Combining robotics with enhanced serotonin-driven cortical plasticity improves post-stroke motor recovery.

Despite recent progresses in robotic rehabilitation technologies, their efficacy for post-stroke motor recovery is still limited. Such limitations might stem from the insufficient enhancement of plasticity mechanisms, crucial for functional recovery. Here, we designed a clinically relevant strategy that combines robotic rehabilitation with chemogenetic stimulation of serotonin release to boost plasticity. These two approaches acted synergistically to enhance post-stroke motor performance. Indeed, mice treated with our combined therapy showed substantial functional gains that persisted beyond the treatment period and generalized to non-trained tasks. Motor recovery was associated with a reduction in electrophysiological and neuroanatomical markers of GABAergic neurotransmission, suggesting disinhibition in perilesional areas. To unveil the translational potentialities of our approach, we specifically targeted the serotonin 1A receptor by delivering Buspirone, a clinically approved drug, in stroke mice undergoing robotic rehabilitation. Administration of Buspirone restored motor impairments similarly to what observed with chemogenetic stimulation, showing the immediate translational potential of this combined approach to significantly improve motor recovery after stroke.

A simple foot pedal device in a horizontal bore imaging facility replicates weightbearing outcomes for Hallux Valgus patients.

BACKGROUND: Weightbearing images are important to the diagnosis of foot pathologies as are the three dimensional views available from CT and MRI. Standard three-dimensional imaging hardware, however, does not have a simple tool to obtain weightbearing images. The current research aimed to design, build and test a simple device to apply load in a horizontal bore imaging facility. METHODS: With the immediate need in hallux valgus studies, hallux valgus subjects were imaged using the new loading device, which could be easily transported and had no additional electronics. RESULTS: Testing showed that the usual angular measures of the foot (intermetatarsal and hallux valgus) replicated the results from the standard of care standing plain film results. With application of load, HV angle changed from 29.9° non-weightbearing to 32.2° weightbearing, while IM angle changed from nonweightbearing 15.8° to weightbearing 16.5°. CONCLUSION: The pedal-like device can provide weightbearing images in a horizontal bore MRI facility.

Landau-Type Theory of Planar Crystal Plasticity.

We show that nonlinear continuum elasticity can be effective in modeling plastic flows in crystals if it is viewed as a Landau theory with an infinite number of equivalent energy wells whose configuration is dictated by the symmetry group GL(2,Z). Quasistatic loading can be then handled by athermal dynamics, while lattice-based discretization can play the role of regularization. As a proof of principle, we study dislocation nucleation in a homogeneously sheared 2D crystal and show that the global tensorial invariance of the elastic energy foments the development of complexity in the configuration of collectively nucleating defects. A crucial role in this process is played by the unstable higher symmetry crystallographic phases, typically thought to be unrelated to plastic flow.

A versatile robotic platform for the design of natural, three-dimensional reaching and grasping tasks in monkeys.

OBJECTIVE: Translational studies on motor control and neurological disorders require detailed monitoring of sensorimotor components of natural limb movements in relevant animal models. However, available experimental tools do not provide a sufficiently rich repertoire of behavioral signals. Here, we developed a robotic platform that enables the monitoring of kinematics, interaction forces, and neurophysiological signals during user-defined upper limb tasks for monkeys. APPROACH: We configured the platform to position instrumented objects in a three-dimensional workspace and provide an interactive dynamic force-field. MAIN RESULTS: We show the relevance of our platform for fundamental and translational studies with three example applications. First, we study the kinematics of natural grasp in response to variable interaction forces. We then show simultaneous and independent encoding of kinematic and forces in single unit intra-cortical recordings from sensorimotor cortical areas. Lastly, we demonstrate the relevance of our platform to develop clinically relevant brain computer interfaces in a kinematically unconstrained motor task. SIGNIFICANCE: Our versatile control structure does not depend on the specific robotic arm used and allows for the design and implementation of a variety of tasks that can support both fundamental and translational studies of motor control.

Peritoneal mesothelioma mortality in Italy: Spatial analysis and search for asbestos exposure sources.

BACKGROUND: This study is part of a national plan of epidemiological surveillance of malignant mesothelioma (MM) mortality in Italy. The paper shows the results of malignant peritoneal mesothelioma (MPeM) mortality study in Italian Regions and municipalities. METHODS: National Bureau of Statistics data for MPeM municipal mortality (ICD-10, Code C45.1) were analyzed in the time-window 2003-2014: mortality standardized rates (reference Italian population, census 2011), temporal trends of the annual national rates, Standardized Mortality Ratios and a municipal clustering analysis were performed. RESULTS: 747 deaths for MPeM were recorded (0.10/100,000): 464 in men (0.14/100,000) and in 283 women (0.07/100,000). No significant MPeM mortality temporal trend was found. Seventeen municipalities showed excesses of mortality for MPeM in at least one gender and/or overall population. Four clusters in male population, and one in women were identified. CONCLUSIONS: The study identifies some areas where remediation activities and/or health care actions may be warranted.

Detection and genotyping of HPV-DNA through different types of diagnostic platforms in liquid-based cervical-cytology samples.

BACKGROUND: At present cervical cancer represents the second most common cancer in women worldwide and it reaches a global mortality rate of 52%. Only the early detection and the adequate treatment of pre-neoplastic lesions and early-stage cervical cancer decrease the mortality rate for this type of cancer. Cervical carcinoma screening, as a method of second prevention, is currently feasible through molecular research of high-risk HPV genotypes and in lots of organized screening programs the Pap-test is performed only in women with positive HPV-test. Currently, there are various diagnostic platforms detecting and molecular genotyping HPV, which are based on different procedures, determining uneven viral genotypes panels and using diverse type of vials to collect and store the samples. Previous studies have pointed out that DNA-HPV test can be negative in pre-neoplastic lesions, even of high grade, or in presence of cervical cancer. Therefore, it's important to assess the risk of false negative diagnoses using DNA-HPV molecular test, because in this circumstance women do not undergo immediately Pap-test, but they are submitted to second round screening with DNA-HPV test after 5 years: this protocol could increase the incidence of "interval cancers". The present study aims at comparing the results of HPV detection and genotyping on liquid based cervical cytology, using some of the most relevant diagnostic platforms in commerce. METHODS: The study is based on a group of patients which went to their private gynecologist in a contest of opportunistic screening. The vial used in the examined population has been EASYPREP® preservative solution (YD Diagnostics CORP-Republic of Korea); liquid-based cervical cytology sampling has been done using a single device (plastic brush), allowing to collect simultaneously cytological material from exocervix and endocervix (Rovers® Cervex-Brush®). The diagnostic platforms employed have been the following: A) Digene HC2 HPV DNA Test, on RCS System (QIAGEN); B) BD Onclarity™ HPV test, on automate platform BD Viper™ LT (Becton Dickinson); C) Xpert® HPV, on GeneXpert® Infinity Systems platform (Cepheid). Every platform researched high-risk HPV genotypes panels (hr-HPV). Part of the clinical records has also been analyzed through PCR and genes L1 and E6/E7 complete sequencing, in order to further typing the viral population. RESULTS: We have examined 1284 samples of women aged 16 to 73 years: 1125 have been tested using HC2 procedure, 272 samples with Onclarity method, 159 with Xpert® method and 55 samples have been analyzed using PCR and sequencing of gene L1 and gene E6/E7. HPV-DNA was detected with Onclarity method in 15,07%, with Xpert® method in 13,83% and using HC2 procedure in 12,27% of samples. The comparison between the three molecular methods revealed diagnostic discrepancies in 3,14% of our records between Onclarity test and Xpert® method and in 2,20% (6/272) between HC2 test and Onclarity test. Globally, in 431 tests, compared using different diagnostic platforms, discrepant diagnoses, referring to hr-HPV presence or to detected genotype, have been observed 11 times (2,55%). Genotype 16 appeared the most expressed in the positive samples (20,99%), whereas genotype 18 resulted the less expressed in the examined population (4,94%). DISCUSSION: The present study highlights the following: 1) Positive results' percentage for high-risk HPV-DNA genotypes, deriving from the three diagnostic platforms used and with the same vial to collect and store samples, does not significantly vary on the basis of the type of equipment and it is congruent with the Italian percentage already detected during organized screening programs. 2) Even the molecular diagnostic approach could give false negative results, preventing the detection in the screened population of cervical HPV-related lesions and theoretically endangering women to develop "interval cancer". 3) In the population examined, genotype 16 has been the most expressed, whereas genotype 18 was among the less frequently detected. Other genotypes often noticed have been: 56-59-66 (Onclarity P3 group), 31, 51 and 35-39-68 (Onclarity P2 group). This remark emphasizes the importance of HPV infection and genotypes distribution's continuous monitoring, considering that HPV-vaccines planned in Italy in the "National vaccination prevention program 2017-2019" are not specific for the majority of these genotypes. 4) The necessity to improve the screening program to identify cervical carcinomas and pre-neoplastic cervical lesions is remarked by the detection during HPV-test of possible coinfection (present at least in 8,76% of our records). In fact, the risk of development of cervical cancer might be associated with type-specific interactions between genotypes in multiple infections and, in addition, other genotypes, not targeted by quadrivalent HPV-vaccine, can increase the risk of cervical carcinoma. 5) As there's a different combination of HPV-genotypes in diagnostic categories used by the HPV screening platforms, it's important that anyone who is in charge of this diagnostic analysis promotes among clinicians the adequate rendition of the laboratory's data in the patient records, reporting both the diagnostic result and the method through which it has been obtained.

Piecewise affine stress-free martensitic inclusions in planar nonlinear elasticity.

We consider a partial differential inclusion problem which models stress-free martensitic inclusions in an austenitic matrix, based on the standard geometrically nonlinear elasticity theory. We show that for specific parameter choices there exist piecewise affine continuous solutions for the square-to-oblique and the hexagonal-to-oblique phase transitions. This suggests that for specific crystallographic parameters the hysteresis of the phase transformation will be particularly small.

Weight-bearing recommendations after first metatarsophalangeal joint arthrodesis fixation: a biomechanical comparison.

BACKGROUND: This study sought to determine whether several metatarsophalangeal (MTP) fusion techniques require complete immobilization or if some level of weight-bearing could be recommended after surgery. A comparison of synthetic composite to actual bone was included in order to examine the validity of the testing conditions. METHODS: Four MTP fusion modalities were tested in synthetic composite bone models: unlocked plating, locked plating, crossed lag screws, and an unlocked plate with a single lag screw. Stiffness was calculated and then used to find the two most rigid constructs; the load to failure was recorded. Stiffness and load to failure testing for the two more rigid constructs in paired cadaveric bones were followed. RESULTS: The unlocked plate plus screw and crossed screw constructs were stiffest (p < 0.008). Loads to failure of the unlocked plate plus screw and crossed screws in synthetic bone were 131 and 101 N, respectively and in cadaveric bone were 154 and 94 N, respectively, which are less than the estimated 25% body weight required at the MTP joint. The plate plus screws were statistically more stiff than crossed screws (p = 0.008), but there was no statistical difference between synthetic and cadaveric bone in load to failure (p = 0.296). CONCLUSIONS: The plate plus screw offered the greatest stiffness; the failure test showed that no construct could withstand weight-bearing as tolerated; and, synthetic composite models of the MTP joint did not provide the consistent results in stiffness and failure.

Multicomponent Electron-Hole Superfluidity and the BCS-BEC Crossover in Double Bilayer Graphene.

Superfluidity in coupled electron-hole sheets of bilayer graphene is predicted here to be multicomponent because of the conduction and valence bands. We investigate the superfluid crossover properties as functions of the tunable carrier densities and the tunable energy band gap E_{g}. For small band gaps there is a significant boost in the two superfluid gaps, but the interaction-driven excitations from the valence to the conduction band can weaken the superfluidity, even blocking the system from entering the Bose-Einstein condensate (BEC) regime at low densities. At a given larger density, a band gap E_{g}∼80-120 meV can carry the system into the strong-pairing multiband BCS-BEC crossover regime, the optimal range for realization of high-T_{c} superfluidity.

PO-40 - Real-life use of non-vitamin k antagonist oral anticoagulants in patients with cancer associated venous thromboembolism: data from a prospective cohort.

INTRODUCTION: Cancer associated thrombosis (CAT) has an increased risk of recurrent venous thromboembolism (VTE). Type, stage of cancer and chemotherapy (CHT) influence thromboembolic risk. The use of novel oral anticoagulants (NOACs) is controversial in patients with CAT. AIM: The aim of this study is to assess mortality, recurrent VTE and bleeding complications in patients with CAT and in patients without cancer receiving NOACs. MATERIALS AND METHODS: Consecutive patients with acute objectively confirmed VTE receiving NOACs within 1 month from diagnosis are included from September 2013 in an ongoing prospective cohort study. Characteristics of patients and outcome are reported according to the presence of CAT. Chi-squared test and Student' t-test are used. RESULTS: As for November 10(th) 2015, 472 patients were included in the study: 78 with CAT (16.5%). Lung, breast, gastrointestinal and genitourinary cancer was observed in 16%, 24%, 20% and 24% of patients with CAT, respectively. 31 patients with CAT (40%) were on CHT or radiotherapy (RT). 10 patients with CAT (13%) had at least an additional risk factor for VTE (4 had a CVC related thrombosis) and 34 (43.5%) were inpatients. Baseline characteristics of patients with and without CAT are reported in the Table. Pulmonary embolism was index VTE in 152 patients: 24.4% of patients with CAT and in 33.8% of those without cancer (p=0.10). DVT only was present in 320 patients and 78 had both DVT and PE. Among NOACs patients, 312 (66%) received initial loading dose: 61% of those with CAT and 67% without. 53 (11%) received reduced maintenance doses (10% with CAT, 11% without). As for nowadays, 272 patients had at least 3 months of follow-up, the mean follow-up being 8.6 months. 20 patients died (7.3%): 17 were cancer related deaths. Non cancer related death occurred in 1 patient with CAT (2%) and in 2 patients without (0.9%). No fatal bleedings or fatal VTE recurrences occurred. Patients recruitment and follow-up is currently ongoing aimed at assessing mortality, recurrent VTE and bleeding complications. Updated results on clinical outcomes will be presented at the congress. CONCLUSIONS: Patients with CAT receiving NOACs are treated as patients without CAT in terms of use of loading doses and maintenance treatment. Upper arm thrombosis is more frequently involved in CAT patients and proximal lower vein in patients without CAT. Non cancer related mortality was higher in CAT patients but no fatal recurrences or fatal bleedings were observed so far.

Minimally invasive infrapubic inflatable penile prosthesis implant for erectile dysfunction: evaluation of efficacy, satisfaction profile and complications.

Erectile dysfunction (ED), the second most common male sexual disorder, has an important impact on man sexuality and quality of life affecting also female partner's sexual life. ED is usually related to cardiovascular disease or is an iatrogenic cause of pelvic surgery. Many non-surgical treatments have been developed with results that are controversial, while surgical treatment has reached high levels of satisfaction. The aim is to evaluate outcomes and complications related to prosthesis implant in patients suffering from ED not responding to conventional medical therapy or reporting side effects with such a therapy. One hundred eighty Caucasian male suffering from ED were selected. The patient population were divided into two groups: 84 patients with diabetes and metabolic syndrome (group A) and 96 patients with dysfunction following laparoscopic radical prostatectomy for prostate cancer (group B). All subjects underwent primary inflatable penile prosthesis implant with an infrapubic minimally invasive approach. During 12 months of follow-up, we reported 3 (1.67%) explants for infection, 1 (0.56%) urethral erosion, 1 (0.56%) prosthesis extrusion while no intraoperative complications were reported. Mean International Index of Erectile Function-5 (IIEF-5) was 8.2 ± 4.0 and after the surgery (12 months later) was 20.6 ± 2.7. The improvement after the implant is significant in both groups without a statistically significant difference between the two groups (P-value 0.65). Mean Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) score 1 year after the implant is 72.2 ± 20.7, and there was no statistically significant difference between groups A and B (P-value 0.55). Implantation of an inflatable prosthesis, for treatment of ED, is a safe and efficacious approach; and the patient and partner satisfaction is very high. Surgical technique should be minimally invasive and latest technology equipment should be implanted in order to decrease after surgery common complications (infection and mechanical failure).

The endogenous caspase-8 inhibitor c-FLIPL regulates ER morphology and crosstalk with mitochondria.

Components of the death receptor-mediated pathways like caspase-8 have been identified in complexes at intracellular membranes to spatially restrict the processing of local targets. In this study, we report that the long isoform of the cellular FLICE-inhibitory protein (c-FLIP(L)), a well-known inhibitor of the extrinsic cell death initiator caspase-8, localizes at the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs). ER morphology was disrupted and ER Ca(2+)-release as well as ER-mitochondria tethering was decreased in c-FLIP(-/-) mouse embryonic fibroblasts (MEFs). Mechanistically, c-FLIP ablation resulted in enhanced basal caspase-8 activation and in caspase-mediated processing of the ER-shaping protein reticulon-4 (RTN4) that was corrected by re-introduction of c-FLIP(L) and caspase inhibition, resulting in the recovery of a normal ER morphology and ER-mitochondria juxtaposition. Thus, the caspase-8 inhibitor c-FLIP(L) emerges as a component of the MAMs signaling platforms, where caspases appear to regulate ER morphology and ER-mitochondria crosstalk by impinging on ER-shaping proteins like the RTN4.

Sterically driven synthesis of ruthenium and ruthenium-silver N-heterocyclic carbene complexes.

A straightforward and efficient synthetic route to novel Ru N-heterocyclic carbene (NHC) complexes by transmetallation of non-bulky silver NHC to ruthenium dicarbonyl tetraarylcyclopentadienone is described. The same procedure with sterically demanding NHC leads to unprecedented heterobimetallic Ru-Ag(NHC) complexes.

An unanticipated role for survivin in organ transplant damage.

Ischemia/reperfusion (I/R) injury is a major determinant of graft survival in kidney transplantation. Survivin, an inhibitor of apoptosis that participates in the control of mitosis and cell cycle progression, has been implicated in renal protection and repair after I/R injury; however, no study has been performed in the transplant setting. We investigated the role of survivin in modulating posttransplant I/R injury in syngeneic and allogeneic kidney grafts, and studied whether protection from I/R injury impacted on the recipient immune system, on chronic allograft nephropathy and rejection. We used genetically engineered mice with survivin haploinsufficiency and WT mice in which survivin over-expression was induced by gene-delivery. Survivin haploinsufficiency in syngeneic grafts was associated with exuberant I/R tissue injury, which triggered inflammation eventually resulting in graft loss. Conversely, survivin over-expression in the grafts minimized I/R injury and dysfunction in syngeneic grafts and in a clinically relevant fully MHC-mismatched allogeneic combination. In the latter, survivin over-expression translated into limited anti-donor adaptive immune response and less long-term allograft injury with protection from renal parenchymal damage. Our data support survivin over-expression in the graft as a novel target for protocols aimed at limiting tissue damage at the time of transplant ultimately modulating the recipient immune system.

The risk of transfusion-transmitted HIV from blood donations of men who have sex with men, 12 months after last sex with a man: 2005-2007 estimates from England and Wales.

The risk of transfusion-transmitted HIV infection under (i) permanent exclusion and (ii) 12-month deferral of MSM in England and Wales during 2005-2007 was estimated. Assuming equal compliance with both scenarios, estimated risk under a 12-month deferral (0.228/million donations [range 0·168-0·306/million donations]) was only marginally greater (0·5%) than that under lifetime exclusion (0·227/million donations [range 0·157-0.318/million donations]), with one extra-HIV infectious donation every 455 years. Poorer compliance of MSM with a 12-month deferral would be expected to increase the estimated risk, whereas improved compliance could decrease risk by up to 29·1%.

[Hepatitis B vaccination coverage and booster dose: results from a survey on healthcare students]. / Copertura vaccinale anti-epatite B e dose di rinforzo: risultati di uno studio su una popolazione universitaria.

This study assessed the immunisation status against hepatitis B in healthcare students and residents, before their hospital internship, as suggested by the "National Immunization Prevention Plan 2012-2014". The concentration of antibodies against hepatitis B was measured in 2,491 subjects (70.90% women), born between 1980 and 1993 and visited between January 1st 2000 and July 15th 2012. Personal and serologic data were collected for each subjects. Individuals with antibody less than 10 mIU/mL (327, 13.3%) were given a booster dose and re-tested 2 months later. The multivariate logistic regression evidenced that immunization is influenced by the gender, the age at first vaccination, the time elapsed between first vaccination and antibody measurement. This study confirms the importance of measuring the concentration of antibodies against hepatitis B among healthcare students, even if they have previously been vaccinated, according to the "National Immunization Prevention Plan 2012-2014".