Cognitive treatment for panic disorder.
Several kinds of evidence indicate that there are important psychological causes of panic disorder as well as the biological causes that have been demonstrated by others. These psychological causes are fears that physical symptoms of anxiety will be followed by an immediate medical emergency: for example, that palpitations will be followed by a heart attack. Evidence is presented to show (a) that such fears are more frequent among panic disorder patients than other anxious patients; (b) that activating the fears can produce panic; and (c) that reducing the fears can attenuate the effects of procedures that produce panic. For panic disorder, cognitive therapy, which reduces these specific fears, gives results comparable to those of imipramine and alprazolam. If further research confirms that these therapeutic effects of cognitive therapy are sustained well beyond the end of treatment, cognitive therapy could be the treatment of choice for panic disorder.


Genome mapping and expression analyses of human intronic noncoding RNAs reveal tissue-specific patterns and enrichment in genes related to regulation of transcription.
RNAs transcribed from intronic regions of genes are involved in a number of processes related to post-transcriptional control of gene expression. However, the complement of human genes in which introns are transcribed, and the number of intronic transcriptional units and their tissue expression patterns are not known. A survey of mRNA and EST public databases revealed more than 55,000 totally intronic noncoding (TIN) RNAs transcribed from the introns of 74% of all unique RefSeq genes. Guided by this information, we designed an oligoarray platform containing sense and antisense probes for each of 7,135 randomly selected TIN transcripts plus the corresponding protein-coding genes. We identified exonic and intronic tissue-specific expression signatures for human liver, prostate and kidney. The most highly expressed antisense TIN RNAs were transcribed from introns of protein-coding genes significantly enriched (p = 0.002 to 0.022) in the 'Regulation of transcription' Gene Ontology category. RNA polymerase II inhibition resulted in increased expression of a fraction of intronic RNAs in cell cultures, suggesting that other RNA polymerases may be involved in their biosynthesis. Members of a subset of intronic and protein-coding signatures transcribed from the same genomic loci have correlated expression patterns, suggesting that intronic RNAs regulate the abundance or the pattern of exon usage in protein-coding messages. We have identified diverse intronic RNA expression patterns, pointing to distinct regulatory roles. This gene-oriented approach, using a combined intron-exon oligoarray, should permit further comparative analysis of intronic transcription under various physiological and pathological conditions, thus advancing current knowledge about the biological functions of these noncoding RNAs.


The Intraoperative Effect of Methadone on Somatosensory Evoked Potentials.
Evoked potentials (EP), both somatosensory evoked potentials (SSEP) and transcranial motor evoked potentials (TcMEP), are often used during complex spine surgery to monitor the integrity of spinal pathways during operations in or around the spine. Changes in these monitored EP signals (increased latency and decreased amplitude) may result from ischemia, direct surgical injury, changes in blood pressure, hypoxia, changes in CO2 tension, and anesthetic agents. Typically, a clinically significant change for SSEPs is defined as an increase in latency >10% or a decrease of amplitude >50%. A clinically significant change for TcMEPs is much more complex but is also described in terms of large signal loss or decrease. Opioids have been shown to both increase latency and decrease the amplitude of SSEPs, although this change is usually not clinically significant. There has been a renewed interest in methadone for use in spine and other complex surgeries. However, the effect of methadone on intraoperative monitoring of SSEPs and TcMEPs is unknown. We present the first study to directly look at the effects of methadone on SSEP and TcMEP monitoring during complex spine surgery. The goal of this study was to observe the effect of methadone on an unrandomized set of patients. The primary endpoint was methadone's effect on SSEPs, and the secondary endpoint was methadone's effect on TcMEPs. Adult patients undergoing spine surgery requiring intraoperative neuromonitoring were induced with general anesthesia and had a baseline set of SSEPs and TcMEPs recorded. Next, methadone dosed 0.2 mg/kg/lean body weight was given. Repeat SSEPs and TcMEPs were recorded at 5, 10, and 15 minutes, with the timing based on distribution half-life of methadone between 6 and 8 minutes. Postoperatively, adverse events from methadone administration were collected. There was a statistically significant difference found in SSEPs for N20 latency (95% confidence interval [CI], 0.17-0.53; P=0.028), P37 latency (95% CI, 0.65-1.25; P=0.001), and N20 amplitude (95% CI, 0.09-0.32; P=<0.001), but not for P37 amplitude (95% CI, -0.19 to 0.00; P=0.634). There was no significant effect found for TcMEPs, the secondary endpoint of the study, and there were minimal adverse events recorded postoperatively. The data demonstrate that a single intravenous dose of methadone has a statistically significant difference on the amplitude and latency of SSEPs. However, this statistical difference does not translate into a clinical significance.


Self-assembly of a giant molecular Solomon link from 30 subcomponents.
The synthesis of topologically complex structures, such as links and knots, is one of the current challenges in supramolecular chemistry. The so-called Solomon link consists of two doubly interlocked rings. Despite being a rather simple link from a topological point of view, only few molecular versions of this link have been described so far. Here, we report the quantitative synthesis of a giant molecular Solomon link from 30 subcomponents. The highly charged structure is formed by assembly of 12 cis-blocked Pt(2+) complexes, six Cu(+) ions, and 12 rigid N-donor ligands. Each of the two interlocked rings is composed of six repeating Pt(ligand) units, while the six Cu(+) ions connect the two rings. With a molecular weight of nearly 12 kDa and a diameter of 44.2 Å, this complex is the largest non-DNA-based Solomon link described so far. Furthermore, it represents a molecular version of a "stick link".


Design of a Lyme Disease Vaccine as an Active Learning Approach in a Novel Interdisciplinary Graduate-Level Course.
A biomedical sciences graduate program needed an introductory class that would develop skills for students interested in a wide variety of disciplines, such as microbiology or cancer biology, and a diverse array of biomedical careers. Faculty created a year-long student-centered course, Scientific Discovery, to serve this need. The course was divided into four modules with progressive skill outcomes. Each module had a focus related to each of the major research areas of the collective faculty: molecular biology, biochemistry, neuroscience, and infectious disease. First-year graduate students enter the program with relevant college-level biology and chemistry coursework but not in-depth content knowledge of any of the focus areas. Each module features a biomedical problem for the students to gain specific content knowledge while developing skills outcomes, such as the ability to conduct scholarly inquiry. In 2015, the theme of the infectious disease module was to create an effective human vaccine to prevent Lyme disease. The module required students to learn fundamental concepts of microbiology and immunology and then apply that knowledge to design their own Lyme disease vaccine. The class culminated with students communicating their creative designs in the form of a "white paper" and a pitch to "potential investors." By the end of the module, students had developed fundamental knowledge, applied that knowledge with great creativity, and met the skills learning outcomes, as evidenced by their ability to conduct scholarly inquiry and apply knowledge gained during this module to a novel problem, as part of their final exam.


Tax subsidization of personal assistance services.
Personal assistance services (PAS) is the term used to describe the range of assistance, services, and supports many people with disabilities and older Americans need to remain in their homes and communities. The Americans with Disabilities Act requires that people with disabilities receive essential services in the communities of their choice rather than in institutional settings. PAS availability often determines whether persons with disabilities become institutionalized or remain in their communities. PAS, however, are not inexpensive or broadly available. Strategies are needed to improve their availability to people with disabilities and the elderly. We sought to analyze 8 provisions of the Internal Revenue Code for their utility to make PAS more affordable and available. The authors conducted a legal analysis of 8 statutory provisions, as interpreted by regulations, court decisions, and other authoritative sources. Each of the tax provisions analyzed covers some PAS expenses incurred by an individual or family. Favorable tax treatment is impacted by the nature and amount of expenses and by the location and conditions of services. The current limitations and complexities of legal interpretations and the fact that many individuals with disabilities are uninformed about these tax provisions present challenges and opportunities. As the need for PAS grows, reform of tax policy is an important complement to health care and long-term services and supports for people with disabilities. To increase utilization of current beneficial tax provisions that subsidize the cost of PAS, individuals with disabilities and tax preparers must become better informed about using these provisions.


Immune responses during human schistosomiasis. XII. Differential responsiveness in patients with hepatosplenic disease.
Thirty-four hospitalized patients and 12 ambulatory patients, all with hepatosplenic schistosomiasis mansoni were evaluated in regard to their peripheral blood mononuclear (PBMN) cell responses to schistosomal antigenic preparations and compared with groups of 40 patients with the hepatointestinal form and 39 patients with the more common, chronic intestinal form of schistosomiasis mansoni. PBMN cell blastogenic responses were measured upon exposure to schistosomal egg antigens (SEA), adult worm antigens (SWAP) and a cercarial antigenic preparation (CERC). All groups had some individuals who did not respond to some or all of these preparations. In the hospitalized hepatosplenic group greater than 50% did not respond to SEA. Analysis of the responses in each group revealed that all responders could be subdivided into moderate and high responders. High responders to SEA had experimental minus control values of greater than 8,000 counts per minute (CPM). For SWAP and CERC, this arbitrary cut-off value was greater than 25,000 CPM and greater than 11,000 CPM, respectively. The percent of high SEA responders in the groups differed considerably. This was 23% in the chronic intestinal group, 40% in the chronic hepatointestinal group, 67% for ambulatory hepatosplenic patients and 20% for hospitalized hepatosplenic patients. Previous studies had demonstrated that 94% of patients with early (2-3 month) acute schistosomiasis mansoni were high responders to SEA and none were nonresponders. Furthermore, at the other end of the spectrum, 100% of former schistosomiasis mansoni patients (treated and cured 7-35 years previously) were high responders to SEA. None were nonresponders to any of the antigen preparations. It is proposed that during acute infection all patients express vigorous responses to SEA. Upon continued infection most patients (75%) modulate this florid response. However, continued high responders comprise 40% of the chronic hepatointestinal cases and almost 70% of the ambulatory hepatosplenic patients. These latter 2 groups may likely represent early forms of the severe clinical disease found in the hospitalized hepatosplenic patient population. Fifty percent of the hospitalized group appear anergic and no longer respond to SEA, while only 20% are high responders. Long after chemotherapy it appears that the anti-SEA regulatory mechanisms of former chronic patients have subsided, leaving strong anti-SEA responsiveness.


Immunolocalization of stromelysin, tumor necrosis factor (TNF) alpha, and TNF receptors in atrophied canine articular cartilage treated with hyaluronic acid and transforming growth factor beta.
To evaluate the ability of hyaluronic acid (HA), with and without transforming growth factor beta (1GF-beta), to stabilize the catabolic processes associated with atrophy of articular cartilage. 20 adult, skeletally normal, hound-type dogs. Dogs (20 to 30 kg) were randomly assigned to 1 of 5 groups. One group served as untreated controls. Bivalve casts were placed on the left hind limbs of the remaining 16 dogs to limit weightbearing and motion of the limb for 92 days. One group served as the cast control. Beginning on day 56, 3 groups received aseptic intra-articular injections in the left stifles of either 5 mg of HA or 5 mg of HA containing either 20 or 50 micrograms of TGF-beta. Intraarticular injections were repeated at 4-day intervals until the end of the study. Or day 92, stifles were harvested at necroscropy. Medial femoral condyle were histologically processed, and the articular cartilage was stained for the presence of proteoglycans, stromelysin, tumor necrosis facto (TNF) alpha, and TNF receptors (p55 and p75). Decreased metachromasia was evident in the cartilage matrix of all cast groups, with the smallest decrease in the HA-treated group. Stromelysin was immunolocalized in articular cartilage of the cast (left) limbs of cast control and both HA/TGF-beta-treated groups. TNF-alpha was localized in articular cartilage of all cast (left) and right limbs, except those of the HA-treated group. Receptors for TNF were observed in both limbs of untreated control and cast control groups and cast limbs of HA/TGF-3-treated groups. The receptors were not localized in the right limbs of the HA with or without TGF-beta-treated groups. TGF-beta did not decrease stromelysin or TNF-alpha or receptors at the doses used. HA may mediate a chondrostabilizing influence on articular cartilage by down-regulating TNF-alpha importantly. HA appeared to exert its inhibitory influence on TNF-alpha, as well as stromelysin and TNF receptors, on a systemic basis. Results provide insight into the mode of action of HA as a therapeutic agent for arthritis and its stabilizing influence on cartilage metabolism.


Laser-assisted lateral optical fiber processing for selective infiltration.
We propose a new technique to perform precise selective infiltration of an air hole in the photonic crystal fiber (PCF). To carry out the infiltration process, the end face of the PCF is covered by a mask, which is fabricated by femtosecond laser inscription from the lateral direction. This proposed method overcomes the conventional limitation of maximum mask thickness. An analytical model is further proposed and demonstrated accurate determinations of the fabricated channel diameter in the mask.


Unique proteomic signatures distinguish macrophages and dendritic cells.
Monocytes differentiate into heterogeneous populations of tissue macrophages and dendritic cells (DCs) that regulate inflammation and immunity. Identifying specific populations of myeloid cells in vivo is problematic, however, because only a limited number of proteins have been used to assign cellular phenotype. Using mass spectrometry and bone marrow-derived cells, we provided a global view of the proteomes of M-CSF-derived macrophages, classically and alternatively activated macrophages, and GM-CSF-derived DCs. Remarkably, the expression levels of half the plasma membrane proteins differed significantly in the various populations of cells derived in vitro. Moreover, the membrane proteomes of macrophages and DCs were more distinct than those of classically and alternatively activated macrophages. Hierarchical cluster and dual statistical analyses demonstrated that each cell type exhibited a robust proteomic signature that was unique. To interrogate the phenotype of myeloid cells in vivo, we subjected elicited peritoneal macrophages harvested from wild-type and GM-CSF-deficient mice to mass spectrometric and functional analysis. Unexpectedly, we found that peritoneal macrophages exhibited many features of the DCs generated in vitro. These findings demonstrate that global analysis of the membrane proteome can help define immune cell phenotypes in vivo.


Cloning, expression, and properties of a nonneuronal secreted acetylcholinesterase from the parasitic nematode Nippostrongylus brasiliensis.
We have isolated a full-length cDNA encoding an acetylcholinesterase secreted by the nematode parasite Nippostrongylus brasiliensis. The predicted protein is truncated in comparison with acetylcholinesterases from other organisms such that the carboxyl terminus aligns closely to the end of the catalytic domain of the vertebrate enzymes. The residues in the catalytic triad are conserved, as are the six cysteines which form the three intramolecular disulfide bonds. Three of the fourteen aromatic residues which line the active site gorge in the Torpedo enzyme are substituted by nonaromatic residues, corresponding to Tyr-70 (Thr), Trp-279 (Asn), and Phe-288 (Met). High level expression was obtained via secretion from Pichia pastoris. The purified enzyme behaved as a monomeric hydrophilic species. Although of invertebrate origin and possessing the above substitutions in the active site gorge residues, the enzyme efficiently hydrolyzed acetylthiocholine and showed minimal activity against butyrylthiocholine. It displayed excess substrate inhibition with acetylthiocholine at concentrations over 2. 5 mM and was highly sensitive to both active site and "peripheral" site inhibitors. Northern blot analysis indicated a progressive increase in mRNA for AChE B in parasites isolated from 6 days postinfection.


Taxonomic Study of Linaria depauperata and L. supina Complexes in Eastern Spain.
Morphological characteristics were studied in two groups of closely related taxa of section Supinae , Linaria depauperata and L. supina , from eastern Spain. Vegetative, floral and seed characteristics were of little use in distinguishing between these taxa as the ranges for all the taxa studied overlapped. Flower colour could be used as a diagnostic character for some but not all of these taxa. Seed coat characters were of high taxonomic value, both when trying to distinguish among these two groups, and the taxa included within them, and also when establishing relationships among the taxa studied. Some differences were found in the indumentum distribution and density. Three types of trichomes were identified, two of them eglandular and common to all taxa. The third type of trichome was a simple gland, that varied in the number of cells in the stalk and gland. Trichome length and wall width of stalk cells allowed several groups of taxa to be distinguished. Similarity relationships among the samples studied are shown in a UPGMA phenogram. According to these results, two new species, L. cardonica and L. sulphurea , are described. L. arabiniana is conspecific with L. depauperata subsp. hegelmaieri . A key to identify the different taxa is provided.


A role for cofilin and LIM kinase in Listeria-induced phagocytosis.
The pathogenic bacterium Listeria monocytogenes is able to invade nonphagocytic cells, an essential feature for its pathogenicity. This induced phagocytosis process requires tightly regulated steps of actin polymerization and depolymerization. Here, we investigated how interactions of the invasion protein InlB with mammalian cells control the cytoskeleton during Listeria internalization. By fluorescence microscopy and transfection experiments, we show that the actin-nucleating Arp2/3 complex, the GTPase Rac, LIM kinase (LIMK), and cofilin are key proteins in InlB-induced phagocytosis. Overexpression of LIMK1, which has been shown to phosphorylate and inactivate cofilin, induces accumulation of F-actin beneath entering particles and inhibits internalization. Conversely, inhibition of LIMK's activity by expressing a dominant negative construct, LIMK1(-), or expression of the constitutively active S3A cofilin mutant induces loss of actin filaments at the phagocytic cup and also inhibits phagocytosis. Interestingly, those constructs similarly affect other actin-based phenomenons, such as InlB-induced membrane ruffling or Listeria comet tail formations. Thus, our data provide evidence for a control of phagocytosis by both activation and deactivation of cofilin. We propose a model in which cofilin is involved in the formation and disruption of the phagocytic cup as a result of its local progressive enrichment.


Comparison of psychotherapies for adult depression to pill placebo control groups: a meta-analysis.
The effects of antidepressants for treating depressive disorders have been overestimated because of selective publication of positive trials. Reanalyses that include unpublished trials have yielded reduced effect sizes. This in turn has led to claims that antidepressants have clinically insignificant advantages over placebo and that psychotherapy is therefore a better alternative. To test this, we conducted a meta-analysis of studies comparing psychotherapy with pill placebo. Ten 10 studies comparing psychotherapies with pill placebo were identified. In total, 1240 patients were included in these studies. For each study, Hedges' g was calculated. Characteristics of the studies were extracted for subgroup and meta-regression analyses. The effect of psychotherapy compared to pill placebo at post-test was g = 0.25 [95% confidence interval (CI) 0.14-0.36, I² = 0%, 95% CI 0-58]. This effect size corresponds to a number needed to treat (NNT) of 7.14 (95% CI 5.00-12.82). The psychotherapy conditions scored 2.66 points lower on the Hamilton Depression Rating Scale (HAMD) than the placebo conditions, and 3.20 points lower on the Beck Depression Inventory (BDI). Some indications for publication bias were found (two missing studies). We found no significant differences between subgroups of the studies and in meta-regression analyses we found no significant association between baseline severity and effect size. Although there are differences between the role of placebo in psychotherapy and pharmacotherapy research, psychotherapy has an effect size that is comparable to that of antidepressant medications. Whether these effects should be deemed clinically relevant remains open to debate.


Fisetin Alleviates Atrial Inflammation, Remodeling, and Vulnerability to Atrial Fibrillation after Myocardial Infarction.
Atrial inflammation and fibrosis are the critical processes involved in atrial fibrillation (AF) after myocardial infarction (MI). Fisetin is a dietary flavonoid that has shown forceful anti-inflammatory and anti-proliferative properties in diverse models of disease. However, fisetin's role in atrial inflammation, fibrosis, and AF vulnerability post-MI remains completely unknown.Rats were subjected to MI surgery, by left anterior descending coronary artery ligation or sham operation, and treated with DMSO or fisetin via intraperitoneal injection. After 28 days, echocardiographic parameters were performed, and AF inducibility was tested. We further evaluated the inflammation, fibrosis of left atria (LA), and related signal pathways by RT-PCR, Western blot, and staining analysis.Compared to the MI group, fisetin treatment improved cardiac function, inhibited macrophage recruitment into the LA and production of IL-1β and TNF-α, and attenuated adverse atrial fibrosis following acute myocardial infarction (AMI). Electrophysiological recordings, using an isolated perfused heart, showed that MI-induced higher inducibility of AF and prolonged AF duration, interatrial conduction time (IACT), atrial effective refractory period (AERP) were significantly alleviated by fisetin. Mechanistically, fisetin markedly increased phosphorylated AMPK (p-AMPK) levels and suppressed NF-κB p65, p38MAPK, and smad3 phosphorylation in the LA post-MI.We demonstrate that fisetin improves LA expansion, cardiac function, atrial inflammation, fibrosis, and vulnerability to AF following MI by possibly regulating AMPK/NF-κB p65 and p38MAPK/smad3 signaling pathways.


Q-switched Nd:YAG optical vortex lasers.
Q-switched operation of a high-quality Nd:YAG optical vortex laser with the first order Laguerre-Gaussian mode and well-determined helical wavefronts using a fiber-based pump beam conditioning scheme is reported. A simple two-mirror resonator incorporating an acousto-optic Q-switch was employed, along with an etalon and a Brewster plate to enforce the particular helicity of the output. The laser yielded Q-switched pulses with ~250 μJ pulse energy and ~33 ns pulse duration (FWHM) at a 0.1 kHz repetition rate for 5.1 W of absorbed pump power. The handedness of the helical wavefronts was preserved regardless of the repetition rates. The prospects of further power scaling and improved laser performance are discussed.


2017 Lush Science Prize.
Now in its sixth year, the Lush Prize supports animal-free testing by awarding money prizes of up to £350,000 to the most effective projects and individuals who have been working towards the goal of replacing animals in product or ingredient safety testing. Prizes are awarded for developments in five strategic areas: Science; Lobbying; Training; Public Awareness; and Young Researchers. In the event of a major breakthrough leading to the replacement of animal tests in the area of 21st Century Toxicology, a Black Box Prize (equivalent to the entire annual fund) is awarded. The Science Prize is awarded to the researchers whose work the judging panel believe has made the most significant contribution to the replacement of animal testing in the preceding year. This Background Paper outlines the research projects that were shortlisted and presented to the judging panel as potential candidates for the 2017 Lush Science Prize. This process involved reviewing recent work of the relevant scientific institutions and projects in this area, such as the OECD, Human Toxome Project, UK NC3Rs, US Tox21 programme, ToxCast programme and the Human Toxicology Project Consortium. Recent developments in toxicity testing research were also identified by searching for relevant published papers in the literature, and analysing abstracts from conferences focusing on animal replacement in toxicity testing that had been held in the preceding 12 months -- for example, the 2016 EUSAAT-Linz conference and the 2017 Society of Toxicology annual conference.


Housing status among formerly homeless dually diagnosed adults.
Residential outcomes of homeless adults with severe mental illness and a substance use disorder were studied over 18 months during which participants received integrated dual diagnosis services and housing supports based on a continuum model. Interviews with 158 participants at baseline and at six-, 12-, and 18-month follow-ups assessed housing status, residential history, substance abuse and progress toward recovery, psychiatric symptoms, and quality of life. Complete data were available for 122 participants. If participants lived continuously in high-quality housing with no housing loss or nights of homelessness during the final six months of the study, they were classified as having stable housing. Of the 122 participants for whom complete data were available, 64 (52 percent) achieved stable housing. Most participants who achieved stable housing first entered staffed and supervised housing and then moved to independent arrangements by the end of the study. Stable housing during the final evaluation period was associated with lower substance use, greater progress toward substance abuse recovery, and higher quality of life. Final housing status was not predicted by baseline variables but was predicted by progress toward recovery during months 0 to 6 and 6 to 12 and by less severe drug use during months 6 to 12. Participants who abused no illicit drugs during months 6 to 12 were almost three times as likely to achieve stable housing as those who abused illicit drugs. Housing stability is strongly mediated by substance abuse and progress toward recovery. Nevertheless, when formerly homeless persons with dual diagnoses are provided integrated dual diagnosis treatment, they can gradually achieve stable housing.


Benefits of rebuilding global marine fisheries outweigh costs.
Global marine fisheries are currently underperforming, largely due to overfishing. An analysis of global databases finds that resource rent net of subsidies from rebuilt world fisheries could increase from the current negative US$13 billion to positive US$54 billion per year, resulting in a net gain of US$600 to US$1,400 billion in present value over fifty years after rebuilding. To realize this gain, governments need to implement a rebuilding program at a cost of about US$203 (US$130-US$292) billion in present value. We estimate that it would take just 12 years after rebuilding begins for the benefits to surpass the cost. Even without accounting for the potential boost to recreational fisheries, and ignoring ancillary and non-market values that would likely increase, the potential benefits of rebuilding global fisheries far outweigh the costs.


Post-Stroke Psychiatric and Cognitive Symptoms in West Asia, South Asia and Africa: A Systematic Review and Meta-Analysis.
Recent research has shown that the prevalence of stroke incidents and the number of survivors in developing countries surpass those from developed countries. This study aimed to enumerate the prevalence of post-stroke psychiatric and cognitive symptoms among stroke survivors from West and South Asia and Africa through a systematic review and meta-analysis. Data from each country was systematically acquired from five major databases (PsycINFO, Web of Science, Scopus, PubMed/Medline, and Google Scholar (for any missing articles and grey literature)). Meta-analytic techniques were then used to estimate the prevalence of various post-stoke psychiatric and cognitive symptoms. A total of 36 articles were accrued from 11 countries, of which 25 were evaluated as part of the meta-analysis. The pooled prevalence of post-stroke depression as per the Hospital Anxiety and Depression Scale (HADS), Hamilton Depression Rating Scale, Patient Health Questionnaire, Schedules for Clinical Assessment in Neuropsychiatry (SCAN), Geriatric Depression Scale, and the Montgomery-Asberg Depression Rating Scale ranged from 28.00 to 50.24%. Pooled prevalence of post-stroke anxiety based on the HADS and SCAN was 44.19% and 10.96%, respectively. The pooled prevalence of post-stroke cognitive impairment as per the Mini-Mental Status Examination was 16.76%. This present review has suggested that both psychiatric and cognitive symptoms are common among stroke survivors. Concerted efforts are needed to institute robust studies using culturally sensitive measures to contemplate mechanisms that address the unmet needs of this vulnerable population.


Associations between age-related macular degeneration, Alzheimer disease, and dementia: record linkage study of hospital admissions.
The potential association between age-related macular degeneration (AMD) and Alzheimer disease (AD) is uncertain and has implications for understanding disease pathogenesis, referral, and treatments. To determine whether individuals admitted to the hospital with AMD were significantly more or less likely to develop AD or dementia in the following years, as well as to assess whether people with AD or dementia were significantly more or less likely to be admitted to the hospital for AMD treatment in the years following diagnosis of dementia. An AMD cohort of 65,894 people was constructed from English National Health Service, linked hospital episode statistics from January 1, 1999, through February 28, 2011, by identifying computerized record abstracts for all people with an admission or day case care for AMD. A dementia cohort (168,092 people) and a reference cohort (>7.7 million people) were constructed in similar ways. Risk of AD or dementia following AMD and risk of AMD following AD or dementia. Rate ratios were calculated based on standardized rates of AD and dementia in the AMD cohort, as well as standardized rates of AMD in the AD and dementia cohort, relative to those in the reference cohort. RESULTS The risk of AD or dementia following AMD was not elevated. The rate ratio was 0.86 (95% CI, 0.67-1.08) for AD and 0.91 (0.79-1.04) for dementia. The likelihood of being admitted for AMD following AD or dementia was very low: the rate ratio was 0.04 (0.01-0.10) for people with AD and 0.07 (0.04-0.11) for those with dementia. These neurodegenerative conditions may share environmental risk factors and histopathologic features. However, considering AD and other dementia after AMD, their coexistence at the individual level is no different from that expected by chance. Our data also suggest that patients in England with dementia may be substantially less likely to receive AMD treatment. Further research is required to determine whether people with dementia receive appropriate investigation and treatment for AMD, as well as identify and address potential barriers.


Tau-independent Phase Analysis: A Novel Method for Accurately Determining Phase Shifts.
Estimations of period and phase are essential in circadian biology. While many techniques exist for estimating period, comparatively few methods are available for estimating phase. Current approaches to analyzing phase often vary between studies and are sensitive to coincident changes in period and the stage of the circadian cycle at which the stimulus occurs. Here we propose a new technique, tau-independent phase analysis (TIPA), for quantifying phase shifts in multiple types of circadian time-course data. Through comprehensive simulations, we show that TIPA is both more accurate and more precise than the standard actogram approach. TIPA is computationally simple and therefore will enable accurate and reproducible quantification of phase shifts across multiple subfields of chronobiology.


Multicenter assessment of morbidity associated with cerebral arteriovenous malformation hemorrhages.
The optimal management strategy for unruptured cerebral arteriovenous malformations (AVMs) is controversial since the ARUBA trial (A Randomized trial of Unruptured Brain AVMs). An accurate understanding of the morbidity associated with AVM hemorrhages may help clinicians to formulate the best treatment strategy for unruptured AVMs. To determine the morbidity associated with initial cerebral AVM rupture in patients presenting to tertiary medical centers. Retrospective chart reviews from three tertiary academic medical centers were performed for the period between 2008 and 2014. All patients admitted with intracranial hemorrhage due to untreated AVMs were included in this study. Patient-specific variables, including demographics, imaging characteristics, neurologic examination results, and clinical outcome, were analyzed and recorded. 101 Patients met the inclusion criteria. Admission National Institutes of Health Stroke Scale (NIHSS) scores were 0, 1-9, and ≥10 in 26%, 29%, and 45% of patients, respectively. Hematoma locations were subarachnoid, intraventricular, intraparenchymal, and combined in 5%, 11%, 32%, and 52% of patients, respectively. Deep venous drainage was present in 43% of AVMs; AVM-associated aneurysms were present in 44% of patients. Emergent hematoma evacuations were performed in 37% of patients and 8% of patients died while in hospital. At discharge, of those who survived, NIHSS scores of ≥1 and ≥10 were found in 69% and 23%, respectively. At the 90-day follow-up, 34% had a modified Rankin Scale (mRS) score >2. Patients with admission NIHSS score ≥10 had significantly higher rates of midline shift, surgical hematoma evacuation, and follow-up mRS ≥3 (p<0.05). The morbidity associated with cerebral AVM rupture appeared to be higher in our study than previously reported. Morbidity from AVM rupture should be considered as an important factor, together with variables such as risk of AVM rupture and procedural risk, in determining the optimal treatment strategy for unruptured cerebral AVMs.


Orodispersible Polymer Films with the Poorly Water-Soluble Drug, Olanzapine: Hot-Melt Pneumatic Extrusion for Single-Process 3D Printing.
Amorphous solid dispersions (ASDs) improve the oral delivery of poorly water-soluble drugs. ASDs of olanzapine (OLZ), which have a high melting point and low solubility, are performed using a complicated process. Three-dimensional (3D) printing based on hot-melt pneumatic extrusion (HMPE) is a simplified method for producing ASDs. Unlike general 3D printing, printlet extrusion is possible without the preparation of drug-loaded filaments. By heating powder blends, direct fused deposition modeling (FDM) printing through a nozzle is possible, and this step produces ASDs of drugs. In this study, we developed orodispersible films (ODFs) loaded with OLZ as a poorly water-soluble drug. Various ratios of film-forming polymers and plasticizers were investigated to enhance the printability and optimize the printing temperature. Scanning electron microscopy (SEM) showed the surface morphology of the film for the optimization of the polymer carrier ratios. Differential scanning calorimetry (DSC) was used to evaluate thermal properties. Powder X-ray diffraction (PXRD) confirmed the physical form of the drug during printing. The 3D printed ODF formulations successfully loaded ASDs of OLZ using HMPE. Our ODFs showed fast disintegration patterns within 22 s, and rapidly dissolved and reached up to 88% dissolution within 5 min in the dissolution test. ODFs fabricated using HMPE in a single process of 3D printing increased the dissolution rates of the poorly water-soluble drug, which could be a suitable formulation for fast drug absorption. Moreover, this new technology showed prompt fabrication feasibility of various formulations and ASD formation of poorly water-soluble drugs as a single process. The immediate dissolution within a few minutes of ODFs with OLZ, an atypical antipsychotic, is preferred for drug compliance and administration convenience.


An IgG monoclonal antibody to group B meningococci cross-reacts with developmentally regulated polysialic acid units of glycoproteins in neural and extraneural tissues.
The structurally similar polysialic acid capsules of group B meningococci and Escherichia coli K1 are poor immunogens, and attempts are currently being made to improve their immunogenicity by chemical modifications. An IgG monoclonal antibody to these polysialic acid capsules was used for the study of the presence of structurally similar components in tissue glycoproteins to investigate the reasons for the poor immunogenicity and to evaluate potential dangers in active or passive immunization. By immunoblotting polysialic acid was detected outside the brain in newborn rat kidney, heart, and muscle. It appeared in immunoblots as one component and with similar mobility to the neural cell adhesion molecule N-CAM. Specificity studies of the antibody and endosialidase treatment showed that the polysialic acid glycans detected were composed of chains as long as eight sialic acid residues or more. The polysialic acid was not detected in the corresponding tissues of the adult animal. These results indicate that polysialic acid units are developmentally regulated components of both neural and extraneural tissues, and are bound to components with properties similar to a known cell-adhesion molecule. This together with the presence of low amounts of polysialic acid even in the adult brain, suggests potential hazards in vaccination trials and suggested immunotherapy of meningitis caused by group B meningococci or E. coli K1, which should be carefully assessed.


The dynamics of the onset of frictional slip.
The way in which a frictional interface fails is critical to our fundamental understanding of failure processes in fields ranging from engineering to the study of earthquakes. Frictional motion is initiated by rupture fronts that propagate within the thin interface that separates two sheared bodies. By measuring the shear and normal stresses along the interface, together with the subsequent rapid real-contact-area dynamics, we find that the ratio of shear stress to normal stress can locally far exceed the static-friction coefficient without precipitating slip. Moreover, different modes of rupture selected by the system correspond to distinct regimes of the local stress ratio. These results indicate the key role of nonuniformity to frictional stability and dynamics with implications for the prediction, selection, and arrest of different modes of earthquakes.


Photodynamic therapy of experimental choroidal neovascularization using lipoprotein-delivered benzoporphyrin.
To investigate photodynamic therapy of experimental choroidal neovascularization using benzoporphyrin derivative monoacid (Verteporfin). Photodynamic therapy using benzoporphyrin derivative monoacid was investigated in cynomolgus monkeys. Following intravenous injection of benzoporphyrin derivative monoacid (1 to 2 mg/kg) complexed with low-density lipoprotein, the eyes were irradiated with 692-nm light at a fluence of 50 to 150 J/cm2 and irradiance of 150 to 600 mW/cm2. Choroidal neovascularization was documented before photodynamic therapy and closure was demonstrated by fundus photography, fluorescein angiography, and light and electron microscopic examination. Following photodynamic therapy, vessels within choroidal neovascularization were occluded, and there was damage to the choroidal neovascularization endothelium and the subjacent choriocapillaris. Damage to the retinal pigment epithelium and photoreceptors was also observed. Photodynamic therapy with lipoprotein-delivered benzoporphyrin derivative monoacid was effective in this animal model of choroidal neovascularization and may be a promising, potentially selective, therapy for choroidal neovascularization.


Implications of genetic risk information in families with a high density of bipolar disorder: an exploratory study.
While major susceptibility genes for bipolar disorder are yet to be identified, the opportunity exists to systematically ascertain the important issues and societal implications of genetic risk determination for bipolar disorder prior to these technological advances becoming widely available. This study explores, in a sample of families with a high density of bipolar disorder: (i) attitudes to predictive genetic and prenatal testing, using different risk frames; (ii) attributions for bipolar disorder, in particular the degree to which a genetic model is endorsed; and (iii) the impact of these attributions on the perceived stigma of bipolar disorder. A qualitative methodology was selected as most appropriate as no previous research has examined this issue. Participants were ascertained through a molecular genetics study of bipolar disorder. In-depth interviews were conducted with 21 members of families with a high density of bipolar disorder. Most participants reported being interested in genetic testing if it gave a definitive answer, while expressed interest in testing was lower if it gave a probable answer only. Almost all stressed that a genetic susceptibility and environmental factors interacted. Most participants felt that a genetic explanation was likely to decrease the stigma associated with bipolar disorder as it shifted the locus of control and responsibility away from the individual towards the role of heredity. Findings indicate that expressed interest in genetic testing depends on the certainty imparted by the test. Results suggest that families with bipolar disorder are likely to benefit psychologically from information about the genetic basis of bipolar disorder.


Prostate cancer, version 1.2014.
The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer. This report highlights notable recent updates. Radium-223 dichloride is a first-in-class radiopharmaceutical that recently received approval for the treatment of patients with symptomatic bone metastases and no known visceral disease. It received a category 1 recommendation as both a first-line and second-line option. The NCCN Prostate Cancer Panel also revised recommendations on the choice of intermittent or continuous androgen deprivation therapy based on recent phase III clinical data comparing the 2 strategies in the nonmetastatic and metastatic settings.


Defective T cell-mediated, isotype-specific immunoglobulin regulation in B cell chronic lymphocytic leukemia.
The consistent occurrence of T cell abnormalities in patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that the non-neoplastic host T cells may be involved in the pathogenesis of this B cell neoplasm. Because potential defects of immunoglobulin regulation are evident in B-CLL patients, we investigated one aspect of this by studying the T cell-mediated immunoglobulin isotype-specific immunoregulatory circuit in B-CLL. The existence of class-specific immunoglobulin regulatory mechanisms mediated by Fc receptor-bearing T cells (FcR + T) through soluble immunoglobulin binding factors (IgBFs) has been well established in many experimental systems. IgBFs can both suppress and enhance B cell activity in an isotype-specific manner. We investigated the apparently abnormal IgA regulation in a B-CLL patient (CLL249) whose B cells secrete primarily IgA in vitro. Enumeration of FcR + T cells showed a disproportionate increase in IgA FcR + T cells in the peripheral blood of this patient. Our studies showed that the neoplastic B cells were not intrinsically unresponsive to the suppressing component of IgABF produced from normal T cells, but rather the IgABF produced by the CLL249 host T cells was defective. CLL249 IgABF was unable to suppress IgA secretion by host or normal B cells and enhanced the in vitro proliferation of the host B cells. Size fractionation of both normal and CLL249 IgABF by gel-filtration high-performance liquid chromatography (HPLC) demonstrated differences in the ultraviolet-absorbing components of IgABF obtained from normal T cells v that from our patient with defective IgA regulation. Such T cell dysfunction may not be restricted to IgA regulation, since we have found similar expansion of isotype-specific FcR + T cells associated with expansion of the corresponding B cell clone in other patients with B-CLL. These data suggest that this T cell-mediated regulatory circuit could be significantly involved in the pathogenesis of B-CLL.


The role of His66 and His72 in the reaction mechanism of bovine liver low-M(r) phosphotyrosine protein phosphatase.
Site-directed mutagenesis of a synthetic gene coding for low-M(r) phosphotyrosine protein phosphatase from bovine liver has been carried out. The two histidine residues in the enzyme have been mutated to glutamine; both single and double mutants were produced. The mutated and non-mutated sequences have been expressed in Escherichia coli as fusion proteins, in which the low-M(r) phosphotyrosine protein phosphatase was linked to the C-terminal end of the maltose-binding protein. The fusion enzymes were easily purified by single-step affinity chromatography. The mutants were studied for their kinetic properties. Both single mutants showed decreased kcat. values (30 and 7% residual activities for His66 and His72 respectively), and alterations of the Ki values relative to four-competitive inhibitors were observed. The kinetic mechanism of p-nitrophenyl phosphate hydrolysis in the presence of both single mutants was determined and compared with that of the non-mutated enzyme. The rate-determining step of the catalytic process of the His66-->Gln mutant was the same as that found for non-mutated enzyme, whereas for the His72-->Gln mutant, both the kinetic constant of the step that causes the formation of a phosphoenzyme covalent intermediate, and the kinetic constant of the step that causes the dephosphorylation of the enzyme covalent intermediate, determined the kcat. value. This observation was confirmed by phosphoenzyme covalent intermediate trapping experiments. The participation of both histidine residues (His66 and His72) at the active site is strongly suggested by the results of diethyl pyrocarbonate inactivation of both single mutants, each containing a single histidine residue. Both mutants are completely inactivated by diethyl pyrocarbonate treatment; the competitive inhibitor Pi protects both mutants from inactivation. The His66/His72 double mutant was completely inactive.


Polymorphisms of eNOS, catalase, and myeloperoxidase genes in prostate cancer in Turkish men: preliminary results.
Prostate cancer (PCa) is the most common type of neoplasm in European males. Genetic and epigenetic factors contribute to PCa development and progression. In this study, we aimed to assess the relationship between PCa and polymorphisms in the genes encoding endothelial nitric oxide synthase (eNOS), catalase (CAT), and myeloperoxidase (MPO). In total, 193 patients were included in the study. Patients were divided into three groups: PCa (78), benign prostate hyperplasia (40), and control males (75). The parameters assessed included body mass index (BMI), smoking habits, presence of prostatism, prostate-specific antigen (PSA) levels, Gleason scores of prostate specimens, as well as polymorphisms in eNOS-G894T, CAT- 262T, and MPO G-463T genes. BMI and smoking status of controls and patient groups showed no significant difference. CAT-262T gene polymorphism was found to be homozygous in 35.4% of PCa patients, which was 4.02-fold that in the controls (P = 0.006). There was no statistically significant difference in eNOS-G894T and MPO G-463T gene polymorphisms between any of the groups. In conclusion, we found catalase levels to be associated with PCa diagnosis and PSA value. We did not find any significant differences between groups for other polymorphisms, but we believe that further studies with a large sample size may be needed before drawing definite conclusions.


An exploratory study of the relationship between face recognition memory and the volume of medial temporal lobe structures in healthy young males.
A rigorous new methodology was applied to the study of structure function relationships in the living human brain. Face recognition memory (FRM) and other cognitive measures were made in 29 healthy young male subjects (mean age = 21.7 years) and related to volumetric measurements of their cerebral hemispheres and of structures in their medial temporal lobes, obtained using the Cavalieri method in combination with high resolution Magnetic Resonance Imaging (MRI. Greatest proportional variability in volumes was found for the lateral ventricles (57%) for the cerebral hemispheres (8%) in the mean volumes of the hippocampus, parahippocampal gyrus, amygdala, caudate nucleus, temporal pole and temporal lobe on the right and left sides of the brain. The volumes of the right and left parahippocampal gyrus, temporal pole, temporal lobe, and left hippocampus were, prior to application of the Bonferroni correction to take account of 12 multiple comparisons, significantly correlated with the volume of the corresponding hemisphere(p < 0.05). The volumes of all structures were highly correlated (p < 0.0002 for all comparisons) between the two cerebral hemispheres. There were no positive relationships between structure volumes and FRM score. However, the volume of the right amygdala was, prior to application of the Bonferroni correction to take account of 38~multiple comparisons, found to be significantly smaller in the five most consistent high scorers compared to the five most consistent low scorers (t = 2.77,p = 0.025). The implications for possible relationships between healthy medial temporal lobe structures and memory are discussed.


Stress-responsive pathways and small RNA changes distinguish variable developmental phenotypes caused by MSH1 loss.
Proper regulation of nuclear-encoded, organelle-targeted genes is crucial for plastid and mitochondrial function. Among these genes, MutS Homolog 1 (MSH1) is notable for generating an assortment of mutant phenotypes with varying degrees of penetrance and pleiotropy. Stronger phenotypes have been connected to stress tolerance and epigenetic changes, and in Arabidopsis T-DNA mutants, two generations of homozygosity with the msh1 insertion are required before severe phenotypes begin to emerge. These observations prompted us to examine how msh1 mutants contrast according to generation and phenotype by profiling their respective transcriptomes and small RNA populations. Using RNA-seq, we analyze pathways that are associated with MSH1 loss, including abiotic stresses such as cold response, pathogen defense and immune response, salicylic acid, MAPK signaling, and circadian rhythm. Subtle redox and environment-responsive changes also begin in the first generation, in the absence of strong phenotypes. Using small RNA-seq we further identify miRNA changes, and uncover siRNA trends that indicate modifications at the chromatin organization level. In all cases, the magnitude of changes among protein-coding genes, transposable elements, and small RNAs increases according to generation and phenotypic severity. Loss of MSH1 is sufficient to cause large-scale regulatory changes in pathways that have been individually linked to one another, but rarely described all together within a single mutant background. This study enforces the recognition of organelles as critical integrators of both internal and external cues, and highlights the relationship between organelle and nuclear regulation in fundamental aspects of plant development and stress signaling. Our findings also encourage further investigation into potential connections between organelle state and genome regulation vis-á-vis small RNA feedback.


Etiology of invasive bacterial infections in immunocompetent children in Korea (1996-2005): a retrospective multicenter study.
The purpose of this study was to identify the major etiological agents responsible for invasive bacterial infections in immunocompetent Korean children. We retrospectively surveyed invasive bacterial infections in immunocompetent children caused by eight major pediatric bacteria, namely Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pyogenes, Listeria monocytogenes, and Salmonella species that were diagnosed at 18 university hospitals from 1996 to 2005. A total of 768 cases were identified. S. agalactiae (48.1%) and S. aureus (37.2%) were the most common pathogens in infants younger than 3 months. S. agalactiae was a common cause of meningitis (73.0%), bacteremia without localization (34.0%), and arthritis (50%) in this age group. S. pneumoniae (45.3%) and H. influenzae (20.4%) were common in children aged 3 months to 5 yr. S. pneumoniae was a common cause of meningitis (41.6%), bacteremia without localization (40.0%), and bacteremic pneumonia (74.1%) in this age group. S. aureus (50.6%), Salmonella species (16.9%), and S. pneumoniae (16.3%) were common in older children. A significant decline in H. influenzae infections over the last 10 yr was noted. S. agalactiae, S. pneumoniae, and S. aureus are important pathogens responsible for invasive bacterial infections in Korean children.


A workforce-based study of occupational exposures and asthma symptoms in cleaning workers.
To study associations between use of cleaning products and asthma symptoms in cleaning workers. Information on respiratory symptoms, history of asthma, workplaces, use of cleaning products and acute inhalation incidents were obtained through a self-administered questionnaire. 917 employees of 37 cleaning companies in Barcelona were studied. 761 (83%) were current cleaners, 86 (9%) former cleaners and 70 (8%) had never worked as cleaners. Multivariable logistic regression analyses were used to evaluate the associations between specific exposures among current cleaners and wheeze without having a cold, chronic cough and current asthma. Associations with an asthma symptom score were also studied using negative binomial regression analyses to report mean ratios. After adjusting for sex, age, nationality and smoking status, the prevalence of current asthma was non-significantly higher among current (OR 1.9; 95% CI 0.5 to 7.8) and former cleaners (OR 1.9; CI 0.6 to 5.5) than in never cleaners. Cleaners working in hospitals during the last year had a significantly increased prevalence of wheeze, current asthma and a 1.8 (95% CI 1.2 to 2.8) times higher mean asthma score. Use of hydrochloric acid was strongly associated with asthma score (mean ratio 1.7; 95% CI 1.1 to 2.6). Use of ammonia, degreasers, multiple purpose products and waxes was also associated with asthma score. Cleaning work in places with high demand for disinfection, high cleaning standards and use of cleaning products containing respiratory irritants is associated with higher risk of asthma symptoms. This suggests irritants have an important role in cleaning-related asthma.


Particle sizing methods for the detection of protein aggregates in biopharmaceuticals.
Protein aggregation is a common biological phenomenon which is responsible for degenerative diseases and is problematic in the pharmaceutical industry. According to the rules provided by regulatory agencies, industry is supposed to assess the product quality regarding the presence of subvisible particles. Also, they should evaluate the technologies that are used to measure these particles. Therefore, US FDA and industry have been looking for methods capable of accurately characterizing the protein products. Four sizing techniques reviewed here are good candidates to be used for characterization of protein and their aggregates: dynamic light scattering, size-exclusion chromatography, electron microscopy and Taylor dispersion analysis. The first three are more established techniques while the last one is a more recent and growing technique.


Triaging women with acute coronary syndrome: a review of the literature.
This article analyzes the literature describing factors affecting nurses' triage of emergency department (ED) patients with potential acute coronary syndrome (ACS), with particular attention paid to gender-based differences. Acute coronary syndrome is one of the most time-critical conditions requiring ED nurse triage. This literature review will provide examination of how triage nurses prioritize patients with possible ACS, reflecting on challenges specifically associated with evaluating women for ACS in the ED. The article presents a description of the research findings that may help improve the timely revascularization of ACS in women. An electronic search of EBSCOhost CINAHL, Health Source Nursing Academic Edition, MEDLINE, Psychology and Behavioral Sciences Collection databases, online theses, the Cochrane Library, the Joanna Briggs Institute, and National Guideline Clearinghouse resources were used to identify all relevant scientific articles published between 1990 and 2010. Google and Google Scholar search engines were used to undertake a broader search of the World Wide Web to improve completeness of the search. This search technique was augmented by hand searching these articles' reference lists for publications missed during the primary search. : Review of the literature suggests factors such as patient age, sex, and symptoms at ED presentation affect the accuracy of nurses' triage of ACS, particularly for women. However, research examining delays due to ED triage is scant and has predominantly been undertaken by one researcher. Little research has examined triage of ACS specifically in women. The literature search revealed a small number of articles describing challenges associated with nurse triage of women with ACS. Although most of this published research is North American, the themes uncovered are well supported by broader international research on acute assessment and management of women's ACS. These include the following: gender-based differences in the presentation of ACS can preclude early identification of ACS, advanced patient age often correlates with missed or delayed diagnosis of ACS, and there appears to be a general bias against managing women for ACS in parity with men's disease. : Early reperfusion therapy is critical for optimal health outcomes in ACS. Triage nurses are ideally placed to minimize time to treatment for ACS. An understanding of the issues related to clinical decision making and triage allocation of women with ACS at triage is necessary to ensure appropriate treatment.


Effect of multimodal analgesia with paravertebral blocks on biochemical recurrence in men undergoing open radical prostatectomy.
Recent studies suggest that anesthetic technique during radical prostatectomy for prostate cancer may affect recurrence or progression. This association has previously been investigated in series that employ epidural analgesia. The objective of this study is to determine the association between the use of a multimodal analgesic approach incorporating paravertebral blocks and risk of biochemical recurrence following open radical prostatectomy. Using a prospective database of 3,029 men undergoing open radical prostatectomy by a single surgeon, we identified 2,909 men who received no neoadjuvant androgen deprivation and had at least 1 year of follow up. We retrospectively compared patients who received general analgesia with opioid analgesia (1999-2003, n = 662) to those who received general analgesia with multimodal analgesia incorporating paravertebral blocks (2003-2014, n = 2,247). The primary outcome was time to biochemical recurrence. Biochemical recurrence-free interval was assessed using the Kaplan-Meier technique and compared using a multivariate Cox-proportional hazards regression model. In total, 395 patients (14%) experienced biochemical recurrence following radical prostatectomy, including 265 (12%) who received multimodal analgesia and 130 (20%) who did not (adjusted P = 0.27). After adjusting for age, race, body mass index, preoperative prostate specific antigen, grade, stage, perineural invasion, margin status, percent of tumor in the gland, and diameter of the dominant nodule, there was no difference in recurrence-free interval between groups (HR = 0.92, 95% CI: 0.73-1.17). Use of a multimodal analgesic approach incorporating paravertebral blocks is not associated with a reduced risk of biochemical recurrence following radical prostatectomy.


Linking objective measures of physical activity and capability with brain structure in healthy community dwelling older adults.
Maintaining high levels of daily activity and physical capability have been proposed as important constituents to promote healthy brain and cognitive aging. Studies investigating the associations between brain health and physical activity in late life have, however, mainly been based on self-reported data or measures designed for clinical populations. In the current study, we examined cross-sectional associations between physical activity, recorded by an ankle-positioned accelerometer for seven days, physical capability (grip strength, postural control, and walking speed), and neuroimaging based surrogate markers of brain health in 122 healthy older adults aged 65-88 years. We used a multimodal brain imaging approach offering complementary structural MRI based indicators of brain health: global white matter fractional anisotropy (FA) and mean diffusivity (MD) based on diffusion tensor imaging, and subcortical and global brain age based on brain morphology inferred from T1-weighted MRI data. In addition, based on the results from the main analysis, follow-up regression analysis was performed to test for association between the volume of key subcortical regions of interest (hippocampus, caudate, thalamus and cerebellum) and daily steps, and a follow-up voxelwise analysis to test for associations between walking speed and FA across the white matter Tract-Based Spatial Statistics (TBSS) skeleton. The analyses revealed a significant association between global FA and walking speed, indicating higher white matter integrity in people with higher pace. Voxelwise analysis supported widespread significant associations. We also found a significant interaction between sex and subcortical brain age on number of daily steps, indicating younger-appearing brains in more physically active women, with no significant associations among men. These results provide insight into the intricate associations between different measures of brain and physical health in old age, and corroborate established public health advice promoting physical activity.


Unusual Larva in the CSF and Unique MRI Findings in a Case of Eosinophilic Meningitis.
Eosinophilic meningitis may be caused by non-infectious and infectious agents. Angiostrongylus cantonensis is the commonest causative agent of eosinophilic meningitis. Rats are the primary hosts of this parasite. Humans get infected by ingestion of raw or inadequately cooked hosts (snails or monitor lizard) or food contaminated with the infective third-stage larvae. A 16-year-old boy was admitted to our hospital with history of fever, headache, and altered sensorium. Magnetic resonance imaging of the brain showed unique findings. Cerebrospinal fluid (CSF) examination showed eosinophilia and the CSF wet mount identified a larva. Patient history revealed ingestion of monitor lizard 2 weeks prior to onset of symptoms. Hence, a diagnosis of eosinophilic meningitis caused by A. cantonensis was made. He was treated with oral albendazole and steroids, resulting in gradual improvement. A. cantonensis as a cause of eosinophilic meningitis is a possibility in patients who present with headache and vomiting after eating raw meat (monitor lizard). To the best of our knowledge, this is a very rare case being reported from India where the larva was identified during the microscopic examination of the CSF.


Clinical Diagnoses Leading to Suspension in Army Aircrew: An Epidemiological Study.
There have been few large-scale epidemiological examinations of military aircrew populations reported in recent literature. This study examined 10 yr of medical records contained in the U.S. Army Aeromedical Electronic Resource Office (AERO) in an effort to identify the most prevalent conditions affecting Army aviator career longevity. This study was a retrospective epidemiological review; data were retrieved on 24,568 rated aircrew patients from the AERO database, of whom 5.2% were women. The dataset was composed of a total of 181,471 cases between June 2005 and June 2015. Age ranged from 17 to 73 yr. The data were examined in terms of raw ICD-9 diagnostic codes, derived systems-based categories, and occupational consequences. The top 10 diagnoses, causes for waiver, and permanent suspension of aircrew were determined both in terms of the ICD-9 codes and the system groupings. Leading waiver causes included hypertension (11.5%), hearing loss (9.7%), spinal disorder (14.4%), and obstructive sleep apnea (5.2%). Leading permanent suspension causes were psychiatric disorders (28.2%), particularly PTSD, being the leading cause, with spinal pathology (16.1%) second. In almost all diagnostic groupings the Spearman's rho correlation coefficients between age and diagnosis presence were positively related, although often with no association with negative occupational outcome. This study revealed the leading medical causes of waiver and suspension from flying duties, producing evidence to inform leadership understanding of disease prevalence and its subsequent impact on flying status. This is of prime importance to help direct policy and implement strategies for health protection.Curry IP, Kelley AM, Gaydos SJ. Clinical diagnoses leading to suspension in Army aircrew: an epidemiological study. Aerosp Med Hum Perform. 2018; 89(7):587-592.


A standardized framework for testing the performance of sleep-tracking technology: step-by-step guidelines and open-source code.
Sleep-tracking devices, particularly within the consumer sleep technology (CST) space, are increasingly used in both research and clinical settings, providing new opportunities for large-scale data collection in highly ecological conditions. Due to the fast pace of the CST industry combined with the lack of a standardized framework to evaluate the performance of sleep trackers, their accuracy and reliability in measuring sleep remains largely unknown. Here, we provide a step-by-step analytical framework for evaluating the performance of sleep trackers (including standard actigraphy), as compared with gold-standard polysomnography (PSG) or other reference methods. The analytical guidelines are based on recent recommendations for evaluating and using CST from our group and others (de Zambotti and colleagues; Depner and colleagues), and include raw data organization as well as critical analytical procedures, including discrepancy analysis, Bland-Altman plots, and epoch-by-epoch analysis. Analytical steps are accompanied by open-source R functions (depicted at https://sri-human-sleep.github.io/sleep-trackers-performance/AnalyticalPipeline_v1.0.0.html). In addition, an empirical sample dataset is used to describe and discuss the main outcomes of the proposed pipeline. The guidelines and the accompanying functions are aimed at standardizing the testing of CSTs performance, to not only increase the replicability of validation studies, but also to provide ready-to-use tools to researchers and clinicians. All in all, this work can help to increase the efficiency, interpretation, and quality of validation studies, and to improve the informed adoption of CST in research and clinical settings.


Stimulus detection rate and latency, firing rates and 1-40Hz oscillatory power are modulated by infra-slow fluctuations in a bistable attractor network model.
Recordings of membrane and field potentials, firing rates, and oscillation amplitude dynamics show that neuronal activity levels in cortical and subcortical structures exhibit infra-slow fluctuations (ISFs) on time scales from seconds to hundreds of seconds. Similar ISFs are salient also in blood-oxygenation-level dependent (BOLD) signals as well as in psychophysical time series. Functional consequences of ISFs are not fully understood. Here, they were investigated along with dynamical implications of ISFs in large-scale simulations of cortical network activity. For this purpose, a biophysically detailed hierarchical attractor network model displaying bistability and operating in an oscillatory regime was used. ISFs were imposed as slow fluctuations in either the amplitude or frequency of fast synaptic noise. We found that both mechanisms produced an ISF component in the synthetic local field potentials (LFPs) and modulated the power of 1-40Hz oscillations. Crucially, in a simulated threshold-stimulus detection task (TSDT), these ISFs were strongly correlated with stimulus detection probabilities and latencies. The results thus show that several phenomena observed in many empirical studies emerge concurrently in the model dynamics, which yields mechanistic insight into how infra-slow excitability fluctuations in large-scale neuronal networks may modulate fast oscillations and perceptual processing. The model also makes several novel predictions that can be experimentally tested in future studies.


Features of syndrome X in first-degree relatives of NIDDM patients.
To determine whether the features of syndrome X are more common in first-degree relatives of non-insulin-dependent diabetes mellitus (NIDDM) patients than in control subjects with no family history of diabetes. A total of 154 first-degree relatives from 60 families with two or more NIDDM patients and 154 age- and sex-matched control subjects were studied. All subjects underwent a 75-g oral glucose tolerance test and baseline lipid blood and anthropometric measures. The features of syndrome X that were studied were obesity, hypertension, dyslipidemia (high triglyceride levels and low high-density lipoprotein [HDL] cholesterol concentrations), impaired glucose tolerance (World Health Organization criteria), and insulin resistance (as assessed by the homeostasis model assessment). Relatives were heavier than control subjects (body mass index 27.5 +/- 5.2 vs. 25.2 +/- 4.6 kg/m2, respectively [mean +/- SD], P < 0.0002), had lower HDL cholesterol concentrations (1.2 +/- 0.3 vs. 1.4 +/- 0.4 mmol/l, P < 0.001), were more insulin-resistant (2.3 [0.7-7.6] vs. 1.6 [0.5-5.1], geometric mean [95% confidence intervals], P < 0.0001), and had more individuals classified as having impaired glucose tolerance (28 of 154 [18%] vs. 7 of 154 [7%], chi 2, P < 0.001). The differences in insulin resistance and HDL cholesterol concentrations between the groups were independent of obesity. Features of syndrome X occur more frequently in relatives of NIDDM patients than in control subjects with no family history of diabetes.


Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI).
Thrombin-activatable procarboxypeptidase B (proCPB or thrombin-activatable fibrinolysis inhibitor or TAFI) is a plasma procarboxypeptidase that is activated by the thrombin-thrombomodulin complex on the vascular endothelial surface. The activated CPB removes the newly exposed carboxyl terminal lysines in the partially digested fibrin clot, diminishes tissue plasminogen activator and plasminogen binding, and protects the clot from premature lysis. We have recently shown that CPB is catalytically more efficient than plasma CPN, the major plasma anaphylatoxin inhibitor, in inhibiting bradykinin, activated complement C3a, C5a, and thrombin-cleaved osteopontin in vitro. Using a thrombin mutant (E229K) that has minimal procoagulant properties but retains the ability to activate protein C and proCPB in vivo, we showed that infusion of E229K thrombin into wild-type mice reduced bradykinin-induced hypotension but it had no effect in proCPB-deficient mice, indicating that the beneficial effect of E229K thrombin is mediated through its activation of proCPB and not protein C. Similarly proCPB-deficient mice displayed enhanced pulmonary inflammation in a C5a-induced alveolitis model and E229K thrombin ameliorated the magnitude of alveolitis in wild-type but not proCPB-deficient mice. ProCPB-deficient mice also displayed enhanced arthritis in an inflammatory arthritis model. Thus, our in vitro and in vivo data support the thesis that thrombin-activatable CPB has broad anti-inflammatory properties. By specific cleavage of the carboxyl terminal arginines from C3a, C5a, bradykinin and thrombin-cleaved osteopontin, it inactivates these active inflammatory mediators. Along with the activation of protein C, the activation of proCPB by the endothelial thrombin-thrombomodulin complex represents a homeostatic feedback mechanism in regulating thrombin's pro-inflammatory functions in vivo.


What counts as success in genetic counselling?
The question of what counts as a successful outcome of the process of genetics counselling has recently become central because of the increasing calls for efficiency in health care, and for means of measuring efficiency. Angus Clarke has drawn attention to this trend, and has argued against both a measure in terms of the number of terminations of pregnancy performed as a result of counselling, and an assessment in terms of the contribution of genetics counselling to a national eugenics policy. He suggests instead a measure of workload. There are good arguments for supporting Clarke's position up to a point. In looking for an appropriate measure, much turns on how genetics counselling is defined. It is here understood in the context of an autonomy model of health care. It is argued that there is a contradiction between such an interpretation and the termination measure of outcome. The political philosophy underlying this outcome is also defective. Workload is not sufficient as a measure of outcome however; it is essential to look at the proper goals of an activity. It is argued that these must be connected in some way with the genetic health of the population; that the promotion of reproductive autonomy itself is not sufficient as a goal. The concern for genetic health, however, is interpreted in a way that avoids Clarke's concerns about a national eugenics policy.


Nonlinear optics of fibre event horizons.
The nonlinear interaction of light in an optical fibre can mimic the physics at an event horizon. This analogue arises when a weak probe wave is unable to pass through an intense soliton, despite propagating at a different velocity. To date, these dynamics have been described in the time domain in terms of a soliton-induced refractive index barrier that modifies the velocity of the probe. Here we complete the physical description of fibre-optic event horizons by presenting a full frequency-domain description in terms of cascaded four-wave mixing between discrete single-frequency fields, and experimentally demonstrate signature frequency shifts using continuous wave lasers. Our description is confirmed by the remarkable agreement with experiments performed in the continuum limit, reached using ultrafast lasers. We anticipate that clarifying the description of fibre event horizons will significantly impact on the description of horizon dynamics and soliton interactions in photonics and other systems.


Modulating presence and impulsiveness by external stimulation of the brain.
"The feeling of being there" is one possible way to describe the phenomenon of feeling present in a virtual environment and to act as if this environment is real. One brain area, which is hypothesized to be critically involved in modulating this feeling (also called presence) is the dorso-lateral prefrontal cortex (dlPFC), an area also associated with the control of impulsive behavior. In our experiment we applied transcranial direct current stimulation (tDCS) to the right dlPFC in order to modulate the experience of presence while watching a virtual roller coaster ride. During the ride we also registered electro-dermal activity. Subjects also performed a test measuring impulsiveness and answered a questionnaire about their presence feeling while they were exposed to the virtual roller coaster scenario. Application of cathodal tDCS to the right dlPFC while subjects were exposed to a virtual roller coaster scenario modulates the electrodermal response to the virtual reality stimulus. In addition, measures reflecting impulsiveness were also modulated by application of cathodal tDCS to the right dlPFC. Modulating the activation with the right dlPFC results in substantial changes in responses of the vegetative nervous system and changed impulsiveness. The effects can be explained by theories discussing the top-down influence of the right dlPFC on the "impulsive system".


Effect of Linum usitatissimum L. (linseed) oil on mild and moderate carpal tunnel syndrome: a randomized, double-blind, placebo-controlled clinical trial.
Carpal tunnel syndrome is known as the most common entrapment neuropathy. Conservative treatments cannot reduce the symptomatic severity satisfactorily; therefore, effectiveness of Linum usitatissimum L. (linseed) oil on carpal tunnel syndrome, as a complementary treatment, was evaluated in the current study. Linseed oil is a well-known preparation in Iranian traditional medicine and its analgesic, anti-inflammatory and anti-oxidative effects have been shown in previous studies. A randomized, double-blind, placebo-controlled clinical trial was conducted. One hundred patients (155 hands) with idiopathic mild to moderate carpal tunnel syndrome aged between 18 and 65 years old were randomized in two parallel groups. These two groups were treated during 4 weeks with topical placebo and linseed oil. In addition, a night wrist splint was prescribed for both groups. Symptomatic severity and functional status were measured using Boston Carpal Tunnel Questionnaire. In addition, median sensory nerve conduction velocity, motor distal latency, sensory distal latency and compound latency as electrodiagnostic parameters were measured at baseline and after the intervention period. After the intervention, significant improvement was observed regarding Boston Carpal Tunnel Questionnaire symptomatic severity and functional status mean differences (p <0.001) in the linseed oil group compared with those in the placebo group. Also, regarding the mean differences of both groups, significant improvement of nerve conduction velocity of the median nerve was seen in the linseed oil group by a value of 2.38 m/sec (p < 0.05). However, motor distal latency and sensory distal latency of the median nerve showed no between-group significant changes (p = 0.14 for both items). Finally, compound latency was improved slightly in the case group, comparing mean differences between the groups (p <0.05). No significant adverse events were reported from using linseed oil. It seems that linseed oil could be effective in the management of mild and moderate carpal tunnel syndrome, especially in improving the severity of symptoms and functional status. In addition, its effect on electerodiagnostic parameters, especially on the nerve conduction velocity, can be considered as a valuable point.


C-H Functionalizations by Palladium Carboxylates: The Acid Effect.
Finding optimal reaction conditions is usually complex, requires many experiments, and is therefore demanding in terms of human, financial, and environmental resources. This work provides a simple workflow for easier design of popular palladium-catalyzed C-H functionalization reactions, where the active palladium catalysts contain carboxylate ligands. The key factor for optimizing reaction conditions is to find a balance between two opposing effects of the carboxylic acid in the reaction mixture: generation of more reactive palladium catalyst versus deactivation of a substrate by its protonation.


Atrial-Esophageal Fistula After Catheter Ablation: Diagnosing and Managing a Rare Complication of a Common Procedure.
BACKGROUND Atrial fibrillation is considered the most common cardiac arrhythmias in the United States with rate and rhythm control strategies traditionally used for management. If patients are intolerant to class I or class III anti-arrhythmic medications, catheter ablation may be used as a rhythm control strategy. As catheter ablation becomes more commonplace, so too do the procedure-related complications, which include tamponade, total arterio-venous fistula, pulmonary vein stenosis, and atrial-esophageal fistula. CASE REPORT A 67-year-old male underwent catheter ablation for atrial fibrillation and subsequently presented with complaints of fever and chills. Initial workup for a source of infection included a computed tomography (CT) scan and transesophageal echocardiogram which did not reveal any abnormalities. Antibiotic therapy was initiated, and multiple CT scans were performed; eventually patient was found to have an atrial-esophageal fistula, secondary to thermal injury. The patient underwent thoracotomy and full thickness necrosis of the posterior left atrium and pericardium near the base of the left inferior pulmonary vein was visualized, with a roughly nickel sized orifice, which was repaired. The patient had an uneventful recovery and was doing well on follow-up. CONCLUSIONS Atrial-esophageal fistula is a rare but lethal complication of atrial fibrillation ablation. While imaging modalities have improved and can detect the condition, they can also yield ambivalent findings which can challenge patient care. It is important for clinicians to maintain a heightened awareness of this complication in post-ablation patients and utilize clinical history and not rely solely on imaging to diagnose and treat this complication.


Cloning and functional expression of a degradation-resistant novel isoform of p27Kip1.
p27(Kip1) is an inhibitor of cyclin-dependent kinases. It has been implicated as having a role in the induction of growth arrest at the G(1) phase of the cell cycle in response to anti-mitogenic signals such as cell contact and serum starvation. Proteasome-mediated degradation plays an important role in the rapid inactivation of p27(Kip1), causing quiescent cells to re-enter the cell cycle. Although the existence of a second isoform has been suggested, no such isoform was isolated. Through screening of a cDNA library derived from growth-arrested confluent porcine endothelial cells, we obtained clones for a novel isoform of p27(Kip1) in addition to the original isoform. The novel isoform differed from the original isoform at the C-terminus. The tissue-specific expression of the original and novel isoforms was demonstrated at the mRNA and protein levels. An in vitro degradation assay demonstrated this novel isoform to be resistant to proteasome-mediated destruction. The expression as a fusion protein with green fluorescent protein revealed this isoform to be targeted to the nucleus by a bipartite nuclear-localization signal with a C-terminal part different from that of the original isoform. The expression of the novel isoform caused the growth arrest of HeLa cells and an accumulation of cells in the G(0)/G(1) phase, and this effect was similar to that seen with the original isoform. The present study suggests that the novel isoform functions as a negative regulator of the cell cycle, and may play a distinct role. The novel isoform was named p27(Kip1R) because of its resistance to degradation.


Effect of pollination on accumulation of ACC synthase and ACC oxidase transcripts, ethylene production and flower petal abscission in geranium (Pelargonium x hortorum L.H. Bailey).
Self-pollination of diploid zonal geranium (Pelargonium x hortorum L.H. Bailey) florets leads to a dramatic rise in ethylene production, followed by abscission within 4 h. Neither wounding of the stigma, pollination with tetraploid pollen, nor heat-killed self pollen could elicit as much ethylene production and petal abscission as self-pollination. A cDNA sharing sequence identity with ACC synthase (GACS2) and three different cDNAs sharing sequence identity with ACC oxidase (GACO1, GACO2, GACO3) were isolated from geranium pistils. Transcripts hybridizing with these probes increased slightly in response to self-pollination, but the degree of accumulation in response to various treatments did not correlate with ethylene production. When calculated on a per-plant-part basis, transcripts hybridizing with GACS2 were equally distributed among the stigma+style, sterile ovary, and ovary tissues, but transcripts hybridizing with the three ACC oxidase clones were differentially distributed. All transcripts were differentially expressed among the other tissues of the plant, with GACO1 being the most widely distributed. Ethylene production in geranium pistils was not autocatalytic. Propylene failed to induce ethylene production and ethylene did not induce the accumulation of ACC synthase or ACC oxidase transcripts. ACC accumulated in the stigma and style, and to a smaller extent in the sterile ovary, after pollination. These data support a model of pollination-induced ethylene production by post-transcriptional regulation of ethylene biosynthetic gene expression.


Extended follow-up following a phase 2b randomized trial of the candidate malaria vaccines FP9 ME-TRAP and MVA ME-TRAP among children in Kenya.
"FFM ME-TRAP" is sequential immunisation with two attenuated poxvirus vectors (FP9 and modified vaccinia virus Ankara) delivering the pre-erythrocytic malaria antigen ME-TRAP. Over nine months follow-up in our original study, there was no evidence that FFM ME-TRAP provided protection against malaria. The incidence of malaria was slightly higher in children who received FFM ME-TRAP, but this was not statistically significant (hazard ratio 1.5, 95% CI 1.0-2.3). Although the study was unblinded, another nine months follow-up was planned to monitor the incidence of malaria and other serious adverse events. 405 children aged 1-6 yrs were initially randomized to vaccination with either FFM ME-TRAP or control (rabies vaccine). 380 children were still available for follow-up after the first nine months. Children were seen weekly and whenever they were unwell for nine months monitoring. The axillary temperature was measured, and blood films taken when febrile. The primary analysis was time to parasitaemia >2,500/microl. During the second nine months monitoring, 49 events met the primary endpoint (febrile malaria with parasites >2,500/microl) in the Intention To Treat (ITT) group. 23 events occurred among the 189 children in the FFM ME-TRAP group, and 26 among the 194 children in the control group. In the full 18 months of monitoring, there were 63 events in the FFM ME-TRAP group and 60 in the control group (HR = 1.2, CI 0.84-1.73, p = 0.35). There was no evidence that the HR changed over the 18 months (test for interaction between time and vaccination p = 0.11). Vaccination with FFM ME-TRAP was not protective against malaria in this study. Malaria incidence during 18 months of surveillance was similar in both vaccine groups. Controlled-Trials.com ISRCTN88335123.


Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma.
Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis. A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses). Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)


Assessment of pancreatic β-cell function: review of methods and clinical applications.
Type 2 diabetes mellitus (T2DM) is characterized by a progressive failure of pancreatic β-cell function (BCF) with insulin resistance. Once insulin over-secretion can no longer compensate for the degree of insulin resistance, hyperglycemia becomes clinically significant and deterioration of residual β-cell reserve accelerates. This pathophysiology has important therapeutic implications. Ideally, therapy should address the underlying pathology and should be started early along the spectrum of decreasing glucose tolerance in order to prevent or slow β-cell failure and reverse insulin resistance. The development of an optimal treatment strategy for each patient requires accurate diagnostic tools for evaluating the underlying state of glucose tolerance. This review focuses on the most widely used methods for measuring BCF within the context of insulin resistance and includes examples of their use in prediabetes and T2DM, with an emphasis on the most recent therapeutic options (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists). Methods of BCF measurement include the homeostasis model assessment (HOMA); oral glucose tolerance tests, intravenous glucose tolerance tests (IVGTT), and meal tolerance tests; and the hyperglycemic clamp procedure. To provide a meaningful evaluation of BCF, it is necessary to interpret all observations within the context of insulin resistance. Therefore, this review also discusses methods utilized to quantitate insulin-dependent glucose metabolism, such as the IVGTT and the euglycemic-hyperinsulinemic clamp procedures. In addition, an example is presented of a mathematical modeling approach that can use data from BCF measurements to develop a better understanding of BCF behavior and the overall status of glucose tolerance.


Combining evidence and values in priority setting: testing the balance sheet method in a low-income country.
Procedures for priority setting need to incorporate both scientific evidence and public values. The aim of this study was to test out a model for priority setting which incorporates both scientific evidence and public values, and to explore use of evidence by a selection of stakeholders and to study reasons for the relative ranking of health care interventions in a setting of extreme resource scarcity. Systematic search for and assessment of relevant evidence for priority setting in a low-income country. Development of a balance sheet according to Eddy's explicit method. Eight group interviews (n-85), using a modified nominal group technique for eliciting individual and group rankings of a given set of health interventions. The study procedure made it possible to compare the groups' ranking before and after all the evidence was provided to participants. A rank deviation is significant if the rank order of the same intervention differed by two or more points on the ordinal scale. A comparison between the initial rank and the final rank (before deliberation) showed a rank deviation of 67%. The difference between the initial rank and the final rank after discussion and voting gave a rank deviation of 78%. Evidence-based and deliberative decision-making does change priorities significantly in an experimental setting. Our use of the balance sheet method was meant as a demonstration project, but could if properly developed be feasible for health planners, experts and health workers, although more work is needed before it can be used for laypersons.


Subspecialty training in Europe: a report by the European Network of Young Gynaecological Oncologists.
ESGO (European Society of Gynaecological Oncology) and partners are continually improving the developmental opportunities for gynaecological oncology fellows. The objectives of this survey were to evaluate the progress in the infrastructure of the training systems in Europe over the past decade. We also evaluated training and assessment techniques, the perceived relevance of ENYGO (European Network of Young Gynaecological Oncologists) initiatives, and unmet needs of trainees. National representatives of ENYGO from 39 countries were contacted with an electronic survey. A graduation in well/moderately/loosely-structured training systems was performed. Descriptive statistical analysis and frequency tables, as well as two-sided Fisher's exact test, were used. National representatives from 33 countries answered our survey questionnaire, yielding a response rate of 85%. A national fellowship is offered in 22 countries (66.7%). A logbook to document progress during training is mandatory in 24 (72.7%) countries. A logbook of experience is only utilized in a minority of nations (18%) for assessment purposes. In 42.4% of countries, objective assessments are recognized. Trainees in most countries (22 (66.7%)) requested additional training in advanced laparoscopic surgery. 13 (39.4%) countries have a loosely-structured training system, 11 (33.3%) a moderately-structured training system, and 9 (27.3%) a well-structured training system. Since the last publication in 2011, ENYGO was able to implement new activities, workshops, and online education to support training of gynaecological oncology fellows, which were all rated by the respondents as highly useful. This survey also reveals the limitations in establishing more accredited centers, centralized cancer care, and the lack of laparoscopic training.


Needs and experiences of caregivers for family members dying with Parkinson disease.
The caregiver burdens and unmet needs of patients with Parkinson disease (PD) in the final months of life are poorly documented. We surveyed 47 family caregivers of PD patients a median of 18 months after death. We measured caregiver preparedness for their role, assistance provided the patient, and types and settings of care received by the patient. Typical caregivers were older female spouses. Though 66% of patients resided in a care facility during the last month, over half received care from hospice, 36% from a home health agency, and 43% by privately paid aide in the months before death. Caregivers rated tasks involving physical effort as most difficult. While most caregivers felt prepared for their role, one-third or more were unprepared for the stress and physical strain encountered. These data suggest that increasing education and assistance with physical tasks may address unmet needs of PD caregivers.