In situ identification by fluorescently labeled oligonucleotide probes of morphologically similar, closely related ciliate species.
Ciliate protozoa are important members of microbial communities in which they play specific ecological roles. The determination of single species distribution is fundamental for food web analysis, but species recognition, which is mainly based on morphological characters, is often difficult between closely related species. The use of species-specific, purposely designed, fluorescently labeled probes for in situ hybridization is here presented as an easy and fast identification method for three closely related species belonging to the widespread genus Euplotes, namely E. crassus, E. vannus, and E. minuta, that in spite of their remarkable morphological similarity have significant metabolic and ecological differences. These three species can be detected simultaneously, provided the probes employed are bound to different fluorescent dyes: in this way their relative abundance and their population dynamics in the natural environment can be evaluated. As more ciliate sequences become available in databases, species-specific probes can be designed for other ciliates, thus rendering the application of the method of more general importance. The probes used in this study may also provide a tool to prevent erroneous species identification in future studies.


A Transferrin Triggered Pathway for Highly Targeted Delivery of Graphene-Based Nanodrugs to Treat Choroidal Melanoma.
The synthesis of transferrin (Tf)-modified pegylated graphene (PG) and its application as a highly efficient drug delivery carrier for therapy of Ocular Choroidal Melanoma-1 (OCM-1) cells is presented. For the first reported time, nanoscaled PG is prepared using an environmentally friendly ball-milling technique. The unique 2D nanostructure obtained using this PG synthesis approach offers considerable advantages in terms of drug loading and delivery, as well as the conjugation of Tf to PG providing a more targeted delivery vehicle. A highly efficient targeted pathway toward OCM-1 cells triggered by an affinity between Tf and Tf receptors expressed on the surface of OCM-1 cells is reported first here. PG-Tf is observed to easily anchor anticancer drugs such as doxorubicin via π-π stacking. This work performs a Transwell two cells coculture experiment, a 3D in vitro tumor model, and an in vivo mouse model with OCM-1 tumors to demonstrate the composite's therapeutic superiority over conventional systems for the targeted delivery and controlled release of antitumor drugs.


Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial.
Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6-11 years homozygous for F508del-CFTR. In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV1) of 70 or more, and lung clearance index2·5 (LCI2·5) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight (<25 kg vs ≥25 kg) and ppFEV1 severity (<90 vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute change in LCI2·5 from all on-treatment study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473. Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI2·5 from baseline over all study visits up to and including the week 24 visit, least squares mean difference was -1·09 units (95% CI -1·43 to -0·75, p<0·0001) for lumacaftor and ivacaftor versus placebo. For the key secondary endpoint of sweat chloride concentration, the least squares mean difference versus placebo was -20·8 mmol/L (95% CI -23·4 to -18·2, average absolute change at day 15/week 4; p<0·0001). The least squares mean difference compared with placebo in absolute change in ppFEV1 from all on-treatment study visits until week 24 was 2·4 (95% CI 0·4-4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 [43%]) or moderate (98 [48%]). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the lumacaftor and ivacaftor group and 11 (11%) of 101 patients in the placebo group. Treatment with lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI2·5 and ppFEV1, versus placebo in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. The overall safety profile was consistent with previous phase 3 studies of lumacaftor and ivacaftor. Vertex Pharmaceuticals.


Expression of BAG-1 in invasive breast carcinomas.
The purpose of this study was to retrospectively evaluate the expression of BAG-1 in invasive breast carcinomas. The intensity and subcellular distribution of BAG-1 expression was correlated with conventional prognostic factors and with disease-free and overall survival. One hundred forty patients diagnosed with invasive breast cancer in St. John's, Newfoundland, between 1986 and 1996 were included in the study. The median follow-up of the study was 8 years. Expression of BAG-1 was determined by immunohistochemical staining of paraffin-embedded breast tumor tissues. Of the 140 breast carcinomas examined, 77.1% were positive for BAG-1 expression. Except for differentiation, no correlation was observed between BAG-1 expression and conventional prognostic factors such as age, histology, stage, and estrogen and progesterone receptor status. In multivariate analysis, BAG-1 expression was significantly associated with shorter disease-free (P =.0052) and overall survival (P =.0033). Patients whose tumors expressed nuclear BAG-1 tended to have a shorter disease-free (63 v 84 months; P = 0.4493) and overall (69 v 99 months, P =.1009) survival. BAG-1 is overexpressed in the majority of invasive breast carcinomas. Although BAG-1 did not correlate with conventional prognostic factors, its overexpression, especially the nuclear expression, may be associated with a shorter disease-free and overall survival. Our preliminary data strongly indicate that further investigation is warranted to define the role of BAG-1 as an independent prognostic factor in patients with newly diagnosed breast cancer.


REGSTATTOOLS: freeware statistical tools for the analysis of disease population databases used in health and social studies.
The repertoire of statistical methods dealing with the descriptive analysis of the burden of a disease has been expanded and implemented in statistical software packages during the last years. The purpose of this paper is to present a web-based tool, REGSTATTOOLShttp://regstattools.net intended to provide analysis for the burden of cancer, or other group of disease registry data. Three software applications are included in REGSTATTOOLS: SART (analysis of disease's rates and its time trends), RiskDiff (analysis of percent changes in the rates due to demographic factors and risk of developing or dying from a disease) and WAERS (relative survival analysis). We show a real-data application through the assessment of the burden of tobacco-related cancer incidence in two Spanish regions in the period 1995-2004. Making use of SART we show that lung cancer is the most common cancer among those cancers, with rising trends in incidence among women. We compared 2000-2004 data with that of 1995-1999 to assess percent changes in the number of cases as well as relative survival using RiskDiff and WAERS, respectively. We show that the net change increase in lung cancer cases among women was mainly attributable to an increased risk of developing lung cancer, whereas in men it is attributable to the increase in population size. Among men, lung cancer relative survival was higher in 2000-2004 than in 1995-1999, whereas it was similar among women when these time periods were compared. Unlike other similar applications, REGSTATTOOLS does not require local software installation and it is simple to use, fast and easy to interpret. It is a set of web-based statistical tools intended for automated calculation of population indicators that any professional in health or social sciences may require.


Caffeine improves left hemisphere processing of positive words.
A positivity advantage is known in emotional word recognition in that positive words are consistently processed faster and with fewer errors compared to emotionally neutral words. A similar advantage is not evident for negative words. Results of divided visual field studies, where stimuli are presented in either the left or right visual field and are initially processed by the contra-lateral brain hemisphere, point to a specificity of the language-dominant left hemisphere. The present study examined this effect by showing that the intake of caffeine further enhanced the recognition performance of positive, but not negative or neutral stimuli compared to a placebo control group. Because this effect was only present in the right visual field/left hemisphere condition, and based on the close link between caffeine intake and dopaminergic transmission, this result points to a dopaminergic explanation of the positivity advantage in emotional word recognition.


Increased gastric production of interleukin-8 and tumour necrosis factor in patients with Helicobacter pylori infection.
To investigate the role of interleukin-8 (IL-8) and tumour necrosis factor (TNF) in patients infected with Helicobacter pylori. The study population comprised 52 patients with dyspepsia attending for upper gastrointestinal endoscopy. Of these patients, 35 were infected with H pylori. IL-8 and TNF concentrations in plasma, gastric juice, and gastric biopsy homogenate supernatant fluid were measured by radioimmunoassay and L929 cell bioassay, respectively. The concentrations of IL-8 and TNF in gastric juice and gastric biopsy homogenates were substantially greater in patients infected with H pylori. In H pylori positive patients IL-8 concentrations in gastric juice and gastric biopsy homogenates were higher in those with moderate gastritis than in those with mild gastritis. There was a positive correlation between IL-8 and TNF concentrations in gastric juice and gastric biopsy homogenate supernatant fluid from H pylori positive patients. There were no significant differences between H pylori positive and negative patients with respect to IL-8 and TNF plasma concentrations. This study suggests that increased gastric production of IL-8 and TNF may be implicated in the pathogenesis of H pylori associated gastroduodenal disease.


Sleep duration and musculoskeletal injury incidence in physically active men and women: A study of U.S. Army Special Operation Forces soldiers.
In physically demanding occupations or athletic populations, sleep has been shown to be an important factor for both performance and recovery. However, evidence is limited on sleep duration and its association with musculoskeletal injury risk in physically active populations. Therefore, the purpose of this analysis was to evaluate the relationship between sleep duration and musculoskeletal injury incidence in a population of physically active men and women. Data were collected via electronic survey and analyzed for 7,576 soldiers from the United States Army Special Operations Command. This population was mostly men (95%) ≤ 35 years old (70%). The incidence of musculoskeletal injury was 53% over the twelve months before survey administration. After adjusting for other covariates, soldiers who slept ≤ 4 hours were 2.35 (95% CI: 1.89-2.93, p <0.01) times more likely to experience a musculoskeletal injury compared with those who slept eight ≥ 8 hours. When stratified by age (≤ 35 years, > 35 years), older men were found to have significantly higher risk of a musculoskeletal injury than their younger counterparts across all sleep duration groups. These findings suggest that sleep duration may be inversely related to risk of musculoskeletal injury. It is possible that interventions targeted at sleep may have a positive impact on prevention of musculoskeletal injuries within physically active populations.


Vertical GaN nanocolumns grown on graphene intermediated with a thin AlN buffer layer.
We report on the self-assembled growth of high-density and vertically-oriented n-doped GaN nanocolumns on graphene by radio-frequency plasma-assisted molecular beam epitaxy. Graphene was transferred to silica glass, which was used as the substrate carrier. Using a migration enhanced epitaxy grown AlN buffer layer for the nucleation is found to enable a high density of vertical GaN nanocolumns with c-axis growth orientation on graphene. Furthermore, micro-Raman spectroscopy indicates that the AlN buffer reduces damage on the graphene caused by impinging active N species generated by the radio-frequency plasma source during the initial growth stage and nucleation of GaN. In addition, the grown GaN nanocolumns on graphene are found to be virtually stress-free. Micro-photoluminescence measurements show near band-edge emission from wurtzite GaN, exhibiting higher GaN bandgap related photoluminescence intensity relative to a reference GaN bulk substrate and the absence of both yellow luminescence and excitonic defect emission. Transmission electron microscopy reveals the interface of GaN nanocolumns on graphene via a thin AlN buffer layer. Even though the first few monolayers of AlN on top of graphene are strained due to in-plane lattice mismatch between AlN and graphene, the grown GaN nanocolumns have a wurtzite crystal structure without observable defects. The results of this initial work pave the way towards realizing low-cost and high-performance electronic and optoelectronic devices based on III-N semiconductors grown on graphene.


A new and efficient Solid Phase Microextraction approach for analysis of high fat content food samples using a matrix-compatible coating.
The current work presents the optimization of a protocol enabling direct extraction of avocado samples by a new Solid Phase Microextraction matrix compatible coating. In order to further extend the coating life time, pre-desorption and post-desorption washing steps were optimized for solvent type, time, and degree of agitation employed. Using optimized conditions, lifetime profiles of the coating related to extraction of a group of analytes bearing different physical-chemical properties were obtained. Over 80 successive extractions were carried out to establish coating efficiency using PDMS/DVB 65µm commercial coating in comparison with the PDMS/DVB/PDMS. The PDMS/DVB coating was more prone to irreversible matrix attachment on its surface, with consequent reduction of its extractive performance after 80 consecutive extractions. Conversely, the PDMS/DVB/PDMS coating showed enhanced inertness towards matrix fouling due to its outer smooth PDMS layer. This work represents the first step towards the development of robust SPME methods for quantification of contaminants in avocado as well as other fatty-based matrices, with minimal sample pre-treatment prior to extraction. In addition, an evaluation of matrix components attachment on the coating surface and related artifacts created by desorption of the coating at high temperatures in the GC-injector port, has been performed by GCxGC-ToF/MS.


Association of HER2/neu expression with sensitivity to tumor-specific CTL in human ovarian cancer.
To study potential sources of tumor-associated Ags in human ovarian cancer, we have established two ovarian tumor cell lines (OvS1 and OvA2) from two ovarian cancer patients, which express the cellular oncogene HER2/neu. Corresponding tumor infiltrating lymphocyte cultures have also been established and display an autologous tumor-specific pattern of cytotoxicity that is HLA-A2 restricted. To determine the potential relationship between HER2/neu expression and CTL-mediated cytolysis, we first established tumor cell clones from OvS1. These were categorized as high or low expressors of HER2/neu (cOvS1+ or cOvS1-, respectively), and cOvS1+ clones displayed a significantly higher sensitivity to CTL killing as compared with cOvS1- clones. To modulate the expression of HER2/neu, ovarian cancer cells were treated with IFN-gamma. After this exposure, HER2/neu expression was significantly decreased, whereas the expression of HLA Class I was significantly increased. Despite the increase in HLA Class I molecules on the cell surface, CTL-mediated cytolysis of both OvS1 and OvA2 was significantly decreased. IFN-gamma treated cOvS1+ clones displayed a similar decrease in sensitivity to CTL killing, whereas IFN-gamma treated cOvS1- clones displayed an increase or no change in sensitivity to CTL. To confirm this apparent association between HER2/neu expression and CTL recognition, melanoma tumor cell lines that were insensitive to ovarian tumor-specific CTL were transfected with the HER2/neu gene. An HLA-A2+ HER2/neu-transfected melanoma cell line was made sensitive to HLA-A2 restricted ovarian tumor-specific CTL but not to HLA-A2 unrestricted CTL, whereas an HLA-A2- HER2/neu-transfected melanoma remained insensitive to HLA-A2 restricted CTL. These results demonstrate that the sensitivity of ovarian epithelial tumor cells to CTL-mediated lysis is associated with the level of expression of HER2/neu, suggesting that this oncogene product may serve as a source of tumor-associated Ags or as an inducer of such peptides. This is the first time in a human tumor system that oncogene expression has been related to the induction of antigenicity. These results prompt us to approach new strategies for immunotherapy of cancer.


Voltage-assisted photoaligning effect of an azo dye doped in a liquid crystal with negative dielectric anisotropy.
We demonstrate a method of controlling the pretilt angle by field-assisted photoalignment in a vertically-aligned liquid crystal doped with a dichroic azo dye. By dynamically measuring both the pretilt angle and anisotropy in absorbance, we present detailed alignment variations in both the polar and azimuthal directions with the time of laser exposure that induces photoisomerization of the dye molecules. Significant differences in the resulting pretilt as well as optically-absorptive anisotropy are manifested between a regular photoalignment procedure and that in conjunction with a bias voltage during irradiation. It is found that the field-assisted exposure not only speeds up the photoalignment along the polarization direction of the laser beam but also leads to a higher orientational order.


In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells.
Due to its relatively slow clinical progression, B cell chronic lymphocytic leukemia (B-CLL) is classically described as a disease of accumulation rather than proliferation. However, evidence for various forms of clonal evolution suggests that B-CLL clones may be more dynamic than previously assumed. We used a nonradioactive, stable isotopic labeling method to measure B-CLL cell kinetics in vivo. Nineteen patients drank an aliquot of deuterated water (2H2O) daily for 84 days, and 2H incorporation into the deoxyribose moiety of DNA of newly divided B-CLL cells was measured by gas chromatography/mass spectrometry, during and after the labeling period. Birth rates were calculated from the kinetic profiles. Death rates were defined as the difference between calculated birth and growth rates. These analyses demonstrated that the leukemic cells of each patient had definable and often substantial birth rates, varying from 0.1% to greater than 1.0% of the entire clone per day. Those patients with birth rates greater than 0.35% per day were much more likely to exhibit active or to develop progressive disease than those with lower birth rates Thus, B-CLL is not a static disease that results simply from accumulation of long-lived lymphocytes. Rather, it is a dynamic process composed also of cells that proliferate and die, often at appreciable levels. The extent to which this turnover occurs has not been previously appreciated. A correlation between birth rates and disease activity and progression appears to exist, which may help identify patients at risk for worsening disease in advance of clinical deterioration.


Postural and trunk muscle response to sudden release during stoop lifting tasks before and after fatigue of the trunk erector muscles.
The effect of fatigue on the muscular and postural response to sudden release of different stoop lifting loads was studied. Ten male volunteers performed a series of stoop lifting trials before and after fatigue of the erector spinae. Trials were performed using loads of 20, 40, 60, and 80 N, and sudden release of load was triggered randomly on one of the repetitions using an electromagnetic release. The onset of release was registered by an accelerometer, centre of pressure (COP) motion was recorded via a forceplate, and EMG activities of the latissimus dorsi (LD), erector spinae (ES), rectus abdominus (RA), external oblique (EO) and internal oblique (IO) muscles were recorded. A slightly reduced lifting speed was seen after fatigue, particularly at the higher loads, but this had little effect on the perturbing force at release, which was dominated by the release load. A significant effect of fatigue was seen on the antero-posterior COP motion, with the postural disturbance being decreased after fatigue. Fatigue resulted in a significant increase in ES (p = 0.029) and LD (p = 0.015) relaxation times and, while the response patterns (relaxation, contraction or no response) of the anterior trunk muscles (RA, EO, IO) were not always consistent, the proportion of response by relaxation was greater after fatigue. This resulted in a lower incidence but longer duration of co-contraction of the ES-RA, ES-EO and ES-EO muscle groups following fatigue, such that the mean co-contraction duration of these groups showed no significant differences before and after fatigue. The response to sudden release is a balance between maintaining postural stability and at the same time preventing the trunk musculature from overloading the spine and risking tissue injury. While fatigue of the trunk extensors does not appear to increase either the risk of fall or stumble or the incidence of co-contraction following sudden release of stoop lifting tasks, the duration of co-contraction appears to increase following fatigue. Further study is required to quantify the loading on the spine during sudden release of different lifting tasks before and after more realistic fatigue conditions.


Intermediate-term memory for site-specific sensitization in aplysia is maintained by persistent activation of protein kinase C.
Recent studies of long-term synaptic plasticity and long-term memory have demonstrated that the same functional endpoint, such as long-term potentiation, can be induced through distinct signaling pathways engaged by different patterns of stimulation. A critical question raised by these studies is whether different induction pathways either converge onto a common molecular mechanism or engage different molecular cascades for the maintenance of long-term plasticity. We directly examined this issue in the context of memory for sensitization in the marine mollusk Aplysia. In this system, training with a single tail shock normally induces short-term memory (<30 min) for sensitization of tail-elicited siphon withdrawal, whereas repeated spaced shocks induce both intermediate-term memory (ITM) (>90 min) and long-term memory (>24 hr). We now show that a single tail shock can also induce ITM that is expressed selectively at the trained site (site-specific ITM). Although phenotypically similar to the form of ITM induced by repeated trials, the mechanisms by which site-specific ITM is induced and maintained are distinct. Unlike repeated-trial ITM, site-specific ITM requires neither protein synthesis nor PKA activity for induction or maintenance. Rather, the induction of site-specific ITM requires calpain-dependent proteolysis of activated PKC, yielding a persistently active PKC catalytic fragment (PKM) that also serves to maintain the memory in the intermediateterm temporal domain. Thus, two unique forms of ITM that have different induction requirements also use distinct molecular mechanisms for their maintenance.


Failure of Sterne- and Pasteur-like strains of Bacillus anthracis to replicate and survive in the urban bluebottle blow fly Calliphora vicina under laboratory conditions.
This study aimed to elucidate the bacteriological events occurring within the gut of Calliphora vicina, selected as the European representative of blow flies held responsible for the spread of anthrax during epidemics in certain parts of the world. Green-fluorescent-protein-carrying derivatives of Bacillus anthracis were used. These lacked either one of the virulence plasmids pXO1 and pXO2 and were infected, or not infected, with a worm intestine phage (Wip4) known to influence the phenotype and survival of the pathogen. Blood meals were prepared for the flies by inoculation of sheep blood with germinated and, in case of pXO2+ strains, encapsulated cells of the four B. anthracis strains. After being fed for 4 h an initial 10 flies were externally disinfected with peracetic acid to ensure subsequent quantitation representing ingested B. anthracis only. Following neutralization, they were crushed in sterile saline. Over each of the ensuing 7 to 10 days, 10 flies were removed and processed the same way. In the absence of Wip4, strains showed steady declines to undetectable in the total B. anthracis counts, within 7-9 days. With the phage infected strains, the falls in viable counts were significantly more rapid than in their uninfected counterparts. Spores were detectable in flies for longer periods than vegetative bacteria. In line with the findings in both biting and non-biting flies of early workers our results indicate that B. anthracis does not multiply in the guts of blow flies and survival is limited to a matter of days.


Toward a science of learning systems: a research agenda for the high-functioning Learning Health System.
The capability to share data, and harness its potential to generate knowledge rapidly and inform decisions, can have transformative effects that improve health. The infrastructure to achieve this goal at scale--marrying technology, process, and policy--is commonly referred to as the Learning Health System (LHS). Achieving an LHS raises numerous scientific challenges. The National Science Foundation convened an invitational workshop to identify the fundamental scientific and engineering research challenges to achieving a national-scale LHS. The workshop was planned by a 12-member committee and ultimately engaged 45 prominent researchers spanning multiple disciplines over 2 days in Washington, DC on 11-12 April 2013. The workshop participants collectively identified 106 research questions organized around four system-level requirements that a high-functioning LHS must satisfy. The workshop participants also identified a new cross-disciplinary integrative science of cyber-social ecosystems that will be required to address these challenges. The intellectual merit and potential broad impacts of the innovations that will be driven by investments in an LHS are of great potential significance. The specific research questions that emerged from the workshop, alongside the potential for diverse communities to assemble to address them through a 'new science of learning systems', create an important agenda for informatics and related disciplines.


Atomic force microscopy and surface plasmon resonance for real-time single-cell monitoring of bacteriophage-mediated lysis of bacteria.
The growing incidence of multidrug-resistant bacterial strains presents a major challenge in modern medicine. Antibiotic resistance is often exhibited by Staphylococcus aureus, which causes severe infections in human and animal hosts and leads to significant economic losses. Antimicrobial agents with enzymatic activity (enzybiotics) and phage therapy represent promising and effective alternatives to classic antibiotics. However, new tools are needed to study phage-bacteria interactions and bacterial lysis with high resolution and in real-time. Here, we introduce a method for studying the lysis of S. aureus at the single-cell level in real-time using atomic force microscopy (AFM) in liquid. We demonstrate the ability of the method to monitor the effect of the enzyme lysostaphin on S. aureus and the lytic action of the Podoviridae phage P68. AFM allowed the topographic and biomechanical properties of individual bacterial cells to be monitored at high resolution over the course of their lysis, under near-physiological conditions. Changes in the stiffness of S. aureus cells during lysis were studied by analyzing force-distance curves to determine Young's modulus. This allowed observing a progressive decline in cellular stiffness corresponding to the disintegration of the cell envelope. The AFM experiments were complemented by surface plasmon resonance (SPR) experiments that provided information on the kinetics of phage-bacterium binding and the subsequent lytic processes. This approach forms the foundation of an innovative framework for studying the lysis of individual bacteria that may facilitate the further development of phage therapy.


KDM4 Inhibition Targets Breast Cancer Stem-like Cells.
Traditional treatments for breast cancer fail to address therapy-resistant cancer stem-like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here, we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the antitumor properties of QC6352, we established a method to isolate and propagate breast cancer stem-like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Limiting-dilution orthotopic xenografts of these BCSCs regenerated original patient tumor histology and gene expression. QC6352 blocked BCSC proliferation, sphere formation, and xenograft tumor formation. QC6352 also abrogated expression of EGFR, which drives the growth of therapy-resistant triple-negative breast cancer cells. Our findings validate a unique BCSC culture system for drug screening and offer preclinical proof of concept for KDM4 inhibition as a new strategy to treat triple-negative breast cancer. Cancer Res; 77(21); 5900-12. ©2017 AACR.


Complementary and alternative medicine in back pain utilization report.
This systematic review was undertaken to evaluate which complementary and alternative medicine (CAM) therapies are being used for persons with back pain in the United States. MEDLINE, CINHAHL, EMBASE, and Cochrane Central, and a variety of CAM specific databases were searched from 1990 to November 2007. A grey literature search was also undertaken, particularly for clinical practice guidelines (CPG) related to CAM. Standard systematic review methodology was employed. Eligibility criteria included English studies of adults with back pain, and a predefined list of CAM therapies. A total of 103 publications were evaluated; of these 29 did not present CAM therapy use stratified for back pain. There were a total of 65 utilization studies, 43 of which were American. Four publications evaluated the concurrent use of four or more CAM therapies and these suggest that chiropractic/manipulation is the most frequently used modality followed by massage and acupuncture. A limited number of publications evaluated utilization rates within multiple regions of the back and show that CAM was used least for treating the thoracic spine and most for the low back. However, rates of the use of massage were similar for neck and lower back regions. Concurrent use of different CAM or conventional therapies was not well reported. From 11 eligible CPG, only one (for electro-acupuncture) provided recommendations for frequency of use for low back pain of all acuity levels. Eighteen cost publications were reviewed and all but one publication (cost-effectiveness) were cost identification studies. There is limited information on the impact of insurance coverage on costs and utilization specific to back pain. There are a few studies evaluating the relative utilization of various CAM therapies for back pain. For those studies evaluating utilization of individual CAM therapies, the specific characteristics of the therapy, the providers, and the clinical presentation of the back pain patients were not adequately detailed; nor was the overlap with other CAM or conventional treatments.


Evolution of minimally invasive approaches to the sella and parasellar region.
Introduction Given advancements in endoscopic image quality, instrumentation, surgical navigation, skull base closure techniques, and anatomical understanding, the endonasal endoscopic approach has rapidly evolved into a widely utilized technique for removal of sellar and parasellar tumors. Although pituitary adenomas and Rathke cleft cysts constitute the majority of lesions removed via this route, craniopharyngiomas, clival chordomas, parasellar meningiomas, and other lesions are increasingly removed using this approach. Paralleling the evolution of the endonasal route to the parasellar region, the supraorbital eyebrow craniotomy has also been increasingly used as an alternative minimally invasive approach to reach this skull base region. Similar to the endonasal route, the supraorbital route has been greatly facilitated by advances in endoscopy, along with development of more refined, low-profile instrumentation and surgical navigation technology. Objectives This review, encompassing both transcranial and transsphenoidal routes, will recount the high points and advances that have made minimally invasive approaches to the sellar region possible, the evolution of these approaches, and their relative indications and technical nuances. Data Synthesis The literature is reviewed regarding the evolution of surgical approaches to the sellar region beginning with the earliest attempts and emphasizing technological advances, which have allowed the evolution of the modern technique. The surgical techniques for both endoscopic transsphenoidal and supraorbital approaches are described in detail. The relative indications for each approach are highlighted using case illustrations. Conclusions Although tremendous advances have been made in transitioning toward minimally invasive transcranial and transsphenoidal approaches to the sella, further work remains to be done. Together, the endonasal endoscopic and the supraorbital endoscope-assisted approaches are complementary minimally invasive routes to the parasellar region.


An observational study of orthopaedic abstracts and subsequent full-text publications.
Research abstracts are frequently referenced in orthopaedic textbooks and influence orthopaedic care. However, little is known about the quality of information provided in the abstracts, the frequency of publication of complete papers after presentation of abstracts, or any discrepancies between abstracts and published papers. The objective of this study was to determine the quality of information provided in orthopaedic abstracts, rates of publication of full-text articles after presentation of abstracts, predictors of publication of full-text articles, and consistency between abstracts and full-text articles. We retrieved all abstracts from the 1996 scientific program of the sixty-third Annual Meeting of the American Academy of Orthopaedic Surgeons. For each abstract, we recorded the completeness of reporting and key features of the study design, conduct, analysis, and interpretation. A computerized Medline and PubMed search established whether the abstract had been followed by publication of a full-text article. Finally, we evaluated the consistency of reporting between abstracts and final publications. The program included 465 abstracts, 66% of which were on prognostic studies. All abstracts described the study design, and 70.7% of the designs were observational. Key methodological issues were reported in less than half of the abstracts, and information on data analysis was reported in <15%. One hundred and fifty-nine (34%) of the 465 abstracts were followed by publication of a full-text article. The mean time to publication (and standard deviation) was 17.6 +/- 12 months (range, one to fifty-six months). Inconsistencies between the abstract and the full-text article included the primary outcome measure, which differed 14% of the time, and the results, which differed 19% of the time. Two-thirds of the orthopaedic abstracts in this sample were not followed by publication of a full-text paper. The overall quality of reporting in abstracts proved inadequate, and inconsistencies between the final published paper and the original abstract occurred frequently. The routine use of abstracts as a guide to orthopaedic practice needs to be reconsidered.


American Spirit Pack Descriptors and Perceptions of Harm: A Crowdsourced Comparison of Modified Packs.
In 2015, the Food and Drug Administration issued warnings to three tobacco manufacturers who label their cigarettes as "additive-free" and/or "natural" on the grounds that they make unauthorized reduced risk claims. The goal of this study was to examine US adults' perceptions of three American Spirit (AS) pack descriptors ("Made with Organic Tobacco," "100% Additive-Free," and "100% US Grown Tobacco") to assess if they communicate reduced risk. In September 2012, three cross-sectional surveys were posted on Amazon Mechanical Turk. Adult participants evaluated the relative harm of a Marlboro Red pack versus three different AS packs with the descriptors "Made with Organic Tobacco," "100% Additive-Free," or "100% US Grown Tobacco" (Survey 1; n = 461); a Marlboro Red pack versus these AS packs modified to exclude descriptors (Survey 2; n = 857); and unmodified versus modified AS pack images (Survey 3; n = 1001). The majority of Survey 1 participants rated the unmodified AS packs as less harmful than the Marlboro Red pack; 35.4%-58.8% of Survey 2 participants also rated the modified (no claims) packs as less harmful than Marlboro Red. In these surveys, prior use of AS cigarettes was associated with reduced perceptions of risk (adjusted odds ratio [AOR] 1.59-2.40). "Made with Organic Tobacco" and "100% Additive-Free" were associated with reduced perceptions of risk when comparing the modified versus the unmodified AS packs (Survey 3). Data suggest that these AS pack descriptors communicate reduced harm messages to consumers. Findings have implications for regulatory actions related to product labeling and packaging. These findings provide additional evidence that the "Made with Organic Tobacco," "100% Additive-Free," and "100% US Grown" descriptors, as well as other aspects of the AS pack design, communicate reduced harm to non-, current, and former smokers. Additionally, they provide support for the importance of FDA's 2015 warning to Santa Fe Natural Tobacco Company on "100% Additive Free" as an unauthorized modified risk claim.


Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia.
The pathophysiology of severe aplastic anemia (SAA) is immune-mediated destruction of hematopoietic stem and progenitor cells (HSPCs). Most patients respond to immunosuppressive therapies, but a minority transform to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), frequently associated with monosomy 7 (-7). Thirteen SAA patients were analyzed for acquired mutations in myeloid cells at the time of evolution to -7, and all had a dominant HSPC clone bearing specific acquired mutations. However, mutations in genes associated with MDS/AML were present in only 4 cases. Patients who evolved to MDS and AML showed marked progressive telomere attrition before the emergence of -7. Single telomere length analysis confirmed accumulation of short telomere fragments of individual chromosomes. Our results indicate that accelerated telomere attrition in the setting of a decreased HSPC pool is characteristic of early myeloid oncogenesis, specifically chromosome 7 loss, in MDS/AML after SAA, and provides a possible mechanism for development of aneuploidy.


Organizational readiness for implementing change: a psychometric assessment of a new measure.
Organizational readiness for change in healthcare settings is an important factor in successful implementation of new policies, programs, and practices. However, research on the topic is hindered by the absence of a brief, reliable, and valid measure. Until such a measure is developed, we cannot advance scientific knowledge about readiness or provide evidence-based guidance to organizational leaders about how to increase readiness. This article presents results of a psychometric assessment of a new measure called Organizational Readiness for Implementing Change (ORIC), which we developed based on Weiner's theory of organizational readiness for change. We conducted four studies to assess the psychometric properties of ORIC. In study one, we assessed the content adequacy of the new measure using quantitative methods. In study two, we examined the measure's factor structure and reliability in a laboratory simulation. In study three, we assessed the reliability and validity of an organization-level measure of readiness based on aggregated individual-level data from study two. In study four, we conducted a small field study utilizing the same analytic methods as in study three. Content adequacy assessment indicated that the items developed to measure change commitment and change efficacy reflected the theoretical content of these two facets of organizational readiness and distinguished the facets from hypothesized determinants of readiness. Exploratory and confirmatory factor analysis in the lab and field studies revealed two correlated factors, as expected, with good model fit and high item loadings. Reliability analysis in the lab and field studies showed high inter-item consistency for the resulting individual-level scales for change commitment and change efficacy. Inter-rater reliability and inter-rater agreement statistics supported the aggregation of individual level readiness perceptions to the organizational level of analysis. This article provides evidence in support of the ORIC measure. We believe this measure will enable testing of theories about determinants and consequences of organizational readiness and, ultimately, assist healthcare leaders to reduce the number of health organization change efforts that do not achieve desired benefits. Although ORIC shows promise, further assessment is needed to test for convergent, discriminant, and predictive validity.


Role of vector control in the global program to eliminate lymphatic filariasis.
Lymphatic filariasis (LF) is a major cause of acute and chronic morbidity in the tropical and subtropical parts of the world. The availability of safe, single-dose, drug treatment regimens capable of suppressing microfilaremia to very low levels, along with improvements in techniques for diagnosing infection, has resulted in the targeting of this major mosquito-borne disease for global elimination. The Global Program to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000 with the principal objective of breaking the cycles of transmission of Wuchereria bancrofti and Brugia spp. through the application of annual mass drug administrations (MDAs) to entire at-risk populations. Although significant progress in initiating MDA programs in endemic countries has been made, emerging challenges to this approach have raised questions regarding the effectiveness of using MDA alone to eliminate LF without the inclusion of supplementary vector control. Here, we review advances in knowledge of vector ecology, vector-parasite relationships, and both empirical and theoretical evidence regarding vector management to assess the feasibility and strategic value of including vector control in the GPELF initiative to achieve the global elimination of LF.


SGLT2-i improves markers of islet endothelial cell function in db/db diabetic mice.
Islet endothelial cells produce paracrine factors important for islet beta-cell function and survival. Under conditions of type 2 diabetes, islet endothelial cells exhibit a dysfunctional phenotype including increased expression of genes involved in cellular adhesion and inflammation. We sought to determine whether treatment of hyperglycemia with the sodium glucose co-transporter 2 inhibitor empagliflozin, either alone or in combination with metformin, would improve markers of endothelial cell function in islets, assessed ex vivo, and if such an improvement is associated with improved insulin secretion in a mouse model of diabetes in vivo. For these studies, db/db diabetic mice and non-diabetic littermate controls were treated for 6 weeks with empagliflozin or metformin, either alone or in combination. For each treatment group, expression of genes indicative of islet endothelial dysfunction was quantified. Islet endothelial and beta-cell area was assessed by morphometry of immunochemically stained pancreas sections. Measurements of plasma glucose and insulin secretion during an intravenous glucose tolerance test were performed on vehicle and drug treated diabetic animals. We found that expression of endothelial dysfunction marker genes is markedly increased in diabetic mice. Treatment with either empagliflozin or metformin lowered expression of the dysfunction marker genes ex vivo, which correlated with improved glycemic control, and increased insulin release in vivo. Empagliflozin treatment was more effective than metformin alone, with a combination of the two drugs demonstrating the greatest effects. Improving islet endothelial function through strategies such as empagliflozin/metformin treatment may provide an effective approach for improving insulin release in human type 2 diabetes.


Relation between blood pressure control, body mass index, and intensity of medical treatment.
A cross-sectional study was performed to assess the rates of blood pressure (BP) control to a systolic goal (< 140 mmHg), to a diastolic goal (< 90 mmHg), and to both in a sample of 226 treated hypertensive patients. We also examined the association between obesity, BP control, intensity of treatment defined as dose score (summed ranks of doses of all antihypertensive drugs taken), and number of drugs. Of the 226 treated patients (mean age, 60 years; 20.4% women), 67.7% were controlled to the systolic goal, 72.1% were controlled to the diastolic goal, and 53.5% were controlled to both. Patients were divided into four groups according to body mass index (BMI): less than 23, A; 23-24.9, B; 25-26.9, C; and 27 or more, D. There were no differences in the rates of BP control to the systolic goal, to the diastolic goal, or to both among the four groups; however, the dose score and number of drugs administered were higher in patients of group D than in those of the other groups. There was a tendency toward a higher intensity of drug treatment in obese patients with either controlled or uncontrolled BP. The dose score and number of drugs correlated positively with BMI. In representative subgroups (n = 62), serum insulin and the homeostasis model assessment value of insulin resistance were higher in the patients in group D than in the other groups. These findings indicate that hypertensive patients managed in a hypertension clinic had satisfactory BP control in 53.5% of cases. A higher intensity of medical treatment is needed to achieve BP control in obese hypertensive patients characterized by insulin resistance.


Social networks of women with undefined musculoskeletal disorder.
This study was conducted to investigate social integration among, and the availability of social support for, female patients with undefined musculoskeletal disorder compared to women with coronary heart disease. The aim was to elucidate the importance of a clear diagnosis for the social network relationships of these female patients. For the measurement of social support two instruments were used: an abbreviated version of the Interview Schedule for Social Interaction and a condensed version of the Interpersonal Support Evaluation List. After adjustment for age, marital and employment status, significant differences can be recognized between the two groups of patients: MSD-patients interact with fewer people and receive less emotional support. Implications for social work practice and issues for future research are presented.


Oriented collagen nanocoatings for tissue engineering.
Collagens are among the most widely present and important proteins composing the human total body, providing strength and structural stability to various tissues, from skin to bone. In this paper, we report an innovative approach to bioactivate planar surfaces with oriented collagen molecules to promote cells proliferation and alignment. The Langmuir-Blodgett technique was used to form a stable collagen film at the air-water interface and the Langmuir-Schaefer deposition was adopted to transfer it to the support surface. The deposition process was monitored by estimating the mass of the protein layers after each deposition step. Collagen films were then structurally characterized by atomic force, scanning electron and fluorescent microscopies. Finally, collagen films were functionally tested in vitro. To this aim, 3T3 cells were seeded onto the silicon supports either modified or not (control) by collagen film deposition. Cells adhesion and proliferation on collagen films were found to be greater than those on control both after 1 (p<0.05) and 7 days culture. Moreover, the functionalization of the substrate surface triggered a parallel orientation of cells when cultured on it. In conclusion, these data demonstrated that the Langmuir-Schaefer technique can be successfully used for the deposition of oriented collagen films for tissue engineering applications.


Contribution of indirect action to radiation-induced mammalian cell inactivation: dependence on photon energy and heavy-ion LET.
The contribution of indirect action mediated by OH radicals to cell inactivation by ionizing radiations was evaluated for photons over the energy range from 12.4 keV to 1.25 MeV and for heavy ions over the linear energy transfer (LET) range from 20 keV/microm to 440 keV/microm by applying competition kinetics analysis using the OH radical scavenger DMSO. The maximum level of protection provided by DMSO (the protectable fraction) decreased with decreasing photon energy down to 63% at 12.4 keV. For heavy ions, a protectable fraction of 65% was found for an LET of around 200 keV/microm; above that LET, the value stayed the same. The reaction rate of OH radicals with intracellular molecules responsible for cell inactivation was nearly constant for photon inactivation, while for the heavy ions, the rate increased with increasing LET, suggesting a reaction with the densely produced OH radicals by high-LET ions. Using the protectable fraction, the cell killing was separated into two components, one due to indirect action and the other due to direct action. The inactivation efficiency for indirect action was greater than that for direct action over the photon energy range and the ion LET range tested. A significant contribution of direct action was also found for the increased RBE in the low photon energy region.


The first 18 months following food and drug administration approval of lumbar total disc replacement in the United States: reported adverse events outside an investigational device exemption study environment.
Introduction of a new surgical technology may result in higher rates of adverse events compared with rates reported in the study performed to gain regulatory approval. The purpose of our study was to describe the incidence of reported adverse events during the first 18 months following US Food and Drug Administration (FDA) approval of the first lumbar arthroplasty device available in the United States and to discern data trends. Reports of adverse events submitted to the FDA in patients receiving the Charité artificial disc were reviewed and pooled by similarity. We analyzed 135 medical device reports filed with the FDA regarding the Charité artificial disc between October 26, 2004, and April 26, 2006. Sixteen reports were excluded for lack of information regarding cause or because described events were vague or unrelated to the procedure. Rate of adverse events reported to the FDA as a percentage of devices of which the device manufacturer was aware had been dispensed at 6, 12, and 18 months following approval was 0.58%, 2.34%, and 2.13%, respectively. The adverse event reported most frequently through 18 months was anterior migration with reoperation (0.65%); other reported adverse events were, in decreasing order, sizing and malposition errors resulting in reoperation (0.36%), posterior element fracture resulting in reoperation (0.30%), major vascular injury requiring a blood transfusion (0.23%), and subsidence requiring reoperation (0.20%). Three non-device-related patient deaths were reported following FDA approval. The reported rate of sizing/malposition errors leading to reoperation of 0.36% was the same rate as that seen in the investigational device exemption (IDE) study of the Charité artificial disc. All other reported rates were lower than rates of the same events reported in the study. Medical device reporting is an important yet highly anecdotal and incomplete event-tracking process. However, it is the principal means available in the United States for obtaining information on the clinical performance of a device after its approval for sale and does provide some data, albeit imperfect, in this regard. The cumulative medical device reports through the 18 months following FDA approval, measured against the number of devices dispensed, suggests a rate of adverse events that either tracks or is somewhat less than that reported in the IDE study. This suggests that a repeat of the "cage rage," a "lumbar arthroplasty rage," has not yet occurred.


Deregulation of miRNAs-cMYC circuits is a key event in refractory celiac disease type-2 lymphomagenesis.
A percentage of celiac disease (CD) patients develop refractory type-2 disease (RCD2), a condition associated with increased risk of enteropathy-associated T-cell-lymphoma (EATL) and without therapeutic option. Therefore, we profiled the miRNome in series of peripheral T-cell lymphomas (PTCLs), CD, RCD1 or 2 and in the murine interleukin-15 (IL15)-transgenic (TG) model of RCD. The transcriptome was analyzed in 18 intestinal T-cell lymphomas (ITLs). Bioinformatics pipelines provided significant microRNA (miRNA) lists and predicted targets that were confirmed in a second set of patients. Our data show that ITLs have a unique miRNA profile with respect to other PTCLs. The c-MYC regulated miR-17/92 cluster distinguishes monomorphic epitheliotropic ITL (MEITL) from EATL and prognosticates EATL outcome. These miRNAs are decreased in IL15-TG mice upon Janus kinase (JAK) inhibition. The random forest algorithm identified a signature of 38 classifier miRNAs, among which, the miR-200 and miR-192/215 families were progressively lost in RCD2 and ITL-CD, whereas miR-17/92 and C19MC miRNAs were up-regulated. Accordingly, SMAD3, MDM2, c-Myc and activated-STAT3 were increased in RCD2 and EATL tissues while JAK inhibition in IL15-TG mice restored their levels to baseline. Our data suggest that miRNAs circuit supports activation of STAT3 and c-Myc oncogenic signaling in RCD2, thus contributing to lymphomagenesis. This novel understanding might pave the way to personalized medicine approaches for RCD and EATL.


Boswellic acid blocks signal transducers and activators of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1.
Activation of signal transducers and activators of transcription-3 (STAT-3) has been linked with survival, proliferation, chemoresistance, and angiogenesis of tumor cells, including human multiple myeloma (MM). Thus, agents that can suppress STAT3 activation have potential as cancer therapeutics. In our search for such agents, we identified acetyl-11-keto-beta-boswellic acid (AKBA), originally isolated from Boswellia serrata. Our results show that AKBA inhibited constitutive STAT3 activation in human MM cells. AKBA suppressed IL-6-induced STAT3 activation, and the inhibition was reversible. The phosphorylation of both Jak 2 and Src, constituents of the STAT3 pathway, was inhibited by AKBA. Interestingly, treatment of cells with pervanadate suppressed the effect of AKBA to inhibit the phosphorylation of STAT3, thus suggesting the involvement of a protein tyrosine phosphatase. We found that AKBA induced Src homology region 2 domain-containing phosphatase 1 (SHP-1), which may account for its role in dephosphorylation of STAT3. Moreover, deletion of the SHP-1 gene by small interfering RNA abolished the ability of AKBA to inhibit STAT3 activation. The inhibition of STAT3 activation by AKBA led to the suppression of gene products involved in proliferation (cyclin D1), survival (Bcl-2, Bcl-xL, and Mcl-1), and angiogenesis (VEGF). This effect correlated with the inhibition of proliferation and apoptosis in MM cells. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the AKBA-induced apoptosis. Overall, our results suggest that AKBA is a novel inhibitor of STAT3 activation and has potential in the treatment of cancer.


[Hemodialysis and nursing: a pilot study on patient-perceived quality].
Introduction: Dialysis is a form of renal replacement therapy that requires several changes in the relational, emotional, work, and family sphere. It can be a cause of stress due to various factors. Objective: The purpose of our study has been to evaluate the perception of the nursing care received by dialyzed patients. Method: In 2021, a cross sectional study was conducted in Perugia hospital by administering to dialyzed patients a questionnaire built on the Newcastle satisfaction with nursing scale. Results: 30 patients participated in the study: the mean age was 68.9 ±15.1, 66.7% were male, 50% had a high school diploma, 86.7% were retired, and 50% were dialyzed for less than 5 years. Negative perceptions of the assistance received were mainly reported by women, younger patients, and patients who had been in therapy for only a few years. Discussion: Our study highlights several aspects that are fundamental to improving the quality of nursing care. There also needs to be a greater attention to certain types of patients, to improve their experience and consequently their quality of life.


Severity of depressive symptoms as a predictor of mortality: the English longitudinal study of ageing.
Major depressive disorder and subthreshold depression have been associated with premature mortality. We investigated the association between depressive symptoms and mortality across the full continuum of severity. We used Cox proportional hazards models to examine the association between depressive symptom severity, assessed using the eight-item Center for Epidemiological Studies Depression Scale (CES-D; range 0-8), and the risk of all-cause mortality over a 9-year follow-up, in 11 104 members of the English Longitudinal Study of Ageing. During follow-up, one fifth of study members died (N = 2267). Depressive symptoms were associated with increased mortality across the full range of severity (p trend < 0.001). Relative to study members with no symptoms, an increased risk of mortality was found in people with depressive symptoms of a low [hazard ratio (HR) for a score of 2 was 1.59, 95% confidence interval (CI) 1.40-1.82], moderate (score of 4: HR 1.80, 95% CI 1.52-2.13) and high (score of 8: HR 2.27, 95% CI 1.69-3.04) severity, suggesting risk emerges at low levels but plateaus thereafter. A third of participants (36.4%, 95% CI 35.5-37.3) reported depressive symptoms associated with an increased mortality risk. Adjustment for physical activity, physical illnesses, and impairments in physical and cognitive functioning attenuated this association (p trend = 0.25). Depressive symptoms are associated with an increased mortality risk even at low levels of symptom severity. This association is explained by physical activity, physical illnesses, and impairments in physical and cognitive functioning.


Songs of humpback whales.
1) Humpback whales (Megaptera novaeangliae) produce a series of beautiful and varied sounds for a period of 7 to 30 minutes and then repeat the same series with considerable precision. We call such a performance "singing" and each repeated series of sounds a "song." 2) All prolonged sound patterns (recorded so far) of this species are in song form, and each individual adheres to its own song type. 3) There seem to be several song types around which whales construct their songs, but individual variations are pronounced (there is only a very rough species-specific song pattern). 4) Songs are repeated without any obvious pause between them; thus song sessions may continue for several hours. 5) The sequence of themes in successive songs by the same individual is the same. Although the number of phrases per theme varies, no theme is ever completely omitted in our sample. 6) Loud sounds in the ocean, for example dynamite blasts, do not seem to affect the whale's songs. 7) The sex of the performer of any of the songs we have studied is unknown. 8) The function of the songs is unknown.


Reconstituted halogenated hydrocarbon pesticide and pollutant mixtures found in human tissues: effects on the immature male Wistar rat after short-term exposure.
Halogenated hydrocarbon insecticides and polychlorinated biphenyl (PCB) mixtures are routinely detected as residues in human adipose tissue, serum, and milk. Based on average values observed in analytical studies, reconstituted halogenated hydrocarbon pesticide mixtures and PCB mixtures were prepared and administered to immature male Wistar rats. The mixtures were administered at dose levels which approximate the concentrations which would be absorbed by an infant suckling for 180 days (low dose, L), and at three higher dose levels (2 X L, 10 X L, and 100 X L). The pesticide mixture contained isomeric hexachlorocyclohexanes, dieldrin, heptachlor epoxide, oxychlordane, trans-nonachlor, hexachlorobenzene, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane, and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene; the reconstituted PCB mixture contained 13 of the major congeners which have been identified in human milk samples. Administration of the L dose level of the pesticide (0.95 mg/kg), PCB (0.45 mg/kg), and pesticide plus PCB mixture (0.95 + 0.45 mg/kg, respectively) in corn oil on days 1 and 3 did not significantly alter hepatic drug-metabolizing enzyme activities or elicit any observable pathological damage 6 days after the first exposure. In contrast, administration of the higher dose levels of this mixture elicited a dose-dependent induction of several hepatic drug-metabolizing enzymes. Moreover, despite the short duration of exposure to these chemicals, the rats treated with the higher doses (10 X L and 100 X L) of these mixtures exhibited mild alterations in thyroid architecture, changes in hepatocellular nuclei including variations in chromatin distribution, vesiculation of larger nuclei, and frequent appearance of pyknotic shrunken nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)


Anticonvulsant medications extend worm life-span.
Genetic studies have elucidated mechanisms that regulate aging, but there has been little progress in identifying drugs that delay aging. Here, we report that ethosuximide, trimethadione, and 3,3-diethyl-2-pyrrolidinone increase mean and maximum life-span of Caenorhabditis elegans and delay age-related declines of physiological processes, indicating that these compounds retard the aging process. These compounds, two of which are approved for human use, are anticonvulsants that modulate neural activity. These compounds also regulated neuromuscular activity in nematodes. These findings suggest that the life-span-extending activity of these compounds is related to the anticonvulsant activity and implicate neural activity in the regulation of aging.


Timing of deep vein thrombosis formation after aneurysmal subarachnoid hemorrhage.
Deep vein thrombosis (DVT) is a common complication of aneurysmal subarachnoid hemorrhage (aSAH). The time period of greatest risk for developing DVT after aSAH is not currently known. aSAH induces a prothrombotic state, which may contribute to DVT formation. Using repeated ultrasound screening, the hypothesis that patients would be at greatest risk for developing DVT in the subacute post-rupture period was tested. One hundred ninety-eight patients with aSAH admitted to the Oregon Health & Science University Neurosciences Intensive Care Unit between April 2008 and March 2012 were included in a retrospective analysis. Ultrasound screening was performed every 5.2 ± 3.3 days between admission and discharge. The chi-square test was used to compare DVT incidence during different time periods of interest. Patient baseline characteristics as well as stroke severity and hospital complications were evaluated in univariate and multivariate analyses. Forty-two (21%) of 198 patients were diagnosed with DVT, and 3 (2%) of 198 patients were symptomatic. Twenty-nine (69%) of the 42 cases of DVT were first detected between Days 3 and 14, compared with 3 cases (7%) detected between Days 0 and 3 and 10 cases (24%) detected after Day 14 (p < 0.05). The postrupture 5-day window of highest risk for DVT development was between Days 5 and 9 (40%, p < 0.05). In the multivariate analysis, length of hospital stay and use of mechanical prophylaxis alone were significantly associated with DVT formation. DVT formation most commonly occurs in the first 2 weeks following aSAH, with detection in this cohort peaking between Days 5 and 9. Chemoprophylaxis is associated with a significantly lower incidence of DVT.


A Review of Non-1H RF Receive Arrays in Magnetic Resonance Imaging and Spectroscopy.
It is now common practice to use radiofrequency (RF) coils to increase the signal-to-noise ratio (SNR) in 1H magnetic resonance imaging and spectroscopy experiments. Use of array coils for non-1H experiments, however, has been historically more limited despite the fact that these nuclei suffer inherently lower sensitivity and could benefit greatly from an increased SNR. Recent advancements in receiver technology and increased support from scanner manufacturers have now opened greater options for the use of array coils for non-1H magnetic resonance experiments. This paper reviews the research in adopting array coil technology with an emphasis on studies of the most commonly studied non-1H nuclei including 31P, 13C, 23Na, and 19F. These nuclei offer complementary information to 1H imaging and spectroscopy and have proven themselves important in the study of numerous disease processes. While recent work with non-1H array coils has shown promising results, the technology is not yet widely utilized and should see substantial developments in the coming years.


Aberrant glycosylation promotes lung cancer metastasis through adhesion to galectins in the metastatic niche.
Metastasis is the leading cause of cancer-associated deaths. Although dissemination of tumor cells likely occurs early in tumorigenesis, the constituents of the microenvironment play essential rate-limiting roles in determining whether these cells will form clinically relevant tumors. Recent studies have uncovered many molecular factors that contribute to the establishment of a protumorigenic metastatic niche. Here, we demonstrate that galectin-3, whose expression has clinical associations with advanced malignancy and poor outcome, contributes to metastatic niche formation by binding to carbohydrates on metastatic cells. We show that galectin-3 is expressed early during tumorigenesis by both CD11b(+)Gr-1(+) and CD11b(+)Ly-6C(hi) leukocytes. Tumors mobilize these myeloid populations through secretion of soluble factors, including IL6. We find that metastatic cancer cells exhibit elevated presentation of the oncofetal galectin-3 carbohydrate ligand, the Thomsen-Friedenreich antigen, on their surfaces as a result of altered C2GnT2 and St6GalNAc4 glycosyltransferase activity that inhibits further glycosylation of this carbohydrate motif and promotes metastasis. Although clinical observations of elevated serum galectin-3 levels and altered glycosylation have been associated with malignancy, we identify novel roles for glycosyltransferases in promoting adhesion to galectins in the metastatic niche. This identification of a cytokine-leukocyte-glycosylation axis in metastasis provides mechanistic explanations for clinical associations between malignancy and aberrant glycosylation.


In planta comparative transcriptomics of host-adapted strains of Ralstonia solanacearum.
Background. Ralstonia solanacearum is an economically important plant pathogen with an unusually large host range. The Moko (banana) and NPB (not pathogenic to banana) strain groups are closely related but are adapted to distinct hosts. Previous comparative genomics studies uncovered very few differences that could account for the host range difference between these pathotypes. To better understand the basis of this host specificity, we used RNAseq to profile the transcriptomes of an R. solanacearum Moko strain and an NPB strain under in vitro and in planta conditions. Results. RNAs were sequenced from bacteria grown in rich and minimal media, and from bacteria extracted from mid-stage infected tomato, banana and melon plants. We computed differential expression between each pair of conditions to identify constitutive and host-specific gene expression differences between Moko and NPB. We found that type III secreted effectors were globally up-regulated upon plant cell contact in the NPB strain compared with the Moko strain. Genes encoding siderophore biosynthesis and nitrogen assimilation genes were highly up-regulated in the NPB strain during melon pathogenesis, while denitrification genes were up-regulated in the Moko strain during banana pathogenesis. The relatively lower expression of oxidases and the denitrification pathway during banana pathogenesis suggests that R. solanacearum experiences higher oxygen levels in banana pseudostems than in tomato or melon xylem. Conclusions. This study provides the first report of differential gene expression associated with host range variation. Despite minimal genomic divergence, the pathogenesis of Moko and NPB strains is characterized by striking differences in expression of virulence- and metabolism-related genes.


Acoustic grating fringe projector for high-speed and high-precision three-dimensional shape measurements.
A new acoustic grating fringe projector (AGFP) was developed for high-speed and high-precision 3D measurement. A new acoustic grating fringe projection theory is also proposed to describe the optical system. The AGFP instrument can adjust the spatial phase and period of fringes with unprecedented speed and accuracy. Using rf power proportional-integral-derivative (PID) control and CCD synchronous control, we obtain fringes with fine sinusoidal characteristics and realize high-speed acquisition of image data. Using the device, we obtained a precise phase map for a 3D profile. In addition, the AGFP can work in running fringe mode, which could be applied in other measurement fields.


Identification of a potential susceptibility locus for macular telangiectasia type 2.
Macular Telangiectasia type 2 (MacTel) is a relatively rare macular disease of adult onset presenting with distortions in the visual field and leading to progressive loss of visual acuity. For the purpose of a gene mapping study, several pedigrees were ascertained with multiple affected family members. Seventeen families with a total of 71 individuals (including 45 affected or possibly affected) were recruited at clinical centers in 7 countries under the auspices of the MacTel Project. The disease inheritance was consistent with autosomal dominant segregation with reduced penetrance. Genome-wide linkage analysis was performed, followed by analysis of recombination breakpoints. Linkage analysis identified a single peak with multi-point LOD score of 3.45 on chromosome 1 at 1q41-42 under a dominant model. Recombination mapping defined a minimal candidate region of 15.6 Mb, from 214.32 (rs1579634; 219.96 cM) to 229.92 Mb (rs7542797; 235.07 cM), encompassing the 1q41-42 linkage peak. Sanger sequencing of the top 14 positional candidates genes under the linkage peak revealed no causal variants in these pedigrees.


Capnography in the Emergency Department: A Review of Uses, Waveforms, and Limitations.
Capnography has many uses in the emergency department (ED) and critical care setting, most commonly cardiac arrest and procedural sedation. This review evaluates several indications concerning capnography beyond cardiac arrest and procedural sedation in the ED, as well as limitations and specific waveforms. Capnography includes the noninvasive measurement of CO2, providing information on ventilation, perfusion, and metabolism in intubated and spontaneously breathing patients. Since the 1990s, capnography has been utilized extensively for cardiac arrest and procedural sedation. Qualitative capnography includes a colorimetric device, changing color on the amount of CO2 present. Quantitative capnography provides a numeric value (end-tidal CO2), and capnography most commonly includes a waveform as a function of time. Conditions in which capnography is informative include cardiac arrest, procedural sedation, mechanically ventilated patients, and patients with metabolic acidemia. Patients with seizure, trauma, and respiratory conditions, such as pulmonary embolism and obstructive airway disease, can benefit from capnography, but further study is needed. Limitations include use of capnography in conditions with mixed pathophysiology, patients with low tidal volumes, and equipment malfunction. Capnography should be used in conjunction with clinical assessment. Capnography demonstrates benefit in cardiac arrest, procedural sedation, mechanically ventilated patients, and patients with metabolic acidemia. Further study is required in patients with seizure, trauma, and respiratory conditions. It should only be used in conjunction with other patient factors and clinical assessment.


[Bladder cancer with skin metastasis: a case report].
Bladder carcinoma with skin metastasis is extremely rare. We herein report a case of a bladder tumor with skin metastasis. A 68-year-old man was referred to our hospital with macroscopic hematuria. Cystoscopy revealed a trigone papillary tumor. Transurethral resection of bladder tumor (TURBT) was performed and the pathological diagnosis was transitional cell carcinoma (TCC), pT1, G3. Thereafter, he received several courses of TURBT, intravesical chemotherapy (pirarubicin, bacillus Calmette-Guerin and mitomycin C) and intra-arterial chemotherapy because of recurrence. Thirteen years later, he underwent total cystoprostatectomy with neobladder formation. Histological examination revealed muscle-invasive bladder cancer with a staging of T3bNOM0. Two years and three months later, multiple firm nodules with eruptions appeared on the skin in several regions; they were resected and the histological findings revealed TCC. This indicated metastatic spread from the primary bladder TCC. He received only supportive treatment during this period due to renal dysfunction. He died four months after the manifestation of the skin metastasis due to multiple metastases.


Effects of motor imagery training after chronic, complete spinal cord injury.
Abnormalities in brain motor system function are present following spinal cord injury (SCI) and could reduce effectiveness of restorative interventions. Motor imagery training, which can improve motor behavior and modulate brain function, might address this concern but has not been examined in subjects with SCI. Ten subjects with SCI and complete tetra-/paraplegia plus ten healthy controls underwent assessment before and after 7 days of motor imagery training to tongue and to foot. Motor imagery training significantly improved the behavioral outcome measure, speed of movement, in non-paralyzed muscles. Training was also associated with increased fMRI activation in left putamen, an area associated with motor learning, during attempted right foot movement in both groups, despite foot movements being present in controls and absent in subjects with SCI. This fMRI change was absent in a second healthy control group serially imaged without training. In subjects with SCI, training exaggerated, rather than normalized, baseline derangement of left globus pallidus activation. The current study found that motor imagery training improves motor performance and alters brain function in subjects with complete SCI despite lack of voluntary motor control and peripheral feedback. These effects of motor imagery training on brain function have not been previously described in a neurologically impaired population, and were similar to those found in healthy controls. Motor imagery might be of value as one component of a restorative intervention.


Worldwide Expert Agreement on Updated Recommendations for the Treatment of Systemic Sclerosis.
To evaluate agreement of the updated European League Against Rheumatism and European Scleroderma Trials and Research group (EUSTAR) recommendations for treatment of systemic sclerosis (SSc) among international experts. In addition, to determine factors that might influence agreement. Level of agreement (10-point scale: 0 = not at all, 10 = completely agree) and local drug availability (yes/no) were assessed using an online survey. The Web link to the survey was shared with 481 unique e-mail addresses and SSc networks (Scleroderma Clinical Trials Consortium, Australian Scleroderma Interest Group, International Systemic Sclerosis Inception Cohort). Level of agreement was compared between subgroups stratified for participant characteristics. In total, 263 experts participated, of whom n = 209 (79%) completed each single item. The majority were rheumatologists (n = 200, 76%) working in Europe (n = 185; 71%); 59% (n = 156) were EUSTAR members; and 57% (n = 151) had > 10 years of clinical experience. Overall level of agreement was high (mean 8.0, SD 2.5). The 3 highest mean agreements included (1) angiotensin-converting enzyme inhibitors for scleroderma renal crisis (9.2, SD 2.1); (2) blood pressure control in SSc-patients treated with corticosteroids (9.0, SD 2.2); (3) proton pump inhibitors to prevent reflux complications (9.0, SD 2.2). The 3 lowest mean agreements included (1) fluoxetine for Raynaud phenomenon (RP; 4.6, SD 2.8); (2) hematopoietic stem cell transplantation (HSCT) for severe SSc (7.1, SD 2.9); (3) phosphodiesterase inhibitors 5 for RP (7.3, SD 2.7). Agreement differed between Europe and non-Europe for the use of iloprost, bosentan, methotrexate, HSCT, and cyclophosphamide. Treatment availability could partially explain differential agreement for iloprost, bosentan, and HSCT. In general, worldwide expert agreement on updated recommendations for treatment of SSc is high, supporting their value. Differences in agreement are partially explained by geographical area and treatment availability.


Elucidation of molecular events leading to neutrophil apoptosis following phagocytosis: cross-talk between caspase 8, reactive oxygen species, and MAPK/ERK activation.
Phagocytosis of complement-opsonized targets is a primary function of neutrophils at sites of inflammation, and the clearance of neutrophils that have phagocytosed microbes is important for the resolution of inflammation. Our previous work suggests that phagocytosis leads to rapid neutrophil apoptosis that is inhibited by antibody to the beta2 integrin, Mac-1, and requires NADPH oxidase-derived reactive oxygen species (ROS) generated during phagocytosis. Here we report that phagocytosis-induced cell death (PICD) does not occur in Mac-1-deficient murine neutrophils, suggesting that PICD proceeds through a bona fide Mac-1-dependent pathway. A sustained, intracellular oxidative burst is associated with PICD. Furthermore, PICD does not require traditional death receptors, Fas, or tumor necrosis factor (TNF) receptor. TNF but not Fas synergizes with phagocytosis to enhance significantly PICD by increasing the oxidative burst, and this is Mac-1-dependent. Phagocytosis-induced ROS promote cleavage/activation of caspases 8 and 3, key players in most extrinsic ("death receptor") mediated pathways of apoptosis, and caspases 8 and 3 but not caspase 9/mitochondria, are required for PICD. This suggests that ROS target the extrinsic versus the intrinsic ("stress stimulus") apoptotic pathway. Phagocytosis also triggers a competing MAPK/ERK-dependent survival pathway that provides resistance to PICD likely by down-regulating caspase 8 activation. The anti-apoptotic factor granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly enhances ROS generation associated with phagocytosis. Despite this, it completely suppresses PICD by sustaining ERK activation and inhibiting caspase 8 activation in phagocytosing neutrophils. Together, these studies suggest that Mac-1-mediated phagocytosis promotes apoptosis through a caspase 8/3-dependent pathway that is modulated by NADPH oxidase-generated ROS and MAPK/ERK. Moreover, TNF and GM-CSF, likely encountered by phagocytosing neutrophils at inflammatory sites, exploit pro-(ROS) and anti-apoptotic (ERK) signals triggered by phagocytosis to promote or suppress PICD, respectively, and thus modulate the fate of phagocytosing neutrophils.


A large renal pelvic diverticulum, presenting incomplete excretion during tc-99m MAG-3 scintigraphy and tracer accumulation on tc-99m DMSA scintigraphy; a case report.
This case report illustrates the dynamic and static renal scintigraphic images of a patient with an unusual large diverticulum of the renal pelvis. The initial diagnosis by intravenous pyelography (IVP) and ultrasonographic (US) examination was a renal pelvic diverticulum of the left kidney, and the patient was referred to the nuclear medicine department for exploration of the effect of the pelvic diverticulum on renal functions. We performed dynamic renal scintigraphy with technetium-99m (Tc-99m) labeled mercaptoacetyl triglycine (MAG-3) and static renal scintigraphy with Tc-99m labeled dimercaptosuccinic acid (DMSA). In dynamic renal scintigraphy, bilaterally normal concentration function was observed. While right kidney excretion function was normal, an incomplete excretion pattern was seen on the left side. Complete urinary flow obstruction occurred approximately at the 10th minute of the acquisition, which did not seem to respond to the i.v. furosemide application. However, when only the renal cortex was included in the region of interest, the obstructive pattern disappeared. In static renal scintigraphy, a large renal pelvic diverticulum localized antero-medially was clearly visualized in the left-anterior oblique projection, most probably due to accumulation of radiopharmaceutical inside it. This case showed that a renal pelvic diverticulum should be thought of when an incomplete excretion pattern is seen on dynamic renal scintigraphy. Using only a cortical region of interest may also help to distinguish other types of obstructive pattern from diverticulum. Additionally, Tc-99m DMSA scintigraphy may show diverticulum localization with antero-oblique projections in addition to routine projections.


Tropical nighttime warming as a dominant driver of variability in the terrestrial carbon sink.
The terrestrial biosphere is currently a strong carbon (C) sink but may switch to a source in the 21st century as climate-driven losses exceed CO2-driven C gains, thereby accelerating global warming. Although it has long been recognized that tropical climate plays a critical role in regulating interannual climate variability, the causal link between changes in temperature and precipitation and terrestrial processes remains uncertain. Here, we combine atmospheric mass balance, remote sensing-modeled datasets of vegetation C uptake, and climate datasets to characterize the temporal variability of the terrestrial C sink and determine the dominant climate drivers of this variability. We show that the interannual variability of global land C sink has grown by 50-100% over the past 50 y. We further find that interannual land C sink variability is most strongly linked to tropical nighttime warming, likely through respiration. This apparent sensitivity of respiration to nighttime temperatures, which are projected to increase faster than global average temperatures, suggests that C stored in tropical forests may be vulnerable to future warming.


Medicaid Utilization among Middle-age and Older Adults: A Health and Retirement Study Longitudinal Analysis (1998 to 2014).
With over fifteen million older adults in the United States relying on the means-tested Medicaid program for healthcare coverage, there has been concern over rising Medicaid costs among this rapidly growing age group. Few studies have longitudinally examined trends among older beneficiaries over time to identify factors related to Medicaid utilization and to better understand how potential coverage changes might impact this group. This study used the 1998 to 2014 waves of the Health and Retirement Study (N = 8,162) to analyze a representative sample of those aged 50 and older to ascertain demographic, health, and economic factors associated with Medicaid utilization over a sixteen-year period. The analyses showed stable probabilities of accessing the program over time and observed that the most vulnerable older adults make up the pool of Medicaid beneficiaries. There is no evidence of significant asset divestment in order to qualify for benefits. Multivariate analyses further revealed those who were older, female, minority race/ethnicity, less educated, in poorer health, below the federal poverty line, and with lower net wealth had a higher risk of utilizing Medicaid during the observed time period than their counterparts. Findings highlight the importance of monitoring changes in the documented risk factors over time in terms of their impact on Medicaid utilization and underscore the need to consider how these factors may be interrelated.


A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours.
This study evaluated safety, pharmacokinetics, and clinical activity of intravenous and oral rucaparib, a poly(ADP-ribose) polymerase inhibitor, combined with chemotherapy in patients with advanced solid tumours. Initially, patients received escalating doses of intravenous rucaparib combined with carboplatin, carboplatin/paclitaxel, cisplatin/pemetrexed, or epirubicin/cyclophosphamide. Subsequently, the study was amended to focus on oral rucaparib (once daily, days 1-14) combined with carboplatin (day 1) in 21-day cycles. Dose-limiting toxicities (DLTs) were assessed in cycle 1 and safety in all cycles. Eighty-five patients were enrolled (22 breast, 15 ovarian/peritoneal, and 48 other primary cancers), with a median of three prior therapies (range, 1-7). Neutropenia (27.1%) and thrombocytopenia (18.8%) were the most common grade ⩾3 toxicities across combinations and were DLTs with the oral rucaparib/carboplatin combination. Maximum tolerated dose for the combination was 240 mg per day oral rucaparib and carboplatin area under the curve 5 mg ml-1 min-1. Oral rucaparib demonstrated dose-proportional kinetics, a long half-life (≈17 h), and good bioavailability (36%). Pharmacokinetics were unchanged by carboplatin coadministration. The rucaparib/carboplatin combination had radiologic antitumour activity, primarily in BRCA1- or BRCA2-mutated breast and ovarian/peritoneal cancers. Oral rucaparib can be safely combined with a clinically relevant dose of carboplatin in patients with advanced solid tumours (Trial registration ID: NCT01009190).


Novel test procedure to evaluate the treatability of wastewater with ozone.
Organic micropollutants such as pharmaceuticals, estrogens or pesticides enter the environment continuously through the effluent of municipal wastewater treatment plants (WWTPs). Enhanced treatment of wastewater (WW) by ozone (O3) is probably one of the simplest measures for abatement of organic micropollutants to avoid their discharge to the aquatic environment. During ozonation most organic micropollutants present in treated WW are oxidized either by a direct reaction with O3 or by secondarily formed hydroxyl radicals (OH). However, undesired oxidation by-products from the oxidative transformation of matrix components can also be formed. A modular laboratory decision tool based on the findings of previous investigations is presented to test the feasibility of ozonation as an option to upgrade specific WWTPs. These modules consist of investigations to assess (i) the matrix effects on ozone stability, (ii) the efficiency of micropollutant removal, (iii) the oxidation by-product formation, as well as (iv) bioassays to measure specific and unspecific toxicity of the treated WWs. Matrix effects on ozone stability (quantified as O3 and OH exposures) can give first indications on the suitability of an ozonation step. Ozonation of WWs yielding O3 and OH exposures and micropollutant abatement similar to reference values evoked a significant improvement of the water quality as indicated by a broad range of bioassays. Irregular behavior of the ozonation points towards unknown compounds, possibly leading to the formation of undesired degradation products. It has been observed that in such WWs ozonation partly enhanced toxicity. In summary, the presented tiered laboratory test procedure represents a relatively cheap and straight-forward methodology to evaluate the feasibility of ozonation to upgrade specific WWTPs for micropollutant removal based on chemical and biological measurements.


Effects of seating position and appropriate restraint use on the risk of injury to children in motor vehicle crashes.
Currently, many states are upgrading their child restraint laws to include provisions for the use of age-appropriate restraints through 6 to 8 years of age, with some also requiring rear seating for children, enabling the laws to be in closer alignment with best-practice recommendations. To evaluate the relationships of seating position and restraint status to the risk of injury among children in passenger vehicle crashes. This was a cross-sectional study of children <16 years of age who were involved in crashes of insured vehicles in 15 states, with data collected via insurance claims records and a telephone survey. A probability sample of 17980 children in 11506 crashes, representing 229106 children in 146613 crashes, was collected between December 1, 1998, and November 30, 2002. Parent reports were used to define restraint status, seating position, and occurrence of clinically significant injuries, with the use of a previously validated instrument. Approximately 62% of the children used seat belts, 35% used child restraints, and 3% used no restraint. Nearly 4 of 5 children sat in the rear seat, with one half of all children being restrained appropriately for their age in the rear, although this varied according to the age of the child. Overall, 1.6% of children suffered serious injuries, 13.5% had minor injuries, and 84.9% did not have any injury. Unrestrained children in the front were at the highest risk of injury and appropriately restrained children in the rear were at the lowest risk, for all age groups. Inappropriately restrained children were at nearly twice the risk of injury, compared with appropriately restrained children (odds ratio [OR]: 1.8; 95% confidence interval [CI]: 1.4-2.3), whereas unrestrained children were at >3 times the risk (OR: 3.2; 95% CI: 2.5-4.1). The effect of seating row was smaller than the effect of restraint status; children in the front seat were at 40% greater risk of injury, compared with children in the rear seat (OR: 1.4; 95% CI: 1.2-1.7). Had all children in the study population been appropriately restrained in the rear seat, 1014 serious injuries (95% CI: 675-1353 injuries) would have been prevented (with the assumption that restraint effectiveness does not depend on a variety of other driver-related, child-related, crash-related, vehicle-related, and environmental factors). Age-appropriate restraint confers relatively more safety benefit than rear seating, but the 2 work synergistically to provide the best protection for children in crashes. These results support the current focus on age-appropriate restraint in recently upgraded state child restraint laws. However, it is important to note that considerable added benefit would be realized with additional requirements for rear seating.


Prevalence of malaria parasitemia and accuracy of microscopic diagnosis in Haiti, October 1995.
In October 1995 the Ministry of Public Health and Population in Haiti surveyed 42 health facilities for the prevalence and distribution of malaria infection. They examined 1,803 peripheral blood smears from patients with suspected malaria; the overall slide positivity rate was 4.0% (range, 0.0% to 14.3%). The rate was lowest among 1- to 4-year-old children (1.6%) and highest among persons aged 15 and older (5.5%). Clinical and microscopic diagnoses of malaria were unreliable; the overall sensitivity of microscopic diagnosis was 83.6%, specificity was 88.6%, and the predictive value of a positive slide was 22.2%. Microscopic diagnoses need to be improved, and adequate surveillance must be reestablished to identify areas where transmission is most intense. The generally low level of malaria is encouraging and suggests that intensified control efforts targeted to the areas of highest prevalence could further diminish the effect of malaria in Haiti.


Management of the Neck in Squamous Cell Carcinoma of the Oral Cavity and Oropharynx: ASCO Clinical Practice Guideline.
The aim of the current work is to provide evidence-based recommendations to practicing physicians and others on the management of the neck in patients with squamous cell carcinoma of the oral cavity and oropharynx. ASCO convened an Expert Panel of medical oncology, surgery, radiation oncology, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 1990 through 2018. Outcomes of interest included survival, regional disease control, neck recurrence, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. The literature search identified 124 relevant studies to inform the evidence base for this guideline. Six clinical scenarios were devised; three for oral cavity cancer and three for oropharynx cancer, and recommendations were generated for each one. For oral cavity cancers, clinical scenarios focused on the indications for and the hallmarks of a high-quality neck dissection, indications for postoperative radiotherapy or chemoradiotherapy, and whether radiotherapy alone is sufficient elective treatment of an undissected neck compared with high-quality neck dissection. For oropharynx cancers, clinical scenarios focused on hallmarks of a high-quality neck dissection, factors that would favor operative versus nonoperative primary management, and clarifying criteria for an incomplete response to definitive chemoradiation for which salvage neck dissection would be recommended. Consensus was reached and recommendations were made for all six clinical scenarios. Additional information is available at www.asco.org/head-neck-cancer-guidelines .