Automated source of squeezed vacuum states driven by finite state machine based software.

In the last few decades, much effort has been made for the production of squeezed vacuum states in order to reduce quantum noise in the audio-frequency band. This technique has been implemented in all running gravitational-wave interferometric detectors and helped to improve their sensitivity. While the detectors are acquiring data for astrophysical observations, they must be kept in the operating condition, also called "science mode," that is, a state that requires the highest possible duty-cycle for all the instrumental parts and controls. We report the development of a highly automated setup for the generation of optical squeezed states, where all the required control loops are supervised by a software based on finite state machines; we took special care to grant ease of use, stability of operation, and possibility of auto-recovery. Moreover, the setup has been designed to be compatible with the existing software and hardware infrastructure of the Virgo detector. In this paper, we discuss the optical properties of this squeezing setup, the locking techniques, and the automation algorithms.

Group A rotavirus genotypes in hospital-acquired gastroenteritis in Italy, 2012-14.

BACKGROUND: Group A rotaviruses (RVA) are the leading cause of acute gastroenteritis (AGE) in young (aged <5 years) children, causing ∼250,000 deaths worldwide, mostly in developing countries. Differences on nucleotide sequences of VP7 (G-type) and VP4 (P-type) genes are the basis for the binary RVA nomenclature. Although at least 32 G-types and 47 P-types of rotavirus are presently known, most RVA infections in humans worldwide are related to five major G/P combinations: G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8]. AIM: To provide the hospitals of the Italian surveillance network with update information on RVA AGE. METHODS: During RVA gastroenteritis surveillance in Italy in 2012-14, a total of 2341 RVA-positive faecal samples were collected from children hospitalized with AGE, and RVA strains were genotyped following standard EuroRotaNet protocols. FINDINGS: Most strains analysed belonged to the five major human genotypes and 118 out of 2341 (5.0%) were reported to be hospital-acquired. Comparison of the distributions of the RVA genotypes circulating in the community or associated with nosocomial infections showed a different distribution of genotypes circulating inside the hospital wards, with respect to those observed in the community. G1P[8] and G9P[8] RVA strains were detected frequently, whereas G12P[8] caused a single large nosocomial outbreak. CONCLUSION: The information from this study will be useful to implement guidelines for preventing RVA AGE and optimizing the management of patients in hospital wards.

Collaboration to Accelerate Proteogenomics Cancer Care: The Department of Veterans Affairs, Department of Defense, and the National Cancer Institute's Applied Proteogenomics OrganizationaL Learning and Outcomes (APOLLO) Network.

A tri-federal initiative arising out of the Cancer Moonshot has resulted in the formation of a program to utilize advanced genomic and proteomic expression platforms on high-quality human biospecimens in near-real-time in order to identify potentially actionable therapeutic molecular targets, study the relationship of molecular findings to cancer treatment outcomes, and accelerate novel clinical trials with biomarkers of prognostic and predictive value.

Data Sharing, Clinical Trials, and Biomarkers in Precision Oncology: Challenges, Opportunities, and Programs at the Department of Veterans Affairs.

Cancer genomic research reveals that a similar cancer clinical phenotype (e.g., non-small cell lung cancer) can arise from various mutations in tumor DNA. Thus, organ of origin is not a definitive classification. Further, targeted therapy for cancer patients (precision oncology) capitalizes on knowledge of individual patient mutational status to deliver treatment directed against the protein products of these mutations with the goal of reducing toxicity and enhancing efficacy relative to traditional nontargeted chemotherapy.

Sub-Femto-g Free Fall for Space-Based Gravitational Wave Observatories: LISA Pathfinder Results.

We report the first results of the LISA Pathfinder in-flight experiment. The results demonstrate that two free-falling reference test masses, such as those needed for a space-based gravitational wave observatory like LISA, can be put in free fall with a relative acceleration noise with a square root of the power spectral density of 5.2±0.1 fm s^{-2}/sqrt[Hz], or (0.54±0.01)×10^{-15} g/sqrt[Hz], with g the standard gravity, for frequencies between 0.7 and 20 mHz. This value is lower than the LISA Pathfinder requirement by more than a factor 5 and within a factor 1.25 of the requirement for the LISA mission, and is compatible with Brownian noise from viscous damping due to the residual gas surrounding the test masses. Above 60 mHz the acceleration noise is dominated by interferometer displacement readout noise at a level of (34.8±0.3) fm/sqrt[Hz], about 2 orders of magnitude better than requirements. At f≤0.5 mHz we observe a low-frequency tail that stays below 12 fm s^{-2}/sqrt[Hz] down to 0.1 mHz. This performance would allow for a space-based gravitational wave observatory with a sensitivity close to what was originally foreseen for LISA.

Efficacy and Mechanisms of Action of Fecal Microbiota Transplantation in Ulcerative Colitis: Pitfalls and Promises From a First Meta-Analysis.

BACKGROUND: Inflammatory bowel disease (IBD) is the results of a chronic inflammatory process deriving from disequilibrium between self-microbiota composition and immune response. METHODS: New evidence, coming from Clostridium difficile infection, clearly showed that active and powerful modulation of microbiota composition by fecal microbiota composition (FMT) is safe, easy to perform, and efficacious, opening new frontiers in gastrointestinal and extra-intestinal diseases. FMT has been proposed also for IBD as well as other non-gastrointestinal conditions related to intestinal microbiota dysfunctions, with good preliminary data. RESULTS: In this setting, ulcerative colitis (UC) represents one of the most robust potential indications for FMT after C difficile colitis. CONCLUSIONS: In the present review, we focus on FMT and its application on ulcerative colitis, clarifying mechanisms of actions and efficacy data, trough completion of a meta-analysis on available randomized, controlled trial data in UC. Because microbiota is so crucially involved in this topic, a short review of microbial alterations in UC will also be performed.

Approaching Free Fall on Two Degrees of Freedom: Simultaneous Measurement of Residual Force and Torque on a Double Torsion Pendulum.

A torsion pendulum with 2 soft degrees of freedom (DOFs), realized by off-axis cascading two torsion fibers, has been built and operated. This instrument helps characterize the geodesic motion of a test mass for LISA Pathfinder or any other free-fall space mission, providing information on cross talk and other effects that cannot be detected when monitoring a single DOF. We show that it is possible to simultaneously measure both the residual force and the residual torque acting on a quasifree test mass. As an example of the investigations that a double pendulum allows, we report the measurement of the force-to-torque cross talk, i.e., the amount of actuation signal, produced by applying a force on the suspended test mass, that leaks into the rotational DOF, detected by measuring the corresponding (unwanted) torque.

Sporadic isolation of sabin-like polioviruses and high-level detection of non-polio enteroviruses during sewage surveillance in seven Italian cities, after several years of inactivated poliovirus vaccination.

Sewage surveillance in seven Italian cities between 2005 and 2008, after the introduction of inactivated poliovirus vaccination (IPV) in 2002, showed rare polioviruses, none that were wild-type or circulating vaccine-derived poliovirus (cVDPV), and many other enteroviruses among 1,392 samples analyzed. Two of five polioviruses (PV) detected were Sabin-like PV2 and three PV3, based on enzyme-linked immunosorbent assay (ELISA) and PCR results. Neurovirulence-related mutations were found in the 5'noncoding region (5'NCR) of all strains and, for a PV2, also in VP1 region 143 (Ile>Thr). Intertypic recombination in the 3D region was detected in a second PV2 (Sabin 2/Sabin 1) and a PV3 (Sabin 3/Sabin 2). The low mutation rate in VP1 for all PVs suggests limited interhuman virus passages, consistent with efficient polio immunization in Italy. Nonetheless, these findings highlight the risk of wild or Sabin poliovirus reintroduction from abroad. Non-polio enteroviruses (NPEVs) were detected, 448 of which were coxsackievirus B (CVB) and 294 of which were echoviruses (Echo). Fifty-six NPEVs failing serological typing were characterized by sequencing the VP1 region (nucleotides [nt] 2628 to 2976). A total of 448 CVB and 294 Echo strains were identified; among those strains, CVB2, CVB5, and Echo 11 predominated. Environmental CVB5 and CVB2 strains from this study showed high sequence identity with GenBank global strains. The high similarity between environmental NPEVs and clinical strains from the same areas of Italy and the same periods indicates that environmental strains reflect the viruses circulating in the population and highlights the potential risk of inefficient wastewater treatments. This study confirmed that sewage surveillance can be more sensitive than acute flaccid paralysis (AFP) surveillance in monitoring silent poliovirus circulation in the population as well as the suitability of molecular approaches to enterovirus typing.

Epidemiology of rotavirus diarrhoea in Albania.

The aim of the study was to estimate the prevalence of rotavirus disease in children<5 years old in Tirana, Albania, and to monitor and characterize the rotavirus genotypes. Rotavirus was detected in 21% of samples, more frequently in children under 2 years of age, which accounted for 80.8% of all positive cases. Among all rotavirus-positive samples collected, G4P[8] was the most prevalent genotype (38%), followed by G1P[8] (36.6%). The use of safe and effective rotavirus vaccines for the prevention of severe diarrhoea and the reduction of treatment costs will be of great importance for Albania.

Aseptic meningitis outbreak caused by echovirus 30 in two regions in Bulgaria, May-August 2012.

An aseptic meningitis outbreak emerged in two regions in Bulgaria in 2012 and echovirus 30 (E30) was established as the aetiological agent by cell culture isolation, serological test, and molecular-based techniques. A total of 157 patients with aseptic meningitis were investigated, of which 117 were confirmed as having E30-associated disease. Molecular analysis of 12 E30 isolates revealed 99-100% nucleotide and amino-acid identity between them and a close correlation with a Greek strain involved in an E30 outbreak in 2012. Children aged 5-14 years were mainly affected, which could reflect the absence of E30 epidemics in Bulgaria for a period of 11 years. The first case with E30 isolation (a 2-year-old patient from Plovdiv) was notified at the end of April 2012. This was most likely the index case, from which the spread of the virus started, causing sporadic cases first, which later led to an aseptic meningitis outbreak facilitated by person-to-person viral transmission.

Molecular characterization of human G8P[4] rotavirus strains in Italy: proposal of a more complete subclassification of the G8 genotype in three major lineages.

In 2011, two children with acute rotavirus gastroenteritis were hospitalized in Sardinia, Italy. Two RVA strains with G8P[4] genotype were detected in their stools, and were named SS56/2011 and SS65/2011. The aim of the study was to characterize these two rare strains, collected within a national RVA gastroenteritis surveillance program. Eight of the 11 RVA genes were sequenced and phylogenetic analysis performed. VP7 amino acid sequence was also analyzed. Sequencing of genes encoding the VP4, VP6, VP7, and NSP1-5 proteins classified both strains as G8-P[4]-I2-A2-N2-T2-E2-H2, not detected previously in Italy. Phylogenetic analysis revealed that most genes of Italian RVA strains were closely similar to typical DS-1 like strains circulating worldwide, whereas the VP7 gene was strictly related to G8 strains firstly reported in Africa. This finding of G8P[4] RVA strains with a DS-1 like genomic constellation also in a southern European country further confirms the wide circulation of this uncommon genotype in the world. Comparison of the deduced amino acid sequence of the VP7 capsid protein of the Italian G8P[4] RVA strains with sequences reported previously suggests that the G8 genotype should be divided into three major lineages.

Calibration of Ph. Eur. BRP batch 4 for oral poliomyelitis vaccine (OPV).

Poliomyelitis (polio) is a highly infectious disease that affects mostly young children and which may lead to paralysis and death. Prevalence of polio has considerably decreased. However, the effort of global eradication through immunisation needs to be continued to prevent infection risks in non-vaccinated populations by wild, as well as vaccine-derived, polioviruses. In addition, the stockpile of oral poliomyelitis vaccine (OPV) must be maintaine for emergency cases even after eradication. To this end relevant reference standards must be available for the quality control (QC) of polio vaccines. Stocks of the European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP) batch 3 for the assay of OPV are dwindling and therefore a collaborative study was initiated by the European Directorate for the Quality of Medicines and HealthCare (EDQM) with the goal to establish a replacement batch as a working standard. Ten laboratories took part in the collaborative study to calibrate the candidate BRP (cBRP), a commercial trivalent OPV containing live attenuated poliovirus types 1, 2 and 3 (Sabin strain), against the WHO 2(nd) International Reference Reagent (IRR) for OPV and, for the sake of continuity, to compare it to the BRP batch 3. Based on the results of the collaborative study, the cBRP appears suitable as a reference standard and the potencies assigned are 7.28, 6.34, 7.01, and 7.52 log10CCID50/mL (CCID50: 50 % Cell Culture Infective Dose) for poliovirus type 1, 2 and 3 and for the total virus content respectively. The cBRP was adopted by the Ph. Eur. Commission at its 146(th) session in June 2013 as Ph. Eur. BRP batch 4 for OPV.

Detection and distribution of culturable Human Enteroviruses through environmental surveillance in Milan, Italy.

AIMS: Human Enteroviruses (HEVs) infections have a significant impact on public health, being implicated in outbreaks of meningitis, encephalitis, hand-foot-mouth disease and other acute and chronic manifestation. In the strategic plan for poliomyelitis eradication, the environmental surveillance of poliovirus (PV) has been identified by the World Health Organization (WHO) as an activity that can complement the surveillance of polio. Having wastewater samples available for PV surveillance allows us to study nonpolio enteroviruses (NPEVs) circulating in the study population, which are widely spread. METHODS AND RESULTS: This study was carried out according to the WHO guidelines for environmental surveillance of PV and analysed the circulation of PV and NPEVs through the isolation of viruses in cell cultures in Milan area; from 2006 to 2010, 321 wastewater samples were collected, regularly over time, at the inlet of three diverse waste water treatment plants (WWTPs). Culturable HEVs were isolated in 80% of sewage samples: all isolates belonged to the HEV-B group and those circulating more intensely were CVB5 and Echo 6, while CVB4 was the predominant serotype found in 2010. In this study, two type 2 PVs were isolated, both characterized as Sabin like. CONCLUSION: Environmental monitoring of HEVs in Milan has proved to be an interesting tool to investigate the circulation and distribution of viruses. SIGNIFICANCE AND IMPACT OF THE STUDY: The detection of PV and other NPEV could be predictive of possible re-emergence of these viruses with an impact on public health. NPEV monitoring could also be a powerful public health tool to investigate the possible role of NPEV in different clinical manifestations.

Genetic diversity of G9P[8] rotavirus strains circulating in Italy in 2007 and 2010 as determined by whole genome sequencing.

This study reports the molecular characterization of G9P[8] rotavirus strains from children with acute diarrhea identified in different cities of Italy, in 2007 and 2010. Seventeen samples exhibited a G9P[8] genotype by RT-PCR and semi-nested PCR. Preliminary sequence analysis of the VP7 and VP8(*) encoding genes revealed nucleotide identities ranging between 96% and 100%. Full genome sequencing of four G9P[8] strains selected in different cities or years showed that the investigated Italian strains possessed a complete Wa-like genotype constellation. However, phylogenetic analyses assigned strains to different clusters reflecting point mutations and possibly earlier reassortment between Wa-like RVA strains. Deduced amino acid sequence of the VP7 and VP4 genes for the G9P[8] strains revealed at least five substitutions in relevant antigenic sites of both proteins.

Evaluation of brain-derived neurotrophic factor in menstrual blood and its identification in human endometrium.

The presence of high-affinity brain-derived neurotrophic factor receptor Trk B in mouse and in human fetal oocytes, together with the presence of neurotrophins in human follicular fluid suggests a paracrine role for brain-derived neurotrophic factor (BDNF) in female biology. This study aims to evaluate if BDNF is present and quantitatively determined in human menstrual blood and endometrium. Twenty-one women were studied and subdivided in two groups: A, 11 fertile women (27 ± 2 days cycle length) and B, 10 anovulatory women and/or women with inadequate luteal phase (36 ± 2 days cycle length). In fertile women menstrual BDNF levels was higher than plasma (679.3 ± 92.2 vs 301.9 ± 46.7 pg/ml p <0.001). Similarly, in Group B, BDNF in menstrual blood was higher than plasma (386.1 ± 85.2 vs 166.8 ± 24.1 pg/ml p < 0.001). Moreover, both menstrual and plasma BDNF concentrations in Group A were significantly higher respect to Group B (679.3 ± 92.2 vs 386.1 ± 85.2 pg/ml p < 0.001; 301.9 ± 46.7 vs 166.8 ± 24.1 pg/ml p < 0.001). Immunohistochemistry evidence of BDNF in endometrium, during follicular and luteal phase, was also shown. The detection of BDNF in the human menstrual blood and endometrium further supports the role of this neurotrophin in female reproductive function.

c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression.

Despite 35 years of clinical trials, there is little improvement in 1-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates a dire need to develop new therapies. Here, we found a previously unrecognized role for c-Abl and Arg in melanoma progression. We demonstrate that the kinase activities of c-Abl and Arg are elevated in primary melanomas (60%), in a subset of benign nevi (33%) and in some human melanoma cell lines. Using siRNA and pharmacological approaches, we show that c-Abl/Arg activation is functionally relevant because it is requiredfor melanoma cell proliferation, survival and invasion. Significantly, we identify the mechanism by which activated c-Abl promotes melanoma invasion by showing that it transcriptionally upregulates matrix metalloproteinase-1 (MMP-1), and using rescue approaches we demonstrate that c-Abl promotes invasion through a STAT3 → MMP-1 pathway. Additionally, we show that c-Abl and Arg are not merely redundant, as active Arg drives invasion in a STAT3-independent manner, and upregulates MMP-3 and MT1-MMP, in addition to MMP-1. Most importantly, c-Abl and Arg not only promote in vitro processes important for melanoma progression, but also promote metastasis in vivo, as inhibition of c-Abl/Arg kinase activity with the c-Abl/Arg inhibitor, nilotinib, dramatically inhibits metastasis in a mouse model. Taken together, these data identify c-Abl and Arg as critical, novel, drug targets in metastatic melanoma, and indicate that nilotinib may be useful in preventing metastasis in patients with melanomas harboring active c-Abl and Arg.

Assessment of psychosocial adjustment in patients with temporal lobe epilepsy using a standard measure.

Despite the growing evidence of poor psychosocial adjustment, at present there is no formal method of assessment of social adjustment in patients with temporal lobe epilepsy (TLE). First, we assessed social adjustment in patients with TLE using a self-report questionnaire and compared the results with those from quality-of-life (QOL) scales. Second, we verified the influence of cognitive performance and clinical variables of epilepsy on social adjustment and QOL. We evaluated 35 people with TLE and 38 healthy controls. Patients had worse social adjustment, and it was correlated with worse perception of cognitive function. Attention and verbal memory dysfunctions were negatively correlated with social adjustment. However, there was no significant correlation between cognitive performance and QOL. Regarding clinical variables, persons with left TLE showed worse social adjustment and patients with frequent seizures showed worse QOL. These findings indicate the relevance of evaluating social adjustment and emphasize the importance of cognitive rehabilitation to improved social adjustment.

Rotavirus genotypes co-circulating in Europe between 2006 and 2009 as determined by EuroRotaNet, a pan-European collaborative strain surveillance network.

EuroRotaNet, a laboratory network, was established in order to determine the diversity of co-circulating rotavirus strains in Europe over three or more rotavirus seasons from 2006/2007 and currently includes 16 countries. This report highlights the tremendous diversity of rotavirus strains co-circulating in the European population during three years of surveillance since 2006/2007 and points to the possible origins of these strains including genetic reassortment and interspecies transmission. Furthermore, the ability of the network to identify strains circulating with an incidence of ≥1% allowed the identification of possible emerging strains such as G8 and G12 since the beginning of the study; analysis of recent data indicates their increased incidence. The introduction of universal rotavirus vaccination in at least two of the participating countries, and partial vaccine coverage in some others may provide data on diversity driven by vaccine introduction and possible strain replacement in Europe.

Assessment of biosand filter performance in rural communities in southern coastal Nicaragua: an evaluation of 199 households.

INTRODUCTION: Lack of access to safe drinking water is a major health issue for more than one billion people globally. In areas where community-wide water treatment is not possible, point-of-use (POU) solutions are necessary. The biosand filter (BSF) is one of several such POU technologies available to treat water in the home to reduce the risk of infection. This study was conducted to evaluate the use and performance of BSFs in the rural communities surrounding San Juan del Sur, Nicaragua. Approximately 600 filters had been installed in this area over the preceding 2 years by local workers supported by US and Canadian NGOs. METHODS: This field study was conducted In July and August 2009. Unannounced household visits were carried out by US volunteers supported by a local interpreter and driver. Visits were made to a convenience sample of 199 households where BSFs had been in place for an average of 12 months. Water for analysis was collected from wells, filter spouts and storage buckets and an 11 item questionnaire was administered. Laboratory analyses were performed on water samples using the membrane filtration method to determine Escherichia coli colony forming units (CFUs). RESULTS: Forty-five of 199 households visited had discontinued use of their BSF. In the 154 households tested, median CFU of E. coli per 100 mL of water from the source, filter spout and storage vessel were 313, 72, and 144, respectively. Median bacterial removal efficiency for the filters was 80%. Although biosand filtration reduced CFUs in 74% of households in which it was used, in only 26 cases (17%) did it reduce CFUs to <10 CFUs/100 mL. Recontamination was an important problem and reduced the overall efficacy (from well to storage bucket) to 48%. Participants were generally satisfied with their filter's performance, citing improved health and better tasting water. CONCLUSION: Water quality testing of BSFs deployed in the field showed results somewhat inferior to previous reports. Possible explanations include lack of use of best practices and the inclusion of some filers in the analysis that may not have been in active use. Despite these results and high rates of recontamination in the storage bucket, most households members were pleased with their filters and claimed that their use had enhanced their health. This inconsistency could be due to inaccurate responses to the questionnaire for purposes of secondary gain.