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Purpose: The present study evaluated the efficacy of a nursing educational intervention in alleviating the level of parental anxiety in the parents of children who required heart surgery for the first time., Design and Methods: A comparative study was used to explore the parents of children who had to undergo cardiac surgery. Parents of children were randomized into 2 groups: 1) control group and 2) experimental group or parents that received the educational intervention about PICU stay., Result: The results of STAY-1 showed that the average anxiety score of group 1 was lower than that of group 2 (63.0 [SD=3.5] vs. 70.4 [SD=2.8])., Conclusion: In order to decrease levels of parental anxiety and stress prior to paediatric surgery, parents should be adequately informed about planned therapeutic procedures., Practice Implications: We speculate that pre-surgery parent education on what to expect before, during and after their child's cardiac surgery may improve parents' knowledge and satisfaction and decrease anxiety., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Tuberculosis (TB) is an ancient and deadly disease characterized by complex host-pathogen dynamics playing out over multiple time and length scales and physiological compartments. Computational modeling can be used to integrate various types of experimental data and suggest new hypotheses, mechanisms, and therapeutic approaches to TB. Here, we offer a first-time comprehensive review of work on within-host TB models that describe the immune response of the host to infection, including the formation of lung granulomas. The models include systems of ordinary and partial differential equations and agent-based models as well as hybrid and multi-scale models that are combinations of these. Many aspects of M. tuberculosis infection, including host dynamics in the lung (typical site of infection for TB), granuloma formation, roles of cytokine and chemokine dynamics, and bacterial nutrient availability have been explored. Finally, we survey applications of these within-host models to TB therapy and prevention and suggest future directions to impact this global disease.

Primary distal renal tubular acidosis is a rare genetic disease. Mutations in SLC4A1, ATP6V0A4, and ATP6V1B1 genes have been described as the cause of the disease, transmitted as either an autosomal dominant or recessive trait. Particular clinical features, such as sensorineural hearing loss, have been mainly described in association with mutations in one gene instead of the others. Nevertheless, the diagnosis of distal renal tubular acidosis is essentially based on clinical and laboratory findings, and the series of patients described so far are usually represented by small cohorts. Therefore, a strict genotype-phenotype correlation is still lacking, and questions about whether clinical and laboratory data should direct the genetic analysis remain open. Here, we applied next-generation sequencing in 89 patients with a clinical diagnosis of distal renal tubular acidosis, analyzing the prevalence of genetic defects in SLC4A1, ATP6V0A4, and ATP6V1B1 genes and the clinical phenotype. A genetic cause was determined in 71.9% of cases. In our group of sporadic cases, clinical features, including sensorineural hearing loss, are not specific indicators of the causal underlying gene. Mutations in the ATP6V0A4 gene are quite as frequent as mutations in ATP6V1B1 in patients with recessive disease. Chronic kidney disease was frequent in patients with a long history of the disease. Thus, our results suggest that when distal renal tubular acidosis is suspected, complete genetic testing could be considered, irrespective of the clinical phenotype of the patient., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Introduction: In healthcare, smartphone is becoming an important tool among nursing population. With the smartphones, it was possible to implement new care models. However, if used incorrectly, it could be the cause of nurses' distraction and nosocomial infection., Aim: To analyze the various apps used by the nursing population and describe the smartphones' positive and negative aspects on health care by review the literature., Method: PubMed, CINAHL, SCOPUS e Web of Knowledge, Google Schoolar, databases were used to perform this study. The following keywords were used: ((nurse* NOT (student* OR physician*)) AND (smartphone* OR phone* OR mobile* OR cellphone) AND (app OR use* OR benefit OR distraction OR stress OR abuse OR work-related)., Results: A total of 34 articles were included in the review. Medical calculation, heart measurement and chronic patient-nurse communication apps were described. While smartphones may cause distraction, nosocomial infection or interference with other medical devices, on the other hand they could improve the well-being, job satisfaction, productivity and decrease stress in nurse population., Conclusions: There are potential benefits of the smartphone use, but the smartphone misuse could have negative consequences on the quality care and patient' safety due to nurses' distraction and interruptions. For this reason, nurses should be careful when they use their smartphone for no work-related activities.

Background and Aim: In the last years we have seen an ever increasing number of patients with haematologic disorders who need hematopoietic stem cell transplantation (HSCT). The whole sector of HSCT results, infact to be in a continous scientific and technological clinical progress, offering a very advanced care. Despite this, some aspects are underconsidered, some of which could be fundamental to determine the success of the care pathway, such as the experience of the illness by the patient. Using a Narrative Based Medicine approach we wanted to investigate clinical, psychosocial and organizational aspects of the patient's journey whilst undergoing HSCT., Method: Various narrative interviews were conducted using non-structured approach. Results were analysed by thematic contents., Results: Psycological dimension is the most compromised: above all emerged sentiments of oppression linked to the isolation period in the Low Bacterial Load (LBL) room. To note are also the different dynamics with which the patients perceive the organisation and hospital structures, and how much these factors can influence their care experience., Conclusions: Results suggest the need in clinical practice of an integration between qualitative and clinical approach, so as to permit the psychosocial and relational necessities to emerge, often unexpressed by patients undergoing HSCT.

Background and Purpose: The purpose of this study was to examine changes in stroke survivor and caregiver quality of life (QOL) and to determine whether changes in survivor physical functioning and caregiver burden (ie, the impact of the physical, psychological, and social demands of caregiving) influence changes in QOL., Methods: Longitudinal design with 226 stroke survivor-caregiver dyads enrolled at survivor discharge from rehabilitation hospitals. Data collection was performed over 12 months. We measured survivor physical functioning, caregiver burden, and QOL (physical, psychological, social, and environmental) in both survivor and caregiver. Multilevel modeling was used to control for the interdependence of the data., Results: Survivors (50% male sex) and caregivers (66% female sex) were 70.8 (SD=11.9) and 52.4 (SD=13.1) years old, respectively. Over the 12 months, stroke survivor's physical (γ=1.59; P <0.001) and psychological (γ=0.86; P <0.05) QOL significantly improved; social and environmental QOL did not P >0.05. Caregiver QOL, on average, did not significantly change over time P >0.05. Improvements in survivor physical functioning were associated with increases in survivor and caregiver physical and psychological QOL and survivor environmental QOL. Decreases in caregiver burden were significantly associated with improvements in caregiver physical, psychological, and environmental QOL but not with survivor QOL., Conclusions: QOL of stroke survivors and caregivers covaries and is greatly impacted by the physical function changes of the survivor. Dyadic approaches to stroke rehabilitation that acknowledge the interdependence of dyads are needed., (© 2017 American Heart Association, Inc.)

Background: Dietary intervention studies are required to deeper understand the variability of gut microbial ecosystem in healthy dogs under different feeding conditions and to improve diet formulations. The aim of the study was to investigate in dogs the influence of a raw based diet supplemented with vegetable foods on faecal microbiome in comparison with extruded food., Methods: Eight healthy adult Boxer dogs were recruited and randomly divided in two experimental blocks of 4 individuals. Dogs were regularly fed a commercial extruded diet (RD) and starting from the beginning of the trial, one group received the raw based diet (MD) and the other group continued to be fed with the RD diet (CD) for a fortnight. After 14 days, the two groups were inverted, the CD group shifted to the MD and the MD shifted to the CD, for the next 14 days. Faeces were collected at the beginning of the study (T0), after 14 days (T14) before the change of diet and at the end of experimental period (T28) for DNA extraction and analysis of metagenome by sequencing 16SrRNA V3 and V4 regions, short chain fatty acids (SCFA), lactate and faecal score., Results: A decreased proportion of Lactobacillus, Paralactobacillus (P < 0.01) and Prevotella (P < 0.05) genera was observed in the MD group while Shannon biodiversity Index significantly increased (3.31 ± 0.15) in comparison to the RD group (2.92 ± 0.31; P < 0.05). The MD diet significantly (P < 0.05) decreased the Faecal Score and increased the lactic acid concentration in the feces in comparison to the RD treatment (P < 0.01). Faecal acetate was negatively correlated with Escherichia/Shigella and Megamonas (P < 0.01), whilst butyrate was positively correlated with Blautia and Peptococcus (P < 0.05). Positive correlations were found between lactate and Megamonas (P < 0.05), Escherichia/Shigella (P < 0.01) and Lactococcus (P < 0.01)., Conclusion: These results suggest that the diet composition modifies faecal microbial composition and end products of fermentation. The administration of MD diet promoted a more balanced growth of bacterial communities and a positive change in the readouts of healthy gut functions in comparison to RD diet.

Background: Late onset intrauterine growth restriction (IUGR) represents one of the main causes of perinatal morbidity/mortality. No guidelines are available on labor induction in IUGRs, even if delivery at 37/38 weeks is suggested. This study aims to assess maternal-fetal variables related to adverse outcome in labor induction for late IUGR., Methods: One hundred cases of induction for late IUGR were retrospectively revised on fetal weight, MCA, UA, CPR and uterine artery (utA) Doppler, oligohydramnios, Bishop score, start of induction, augmentation. The variables were matched with the following adverse outcomes: CS or vacuum extractor delivery (IVD); NICU admission; low Apgar score; UA pH < 7.10., Results: Regular vaginal delivery occurred in 65% of cases; the rate of CS and IVD was 32% and 5%. UA, MCA and CPR abnormalities were all significantly related to a higher risk of CS. Bishop score < 3 and start of induction by oxitocin resulted statistically associated to CS, while prostaglandins were related to vaginal delivery. No augmentation and oxitocin in labor were positively related to vaginal delivery. Maternal morbidity and Bishop score < 3 showed a significant association with NICU admission., Discussion: Doppler velocimetry of UA, MCA and CPR are useful tools for the identification and management of the late term IUGRs.

Background: Oxidative stress has been related to hypo-response to erythropoiesis-stimulating agents (ESAs) in hemodialysis (HD) patients. The aim of this study was to verify whether vitamin E (ViE) on a synthetic polysulfone dialyzer can improve ESA responsiveness., Methods: This controlled, multicenter study involved 93 HD patients on stable ESA therapy, who were randomized to either ViE-coated polysulfone dialyzer or to a low-flux synthetic dialyzer. The primary outcome measure was the change in ESA resistance index (ERI) from baseline., Results: Mean ERI decreased in the ViE group by 1.45 IU/kg*g/dl and increased in the control group by 0.53 IU/kg*g/dl, with a mean difference of 1.98 IU/kg*g/dl (p = 0.001 after adjusting for baseline ERI, as foreseen by the study protocol). Baseline ERI was inversely related to its changes during follow-up only in the control group (R2 = 0.29)., Conclusions: The ViE dialyzer can improve ESA response in HD patients. Changes in ERI during follow-up are independent from baseline ERI only in the ViE group. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=453442., (© 2017 S. Karger AG, Basel.)

Introduction: An ongoing national multicenter survey [Italian Oncologic Pain multiSetting Multicentric Survey (IOPS-MS)] is evaluating the characteristics of breakthrough cancer pain (BTP) in different clinical settings. Preliminary data from the first 1500 cancer patients with BTP enrolled in this study are presented here., Methods: Thirty-two clinical centers are involved in the survey. A diagnosis of BTP was performed by a standard algorithm. Epidemiological data, Karnofsky index, stage of disease, presence and sites of metastases, ongoing oncologic treatment, and characteristics of background pain and BTP and their treatments were recorded. Background pain and BTP intensity were measured. Patients were also questioned about BTP predictability, BTP onset (≤10 or >10 min), BTP duration, background and BTP medications and their doses, time to meaningful pain relief after BTP medication, and satisfaction with BTP medication. The occurrence of adverse reactions was also assessed, as well as mucosal toxicity., Results: Background pain was well controlled with opioid treatment (numerical rating scale 3.0 ± 1.1). Patients reported 2.5 ± 1.6 BTP episodes/day with a mean intensity of 7.5 ± 1.4 and duration of 43 ± 40 min; 977 patients (65.1%) reported non-predictable BTP, and 1076 patients (71.7%) reported a rapid onset of BTP (≤10 min). Higher patient satisfaction was reported by patients treated with fast onset opioids., Conclusions: These preliminary data underline that the standard algorithm used is a valid tool for a proper diagnosis of BTP in cancer patients. Moreover, rapid relief of pain is crucial for patients' satisfaction. The final IOPS-MS data are necessary to understand relationships between BTP characteristics and other clinical variables in oncologic patients., Funding: Molteni Farmaceutici, Italy.

Objective: To investigate the proportion of stillbirths at term associated with abnormal growth using customized birth weight percentiles and to compare histological placental findings both in underweight stillborn fetuses and in live births., Methods: A retrospective case-control study of 150 singleton term stillbirths. The livebirth control groups included 586 cases of low-risk pregnancies and 153 late fetal growth restriction fetuses. Stillbirths and livebirths from low-risk pregnancies were classified using customized standards for fetal weight at birth, as adequate for gestational age (AGA; 10-90th percentile), small (SGA; <10th percentile) or large for gestational age (LGA; >90th percentile). Placental characteristics in stillbirth were compared with those from livebirths using four categories: inflammation, disruptive, obstructive and adaptive lesions., Results: There was a higher rate of SGA (26% vs 6%, p<0.001) and LGA fetuses (10.6% vs 5.6%, p<0.05) in the stillbirth group. Among stillbirth fetuses, almost half of the SGA were very low birthweight (≤3°percentile) (12% vs 0.3%, p<0.001). The disruptive (7.3% vs 0.17%;p<0.001), obstructive (54.6% vs 7.5%;p<0.001) and adaptive (46.6% vs 35.8%;p<0.001) findings were significantly more common in than in livebirth-low risk. Placental characteristics of AGA and SGA stillbirth were compared with those of AGA and FGR livebirth. In stillbirths-SGA we found a higher number of disruptive (12.8% vs 0%; p<0.001), obstructive (58.9% vs 23.5%;p<0.001) and adaptive lesions (56.4% vs 49%; p 0.47) than in livebirth-FGR., Conclusion: The assessment of fetal weight with customized curves can identify fetuses which have not reached their genetically determined growth potential and are therefore at risk for adverse outcomes. Placental evaluation in stillbirths can reveal chronic histological signs that might be useful to clinical assessment, especially in underweight fetuses., Competing Interests: The authors have declared that no competing interests exist.

The advanced treatment of polluted liquid streams containing traces of pharmaceutical compounds is a major issue, since more and more effluents from pharma labs and wastewaters containing the excretions of medically treated humans and animals are discharged in the conventional wastewater treatment plants without previous effective treatments. Ibuprofen is a widely used non-steroidal anti-inflammatory drug (NSAID), which explains why it is found in wastewaters so often. In this paper, the removal of IBP from simulated water streams was investigated by using a lab-scale experimental device, consisting of a batch reactor equipped with a lamp emitting monochromatic UV light at a fixed wavelength (254 nm) and various intensities. Three sets of experiments were carried out: the first to study IBP concentration as a function of time, at different volumes of treated solutions (V = 10-30 mL); the second to explore the effect of pH on IBP degradation as a function of time (pH = 2.25-8.25) and the third to evaluate the effect of different UV light intensities on IBP degradation (E = 100-400 mJ m -2 ). The IBP initial concentration (IBP 0 ) was varied in the range 30-60 mg L -1 . The results obtained show that the concentration of IBP decreases along with treatment time, with a negative effect of the treated volume, i.e. smaller volumes, such as lower liquid heights, are more easily degraded. Moreover, the higher the pH, the better the IBP degradation; actually, when pH increases from 2.25 to 6.6 and 8.25, the IBP concentration, after an hour of treatment, decreases respectively to 45, 34 and 27 % of its initial value. In addition, as the intensity of light increases from 100 to 400 mJ m -2 , the IBP concentration decreases to 34 % of its initial value. A reaction scheme is put forward in the paper, which well describes the effects of volume, pH and light intensity on the IBP degradation measured experimentally. Moreover, the IBP degradation by-products have been identified.

Purpose: The Mutuality Scale (MS) is composed of four theoretically derived factors (love, shared pleasurable activities, shared values, and reciprocity), but this structure has never been confirmed. Also, research involving the patient's perspective on the MS is limited. In this study, we tested the factorial structure of the MS and its reliability in stroke patients and caregivers., Design and Method: Cross-sectional, with a follow-up after 15 days for test-retest reliability. A total of 248 stroke patients and 163 stroke caregivers completed the MS. Stroke patients and their caregivers were enrolled in 10 rehabilitation hospitals across Italy. MS factorial structure was analyzed using confirmatory factor analysis; internal consistency reliability was evaluated with Cronbach's α and model-based internal consistency index; test-retest reliability was evaluated with intraclass correlation coefficient., Results: Confirmatory factor analysis supported the four-factor structure of MS in its patient and caregiver version (CFI = 0.94; RMSEA = 0.06, for both). Cronbach's αs and model-based internal consistency index were >0.90 and intraclass correlations ranged between 0.66 and 0.93 in MS patient and caregiver version., Implication: This study tested the theoretical dimensions of the MS in stroke patients and their caregivers. From a scientific and clinical point of view, an assessment of stroke patient and caregiver mutuality would allow dyadic approaches to data analysis and care that account for the nonindependence between the stroke patient and the caregiver., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Given the public health challenge and burden of chronic kidney disease, the Italian Society of Nephrology (SIN) promoted acensusof the renal and dialysis units to analyse structural and human resources, organizational aspects, activities and workload referring to theyear 2014., Methods: An online questionnaire, including 64 items exploring structural and human resources, organization aspects, activities and epidemiological data referred to 2014, was sent to chiefs of any renal or dialysis unit., Results: Renal and dialysis activity was performed by over 2718 physicians (45 pmp). The management of the acute renal failure was one of the most frequent activities in the public renal units (12,206 patients in ICU and 140.00 dialysis sessions). There were performed about 9000 AV fistulas and 1700 central vascular catheters insertions. In the census, there are a lot of data regarding organization, workforce and workload of the renal unit in Italy. The benchmark data derived from this census show interesting comparisons between centres, regions and groups of regions. These data realised the clinical management of renal disease in Italy.

Background: Given the public health challenge and burden of chronic kidney disease, the Italian Society of Nephrology (SIN) promoted a census of the renal and dialysis units to analyse structural and human resources, organizational aspects, activities and workload referring to the year 2014., Methods: An online questionnaire, including 64 items exploring structural and human resources, organization aspects, activities and epidemiological data referred to 2014, was sent to chiefs of any renal or dialysis unit., Results: 615 renal units were identified. From these 615 units, 332 were public renal centres (of which 318 centres answered to the census) and 283 were private dialysis centres (of which 113 centres answered to the census). The results show 6 public renal units pmp. Renal biopsies were 4624 (81 pmp). The nephrology beds are about 41 pmp. There are 7.304 nurses working in HD wards, 1.692 in the nephrology wards and only 613 for outpatients clinics. The benchmark data derived from this census show interesting comparisons between centres, regions and groups of regions. These data realised the clinical management of renal disease in Italy.

Background: The role of change in proteinuria as a surrogate end point for randomized trials in immunoglobulin A nephropathy (IgAN) has previously not been thoroughly evaluated., Study Design: Individual patient-level meta-analysis., Setting & Population: Individual-patient data for 830 patients from 11 randomized trials evaluating 4 intervention types (renin-angiotensin system [RAS] blockade, fish oil, immunosuppression, and steroids) examining associations between changes in urine protein and clinical end points at the individual and trial levels., Selection Criteria for Studies: Randomized controlled trials of IgAN with measurements of proteinuria at baseline and a median of 9 (range, 5-12) months follow-up, with at least 1 further year of follow-up for the clinical outcome., Predictor: 9-month change in proteinuria., Outcome: Doubling of serum creatinine level, end-stage renal disease, or death., Results: Early decline in proteinuria at 9 months was associated with lower risk for the clinical outcome (HR per 50% reduction in proteinuria, 0.40; 95% CI, 0.32-0.48) and was consistent across studies. Proportions of treatment effect on the clinical outcome explained by early decline in proteinuria were estimated at 11% (95% CI, -19% to 41%) for RAS blockade and 29% (95% CI, 6% to 53%) for steroid therapy. The direction of the pooled treatment effect on early change in proteinuria was in accord with the direction of the treatment effect on the clinical outcome for steroids and RAS blockade. Trial-level analyses estimated that the slope for the regression line for the association of treatment effects on the clinical end points and for the treatment effect on proteinuria was 2.15 (95% Bayesian credible interval, 0.10-4.32)., Limitations: Study population restricted to 11 trials, all having fewer than 200 patients each with a limited number of clinical events., Conclusions: Results of this analysis offer novel evidence supporting the use of an early reduction in proteinuria as a surrogate end point for clinical end points in IgAN in selected settings., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

In this proof-of-concept study, a methodology is proposed to systematically analyze large data historians of secondary pharmaceutical manufacturing systems using data mining techniques. The objective is to develop an approach enabling to automatically retrieve operation-relevant information that can assist the management in the periodic review of a manufactory system. The proposed methodology allows one to automatically perform three tasks: the identification of single batches within the entire data-sequence of the historical dataset, the identification of distinct operating phases within each batch, and the characterization of a batch with respect to an assigned multivariate set of operating characteristics. The approach is tested on a six-month dataset of a commercial-scale granulation/drying system, where several millions of data entries are recorded. The quality of results and the generality of the approach indicate that there is a strong potential for extending the method to even larger historical datasets and to different operations, thus making it an advanced PAT tool that can assist the implementation of continual improvement paradigms within a quality-by-design framework., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Doppler ultrasound has been extensively used in detecting reno-vascular diseases, showing to be a non-invasive, safe, low cost and repeatable tool. The Renal Resistive Index (RRI) [(peak systolic velocity - end diastolic velocity)/peak systolic velocity] is a semi-quantitative index derived by Doppler evaluation of renal vascular bed. Normally RRI is in the range of 0.47-0.70, it increases with aging and, usually, it shows a difference between the two kidneys less than 5-8 %. RRI is an important prognostic marker in chronic kidney diseases (CKD), both in diabetic and non-diabetic kidney diseases, because, in longitudinal prospective studies, it significantly correlated with hemodynamic (ABPM, SBP, DBP, pulse pressure) and histopathological parameters (glomerular sclerosis, arteriolosclerosis, interstitial fibrosis/tubular atrophy, interstitial infiltration). In acute kidney injury (AKI) RI is a valid tool in differentiating between pre-renal and renal failure and in predicting renal response to vaso-active agents. In addition a RRI >0.74 can predict the onset of AKI in septic patients. Renal Resistive Index is a useful marker in allograft diseases because it has been widely showed a correlation with histological lesions during worsening of renal function, both in acute rejection and in chronic allograft nephropathy. Recent studies suggest its role in the risk of new onset diabetes after transplantation and it could be one of the parameters to evaluate to shift or withdrawal immunological and/or hypertensive therapy., Competing Interests: Compliance with ethical standards Conflict of interests The authors declare that they have no competing or conflicting interests. Informed consent For this type of study formal consent is not required. Human and animal studies The study described in this article does not contain studies with animal and human subjects performed by any of the authors.

Identifying biomarkers for tuberculosis (TB) is an ongoing challenge in developing immunological correlates of infection outcome and protection. Biomarker discovery is also necessary for aiding design and testing of new treatments and vaccines. To effectively predict biomarkers for infection progression in any disease, including TB, large amounts of experimental data are required to reach statistical power and make accurate predictions. We took a two-pronged approach using both experimental and computational modeling to address this problem. We first collected 200 blood samples over a 2- year period from 28 non-human primates (NHP) infected with a low dose of Mycobacterium tuberculosis. We identified T cells and the cytokines that they were producing (single and multiple) from each sample along with monkey status and infection progression data. Machine learning techniques were used to interrogate the experimental NHP datasets without identifying any potential TB biomarker. In parallel, we used our extensive novel NHP datasets to build and calibrate a multi-organ computational model that combines what is occurring at the site of infection (e.g., lung) at a single granuloma scale with blood level readouts that can be tracked in monkeys and humans. We then generated a large in silico repository of in silico granulomas coupled to lymph node and blood dynamics and developed an in silico tool to scale granuloma level results to a full host scale to identify what best predicts Mycobacterium tuberculosis (Mtb) infection outcomes. The analysis of in silico blood measures identifies Mtb-specific frequencies of effector T cell phenotypes at various time points post infection as promising indicators of infection outcome. We emphasize that pairing wetlab and computational approaches holds great promise to accelerate TB biomarker discovery.

Aim: Caregiving of stroke patients has a long trajectory and the experiences of caregi- vers may change over time. Few studies have described the experience of stroke caregi- vers three months after discharge of patients from rehabilitation hospitals. This study describes the experience of stroke caregivers three months after patients are discharged home from a rehabilitation hospital., Method: phenomenological study, Results: Seven themes emerged from analysis: deeply-changed life; re-appreciation of the relationship with patient and family members; increased workload; difficulties in getting support from the national health-care system; lack of preparation for caregiving; difficulties in coordinating caregiving, family and personal life; relief after patient's recovery., Conclusions: A comprehensive understanding of stroke caregivers' experience during the three months after patient discharge can support the development of educational interventions aimed at improving the caregiver preparation for the care of patients.

Background: The aim of the study was to assess the outcome of pregnancies achieved by OD in vitro fertilization compared with those obtained by autologous IVF., Methods: This retrospective cohort study includes 136 consecutive patients who were referred to our centre between 2009 and 2011. According to the mode of conception, they were divided into two groups, whose pregnancy outcomes were analyzed by χ2 Test for unpaired data., Results: Pregnancy-induced hypertension, cesarean section, complications after delivery resulted more frequent in pregnancies from donor oocyte IVF. The other outcomes considered were non-significantly different between the two groups., Conclusions: The risk of developing preeclampsia, cesarean section, and postpartum complications is higher in patients who conceived by donor oocyte IVF than in patients who underwent autologous IVF.

Tuberculosis (TB) is a world-wide health problem with approximately 2 billion people infected with Mycobacterium tuberculosis (Mtb, the causative bacterium of TB). The pathologic hallmark of Mtb infection in humans and Non-Human Primates (NHPs) is the formation of spherical structures, primarily in lungs, called granulomas. Infection occurs after inhalation of bacteria into lungs, where resident antigen-presenting cells (APCs), take up bacteria and initiate the immune response to Mtb infection. APCs traffic from the site of infection (lung) to lung-draining lymph nodes (LNs) where they prime T cells to recognize Mtb . These T cells, circulating back through blood, migrate back to lungs to perform their immune effector functions. We have previously developed a hybrid agent-based model (ABM, labeled GranSim ) describing in silico immune cell, bacterial (Mtb) and molecular behaviors during tuberculosis infection and recently linked that model to operate across three physiological compartments: lung (infection site where granulomas form), lung draining lymph node (LN, site of generation of adaptive immunity) and blood (a measurable compartment). Granuloma formation and function is captured by a spatio-temporal model (i.e., ABM), while LN and blood compartments represent temporal dynamics of the whole body in response to infection and are captured with ordinary differential equations (ODEs). In order to have a more mechanistic representation of APC trafficking from the lung to the lymph node, and to better capture antigen presentation in a draining LN, this current study incorporates the role of dendritic cells (DCs) in a computational fashion into GranSim ., Results: The model was calibrated using experimental data from the lungs and blood of NHPs. The addition of DCs allowed us to investigate in greater detail mechanisms of recruitment, trafficking and antigen presentation and their role in tuberculosis infection., Conclusion: The main conclusion of this study is that early events after Mtb infection are critical to establishing a timely and effective response. Manipulating CD8+ and CD4+ T cell proliferation rates, as well as DC migration early on during infection can determine the difference between bacterial clearance vs. uncontrolled bacterial growth and dissemination., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

Objective: To quantify the influence of fracture geometry and restorative materials rigidity on the stress intensity and distribution of restored fractured central maxillary incisors (CMI) with particular investigation of the adhesive interfaces. Ancillary objectives are to present an innovative technology to measure the in vivo strain state of sound maxillary incisors and to present the collected data., Methods: A validation experimental biomechanics approach has been associated to finite element analysis. FEA models consisted of CMI, periodontal ligament and the corresponding alveolar bone process. Three models were created representing different orientation of the fracture planes. Three different angulations of the fracture plane in buccal-palatal direction were modeled: the fracture plane perpendicular to the long axis in the buccal-palatal direction (0°); the fracture plane inclined bucco-palatally in apical-coronal direction (-30°); the fracture plane inclined palatal-buccally in apical-coronal direction (+30°). First set of computing runs was performed for in vivo FE-model validation purposes. In the second part, a 50N force was applied on the buccal aspect of the CMI models. Ten patients were selected and subjected to the strain measurement of CMI under controlled loading conditions., Results: The main differences were noticed in the middle and incisal thirds of incisors crowns, due to the presence of the incisal portion restoration. The stress intensity in -30° models is increased in the enamel structure close to the restoration, due to a thinning of the remaining natural tissues. The rigidity of the restoring material slightly reduces such phenomenon. -30° model exhibits the higher interfacial stress in the adhesive layer with respect to +30° and 0° models. The lower stress intensity was noticed in the 0° models, restoration material rigidity did not influenced the interfacial stress state in 0° models. On the contrary, material rigidity influenced the interfacial stress state in +30° and -30° models, higher rigidity restoring materials exhibits lower interfacial stress with respect to low rigidity materials., Significance: Fracture planes inclined palatal-buccally in apical-coronal direction (+30°) reduce the interfacial stress intensity and natural tissues stress intensity with respect to the other tested configurations., (Copyright © 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.)

Summary: Mechanical ventilation and early weaning: a qualitative study on patient's experiences in an intensive care unit., Introduction: The weaning from mechanical ventilation of intensive care unit (ICU) patients may cause anxiety. The feelings and experience during this procedure may affect their physical and psychological wellbeing., Aim: To describe patients' feelings during intubation time and weaning., Method: Phenomenological study on 16 patients who underwent an off pump bypass and mechanical ventilation <24 hours. The patients were contacted 5-7 days after discharge from ICU., Results: The analysis of the interviews generated three issues arising from patients' experience: the discomfort mainly for the endotracheal tube, the fear of extubation and sense of safety for the presence of the nurse., Conclusions: Mechanical ventilation and weaning, in spite of the evolution of the anesthetic techniques, continue to generate unpleasant feelings.

Neisseria gonorrhoeae (GC) remains a serious burden in many high-sexual-activity, undertreated populations. Using empirical data from a 2009 study of GC burden among pastoralists in Kaokoveld, Namibia, we expand the standard gonorrhoea transmission model by using locally derived sexual contact data to explore transmission dynamics in a population with high rates of partner exchange and low treatment-seeking behaviour. We use the model to generate ball-park estimates for transmission probabilities and other parameter values for low-level (i.e. less than approx. 1200 copies/20 µl PCR reaction) asymptomatic infections, which account for 74% of all GC infections found in Kaokoveld in 2009, and to describe the impact of asymptomatic, low-level infections on overall prevalence patterns. Our results suggest that GC transmission probabilities are higher than previously estimated, that untreated infections take longer to clear than previously estimated and that a high prevalence of low-level infections is partially due to larger numbers of untreated, asymptomatic infections. These results provide new insights into the natural history of GC and the challenge of syndromic management programmes for the eradication of endemic gonorrhoea., (© 2015 The Author(s) Published by the Royal Society. All rights reserved.)

Objective: Four-and-a-half LIM domain protein-2 (FHL2) is expressed in endothelial cells, vascular smooth muscle cells, and leukocytes. It regulates cell survival, migration, and inflammatory response, but its role in atherogenesis is unknown., Approach and Results: To investigate the role of FHL2 in atherosclerosis, FHL2-deficient mice were crossed with ApoE-deficient mice, to generate ApoE/FHL2-/- mice. After high-fat diet, ApoE/FHL2-/- mice had significantly smaller atherosclerotic plaques than ApoE-/- mice in the aortic sinus, the brachiocephalic artery, and the aorta. This was associated with enhanced collagen and smooth muscle cell contents and a 2-fold reduction in macrophage content within the plaques of ApoE/FHL-2-/- versus ApoE-/- mice. This could be explained, in part, by the reduction in aortic ICAM-1 (intracellular adhesion molecule) mRNA and VCAM-1 (vascular cell adhesion molecule) protein expression in the plaque. Aortic gene expression of the chemokines CX3CL1 and CCL5 was increased in ApoE/FHL2-/- versus ApoE-/- mice. Peritoneal thioglycollate injection elicited equivalent numbers of monocytes and macrophages in both groups, but a significantly lower number of proinflammatory Ly6C high monocytes were recruited in ApoE/FHL2-/- versus ApoE-/- mice. Furthermore, mRNA levels of CX3CR1 were 2-fold higher in monocytes from ApoE/FHL2-/- versus ApoE-/- mice. Finally, we investigated the potential importance of myeloid cell FHL2 deficiency in atherosclerosis. After being irradiated, ApoE-/- or ApoE/FHL2-/- mice were transplanted with ApoE-/- or ApoE/FHL2-/- bone marrow. After high-fat diet, both chimeric groups developed smaller plaques than ApoE-/- transplanted with ApoE-/- bone marrow., Conclusions: These results suggest that FHL2 in both myeloid and vascular cells may play an important role in atherosclerosis by promoting proinflammatory chemokine production, adhesion molecule expression, and proinflammatory monocyte recruitment., (© 2015 American Heart Association, Inc.)

Background: Stroke is the leading cause of disability in adults, and has a significant impact on individuals, families, and society. Returning home after a stroke represents a challenging experience for patients who struggle to adapt to their new life conditions. Although many studies have been conducted on stroke survivors, few studies have focused on the lived experience of patients at three months after they came home after rehabilitation., Aims: The aim of this study was to describe the experience of stroke survivors three months after being discharged home from rehabilitation hospitals., Method: A phenomenological methodology was used to conduct the study. Participants were enrolled from rehabilitation hospitals in the cities of Rome and Naples. Interviews were conducted at the patients' house and data were analysed with a phenomenological approach, Findings: Fifteen stroke survivors were interviewed (mean age 70 years; 12 males). Five themes emerged from the phenomenological analysis of the interviews and the field notes: deeply changed life, vivid memory of the acute phase of the stroke, slowed lives, relief after recovering from stroke, being a burden for family members., Conclusions: The results of this study give an overview of the experience of stroke survivors three months after being discharged home. From a clinical perspective, health care providers need to provide more interventions to help survivors to cope better with life changes and encourage them to adapt to daily life limitations caused by stroke. Also, health care providers should improve support provided to family members of stroke patients., (© The European Society of Cardiology 2014.)

Aim: To describe a new conceptual framework and the research protocol of a study designed to examine the quality of life in stroke survivor-caregiver dyads., Background: Stroke has a significant impact on the patient-caregiver dyad. Few studies have been guided by a specific conceptual framework which considers the interactions among pre-existing situations prior to stroke, the new situation caused by the stroke and the moderating effects of environmental and caregiver-related variables., Design: Longitudinal study., Methods: A sample of stroke survivor-caregiver dyads will be enrolled at patient discharge from rehabilitation hospitals and will be surveyed every 3 months for 1-year. Hypotheses generated from the conceptual framework will test predictors, mediators and moderators of stroke survivor and caregiver quality of life from the pre-existing situation prior to the stroke, the new situation mediation poststroke and situation moderators. The study is supported by a grant from the Centre of Excellence for Nursing Scholarship, Rome, December 2013., Discussion: This study seeks to identify variables in the pre-existing situation prior to the stroke (e.g. living condition), the new situation mediation poststroke (e.g. type of stroke and caregiver burden) as well as situation moderators (e.g. social support) that influence stroke survivor-caregiver dyad's quality of life across the stroke trajectory. Also, the study will inform clinical practice and research by identifying variables that are potentially modifiable and therefore amenable to intervention. The proposed framework will also be helpful for future research focused on stroke survivor-caregiver dyads., (© 2014 John Wiley & Sons Ltd.)

Objective: To investigate whether signs of placental underperfusion (PUP), defined as any maternal and/or fetal vascular pathology, confer an increased risk of neonatal morbidity in late-onset small-for-gestational-age (SGA) fetuses with normal umbilical artery (UA) Doppler indices., Methods: A cohort of 126 SGA singleton fetuses with normal UA Doppler indices that were delivered after 34 weeks' gestation was studied. For each case, the placenta was evaluated histologically for signs of PUP using a hierarchical and standardized classification system. Neonatal morbidity was assessed according to the score calculated from the morbidity assessment index for newborns (MAIN), a validated outcome scale. The independent association between PUP and neonatal morbidity was evaluated using multivariable median regression analysis., Results: In 84 (66.7%) placentae, 97 placental histological findings that qualified as signs of PUP were observed. These PUP cases had a significantly higher incidence of emergency Cesarean section for non-reassuring fetal status (44.1% vs 21.4%, respectively; P = 0.013) and neonatal metabolic acidosis at birth (33.3% vs 14.3%, respectively; P = 0.023), than did those without PUP. The median MAIN score differed significantly between those with PUP and those without (89 vs 0, respectively; P = 0.025). This difference remained significant after adjustment for potential confounders. The proportion of cases with scores indicative of mild to severe morbidity was also significantly higher in the PUP group (31% vs 14.3%, respectively; P = 0.043)., Conclusion: In late-onset SGA fetuses with normal UA Doppler indices, signs of PUP imply a higher neonatal morbidity. These findings allow the phenotypic profiling of fetal growth restriction among the general population of late-onset SGA., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

Lung granulomas are the pathologic hallmark of tuberculosis (TB). T cells are a major cellular component of TB lung granulomas and are known to play an important role in containment of Mycobacterium tuberculosis (Mtb) infection. We used cynomolgus macaques, a non-human primate model that recapitulates human TB with clinically active disease, latent infection or early infection, to understand functional characteristics and dynamics of T cells in individual granulomas. We sought to correlate T cell cytokine response and bacterial burden of each granuloma, as well as granuloma and systemic responses in individual animals. Our results support that each granuloma within an individual host is independent with respect to total cell numbers, proportion of T cells, pattern of cytokine response, and bacterial burden. The spectrum of these components overlaps greatly amongst animals with different clinical status, indicating that a diversity of granulomas exists within an individual host. On average only about 8% of T cells from granulomas respond with cytokine production after stimulation with Mtb specific antigens, and few "multi-functional" T cells were observed. However, granulomas were found to be "multi-functional" with respect to the combinations of functional T cells that were identified among lesions from individual animals. Although the responses generally overlapped, sterile granulomas had modestly higher frequencies of T cells making IL-17, TNF and any of T-1 (IFN-γ, IL-2, or TNF) and/or T-17 (IL-17) cytokines than non-sterile granulomas. An inverse correlation was observed between bacterial burden with TNF and T-1/T-17 responses in individual granulomas, and a combinatorial analysis of pair-wise cytokine responses indicated that granulomas with T cells producing both pro- and anti-inflammatory cytokines (e.g. IL-10 and IL-17) were associated with clearance of Mtb. Preliminary evaluation suggests that systemic responses in the blood do not accurately reflect local T cell responses within granulomas.

Although almost a third of the world's population is infected with the bacterial pathogen Mycobacterium tuberculosis, our understanding of the functions of many immune factors involved in fighting infection is limited. Determining the role of the immunosuppressive cytokine IL-10 at the level of the granuloma has proven difficult because of lesional heterogeneity and the limitations of animal models. In this study, we take an in silico approach and, through a series of virtual experiments, we predict several novel roles for IL-10 in tuberculosis granulomas: 1) decreased levels of IL-10 lead to increased numbers of sterile lesions, but at the cost of early increased caseation; 2) small increases in early antimicrobial activity cause this increased lesion sterility; 3) IL-10 produced by activated macrophages is a major mediator of early antimicrobial activity and early host-induced caseation; and 4) increasing levels of infected macrophage derived IL-10 promotes bacterial persistence by limiting the early antimicrobial response and preventing lesion sterilization. Our findings, currently only accessible using an in silico approach, suggest that IL-10 at the individual granuloma scale is a critical regulator of lesion outcome. These predictions suggest IL-10-related mechanisms that could be used as adjunctive therapies during tuberculosis., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Objective: This study aims to examine whether a first-trimester strategy of secondary prevention for preeclampsia increases anxiety in pregnant women., Methods: The anxiety levels of a cohort of women screened for preeclampsia at first trimester were measured by the Spielberg State-Trait Anxiety Inventory (STAI-S) and compared between women screened as low and high risk. In a subgroup of women, the anxiety levels were additionally measured at second and third trimester. A General Linear Model (GLM) for repeated measurements was performed to adjust for potential confounders (age, nulliparity and socio-economic level)., Results: A total of 255 women (135 low-risk and 120 high-risk) were evaluated. No differences were found in the mean STAI-S scores between low-risk and high-risk women: 35 (SD 9.9) and 34.6 (SD 10.1); p = 0.77. The proportion of women with high anxiety was not significantly different between groups (28/134 [20.7%] vs 24/120 [20%]; p = 0.88). No differences were found in the subgroups (51 low-risk and 50 high-risk) in which the anxiety levels were also measured at second and third trimester: 35.8 (SD 8.8) vs 35.2 (SD 9.7), p = 0.74, and 37.2 (SD 9.4) vs 35.3 (SD 8.6), p = 0.3. These differences remained non-significant after adjustment for potential confounders., Conclusion: A strategy of first-trimester screening for preeclampsia does not increase maternal anxiety., (© 2014 John Wiley & Sons, Ltd.)

Functionalized computed tomography (CT) in combination with labelled cells is virtually non-existent due to the limited sensitivity of X-ray-absorption-based imaging, but would be highly desirable to realise cell tracking studies in entire organisms. In this study we applied in-line free propagation X-ray phase-contrast CT (XPCT) in an allergic asthma mouse model to assess structural changes as well as the biodistribution of barium-labelled macrophages in lung tissue. Alveolar macrophages that were barium-sulfate-loaded and fluorescent-labelled were instilled intratracheally into asthmatic and control mice. Mice were sacrificed after 24 h, lungs were kept in situ, inflated with air and scanned utilizing XPCT at the SYRMEP beamline (Elettra Synchrotron Light Source, Italy). Single-distance phase retrieval was used to generate data sets with ten times greater contrast-to-noise ratio than absorption-based CT (in our setup), thus allowing to depict and quantify structural hallmarks of asthmatic lungs such as reduced air volume, obstruction of airways and increased soft-tissue content. Furthermore, we found a higher concentration as well as a specific accumulation of the barium-labelled macrophages in asthmatic lung tissue. It is believe that XPCT will be beneficial in preclinical asthma research for both the assessment of therapeutic response as well as the analysis of the role of the recruitment of macrophages to inflammatory sites.

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), induces formation of granulomas, structures in which immune cells and bacteria colocalize. Macrophages are among the most abundant cell types in granulomas and have been shown to serve as both critical bactericidal cells and targets for M. tuberculosis infection and proliferation throughout the course of infection. Very little is known about how these processes are regulated, what controls macrophage microenvironment-specific polarization and plasticity, or why some granulomas control bacteria and others permit bacterial dissemination. We take a computational-biology approach to investigate mechanisms that drive macrophage polarization, function, and bacterial control in granulomas. We define a "macrophage polarization ratio" as a metric to understand how cytokine signaling translates into polarization of single macrophages in a granuloma, which in turn modulates cellular functions, including antimicrobial activity and cytokine production. Ultimately, we extend this macrophage ratio to the tissue scale and define a "granuloma polarization ratio" describing mean polarization measures for entire granulomas. Here we coupled experimental data from nonhuman primate TB granulomas to our computational model, and we predict two novel and testable hypotheses regarding macrophage profiles in TB outcomes. First, the temporal dynamics of granuloma polarization ratios are predictive of granuloma outcome. Second, stable necrotic granulomas with low CFU counts and limited inflammation are characterized by short NF-κB signal activation intervals. These results suggest that the dynamics of NF-κB signaling is a viable therapeutic target to promote M1 polarization early during infection and to improve outcome., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

By using next generation sequencing, we have analyzed 108 B chronic lymphocytic leukemia (B-CLL) patients. Among genes involved in the TP53 pathway, we found frequent mutations in ATM (n=18), TP53 (n=10) and NOTCH1 (n=10) genes, rare mutations of NOTCH2 (n=2) and CDKN1A/p21 (n=1) and no mutations in BAX, MDM2, TNFRSF10A and TNFRSF10B genes. The in vitro treatment of primary B-CLL cells with the activator of p53 Nutlin-3 induced the transcription of p53 target genes, without significant differences between the B-CLL without mutations and those harboring either ATM or NOTCH1mutations. On the other hand, the subgroup of TP53mutated B-CLL exhibited a significantly lower induction of the p53 target genes in response to Nutlin-3 as compared to the other B-CLL samples. However, among the TP53mutated B-CLL, those showing mutations in the high hot spot region of the DNA binding domain [273-280 aa] maintained a significantly higher p53-dependent transcriptional activity as compared to the other TP53mutated B-CLL samples. Since the ability to elicit a p53-dependent transcriptional activity in vitro has a positive prognostic significance, our data suggest that ATMmutated, NOTCH1mutated and surprisingly, also a subset of TP53mutated B-CLL patients might benefit from therapeutic combinations including small molecule activator of the p53 pathway.

Objective: To evaluate the psychometric characteristics of the Caregiver Preparedness Scale (CPS) in caregivers of stroke survivors., Background: Caregiver preparedness can have an important impact on both the caregiver and the stroke survivor. The validity and reliability of the CPS has not been tested for the stroke-caregiver population., Methods: We used a cross-sectional design to study a sample of 156 caregivers of stroke survivors. Construct validity of the CPS was evaluated by confirmatory factor analysis (CFA). Internal consistency and test-retest reliability were also evaluated., Results: Caregivers were, on average, 54 year old (SD = 13.2) and most were women (64.7%). CFA supported the unidimensionality of the scale (comparative fit index = 0.98). Reliability was also supported: item-reliability index and item-total correlations above 0.30; composite reliability index = 0.93; Cronbach's alpha = 0.94; factor score determinacy = 0.97; and test-retest reliability = 0.92., Conclusion: The CPS is valid and reliable in caregivers of stroke survivors. Scores on this scale may assist health-care providers in identifying caregivers with less preparedness to provide specific interventions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Nontypeable Haemophilus influenzae (NTHi) is a bacterium that resides within the human pharynx. Because NTHi is human-restricted, its long-term survival is dependent upon its ability to successfully colonize new hosts. Adherence to host epithelium, mediated by bacterial adhesins, is one of the first steps in NTHi colonization. NTHi express several adhesins, including the high molecular weight (HMW) adhesins that mediate attachment to the respiratory epithelium where they interact with the host immune system to elicit a strong humoral response. hmwA, which encodes the HMW adhesin, undergoes phase variation mediated by 7-base pair tandem repeats located within its promoter region. Repeat number affects both hmwA transcription and HMW-adhesin production such that as the number of repeats increases, adhesin production decreases. Cells expressing large amounts of HMW adhesins may be critical for the establishment and maintenance of NTHi colonization, but they might also incur greater fitness costs when faced with an adhesin-specific antibody-mediated immune response. We hypothesized that the occurrence of large deletion events within the hmwA repeat region allows NTHi cells to maintain adherence in the presence of antibody-mediated immunity. To study this, we developed a mathematical model, incorporating hmwA phase variation and antibody-mediated immunity, to explore the trade-off between bacterial adherence and immune evasion. The model predicts that antibody levels and avidity, catastrophic loss rates, and population carrying capacity all significantly affected numbers of adherent NTHi cells within a host. These results suggest that the occurrence of large, yet rare, deletion events allows for stable maintenance of a small population of adherent cells in spite of HMW adhesin specific antibody-mediated immunity. These adherent subpopulations may be important for sustaining colonization and/or maintaining transmission., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: Mutuality, understood as a feeling of intimacy and positive relationship between caregiver and care receiver, is gaining an increasing interest in the scientific arena in the light of socio-demographic change and the increase in chronic degenerative diseases. The purpose of this article is to carry out a critical analysis of the literature on mutuality in order to identify predictors and outcomes., Method: A literature search was carried out the databases PubMed, CINAHL, PsycInfo, and ASSIA Sociological. Twenty (20) articles were selected. By analyzing critically all articles, emerges that mutuality is a key variable in the process of care giving and in mental and physical health of both caregiver and care-receiver. In the caregiver, high levels of mutuality are associated with less stress, depression and burden to a better quality of life and self perceived health; in patients high mutuality is able to speed up the recovery from the disease, to reduce anxiety and depression and to improve the quality of life., Conclusion: Future studies aimed at the study of this variable also in the Italian population could be of support in developing programs to improve quality of life of caregivers and care receiver.

Propagation-based X-ray phase-contrast computed tomography (PBI) has already proven its potential in a great variety of soft-tissue-related applications including lung imaging. However, the strong edge enhancement, caused by the phase effects, often hampers image segmentation and therefore the quantitative analysis of data sets. Here, the benefits of applying single-distance phase retrieval prior to the three-dimensional reconstruction (PhR) are discussed and quantified compared with three-dimensional reconstructions of conventional PBI data sets in terms of contrast-to-noise ratio (CNR) and preservation of image features. The PhR data sets show more than a tenfold higher CNR and only minor blurring of the edges when compared with PBI in a predominately absorption-based set-up. Accordingly, phase retrieval increases the sensitivity and provides more functionality in computed tomography imaging.

The use of multi-scale mathematical and computational models to study complex biological processes is becoming increasingly productive. Multi-scale models span a range of spatial and/or temporal scales and can encompass multi-compartment (e.g., multi-organ) models. Modeling advances are enabling virtual experiments to explore and answer questions that are problematic to address in the wet-lab. Wet-lab experimental technologies now allow scientists to observe, measure, record, and analyze experiments focusing on different system aspects at a variety of biological scales. We need the technical ability to mirror that same flexibility in virtual experiments using multi-scale models. Here we present a new approach, tuneable resolution, which can begin providing that flexibility. Tuneable resolution involves fine- or coarse-graining existing multi-scale models at the user's discretion, allowing adjustment of the level of resolution specific to a question, an experiment, or a scale of interest. Tuneable resolution expands options for revising and validating mechanistic multi-scale models, can extend the longevity of multi-scale models, and may increase computational efficiency. The tuneable resolution approach can be applied to many model types, including differential equation, agent-based, and hybrid models. We demonstrate our tuneable resolution ideas with examples relevant to infectious disease modeling, illustrating key principles at work., (© 2014 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc.)

Background: Whether convective therapies allow better control of serum phosphate (P) is still undefined, and no data are available concerning on-line haemofiltration (HF). The objectives of the study are to evaluate the effect of convective treatments (CTs) on P levels in comparison with low-flux haemodialysis (HD) and to evaluate the correlates of serum phosphate in a post hoc analysis of a randomized clinical trial., Methods: This analysis was performed in the database of a multicentre, open label and randomized controlled study in which 146 chronic HD patients from 27 Italian centres were randomly assigned to HD (70 patients) or CTs: on-line pre-dilution HF (36 patients) or on-line pre-dilution haemodiafiltration (40 patients)., Results: CTs did not affect P (P = 0.526), calcium (Ca) (P = 0.849) and parathyroid hormone levels (P = 0.622). P levels were associated with the use of phosphate binders including aluminium-based phosphate binders (P < 0.001) and sevelamer (P < 0.001), pre-dialysis bicarbonate levels (P < 0.001) and pre-dialysis blood K levels (P < 0.001). On multivariate analysis (generalized linear model), serum P was again largely unassociated with CTs (P = 0.631). Notably, participating centres were by far the strongest independent correlate of serum P, explaining 45.3% of the variance of serum P over the trial and this association was confirmed at multivariate analysis. Bicarbonate (P < 0.001) and, to a weaker extent, serum K (P = 0.032) were independently related to serum P., Conclusions: In comparison with low-flux HD, CTs did not significantly affect serum P levels. Participating centres were the main source of P variability during the trial followed by treatment with phosphate binders, serum bicarbonate and, to a weak extent, serum potassium levels (ClinicalTrials.gov Identifier: NCT011583309)., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Understanding the nature of interpopulation interactions in host-associated microbial communities is critical to understanding gut colonization, responses to perturbations, and transitions between health and disease. Characterizing these interactions is complicated by the complexity of these communities and the observation that even if populations can be cultured, their in vitro and in vivo phenotypes differ significantly. Dynamic models are the cornerstone of computational systems biology and a key objective of computational systems biologists is the reconstruction of biological networks (i.e., network inference) from high-throughput data. When such computational models reflect biology, they provide an opportunity to generate testable hypotheses as well as to perform experiments that are impractical or not feasible in vivo or in vitro. We modeled time-series data for murine microbial communities using statistical approaches and systems of ordinary differential equations. To obtain the dense time-series data, we sequenced the 16S ribosomal RNA (rRNA) gene from DNA isolated from the fecal material of germfree mice colonized with cecal contents of conventionally raised animals. The modeling results suggested a lack of mutualistic interactions within the community. Among the members of the Bacteroidetes, there was evidence for closely related pairs of populations to exhibit parasitic interactions. Among the Firmicutes, the interactions were all competitive. These results suggest future animal and in silico experiments. Our modeling approach can be applied to other systems to provide a greater understanding of the dynamics of communities associated with health and disease.

Rationale: Inhibition of four-and-a-half LIM domain protein-2 (FHL2) attenuates atherosclerotic lesion formation and increases endothelial cell migration. Early outgrowth cells (EOCs) contribute substantially to endothelial repair., Objective: We investigated the role of FHL2 in the regulation of EOCs., Methods and Results: Human EOCs were cultured from peripheral blood. FHL2 knockdown in EOCs by siRNA resulted in increased EOC numbers and reduced apoptosis, as indicated by decreased cleaved caspase-III and reduced Bax/Bcl-2 expression ratio. This was mediated through increased phosphorylation and membrane translocation of sphingosine kinase-1, increased sphingosine-1-phosphate levels, and Akt phosphorylation. FHL2 knockdown increased stromal cell-derived factor-1-induced EOC migration through upregulation of αv/β3, αv/β5, and β2 integrins, associated with increased cortactin expression. Reduced apoptosis, increased EOC migration, and cortactin upregulation by FHL2 siRNA were prevented by CAY10621, the sphingosine kinase-1 inhibitor, and the sphingosine-1-phosphate receptor-1/-3 antagonist VPC23019. These findings were confirmed using spleen-derived EOCs from FHL2(-/-) mice. Apoptosis was decreased and migration increased in endothelial cells exposed to the conditioned medium of FHL2(-/-) versus wild-type (WT) EOCs. These paracrine effects were abolished by VPC23019. Importantly, reendothelialization after focal carotid endothelial injury in WT mice was significantly increased after intravenous injection of FHL2(-/-) versus WT EOCs., Conclusions: Our findings suggest that FHL2 negatively regulates EOC survival, migration, and paracrine function. FHL2 inhibition in EOCs reduces apoptosis and enhances survival and migratory capacity of both EOCs and surrounding endothelial cells by activation of the sphingosine kinase-1/sphingosine-1-phosphate pathway, resulting in improvement of endothelial regeneration.

Objective: To evaluate the prevalence of human herpesviruses (HHV) 1-6 and community-acquired respiratory viruses (CARVs) in specimens from patients with nasal polyposis undergoing functional endoscopic sinus surgery (FESS) and investigate the potential clinical role., Methods: Viral occurrence was evaluated by molecular methods in polyp, turbinate mucosa, and pre- and postoperative scraping specimens from 35 consecutive patients at different time points in relation to FESS., Results: Overall, 21 patients (60%) were positive to at least one virus in at least one specimen; in particular, 12.1% of all specimens for HHV-6 (3/35 polyps, 11/31 turbinates, 1 presurgical scraping) and 10.5% for Epstein-Barr virus (EBV) (8/35 polyps, 3/31 turbinates, 1/29 pre- and 1/29 postsurgical scraping), followed by CMV and HSV-1 (both 1.6%; 1/35 polyps, 1/29 postsurgical scraping and 2/35 polyps, respectively). EBV positivity tended to be higher in polyps, as well as HHV-6 in adjacent healthy turbinate mucosa, although no significant association was found. Only one preoperative cytological specimen was positive to parainfluenza virus-1., Conclusion: No association between the development of nasal polyps, herpesviruses and CARVs seems to exist. However, the higher EBV frequency in polyps could suggest a causative role or persistence in the inflammatory lymphoid tissue.

In this article, the Italian Society of Nephrology discusses the risks for the Medical Specialty in Nephrology and the possible lack of job opportunities by young nephrologists, that arises from the actions taken in the last years by National and Regional Italian Governments. The article reports the main legislative rules required to access the work system both in public and private hospital. Finally, we examined the different criteria and the standards requested for Regional Accreditation by Italian National Health System, and to obtain reimbursement by private and public providers. These requirements might be useful to guarantee both the specificity of nephrology specialty in the assistance to patients affected by kidney diseases, and a stable and qualified job for young nephrologists.

Autophagy is an inducible catabolic process activated during compromised conditions, such as hypoxia. Neonatal encephalopathy (NE) is a syndrome of disturbed neurological function. No absolute prognostic indicators are available at birth to identify neonates at high risk to develop NE. Immunohistochemical staining with LC3 antibody was performed on 40 placentas from uneventful term singleton pregnancies with umbilical artery pH ≤ 7.00 at birth; semi-quantitative analysis was carried-out to estimate autophagy level. 6/40 (15%) neonates developed NE. Placentas from newborns with NE exhibited a higher LC3 expression. Autophagy protein expression in placentas with severe acidosis is a potential marker for poor outcome., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Epstein-Barr virus (EBV) is a γ-herpes virus, responsible for infectious mononucleosis in immunocompetent hosts. Cellular immunity appears rapidly during EBV primary infection, keeping it silent despite long-life persistence in B lymphocytes. Defects of the EBV-specific cellular immunity are supposed to be the basis of post-transplantation lymphoproliferative disorders, promoted by high levels of immunosuppression. We retrospectively reviewed 197 solid organ transplant recipients to investigate EBV-specific lymphocyte responsiveness using Enzyme-linked ImmunoSpot assay (EliSpot), which assesses the EBV-specific interferon (IFN)-γ producing peripheral blood mononuclear cells, and kinetics of EBV infection/reactivation post-transplantation using quantitative real-time polymerase chain reaction (PCR) on whole blood. Overall, 102 of the 197 patients (51.8%) showed EBV responsiveness at the EBV-EliSpot assay: 68 (66.6%) showed a persistently positive EBV response in 3 or more determinations and 34 (33.3%) had transient episodes of nonresponsiveness. Ninety-five (48.2%) patients were persistently EBV nonresponders. EBV-DNAemia data were available for 58 patients: 27.6% presented at least one episode of EBV-DNA occurrence. No differences were found in EBV-EliSpot response stratification between the groups of patients who experienced episodes of EBV reactivation and those without EBV-DNAemia. However, EBV DNAemia peak values tended to be higher in the first year post-transplantation in the group of patients with a persistent positive EBV-specific immune response. EBV viral load quantitation in blood and EliSpot EBV-specific immune response determination may represent a powerful tool for monitoring solid organ transplant recipients, guiding immunosuppression modulation in patients with active EBV replication., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: A high prevalence (60%) of central adrenal insufficiency (CAI) has been reported in Prader-Willi syndrome (PWS) using the metyrapone test. We have assessed CAI in adults with PWS using the low-dose short synacthen test (LDSST)., Design: Basal cortisol and ACTH, and 30-min cortisol after the administration of 1 μg synacthen, were determined in 53 PWS adults (33 females). A peak cortisol value of ≥500 nmol/l was taken as normal. Hormonal profiles were analysed in relation to gender, genotype and phenotype. Deficient patients were retested by high-dose short synachten test (HDSST) or a repeat LDSST., Results: Mean ± SD basal cortisol and ACTH were 336·6 ± 140·7 nmol/l and 4·4 ± 3·7 pmol/l respectively. Cortisol rose to 615·4 ± 135·0 nmol/l after LDSST. Eight (15·1%) patients had a peak cortisol response <500 nmol/l, with a lower mean ± SD (range) basal cortisol of 184·9 ± 32·0 (138·0-231·7) compared with 364·1 ± 136·6 (149·0-744·5) in normal responders (P < 0·001). Seven of the eight patients underwent retesting, with 4 (7·5%) showing persistent suboptimal responses. Basal and peak cortisol correlated in females (r = 0·781, P < 0·001). Logistic regression revealed that only female gender and baseline cortisol were predictors of cortisol peaks (adjusted R square 0·505)., Conclusions: Although CAI can be part of the adult PWS phenotype, it has a lower prevalence (7·5%) than previously reported. Clinicians are advised to test PWS patient for CAI. Our study also shows that basal cortisol is closely correlated with adrenal response to stimulation, indicating that its measurement may be helpful in selecting patients for LDSST., (© 2013 John Wiley & Sons Ltd.)

Macrophages in granulomas are both antimycobacterial effector and host cell for Mycobacterium tuberculosis, yet basic aspects of macrophage diversity and function within the complex structures of granulomas remain poorly understood. To address this, we examined myeloid cell phenotypes and expression of enzymes correlated with host defense in macaque and human granulomas. Macaque granulomas had upregulated inducible and endothelial NO synthase (iNOS and eNOS) and arginase (Arg1 and Arg2) expression and enzyme activity compared with nongranulomatous tissue. Immunohistochemical analysis indicated macrophages adjacent to uninvolved normal tissue were more likely to express CD163, whereas epithelioid macrophages in regions where bacteria reside strongly expressed CD11c, CD68, and HAM56. Calprotectin-positive neutrophils were abundant in regions adjacent to caseum. iNOS, eNOS, Arg1, and Arg2 proteins were identified in macrophages and localized similarly in granulomas across species, with greater eNOS expression and ratio of iNOS/Arg1 expression in epithelioid macrophages as compared with cells in the lymphocyte cuff. iNOS, Arg1, and Arg2 expression in neutrophils was also identified. The combination of phenotypic and functional markers support that macrophages with anti-inflammatory phenotypes localized to outer regions of granulomas, whereas the inner regions were more likely to contain macrophages with proinflammatory, presumably bactericidal, phenotypes. Together, these data support the concept that granulomas have organized microenvironments that balance antimicrobial anti-inflammatory responses to limit pathology in the lungs.