by guidelines developers to improve the quality of recommendations.

Background: Legionella pneumophila is increasingly recognised as a significant cause of sporadic and epidemic community-acquired and nosocomial pneumonia. Many studies describe the frequency and severity of Legionella spp. contamination in spa pools, natural pools, hotels and ships, but there is no study analysing the environmental monitoring of Legionella on board trains. The aims of the present study were to conduct periodic and precise environmental surveillance of Legionella spp. in water systems and water tanks that supply the toilet systems on trains, to assess the degree of contamination of such structures and to determine the effectiveness of decontamination., Methods: A comparative pre-post ecological study was conducted from September 2006 to January 2011. A total of 1,245 water samples were collected from plumbing and toilet water tanks on passenger trains. The prevalence proportion of all positive samples was calculated. The unpaired t-test was performed to evaluate statistically significant differences between the mean load values before and after the decontamination procedures; statistical significance was set at p ≤ 0.05., Results: In the pre-decontamination period, 58% of the water samples were positive for Legionella. Only Legionella pneumophila was identified: 55.84% were serogroup 1, 19.03% were serogroups 2-14 and 25.13% contained both serogroups. The mean bacterial load value was 2.14 × 10(3) CFU/L. During the post-decontamination period, 42.75% of water samples were positive for Legionella spp.; 98.76% were positive for Legionella pneumophila: 74.06% contained serogroup 1, 16.32% contained serogroups 2-14 and 9.62% contained both. The mean bacterial load in the post-decontamination period was 1.72 × 10(3) CFU/L. According to the t-test, there was a statistically significant decrease in total bacterial load until approximately one and a half year after beginning the decontamination programme (p = 0.0097)., Conclusions: This study indicates that systematic environmental surveillance could be a useful approach for assessing the risk of exposure to Legionella bacteria, which still represents a public health threat. According to the study results, an environmental surveillance programme, followed by decontamination procedures where necessary, would decrease the total bacterial count, protecting the health of travellers and workers.

Background: Epitope tags and fluorescent fusion proteins have become indispensable molecular tools for studies in the fields of biochemistry and cell biology. The knowledge collected on the subdomain organization of the two subunits of the adhesion complex dystroglycan (DG) enabled us to insert the 10 amino acids myc-tag at different locations along the α-subunit, in order to better visualize and investigate the DG complex in eukaryotic cells., Results: We have generated two forms of DG polypeptides via the insertion of the myc-tag 1) within a flexible loop (between a.a. 170 and 171) that separates two autonomous subdomains, and 2) within the C-terminal domain in position 500. Their analysis showed that double-tagging (the β-subunit is linked to GFP) does not significantly interfere with the correct processing of the DG precursor (pre-DG) and confirmed that the α-DG N-terminal domain is processed in the cell before α-DG reaches its plasma membrane localization. In addition, myc insertion in position 500, right before the second Ig-like domain of α-DG, proved to be an efficient tool for the detection and pulling-down of glycosylated α-DG molecules targeted at the membrane., Conclusions: Further characterization of these and other myc-permissive site(s) will represent a valid support for the study of the maturation process of pre-DG and could result in the creation of a new class of intrinsic doubly-fluorescent DG molecules that would allow the monitoring of the two DG subunits, or of pre-DG, in cells without the need of antibodies.

Background: The risk of acquisition of antibiotic resistant-bacteria during or shortly after antibiotic therapy is still unclear and it is often confounded by scarce data on antibiotic usage.Primary objective of the study is to compare rates of acquisition of methicillin-resistant Staphylococcus aureus and extended spectrum beta-lactamase-producing Enterobacteriaceae in hospitalised patients, after starting antibiotic therapy., Methods/design: The study, running in three European hospitals, is a multicenter, prospective, longitudinal, observational cohort study funded from the European Community's Seventh Framework Programme [FP7/2007-2013] within the project 'Impact of Specific Antibiotic Therapies on the prevalence of hUman host ResistaNt bacteria' (acronym SATURN). Nasal and rectal screening for methicillin-resistant Staphylococcus aureus and extended spectrum beta-lactamase-producing Enterobacteriaceae will be obtained at hospital admission, discharge, at antibiotic start (t0, within one hour) and at the following intervals: day 3 (t1), 7 (t2), 15 (t3), and 30 (t4). Two nested case-control studies will be performed. The objective of the first study will be to define individual level of risk related to specific antibiotics. Patients acquiring methicillin-resistant Staphylococcus aureus and extended spectrum beta-lactamase-producing Enterobacteriaceae (cases) will be compared with patients not acquiring antibiotic-resistant strains after starting antibiotic therapy (controls; ratio 1:4). To define the impact of antibiotics on new acquisition of target antibiotic-resistant bacteria, a second nested case-control study will be done (ratio 1:4). Control group will be selected among patients not receiving antibiotics, admitted in the same ward on the day of the corresponding case, with negative cultures at admission. Epidemiological, clinical and microbiological data will be prospective collected., Discussion: The rationale of this study is to better understand the impact of antibiotic use on acquisition, selection and transmission of antimicrobial resistant-bacteria in European hospitals., Trial Registration: ClinicalTrials.gov NCT01208519.

Background: The healthcare management literature states that physicians often coordinate their activities within and between organizations through social networks. Previous studies have also documented the relationship between professional networks and physicians' attitudes toward evidence-based medicine (EBM). The present study sought associations between physicians' self-reported attitudes toward EBM and the formation of inter-physician collaborative network ties., Methods: Primary data were collected from 297 clinicians at six hospitals belonging to one of the largest local health units of the Italian National Health Service. Data collection used a survey questionnaire that inquired about professional networks and physicians' characteristics. Social network analysis was performed to describe inter-physician professional networks. Multiple regression quadratic assignment procedures were performed to assess the relationship between self-reported attitudes toward EBM and clinicians' propensity to collaborate., Results: Physicians who reported similar attitudes toward EBM were more likely to exchange information and advice through collaborative relationships (β = 0.0198; p < 0.05). Similarities in other characteristics, such as field of specialization (β = 0.1988; p < 0.01), individual affiliations with hospital sites (β = 0.0845; p < 0.01), and organizational clinical directorates (β = 0.0459; p < 0.01), were also significantly related to physicians' propensity to collaborate., Conclusions: Communities of practice within healthcare organizations are likely to contain separate clusters of physicians whose members are highly similar. Organizational interventions are needed to foster heterophily whenever multidisciplinary cooperation is required to provide effective health care.

Background: Fluconazole (FLC), a triazole antifungal drug, is widely used for the maintenance therapy of cryptococcal meningoencephalitis, the most common opportunistic infection in AIDS patients. In this study, we examined changes in the gene expression profile of the C. neoformans reference strain H99 (serotype A) following FLC treatment in order to investigate the adaptive cellular responses to drug stress., Results: Simultaneous analysis of over 6823 transcripts revealed that 476 genes were responsive to FLC. As expected up-regulation of genes involved in ergosterol biosynthesis was observed, including the azole target gene ERG11 and ERG13, ERG1, ERG7, ERG25, ERG2, ERG3 and ERG5. In addition, SRE1 which is a gene encoding a well-known regulator of sterol homeostasis in C. neoformans was up-regulated. Several other genes such as those involved in a variety of important cellular processes (i.e. lipid and fatty acid metabolism, cell wall maintenance, stress and virulence) were found to be up-regulated in response to FLC treatment. Conversely, expression of AFR1, the major transporter of azoles in C. neoformans, was not regulated by FLC., Conclusions: Short-term exposure of C. neoformans to FLC resulted in a complex altered gene expression profile. Some of the observed changes could represent specific adaptive responses to the antifungal agent in this pathogenic yeast.

Introduction and Objectives: Physical deformities caused by adolescent idiopathic scoliosis (AIS) coupled with conservative treatment of AIS with orthesis unavoidably impacts on patients' quality of life (QoL). The present study aimed at evaluating the QoL in patients affected by AIS treated with brace. The study also sought to determine the ability of different QoL questionnaires to monitor QoL over the course of treatment., Materials and Methods: Data were collected in 108 consecutive patients (96 females, 16 males) affected by AIS admitted to the outpatient orthopaedic clinic of the Catholic University of the Sacred Heart in Rome (Italy). Patients were subjected to full-time (i.e., 22 hrs per day) conservative treatment with the progressive action short brace (PASB), the Lyon brace or a combination of PASB + Lyon brace. Three instruments were used for QoL determination: the Scoliosis Research Society 22 (SRS-22), Bad Sobernheim Stress Questionnaire (BSSQ) and the Brace Questionnaire (BrQ)., Results: A significant correlation was detected among the 3 scores (p < 0.001). The BrQ possesses a higher capacity to detect changes in QoL in relation to the patient gender, type of brace, curve severity at baseline and at the completion of treatment, and curve type. Overall, boys displayed a higher QoL than girls. In all 3 questionnaires, higher QoL scores were determined in patients treated with the PASB compared with those using the Lyon brace. QoL scores were significantly correlated with the curve severity. Higher QoL scores were obtained by participants with thoraco-lumbar curves as compared with those with other curves., Conclusions: The 3 questionnaires are effective in capturing changes in QoL in AIS patients subjected to conservative treatment. However, the BrQ possesses a higher discriminatory capacity compared with the other questionnaires tested. PASB-based treatment is associated with better QoL than the Lyon bracing.

Background: Hospital discharge planning is aimed to decrease length of stay in hospitals as well as to ensure continuity of health care after being discharged. Hospitalized patients in Turin, Italy, who are in need of medical, social and rehabilitative care are proposed as candidates to either discharge planning relying on a care-home model (DPCH) for a period of about 30 days, or routine discharge care. The aim of this study was to evaluate whether a hospital DPCH that was compared with routine care, improved patients' outcomes in terms of reduced hospital readmission and mortality rates in patients aged 64 years and older., Methods: In a retrospective observational cohort study a sample of 380 subjects aged 64 years and over was examined. Participants were discharged from the hospital S. Giovanni Bosco in Turin, Italy from March 1st, 2005 to February 28th, 2006. Of these subjects, 107 received routine discharge care while 273 patients were referred to care-home (among them, 99 received a long-term care intervention (LTCI) afterwards while 174 did not). Data was gathered from various administrative and electronic databases. Cox regression models were used to evaluate factors associated with mortality and hospital readmission., Results: When socio-demographic factors, underlying disease and disability were taken into account, DPCH decreased mortality rates only if it was followed by a LTCI: compared to routine care, the Hazard Ratio (HR) of death was 0.36 (95% Confidence Interval (CI): 0.20 - 0.66) and 1.15 (95%CI: 0.77 - 1.74) for DPCH followed by LTCI and DPCH not followed by LTCI, respectively. On the other hand, readmission rates did not significantly differ among DPCH and routine care, irrespective of the implementation of a LTCI: HRs of hospital readmission were 1.01 (95%CI: 0.48 - 2.24) and 1.18 (95%CI: 0.71 - 1.96), respectively., Conclusion: The use of DPCH after hospital discharge reduced mortality rates, but only when it was followed by a long-term health care plan, thus ensuring continuity of care for elderly participants.

Introduction: The aim of our analysis was to compare the gaining of a major response (disease activity score [DAS] remission or American College of Rheumatology 70% improvement criteria [ACR70]) by switching between all the available biological therapies in rheumatoid arthritis., Methods: A systematic review was performed including studies, published before December 2008, in which a second biological agent was used and clinical outcomes were evaluated after a first biological failure., Results: Nine articles were included. Switching from etanercept and/or infliximab to adalimumab is effective with an ACR70 response ranging from 5% to 33%. Rituximab may be slightly more effective than switching to a second anti-tumor necrosis factor-alpha (anti-TNFalpha), reaching an ACR70 or DAS remission response in 12% and 9%, respectively. Clinical trials confirmed the efficacy in switching to abatacept (gain of effect 10.2%). Tocilizumab allows DAS28 (DAS using 28 joint counts) remission in 30.1% but ACR70 only in 12.4% of patients refractory to anti-TNFalpha., Conclusions: The efficacy of a second biological agent, irrespective of the mode of action, in reaching an ACR70 or DAS remission after a first biologic is observed from 5% to 15% and from 9% to 15.4%, respectively (except in two studies).

Introduction: Type II collagen is a DR4/DR1 restricted target of self-reactive T cells that sustain rheumatoid arthritis. The aim of the present study was to analyze the T-cell receptor repertoire at the onset of and at different phases in rheumatoid arthritis., Methods: We used the CDR3 BV-BJ spectratyping to study the response to human collagen peptide 261-273 in 12 patients with DR4+ rheumatoid arthritis (six at the onset of disease and six during the course of disease) and in five healthy DR4+ relatives., Results: The collagen-specific T-cell repertoire is quite restricted at the onset of disease, involving approximately 10 rearrangements. Within the studied collagen-specific rearrangements, nearly 75% is shared among patients. Although the size of the repertoire used by control individuals is comparable to that of patients, it is characterized by different T-cell receptors. Part of the antigen-specific T-cell repertoire is spontaneously enriched in synovial fluid. The specific T-cell repertoire in the periphery was modulated by therapy and decreased with the remission of the disease. Failure of immunoscopy to detect this repertoire was not due to suppression of collagen-driven proliferation in vitro by CD4+ CD25+ T cells. Clinical relapse of the disease was associated with the appearance of the original collagen-specific T cells., Conclusions: The collagen-specific T-cell receptor repertoire in peripheral blood and synovial fluid is restricted to a limited number of rearrangements in rheumatoid arthritis. The majority of the repertoire is shared between patients with early rheumatoid arthritis and it is modulated by therapy.