A single T cell receptor recognizes structurally distinct MHC/peptide complexes with high specificity.
The 2C T cell is a CD8+, alloreactive T cell, which recognizes cells bearing Ld and Kbm3 class I major histocompatability complex molecules. Here, we characterize an allopeptide, designated dEV-8, that is a ligand in the Kbm3 molecule for the 2C TCR but is not a ligand in the Ld molecule. By biochemical and immunological properties, dEV-8 is distinct from P2Ca, the Ld allopeptide that is also recognized by the 2C TCR. Using the deduced amino acid sequence of dEV-8, we isolate a candidate endogenous source of the peptide. The endogenous protein, MLRQ, contains a peptide sequence identical to dEV-8. This degenerate recognition of two distinct peptide/MHC complexes by a single TCR has important implications for understanding allorecognition.


Do chimpanzees learn reputation by observation? Evidence from direct and indirect experience with generous and selfish strangers.
Can chimpanzees learn the reputation of strangers indirectly by observation? Or are such stable behavioral attributions made exclusively by first-person interactions? To address this question, we let seven chimpanzees observe unfamiliar humans either consistently give (generous donor) or refuse to give (selfish donor) food to a familiar human recipient (Experiments 1 and 2) and a conspecific (Experiment 3). While chimpanzees did not initially prefer to beg for food from the generous donor (Experiment 1), after continued opportunities to observe the same behavioral exchanges, four chimpanzees developed a preference for gesturing to the generous donor (Experiment 2), and transferred this preference to novel unfamiliar donor pairs, significantly preferring to beg from the novel generous donors on the first opportunity to do so. In Experiment 3, four chimpanzees observed novel selfish and generous acts directed toward other chimpanzees by human experimenters. During the first half of testing, three chimpanzees exhibited a preference for the novel generous donor on the first trial. These results demonstrate that chimpanzees can infer the reputation of strangers by eavesdropping on third-party interactions.


Vitamin D Receptor Expression in Plasmablastic Lymphoma and Myeloma Cells Confers Susceptibility to Vitamin D.
Plasmablastic B-cell malignancies include plasmablastic lymphoma and subsets of multiple myeloma and diffuse large B-cell lymphomaDLBCL. These diseases can be difficult to diagnose and treat, and they lack well-characterized cell line models. Here, immunophenotyping and FOXP1 expression profiling identified plasmablastic characteristics in DLBCL cell lines HLY-1 and SU-DHL-9, associated with CTNNAL1, HPGD, RORA, IGF1, and/or vitamin D receptor (VDR) transcription. We demonstrated VDR protein expression in primary plasmablastic tumor cells and confirmed in cell lines expression of both VDR and the metabolic enzyme CYP27B1, which catalyzes active vitamin D3 production. Although Vdr and Cyp27b1 transcription in normal B cells were activated by interleukin 4 (IL-4) and CD40 signaling, respectively, unstimulated malignant plasmablastic cells lacking IL-4 expressed both VDR and CYP27B1. Positive autoregulation evidenced intact VDR function in all plasmablastic lines, and inhibition of growth by active vitamin D3 was both dependent on MYC protein inhibition and could be enhanced by cotreatment with a synthetic ROR ligand SR-1078. Furthermore, a VDR polymorphism, FOK1, was associated with greater vitamin D3-dependent growth inhibition. In summary, HLY-1 provides an important model of strongly plasmablastic lymphoma, and disruption of VDR pathway activity may be of therapeutic benefit in both plasmablastic lymphoma and myeloma.


Diversity of Salmonella serotypes in cull (market) dairy cows at slaughter.
To determine the diversity of Salmonella serotypes isolated from a large population of cull (market) dairy cows at slaughter. Cross-sectional study. Salmonella organisms isolated from the cecal-colon contents of 5,087 market dairy cows. During winter and summer 1996, cecal-colon contents of cull dairy cows at slaughter were obtained from 5 US slaughter establishments. Specimens were subjected to microbiologic culturing for Salmonella spp at 1 laboratory. Identified isolates were compared with Salmonella isolation lists published by the Centers for Disease Control and Prevention (CDC) and the National Veterinary Services Laboratory (NVSL) for approximately the same period. The Simpson diversity index was used to calculate the likelihood that Salmonella isolates selected randomly by establishment were different. Of 58 Salmonella serotypes identified, Salmonella ser. Montevideo was the most prevalent. Two of the top 10 CDC serotypes identified from in 1996, Salmonella ser. Typhimurium and S Montevideo, appeared on our top 10 list; 8 of the top 10 were found on NVSL listings. Thirty-one of 59 S. Typhimurium isolates were identified as DT104 and found at a west slaughter establishment, 30 during the winter and 1 during the summer. The greatest diversity of serotypes was at a southeast establishment during the summer; the least diversity was at a central establishment in the winter. 58 Salmonella serotypes were isolated from market dairy cows at slaughter and could pose a threat for food-borne illness. Salmonella Montevideo was the most frequently isolated serotype and may contribute substantially to salmonellosis in dairy cattle.


Pathogenesis of osteoarthritis-like changes in the joints of mice deficient in type IX collagen.
To examine the pathogenetic mechanisms of osteoarthritis (OA)-like changes in Col9a1-/- mice, which are deficient in type IX collagen. Knee joints and temporomandibular joints (TMJs) from Col9a1-/- mice and their wild-type (Col9a1+/+) littermates were examined by light microscopy. Immunohistochemical staining was performed to examine the expression of matrix metalloproteinase 3 (MMP-3) and MMP-13, degraded type II collagen, and the discoidin domain receptor 2 (DDR-2) in knee joints. Cartilage mechanics were also evaluated for compressive properties by microindentation testing of the tibial plateau and for tensile properties by osmotic loading of the femoral condyle. Histologic analysis showed age-dependent OA-like changes in the knee and TMJs of Col9a1-/- mice starting at the age of 3 months. At the age of 6 months, enhanced proteoglycan degradation was observed in the articular cartilage of the knee and TMJs of the mutant mice. The expression of MMP-13 and DDR-2 protein and the amount of degraded type II collagen were higher in the knee joints of Col9a1-/- mice than in their wild-type littermates at the age of 6 months. Changes in cartilage mechanics were observed in the femoral and tibial plateaus of Col9a1-/- mice at 6 months, including a decrease in the compressive modulus and uniaxial modulus. At 3 and 6 months of age, tibial cartilage in Col9a1-/- mice was found to be more permeable to fluid flow, with an associated compromise in the fluid pressurization mechanism of load support. All of these changes occurred only at medial sites. Lack of type IX collagen in Col9a1-/- mice results in age-dependent OA-like changes in the knee joints and TMJs.


Rapamycin, a potent inhibitor of T-cell function, prevents graft rejection in murine recipients of allogeneic T-cell-depleted donor marrow.
We investigated the ability of the macrolide antifungal agent rapamycin (RAPA) to inhibit the rejection of T-cell-depleted (TCD) donor bone marrow (BM) transplanted into major histocompatibility complex (MHC)-disparate irradiated recipients. RAPA (1.5 mg/kg) was administered for 14 days beginning on the day of transplant. In the present study, we have tested RAPA administration in two types of fully allogeneic BM transplantation (BMT) systems in which host T cells mediate the rejection of TCD BM grafts (DBA/1 transplanted into C57BL/6 and BALB/c transplanted into C57BL/6). In both instances, RAPA administration prevented the rejection of the donor graft, accelerated post-BMT hematopoietic recovery, and did not compromise recipient survival. Sequential post-BMT fluorescence-activated cell sorter analysis of the spleen showed that RAPA administration inhibited host CD4+ and CD8+ T-cell expansion that leads to graft rejection. To further investigate the effect of RAPA on T-cell subpopulations, we used two congenic donor mouse stains with isolated MHC class I (bm1) or class II (bm12) mutations. In these studies, we showed that RAPA administration can inhibit MHC class I-restricted CD8+ or class II-restricted CD4+ T-cell-mediated graft rejection without compromising recipient survival. The RAPA-facilitated alloengraftment is multilineage and durable. We have also shown that RAPA speeds hematopoietic recovery post-BMT. We conclude that RAPA represents a new therapeutic modality for promoting alloengraftment and accelerating hematopoietic recovery.


Attosecond control in photoionization of hydrogen molecules.
We report experiments where hydrogen molecules were dissociatively ionized by an attosecond pulse train in the presence of a near-infrared field. Fragment ion yields from distinguishable ionization channels oscillate with a period that is half the optical cycle of the IR field. For molecules aligned parallel to the laser polarization axis, the oscillations are reproduced in two-electron quantum simulations, and can be explained in terms of an interference between ionization pathways that involve different harmonic orders and a laser-induced coupling between the 1sσ(g) and 2pσ(u) states of the molecular ion. This leads to a situation where the ionization probability is sensitive to the instantaneous polarization of the molecule by the IR electric field and demonstrates that we have probed the IR-induced electron dynamics with attosecond pulses.


Screening-level risk assessment for styrene-acrylonitrile (SAN) trimer detected in soil and groundwater.
A screening-level risk assessment was conducted for styrene-acrylonitrile (SAN) Trimer detected at the Reich Farm Superfund site in Toms River, NJ. Consistent with a screening-level approach, on-site and off-site exposure scenarios were evaluated using assumptions that are expected to overestimate actual exposures and hazards at the site. Environmental sampling data collected for soil and groundwater were used to estimate exposure point concentrations. Several exposure scenarios were evaluated to assess potential on-site and off-site exposures, using parameter values for exposures to soil (oral, inhalation of particulates, and dermal contact) and groundwater (oral, dermal contact) to reflect central tendency exposure (CTE) and reasonable maximum exposure (RME) conditions. Three reference dose (RfD) values were derived for SAN Trimer for short-term, subchronic, and chronic exposures, based upon its effects on the liver in exposed rats. Benchmark (BMD) methods were used to assess the relationship between exposure and response, and to characterize appropriate points of departure (POD) for each RfD. An uncertainty factor of 300 was applied to each POD to yield RfD values of 0.1, 0.04, and 0.03 mg/kg-d for short-term, subchronic, and chronic exposures, respectively. Because a chronic cancer bioassay for SAN Trimer in rats (NTP 2011a) does not provide evidence of carcinogenicity, a cancer risk assessment is not appropriate for this chemical. Potential health hazards to human health were assessed using a hazard index (HI) approach, which considers the ratio of exposure dose (i.e., average daily dose, mg/kg-d) to toxicity dose (RfD, mg/kg-d) for each scenario. All CTE and RME HI values are well below 1 (where the average daily dose is equivalent to the RfD), indicating that there is no concern for potential noncancer effects in exposed populations even under the conservative assumptions of this screening-level assessment.


Development of the proepicardial organ in the zebrafish.
The epicardium is the last layer of the vertebrate heart to form, surrounding the heart muscle during embryogenesis and providing signaling cues essential to the continued growth and differentiation of the heart. This outer layer of the heart develops from a transient structure, the proepicardial organ (PEO). Despite its essential roles, the early signals required for the formation of the PEO and the epicardium remain poorly understood. The molecular markers wt1 and tcf21 are used to identify the epicardial layer in the zebrafish heart, to trace its development and to determine genes required for its normal development. Disruption of lateral plate mesoderm (LPM) migration through knockdown of miles apart or casanova leads to cardia bifida with each bilateral heart associated with its own PEO, suggesting that the earliest progenitors of the epicardium lie in the LPM. Using a gene knockdown approach, a genetic framework for PEO development is outlined. The pandora/spt6 gene is required for multiple cardiac lineages, the zinc-finger transcription factor wt1 is required for the epicardial lineage only and finally, the cell polarity genes heart and soul and nagie oko are required for proper PEO morphogenesis.


Inactivation of a Cdk2 inhibitor during interleukin 2-induced proliferation of human T lymphocytes.
Peripheral blood T lymphocytes require two sequential mitogenic signals to reenter the cell cycle from their natural, quiescent state. One signal is provided by stimulation of the T-cell antigen receptor, and this induces the synthesis of both cyclins and cyclin-dependent kinases (CDKs) that are necessary for progression through G1. Antigen receptor stimulation alone, however, is insufficient to promote activation of G1 cyclin-Cdk2 complexes. This is because quiescent lymphocytes contain an inhibitor of Cdk2 that binds directly to this kinase and prevents its activation by cyclins. The second mitogenic signal, which can be provided by the cytokine interleukin 2, leads to inactivation of this inhibitor, thereby allowing Cdk2 activation and progression into S phase. Enrichment of the Cdk2 inhibitor from G1 lymphocytes by cyclin-CDK affinity chromatography indicates that it may be p27Kip1. These observations show how sequentially acting mitogenic signals can combine to promote activation of cell cycle proteins and thereby cause cell proliferation to start. CDK inhibitors have been shown previously to be induced by signals that negatively regulate cell proliferation. Our new observations show that similar proteins are down-regulated by positively acting signals, such as interleukin 2. This finding suggests that both positive and negative growth signals converge on common targets which are regulators of G1 cyclin-CDK complexes. Inactivation of G1 cyclin-CDK inhibitors by mitogenic growth factors may be one biochemical pathway underlying cell cycle commitment at the restriction point in G1.


Hemodynamics of arterial and venous circulation in the intrauterine fetal evaluation.
The purpose of each antenatal control focuses on the detection and prevention of hypoxic-ischemic injury and fetal death (1)) using modern biophysical tests and Doppler parameters. This study examines the correlation of changes in arterial compared to venous hemodynamics of the fetus and is determined by the most sensitive and most specific Doppler parameter in the assessment of intrauterine fetal status. The study was conducted as prospective and included 119 pregnant women. All subjects underwent NST (nonstres test), and Doppler measurements of blood flow in the umbilical artery (Aum), fetal aorta (Ao) and the central cerebral artery (MCA). In case of borderline and pathological arterial flow was measured through the ductus venozus (DV) and umbilical vein (VU). At birth to the child was determined umbilical artery blood pH and Apgar score (AS) in the first minute. Based on the clinical condition of the newborn and outcome was calculated perinatal morbidity and mortality. In all cases with a pathological arterial flow, which is verified during measurement also the pathological venous flow and confirmed fetal acidemia at birth and low Apgar scores? In this group, the two neonates died in the first week. There is a justification for the analysis of venous flow in the event borderline and pathologic findings in fetal arterial system. It has been proven that the cerebroumbilical (C/U) index is most effective parameter in predicting changes in the venous system and this the most sensitive Doppler parameter in predicting fetal acidosis and the most specific Doppler flow through the central cerebral artery.


Synergistic enhancement of topotecan-induced cell death by ascorbic acid in human breast MCF-7 tumor cells.
Topotecan, a derivative of camptothecin, is an important anticancer drug for the treatment of various human cancers in the clinic. While the principal mechanism of tumor cell killing by topotecan is due to its interactions with topoisomerase I, other mechanisms, e.g., oxidative stress induced by reactive free radicals, have also been proposed. However, very little is known about how topotecan induces free radical-dependent oxidative stress in tumor cells. In this report we describe the formation of a topotecan radical, catalyzed by a peroxidase-hydrogen peroxide system. While this topotecan radical did not undergo oxidation-reduction with molecular O2, it rapidly reacted with reduced glutathione and cysteine, regenerating topotecan and forming the corresponding glutathiyl and cysteinyl radicals. Ascorbic acid, which produces hydrogen peroxide in tumor cells, significantly increased topotecan cytotoxicity in MCF-7 tumor cells. The presence of ascorbic acid also increased both topoisomerase I-dependent topotecan-induced DNA cleavage complex formation and topotecan-induced DNA double-strand breaks, suggesting that ascorbic acid participated in enhancing DNA damage induced by topotecan and that the enhanced DNA damage is responsible for the synergistic interactions of topotecan and ascorbic acid. Cell death by topotecan and the combination of topotecan and ascorbic acid was predominantly due to necrosis of MCF-7 breast tumor cells.


Tibialis anterior moment arm: effects of measurement errors and assumptions.
Accurate estimates of tibialis anterior (TA) muscle force are important in many contexts. Two approaches commonly used to estimate moment arms are the tendon excursion (TE) and geometric (GEO) methods. Previous studies report poor agreement between the two approaches. The purposes of this study were to 1) assess the effect of methodological variations in the two methods of moment arm estimation and 2) determine how these variations affect agreement between the methods. TA moment arms were determined using TE and GEO. Errors associated with tendon stretch/hysteresis, talus rotation relative to the foot, and the location of the line of action were investigated. For TE, large errors in moment arm estimates across the range of motion were found when tendon length changes (P = 0.001) were not corrected for. For GEO, the estimated moment arm was reduced at an ankle angle of -15° when discrepancies between talus and foot rotations were accounted for or when an alternative tendon line of action was used either separately (effect size (ES), 0.46 and 0.58, respectively; P > 0.05) or together (ES, 0.89; P > 0.05). TE-derived moment arms were smaller than GEO-derived moment arms (ES, 0.68-4.86, varying by angle) before accounting for sources of error. However, these differences decreased after error correction (ES, 0.09-1.20, P > 0.05). Nonetheless, the shape of the moment arm-joint angle relation was curvilinear for TE but linear for GEO. Of all methodological modifications, accounting for tendon length changes had the largest effect on TA moment arm estimates. We conclude that the TE method is viable to determine TA moment arms as long as changes in tendon length are accounted for.


Pharmacologic Protection of Mitochondrial DNA Integrity May Afford a New Strategy for Suppressing Lung Ischemia-Reperfusion Injury.
Lung ischemia-reperfusion (IR) injury contributes to post-transplant complications, including primary graft dysfunction. Decades of reports show that reactive oxygen species generated during lung IR contribute to pulmonary vascular endothelial barrier disruption and edema formation, but the specific target molecule(s) that "sense" injury-inducing oxidant stress to activate signaling pathways culminating in pathophysiologic changes have not been established. This review discusses evidence that mitochondrial DNA (mtDNA) may serve as a molecular sentinel wherein oxidative mtDNA damage functions as an upstream trigger for lung IR injury. First, the mitochondrial genome is considerably more sensitive than nuclear DNA to oxidant stress. Multiple studies suggest that oxidative mtDNA damage could be transduced to physiologic dysfunction by pathways that are either a direct consequence of mtDNA damage per se or involve formation of proinflammatory mtDNA damage-associated molecular patterns. Second, transgenic animals or cells overexpressing components of the base excision DNA repair pathway in mitochondria are resistant to oxidant stress-mediated pathophysiologic effects. Finally, published and preliminary studies show that pharmacologic enhancement of mtDNA repair or mtDNA damage-associated molecular pattern degradation suppresses reactive oxygen species-induced or IR injury in multiple organs, including preclinical models of lung procurement for transplant. Collectively, these findings point to the interesting prospect that pharmacologic enhancement of DNA repair during procurement or ex vivo lung perfusion may increase the availability of lungs for transplant and reduce the IR injury contributing to primary graft dysfunction.


The effect of causal chain length on counterfactual conditional reasoning.
We investigated German and Nichols' finding that 3-year-olds could answer counterfactual conditional questions about short causal chains of events, but not long. In four experiments (N = 192), we compared 3- and 4-year-olds' performance on short and long causal chain questions, manipulating whether the child could draw on general knowledge to answer. We failed to replicate German and Nichols' result, finding instead that in two experiments (Experiments 1 and 3) there was no difference in performance on short and long causal chain questions and in two experiments (Experiments 2 and 4) children showed the opposite pattern: short causal chain questions were more difficult than long. These two unexpected patterns of results were replicated in a fifth study (N = 97). Children with lower language ability found short causal chains more difficult than long. Performance by children with higher language ability was unaffected by the length of the causal chain they had to consider. We found no evidence that children showed precocious counterfactual thinking when asked about recent events in a causal chain and conclude that counterfactual thinking develops after 4 years of age.


Bacteria and MAMP-induced morphogenesis of the immune system.
To metazoans, bacteria are more than just potential pathogens. Many examples now document the role of bacterial symbionts in complementing the host for its full development and increasing its digestive and protective functions. Here, we discuss the role of Gram-negative bacteria in the development of intestinal lymphoid tissues and the impact of Segmented Filamentous Bacteria and Bacteroides on intestinal immunity and homeostasis. Furthermore, we discuss the potentially beneficial role of Helicobacter pylori on immunity of the stomach and beyond, even though this bacteria is primarily known for its pathogenicity. Altogether, these and other symbiotic bacteria may manipulate the host and the host immune system through the shedding of MAMPs that cross not only the epithelial barriers, but also permeate the circulation and impact every tissue and function of the host.


Study protocol for iQuit in Practice: a randomised controlled trial to assess the feasibility, acceptability and effectiveness of tailored web- and text-based facilitation of smoking cessation in primary care.
Primary care is an important setting for smoking cessation interventions. There is evidence for the effectiveness of tailored interventions for smoking cessation, and text messaging interventions for smoking cessation show promise. The intervention to be evaluated in this trial consists of two components: (1) a web-based program designed to be used by a practice nurse or other smoking cessation advisor (SCA); the program generates a cessation advice report that is highly tailored to relevant characteristics of the smoker; and (2) a three-month programme of automated tailored text messages sent to the smoker's mobile phone. The objectives of the trial are to assess the acceptability and feasibility of the intervention and to estimate the short-term effectiveness of the intervention in increasing the quit rate compared with usual care alone. The design is a two parallel group randomised controlled trial (RCT). 600 smokers who want to quit will be recruited in up to 30 general practices in the East of England. During a consultation with an SCA, they will be individually randomised by computer program to usual care (Control) or to usual care plus the iQuit system (Intervention). At the four-week follow-up appointment, the SCA will record smoking status and measure carbon monoxide level. There will be two further follow-ups, at eight weeks and six months from randomisation date, by postal questionnaire sent from and returned to the study centre or by telephone interview conducted by a research interviewer. The primary outcome will be self-reported abstinence for at least two weeks at eight weeks. A sample size of 300 per group would give 80% power to detect an increase in quit rate from 20% to 30% (alpha = 0.05, 2-sided test). The main analyses of quit rates will be conducted on an intention-to-treat basis, making the usual assumption that participants lost to follow up are smoking. This trial will focus on acceptability, feasibility and short-term effectiveness. The findings will be used to refine the intervention and to inform the decision to proceed to a pragmatic trial to estimate longer-term effectiveness and cost-effectiveness. ISRCTN56702353.


Assessing vulnerability of marine bird populations to offshore wind farms.
Offshore wind farms may affect bird populations through collision mortality and displacement. Given the pressures to develop offshore wind farms, there is an urgent need to assess population-level impacts on protected marine birds. Here we refine an approach to assess aspects of their ecology that influence population vulnerability to wind farm impacts, also taking into account the conservation importance of each species. Flight height appears to be a key factor influencing collision mortality risk but improved data on flight heights of marine birds are needed. Collision index calculations identify populations of gulls, white-tailed eagles, northern gannets and skuas as of particularly high concern in Scottish waters. Displacement index calculations identify populations of divers and common scoters as most vulnerable to population-level impacts of displacement, but these are likely to be less evident than impacts of collision mortality. The collision and displacement indices developed here for Scottish marine bird populations could be applied to populations elsewhere, and this approach will help in identifying likely impacts of future offshore wind farms on marine birds and prioritising monitoring programmes, at least until data on macro-avoidance rates become available.


Cingulate activity and fronto-temporal connectivity in people with prodromal signs of psychosis.
Schizophrenia is associated with fronto-temporal dysconnectivity, but it is not clear whether this is a risk factor for the disorder or is a consequence of the established illness. The aim of the present study was to use fMRI to investigate fronto-temporal connectivity in subjects with prodromal signs of schizophrenia using the Hayling Sentence Completion Task (HSCT). Thirty participants, 15 with an at risk mental state (ARMS) and 15 healthy controls were scanned whilst completing 80 sentence stems. The congruency and constraint of sentences varied across trials. Dynamic causal modelling (DCM) and Bayesian model selection (BMS) were used to compare alternative models of connectivity in a task related network. During the HSCT ARMS subjects did not differ from Healthy Controls in terms of fronto-temporal activation, i.e. there was neither a main effect of group nor a group-by-task interaction. However, there was both a significant main effect of group and a significant interaction in the anterior cingulate cortex (ACC), with greater ACC activity in the ARMS subjects. A systematic BMS procedure among 14 alternative DCMs including the ACC, middle frontal, and middle temporal gyri revealed intact task-dependent modulation of fronto-temporal effective connectivity in the ARMS group. However, ARMS subjects showed increased endogenous connection strength between the ACC and the middle temporal gyrus relative to healthy controls. Although task related fronto-temporal integration in the ARMS was intact, this may depend on increased engagement of the ACC which was not observed in healthy control subjects.


Characterisation and in vitro and in vivo evaluation of supercritical-CO2-foamed β-TCP/PLCL composites for bone applications.
Most synthetic bone grafts are either hard and brittle ceramics or paste-like materials that differ in applicability from the gold standard autologous bone graft, which restricts their widespread use. Therefore, the aim of the study was to develop an elastic, highly porous and biodegradable β-tricalciumphosphate/poly(L-lactide-co-ε-caprolactone) (β-TCP/PLCL) composite for bone applications using supercritical CO2 foaming. Ability to support osteogenic differentiation was tested in human adipose stem cell (hASC) culture for 21 d. Biocompatibility was evaluated for 24 weeks in a rabbit femur-defect model. Foamed composites had a high ceramic content (50 wt%) and porosity (65-67 %). After 50 % compression, in an aqueous environment at 37 °C, tested samples returned to 95 % of their original height. Hydrolytic degradation of β-TCP/PLCL composite, during the 24-week follow-up, was very similar to that of porous PLCL scaffold both in vitro and in vivo. Osteogenic differentiation of hASCs was demonstrated by alkaline phosphatase activity analysis, alizarin red staining, soluble collagen analysis, immunocytochemical staining and qRT-PCR. In vitro, hASCs formed a pronounced mineralised collagen matrix. A rabbit femur defect model confirmed biocompatibility of the composite. According to histological Masson-Goldner's trichrome staining and micro-computed tomography, β-TCP/PLCL composite did not elicit infection, formation of fibrous capsule or cysts. Finally, native bone tissue at 4 weeks was already able to grow on and in the β-TCP/PLCL composite. The elastic and highly porous β-TCP/PLCL composite is a promising bone substitute because it is osteoconductive and easy-to-use and mould intraoperatively.


Eastern equine encephalomyelitis virus infection in six captive southern cassowaries (Casuarius casuarius).
CASE DESCRIPTION Within a 2-week period, 4 southern cassowaries (Casuarius casuarius) at an exhibit at a Virginia zoo died acutely subsequent to eastern equine encephalitis virus (EEEV) infection. This prompted a search for other EEEV outbreaks in cassowaries, which resulted in the identification of 2 additional cassowaries that died of EEEV infection at a conservation center in Florida. CLINICAL FINDINGS Both juvenile and adult birds were affected. Three of the 6 birds died acutely with no premonitory signs. Clinical disease in the other 3 birds was characterized by lethargy and ataxia. Clinicopathologic findings typically included leukocytosis, hyperuricemia, abnormally high liver enzyme activities, and hyper-β globulinemia, which was indicative of acute inflammation. TREATMENT AND OUTCOME The 3 birds with clinical disease died despite supportive treatment. Gross abnormalities commonly observed during necropsy included coelomitis and evidence of diarrhea. Frequently observed histologic abnormalities were encephalitis, vasculitis, hepatitis, nephritis, and splenitis. The diagnosis of EEEV infection was confirmed by detection of serum anti-EEEV antibodies or detection of viral RNA in brain tissue by use of a reverse-transcriptase PCR assay. CLINICAL RELEVANCE Findings suggested that EEEV can cause high morbidity and mortality rates in southern cassowaries. Clinical disease might be reduced or prevented by vaccination, isolation of ill birds, and mosquito control strategies.


Prophylactic Cranial Irradiation Versus Observation in Radically Treated Stage III Non-Small-Cell Lung Cancer: A Randomized Phase III NVALT-11/DLCRG-02 Study.
Purpose The purpose of the current study was to investigate whether prophylactic cranial irradiation (PCI) reduces the incidence of symptomatic brain metastases in patients with stage III non-small-cell lung cancer (NSCLC) treated with curative intention. Patients and Methods Patients with stage III NSCLC-staged with a contrast-enhanced brain computed tomography or magnetic resonance imaging-were randomly assigned to either observation or PCI after concurrent/sequential chemoradiotherapy with or without surgery. The primary end point-development of symptomatic brain metastases at 24 months-was defined as one or a combination of key symptoms that suggest brain metastases-signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures, and focal neurologic symptoms-and magnetic resonance imaging or computed tomography demonstrating the existence of brain metastasis. Adverse effects, survival, quality of life, quality-adjusted survival, and health care costs were secondary end points. Results Between 2009 and 2015, 175 patients were randomly assigned: 87 received PCI and 88 underwent observation only. Median follow-up was 48.5 months (95% CI, 39 to 54 months). Six (7.0%) of 86 patients in the PCI group and 24 (27.2%) of 88 patients in the control group had symptomatic brain metastases ( P = .001). PCI significantly increased the time to develop symptomatic brain metastases (hazard ratio, 0.23; [95% CI, 0.09 to 0.56]; P = .0012). Median time to develop brain metastases was not reached in either arm. Overall survival was not significantly different between both arms. Grade 1 and 2 memory impairment (26 of 86 v seven of 88 patients) and cognitive disturbance (16 of 86 v three of 88 patients) were significantly increased in the PCI arm. Quality of life was only decreased 3 months post-PCI and was similar to the observation arm thereafter. Conclusion PCI significantly decreased the proportion of patients who developed symptomatic brain metastases with an increase of low-grade toxicity.


Arthritis in rats after systemic injection of streptococcal cells or cell walls.
Further investigation of the biological properties of streptococcal cells and their components has produced a model of erosive synovitis in rats. A single intraperitoneal injection of an aqueous suspension of whole cell sonicate of group A streptococci into Sprague-Dawley rats induced an acute arthritis which evolved into a prolonged inflammatory process characterized by several complete or partial remissions, joint deformity, and ankylosis. The toxic moiety is a peptidoglycan-polysaccharide fragment of the cell wall which persists in tissue. Histologic features of the arthritis include an acute exudative phase followed by an erosive synovitis that leads to destruction of cartilage and subchondral bone and fibrous ankylosis of the joints. The arthropathic properties of whole cell sonicates of several species of streptococci are compared along with studies of the ability of heat-killed, whole cells of groups A, B, and C streptococci to induce arthritis in rats. Whole cells induce arthritis after a latent period of 57-120 days when group A cells are injected and 7-10 days when group B cells are tested.


Unilateral herpes zoster ophthalmicus with bilateral cerebral infarcts in human immunodeficiency virus seropositive patient.
Ischemic stroke is a recognized complication of herpes zoster ophthalmicus. Arterial involvement is usually seen on the side of the rash. It is thought to be due to vessel inflammation by the virus, which travels from the trigeminal ganglion. Few case reports of bilateral and distant site of zoster lesions with stroke in the brain have been described. These reports suggest possibility of contiguous vascular, cerebrospinal fluid (CSF) or hematogenous spread of the virus from the ganglion to the cerebral blood vessels. Therapeutically acyclovir, anticoagulation, and steroids have been used in the treatment of the zoster associated with stroke. We describe a case of immunocompromised patient with ipsilateral zoster ophthalmicus with bilateral anterior circulation strokes, who was treated with above measures and made successful recovery. This report also raises/supports possible CSF/vascular/hematogenous spread of the virus from the ganglion to involve cerebral blood vessels leading to the stroke.


Analysis of miRNA expression under stress in Arabidopsis thaliana.
MicroRNAs (miRNAs) are a class of small, 21-24 nucleotides long, non-coding RNAs involved in the post-transcriptional regulation of gene expression. Using the array analysis on Arabidopsis thaliana infected with the Oil-seed Rape Mosaic Virus (ORMV), we have found 28 up-regulated miRNAs. From them, six were selected for further validation by Northern blot analysis: miRNA172a, miRNA161, miRNA167a&b, miRNA168a&b, miRNA171a, and miRNA159. In addition, 29 miRNAs were detected in plants exposed to drought stress, 13 of those detected miRNAs were up-regulated and 16 down-regulated miRNAs. Out of 29 differentially expressed miRNAs during the abiotic stress, six miRNAs (167a&b, 168a&b, 173, 171b&c, 399d and 447c) were chosen for Northern blot and RT-PCR analysis to confirm the array results. Interestingly, four out of these six miRNAs, 171b&c, 168a&b, 399d, and 447c, showed very high abundance of pri-miRNAs and pre-miRNAs. Furthermore, mature forms of miRNAs171b&c, 399d, and 447c, were not detectable in the rosette leaves, indicating that miRNA processing is tissue specific. In conclusion, using the array analysis we show that 28 miRNAs are involved in the plant response to viral infection and 29 miRNAs are involved in the regulation of drought stress. We also demonstrate that at least some miRNAs involved in the stress response in Arabidopsis thaliana are regulated at the maturation level. One such example is miRNA 171b&c. This miRNA is transcribed in all tissues, evidenced by its detected pri and pre-miRNA forms; however, its mature form is constitutively or transiently expressed depending on the tissue type.


Adenovirus-mediated gene transfer of CTLA-4Ig fusion protein in the suppression of experimental autoimmune arthritis.
Blockade of CD28-B7 interactions with soluble CTLA-4Ig fusion protein (which binds and blocks both B7-1 and B7-2 costimulatory molecules on antigen-presenting cells) has been shown to ameliorate experimental autoimmune diseases such as lupus, experimental autoimmune encephalomyelitis, diabetes, and, in our laboratory, collagen-induced arthritis (CIA). Because prolonged inhibition of this costimulatory pathway may be required, and the adenovirus-mediated gene-transfer technology is very efficient in achieving sustained expression of proteins in vivo, we examined the effects of adenovirally delivered CTLA-4Ig in established murine CIA. Replication-deficient recombinant adenoviruses encoding a chimeric CTLA-4Ig fusion protein, or beta-galactosidase as control, were injected intravenously into male DBA/1 mice once at arthritis onset. Disease activity was monitored by the assessment of clinical score, paw thickness, and type II collagen (CII)-specific cellular and humoral responses for 3 weeks. Groups of mice were also serially injected with a CTLA-4Ig fusion protein and an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody (mAb), and disease activity was compared with that in the adenovirally transfused groups. Both the adenovirally delivered and the recombinant CTLA-4Ig fusion protein suppressed established CIA, whereas anti-CTLA-4 mAb and the control beta-galactosidase adenovirus did not significantly affect the disease course. CII-specific lymphocyte proliferation, interferon-gamma production, and anti-CII antibody levels, both IgG1 and IgG2a, were significantly reduced by CTLA-4Ig treatment. Blockade of the B7-CD28 costimulatory pathway by adenovirus-mediated CTLA-4Ig gene transfer is as effective as the recombinant fusion protein in treating established CIA, without the need for repeated administrations. Significant reduction in pathogenic cellular and humoral responses is achieved even after the onset of arthritis, thus suggesting the valuable therapeutic potential of this gene-transfer method in human rheumatoid arthritis.


Unsupervised ensemble ranking of terms in electronic health record notes based on their importance to patients.
Allowing patients to access their own electronic health record (EHR) notes through online patient portals has the potential to improve patient-centered care. However, EHR notes contain abundant medical jargon that can be difficult for patients to comprehend. One way to help patients is to reduce information overload and help them focus on medical terms that matter most to them. Targeted education can then be developed to improve patient EHR comprehension and the quality of care. The aim of this work was to develop FIT (Finding Important Terms for patients), an unsupervised natural language processing (NLP) system that ranks medical terms in EHR notes based on their importance to patients. We built FIT on a new unsupervised ensemble ranking model derived from the biased random walk algorithm to combine heterogeneous information resources for ranking candidate terms from each EHR note. Specifically, FIT integrates four single views (rankers) for term importance: patient use of medical concepts, document-level term salience, word co-occurrence based term relatedness, and topic coherence. It also incorporates partial information of term importance as conveyed by terms' unfamiliarity levels and semantic types. We evaluated FIT on 90 expert-annotated EHR notes and used the four single-view rankers as baselines. In addition, we implemented three benchmark unsupervised ensemble ranking methods as strong baselines. FIT achieved 0.885 AUC-ROC for ranking candidate terms from EHR notes to identify important terms. When including term identification, the performance of FIT for identifying important terms from EHR notes was 0.813 AUC-ROC. Both performance scores significantly exceeded the corresponding scores from the four single rankers (P<0.001). FIT also outperformed the three ensemble rankers for most metrics. Its performance is relatively insensitive to its parameter. FIT can automatically identify EHR terms important to patients. It may help develop future interventions to improve quality of care. By using unsupervised learning as well as a robust and flexible framework for information fusion, FIT can be readily applied to other domains and applications.


Simultaneous saccharification, filtration and fermentation (SSFF): a novel method for bioethanol production from lignocellulosic biomass.
Simultaneous saccharification, filtration and fermentation (SSFF) was developed for lignocellulosic ethanol production. In SSFF, pretreated lignocellulosic material is enzymatically hydrolyzed in a reactor, while the suspension is continuously pumped through a cross-flow membrane. The retentate goes back to the hydrolysis vessel, while a clear sugar-rich filtrate continuously perfuses through the fermentation vessel before it is pumped back to the hydrolysis vessel. The capacity and life span of the cross-flow filter module was examined for 4 weeks using enzymatically hydrolyzed slurry, initially with 14.4% suspended solids, without clogging or fouling. An ethanol yield of 85.0% of the theoretical yield was obtained in SSFF and a flocculating strain of Saccharomyces cerevisiae was successfully reused for five cultivations of SSFF.


Improving Resiliency in Healthcare Employees.
The high prevalence of stress at the workplace has been well documented; however, few studies have investigated the efficacy of worksite resiliency programs. Therefore, the objec- tive of this project was to examine the impact of a worksite resilience training program on improving resiliency and health behaviors in healthcare employees. Between 2012 and 2016, 137 adult wellness center members of a healthcare institution participating in a single-arm cohort study of a 12-week resiliency training program were assessed at baseline, end of intervention, and at 3-month follow-up. Statistically significant (p ≤ .01) improvements were seen at the end of the intervention and extending to 3 months follow-up for resiliency, perceived stress, anxiety level, quality of life, and health behaviors. These results support the premise that worksite programs designed to improve resiliency in healthcare employees have efficacy in improving resiliency, quality of life and health behaviors. Given the importance of stress and burnout in healthcare employees, future randomized studies are warranted to determine more clearly the impacts of this type of resiliency intervention for improving the wellness of healthcare workers.


Emerging epigenomic landscapes of pancreatic cancer in the era of precision medicine.
Genetic studies have advanced our understanding of pancreatic cancer at a mechanistic and translational level. Genetic concepts and tools are increasingly starting to be applied to clinical practice, in particular for precision medicine efforts. However, epigenomics is rapidly emerging as a promising conceptual and methodological paradigm for advancing the knowledge of this disease. More importantly, recent studies have uncovered potentially actionable pathways, which support the prediction that future trials for pancreatic cancer will involve the vigorous testing of epigenomic therapeutics. Thus, epigenomics promises to generate a significant amount of new knowledge of both biological and medical importance.


Evaluating Trends in Novel Psychoactive Substances Using a Sentinel Population of Electronic Dance Music Festival Attendees.
Electronic dance music (EDM) festivals have become a popular venue for recreational drug use, including the use of traditional stimulants like 3,4-methylenendioxymethamphetamine (MDMA) and novel psychoactive substances (NPS). Using this cohort of people who use drugs recreationally, this study sought to collect biological specimens and self-reported drug use data from EDM festival attendees in the United States to monitor regional and temporal trends related to NPS use and turnover between 2014 and 2017. Oral fluid samples were collected at three United States EDM festival locations, including Miami, Florida (2014 to 2017); Tampa, Florida (2017) and Atlanta, Georgia (2017). Samples were screened by liquid chromatography-quadrupole time-of-flight mass spectrometry and confirmed by liquid chromatography-tandem mass spectrometry. Over the 4 years, 1,233 oral fluid samples were collected. With respect to self-reported drug use, 63% of respondents reported medicinal and/or recreational drug use within the last week. When comparing 4 years of data from Miami (2014 to 2017), NPS trends showed the disappearance of alpha-PVP after 2014 followed by a significant increase in ethylone positivity in 2015 and rapid decrease in 2016. Dibutylone was identified for the first time in Miami 2016, and N-ethyl pentylone was identified for the first time in Miami 2017. Additionally, 3,4-methylenendioxymethamphetamine positivity steadily increased from 2014 to 2017. A comparison across study sites (Miami, Tampa and Atlanta) and specific trends with respect to novel simulant use are described within. Using this opportunistic approach of monitoring drug trends, we have found that peak positivity of novel stimulants usually is within a year of their first detection. Understanding the dynamics of NPS drug markets will allow laboratories to plan for resource allocation and scope updates within a timely fashion to assist with the detection and confirmation of these emerging substances in samples submitted for forensic analysis.


Mechanical Pulmonary Valve Replacement.
Although most valve operations performed annually address lesions of the aortic or mitral valves, the frequency of pulmonary valve replacement (PVR) is increasing because most patients with congenital heart disease are surviving into the adult years. The vast majority of patients, especially children that require PVR, obtain a tissue valve because of the relative good durability and the lack of a need for anticoagulation. Because the need for repeat operation is inevitable for most patients, and the population of adults with congenital heart disease continues to grow, there are increasing situations in which a mechanical pulmonary prosthesis may be appropriate. Most patients being considered for mechanical PVR have a congenital diagnosis and require multi-valve procedures, and quality of life and need for repeat operation(s) are major issues. Mechanical valves are durable but require anticoagulation, which carries its own inherent set of risks. There are conflicting reports regarding the late outcome of mechanical PVR. There are few reports that indicate that, in the pulmonary position, bileaflet valves are at higher risk for complications compared with monodisc valves; however, the majority of these patients were not anticoagulated with warfarin, but simply maintained on aspirin. There is a growing body of literature documenting low rates of thrombosis or pulmonary prosthesis dysfunction when proper anticoagulation and monitoring are applied.


Process trumps potential public good: better vaccine safety through linked cross-jurisdictional immunisation data in Australia.
To provide insights into complexities of seeking access to state and federal cross-jurisdictional data for linkage with the Australian Childhood Immunisation Register (ACIR). We provide recommendations for improving access and receipt of linked datasets involving Australian Government-administered data. We describe requirements for linking eleven federal and state data sources to establish a national linked dataset for safety evaluation of vaccines. The required data linkage methodology for integrating cross-jurisdictional data sources is also described. Extensive negotiation was required with 18 different agencies for 21 separate authorisations and 12 ethics approvals. Three variations of the 'best practice' linkage model were implemented. Australian Government approval requests spanned nearly four years from initial request for data, with a further year before ACIR data transfer to the linkage agency. Integration of immunisation registers with other data collections is achievable in Australia but infeasible for routine and rapid identification of vaccine safety concerns. Lengthy authorisation requirements, convoluted disparate application processes and inconsistencies in data supplied all contribute to delayed data availability. Implications for public health: Delayed data access for safety surveillance prevents timely epidemiological reviews. Poor responsiveness to safety concerns may erode public confidence, compromising effectiveness of vaccination programs through reduced participation.


Genomics and Comparative Genomic Analyses Provide Insight into the Taxonomy and Pathogenic Potential of Novel Emmonsia Pathogens.
Over the last 50 years, newly described species of Emmonsia-like fungi have been implicated globally as sources of systemic human mycosis (emmonsiosis). Their ability to convert into yeast-like cells capable of replication and extra-pulmonary dissemination during the course of infection differentiates them from classical Emmonsia species. Immunocompromised patients are at highest risk of emmonsiosis and exhibit high mortality rates. In order to investigate the molecular basis for pathogenicity of the newly described Emmonsia species, genomic sequencing and comparative genomic analyses of Emmonsia sp. 5z489, which was isolated from a non-deliberately immunosuppressed diabetic patient in China and represents a novel seventh isolate of Emmonsia-like fungi, was performed. The genome size of 5z489 was 35.5 Mbp in length, which is ~5 Mbp larger than other Emmonsia strains. Further, 9,188 protein genes were predicted in the 5z489 genome and 16% of the assembly was identified as repetitive elements, which is the largest abundance in Emmonsia species. Phylogenetic analyses based on whole genome data classified 5z489 and CAC-2015a, another novel isolate, as members of the genus Emmonsia. Our analyses showed that divergences among Emmonsia occurred much earlier than other genera within the family Ajellomycetaceae, suggesting relatively distant evolutionary relationships among the genus. Through comparisons of Emmonsia species, we discovered significant pathogenicity characteristics within the genus as well as putative virulence factors that may play a role in the infection and pathogenicity of the novel Emmonsia strains. Moreover, our analyses revealed a novel distribution mode of DNA methylation patterns across the genome of 5z489, with >50% of methylated bases located in intergenic regions. These methylation patterns differ considerably from other reported fungi, where most methylation occurs in repetitive loci. It is unclear if this difference is related to physiological adaptations of new Emmonsia, but this question warrants further investigation. Overall, our analyses provide a framework from which to further study the evolutionary dynamics of Emmonsia strains and identity the underlying molecular mechanisms that determine the infectious and pathogenic potency of these fungal pathogens, and also provide insight into potential targets for therapeutic intervention of emmonsiosis and further research.


Wheat Germ Agglutinin Bound to the Outer Cuticle of the Seed Gall Nematodes Anguina agrostis and A. tritici.
The presence of wheat germ agglutinin (WGA) on the cuticular surface of the seed gall nematodes Anguina agrostis and Anguina tritici was demonstrated, and the nature of its binding was examined. Crude extracts from the cuticles of A. tritici agglutinated human red blood cells, and only N-acetylglucosamine (GlucNAc) inhibited the agglutination. Distribution of the lectin was visualized by treating live infective juveniles (J2) with rabbit anti-WGA antibody and staining with fluorescein isothiocyanate (FITC)-conjugated goat anti-rabbit IgG. The lectin bound to the outer cuticular surface of the whole body wall. Pretreatment with GlucNAc oligomers did not reduce the fluorescence created by the anti-WGA-WGA binding, indicating at least a partial nonspeciflc adhesion of the WGA to the nematode surface. Proteolytic enzyme pretreatments diminished the fluorescence, whereas lipase and periodate pretreatments increased the fluorescence. Adult females and males were labeled only on the head and tail, whereas eggs were not labeled at all. It was concluded that the WGA on the J2 cuticle originates from the host.


Impairments in Dynamic Postural Control across Concussion Clinical Milestones.
The aim of this study was to assess gait initiation (GI) performance longitudinally across clinical concussion recovery milestones through return to participation (RTP). We recruited 54 collegiate student-athletes, 27 with concussions and 27 matched controls (15 female and 12 male per group). Participants performed five trials of GI at baseline and again at five post-concussion clinical milestones: 1) Acute, the day clinical tests achieved baseline values on the 2) Balance Error Scoring System (BESS), 3) Immediate Post-Concussion Assessment and Cognitive Test ImPACT, 4) Asymptomatic, and 5) RTP Day. GI performance on six outcome measures (anterior/posterior and medial/lateral center of pressure displacements and velocities during the anticipatory postural adjustment [APA] phase and initial step length and velocity) with repeated-measures mixed model and pair-wise post hoc. A reliable change index (RCI) was calculated, and post-concussion participant's performance was compared to the RCI at milestones. There were significant interactions for APA posterior and lateral displacement, APA posterior velocity, step length, and step velocity. The post-hoc tests identified significant deficits across clinical milestones and at RTP for APA posterior and lateral displacement, step length, and step velocity. There were no post-hoc differences for any outcome measure in the control group. At RTP, 85.2-88.9% of concussion participants had at least one outcome measure which exceeded the 80% or 95% RCI. The primary finding of this study was persistent impairments in dynamic postural control, suggesting ongoing neurophysiological impairment despite clinical recovery. These results suggest that collegiate student-athletes may be RTP before neurophysiological recovery and potentially exposing themselves to elevated risk of recurrent concussion or subsequent musculoskeletal injury.


Culture and geographic variation in orangutan behavior.
Although geographic variation in an organism's traits is often seen as a consequence of selection on locally adaptive genotypes accompanied by canalized development [1], developmental plasticity may also play a role [2, 3], especially in behavior [4]. Behavioral plasticity includes both individual learning and social learning of local innovations ("culture"). Cultural plasticity is the undisputed and dominant explanation for geographic variation in human behavior. It has recently also been suggested to hold for various primates and birds [5], but this proposition has been met with widespread skepticism [6-8]. Here, we analyze parallel long-term studies documenting extensive geographic variation in behavioral ecology, social organization, and putative culture of orangutans [9] (genus Pongo). We show that genetic differences among orangutan populations explain only very little of the geographic variation in behavior, whereas environmental differences explain much more, highlighting the importance of developmental plasticity. Moreover, variation in putative cultural variants is explained by neither genetic nor environmental differences, corroborating the cultural interpretation. Thus, individual and cultural plasticity provide a plausible pathway toward local adaptation in long-lived organisms such as great apes and formed the evolutionary foundation upon which human culture was built.


[Severe apnea: an early sign of Pneumocystis carinii pneumonia in an HIV-negative infant].
A few reports in the medical literature suggest an association between Pneumocystis caring and apnea in small infants. This patient, a 1 month 20 days old, HIV negative, infant girl weighing 2,000 grams was admitted to hospital after presenting a severe episode of apnea with cyanosis and bradycardia. She progressively developed bronchopneumonia by P. carinii that required prolonged mechanical ventilation with high ventilatory parameters. The clinical course of this patient illustrates that apnea can be an early sign of P. carinii infection in small infants. Early diagnosis and specific therapy might prevent morbidity and mortality and also decrease the length of hospitalization.


Hyperbilirubinemia in the breast-fed newborn: a controlled trial of four interventions.
A controlled clinical trial was conducted to compare the effect of four different interventions on hyperbilirubinemia in 125 full-term breast-fed infants. Of 1685 term infants who met the inclusion criteria, 126 (7.4%) had a serum bilirubin concentration > or = 291 mumol/L (17 mg/dL). When the bilirubin reached this level, babies were assigned at random to one of four interventions: (1) continue breast-feeding and observe; (2) discontinue breast-feeding, substitute formula; (3) discontinue breast-feeding, substitute formula and administer phototherapy; (4) continue breast-feeding, administer phototherapy. The serum bilirubin concentration reached 342 mumol/L (20 mg/dL) in 24% of infants in group 1, 19% in group 2, 3% in group 3, and 14% in group 4. When phototherapy was used, the decline in serum bilirubin was significantly larger and more rapid (compared with no phototherapy). In the majority of breast-fed infants whose serum bilirubin levels reach 291 mumol/L (17 mg/dL) the bilirubin will decline spontaneously and will not reach 342 mumol/L (20 mg/dL). If the infant is significantly jaundiced and a decision is made to intervene, parents can be given a number of options and can make an informed decision regarding which, if any, intervention they prefer.


Cardiac glycosides suppress the maintenance of stemness and malignancy via inhibiting HIF-1α in human glioma stem cells.
Tissue hypoxia contributes to solid tumor pathogenesis by activating a series of adaptive programs. We previously showed that hypoxia promotes the preferential expansion and maintenance of CD133 positive human glioma stem cells (GSC) in a hypoxia inducible factor 1 alpha (HIF-1α)-dependent mechanism. Here, we examined the activity of digitoxin (DT), a cardiac glycoside and a putative inhibitor of HIF-1α, on human GSC in vitro and in vivo. During hypoxic conditions (1% O2), we observed the effect of DT on the intracellular level of HIF-1α and the extracellular level of vascular endothelial growth factor (VEGF) in human GSC. We found that DT at clinically achievable concentrations, suppressed HIF-1α accumulation during hypoxic conditions in human GSC and established glioma cell lines. DT treatment also significantly attenuated hypoxia-induced expression of VEGF, a downstream target of HIF-1α. Exposure to DT also reduced hypoxia-induced activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Furthermore, DT potently inhibited neurosphere formation, and decreased CD133 expression even at concentrations that were not overtly cytotoxic. Lastly, treatment with DT reduced GSC engraftment in an in vivo xenograft model of glioblastoma. Intraperitoneal injections of DT significantly inhibited the growth of established glioblastoma xenografts, and suppressed expression of HIF-1α and carbonic anhydrase (CA9), a surrogate marker of hypoxia. Taken together, these results suggest that DT at clinically achievable concentration functions as an inhibitor of HIF-1α, worthy of further investigations in the therapy of glioblastoma.


Pump-seed synchronization for MHz repetition rate, high-power optical parametric chirped pulse amplification.
We report on an active synchronization between two independent mode-locked lasers using a combined electronic-optical feedback. With this scheme, seed pulses at MHz repetition rate were amplified in a non-collinear optical parametric chirped pulse amplifier (OPCPA). The amplifier was seeded with stretched 1.5 nJ pulses from a femtosecond Ti:Sapphire oscillator, while pumped with the 1 ps, 2.9 µJ frequency-doubled output of an Yb:YAG thin-disk oscillator. The residual timing jitter between the two oscillators was suppressed to 120 fs (RMS), allowing for an efficient and broadband amplification at 11.5 MHz to a pulse energy of 700 nJ and an average power of 8 W. First compression experiment with 240 nJ amplified pulse energy resulted in a pulse duration of ~10 fs.


Atopic eczema.
Atopic eczema is an itchy inflammatory skin disease with a chronic relapsing-remitting course; it has increased in prevalence in recent decades and now affects up to 25% of school-aged children in the developed world and up to 10% of adults. Recent advances in understanding the aetiology of eczema have focused interest on skin barrier dysfunction as a common precursor and pathological feature. In addition, genetically determined skin barrier dysfunction (associated with mutations in the gene encoding filaggrin) is known to predispose to multiple systemic atopic diseases. First-line treatments for atopic eczema focus on maintaining and repairing the skin barrier (emollients) and reducing inflammation (topical steroids); allergen and irritant avoidance are also important to achieve disease control. Second and third-line treatments include topical calcineurin inhibitors, ultraviolet light and systemic immunosuppressant therapies of which only ciclosporin is licenced for the treatment of atopic eczema in adults. Novel biological therapies are in phase II-III clinical trials.


MDPs with Non-Deterministic Policies.
Markov Decision Processes (MDPs) have been extensively studied and used in the context of planning and decision-making, and many methods exist to find the optimal policy for problems modelled as MDPs. Although finding the optimal policy is sufficient in many domains, in certain applications such as decision support systems where the policy is executed by a human (rather than a machine), finding all possible near-optimal policies might be useful as it provides more flexibility to the person executing the policy. In this paper we introduce the new concept of non-deterministic MDP policies, and address the question of finding near-optimal non-deterministic policies. We propose two solutions to this problem, one based on a Mixed Integer Program and the other one based on a search algorithm. We include experimental results obtained from applying this framework to optimize treatment choices in the context of a medical decision support system.


Serous Retinopathy Associated with Mitogen-Activated Protein Kinase Kinase Inhibition (Binimetinib) for Metastatic Cutaneous and Uveal Melanoma.
To analyze the clinical characteristics of a serous retinopathy associated with mitogen-activated protein kinase kinase (MEK) inhibition with binimetinib treatment for metastatic cutaneous melanoma (CM) and uveal melanoma (UM), and to determine possible pathogenetic mechanisms that may lead to this retinopathy. Prospective observational, cohort-based, cross-sectional study. Thirty CM patients and 5 UM patients treated with the MEK inhibitor binimetinib (CM) or a combination of binimetinib and the protein kinase C inhibitor sotrastaurin (UM). Extensive ophthalmic examination was performed, including Early Treatment of Diabetic Retinopathy Study best-corrected visual acuity, applanation tonometry, slit-lamp examination, indirect ophthalmoscopy, digital color fundus photography, and optical coherence tomography (OCT). In selected cases, additional examinations were performed, including visual field testing and electro-oculography (EOG). Blood samples were obtained from 3 CM patients and 3 UM patients to analyze the presence of autoantibodies against retinal and retinal pigment epithelium (RPE) proteins. Visual symptoms, visual acuity, fundus appearance, characteristics on OCT, fundus autofluorescence (FAF), and EOG. Six CM patients (20%) and 2 UM patients (40%) reported visual symptoms during the study. The median time to the onset of symptoms, which were all mild and transient, was 3.5 days (range, <1 hour to 3 weeks). On OCT, subretinal fluid (SRF) was detected in 77% of CM patients and 60% of UM patients. In the 26 patients with SRF, the fovea was affected in 85%. After the start of the medication, an EOG was performed in 19 eyes of 11 patients; 16 of these eyes (84%) developed SRF on OCT. Fifteen of these eyes (94%) showed an abnormal Arden ratio (<1.65). A broad pattern of anti-retinal antibodies was found in 3 CM patients and 2 UM patients tested, whereas anti-RPE antibodies were detected in all 6 tested patients. A time-dependent and reversible serous retinopathy can develop both in patients with metastatic CM and UM treated with binimetinib. A minority of patients develop visual symptoms, which are generally mild and transient. A cause of binimetinib-associated serous retinopathy may be toxicity of medication, but autoantibodies also may be involved.


MHC variation is related to a sexually selected ornament, survival, and parasite resistance in common yellowthroats.
Hamilton and Zuk proposed that females choose mates based on ornaments whose expression is dependent on their genetically based resistance to parasites. The major histocompatibility complex (MHC) plays an important role in pathogen recognition and is a good candidate for testing the relationships between immune genes and both ornament expression and parasite resistance. We tested the hypothesis that female common yellowthroats prefer to mate with more ornamented males, because it is a signal of their MHC-based resistance to parasites and likelihood of survival. In this species, females prefer males that have larger black facial masks as extrapair mates. Using pyrosequencing, we found that mask size was positively related to the number of different MHC class II alleles, as predicted if greater variation at the MHC allows for the recognition of a greater variety of pathogens. Furthermore, males with more MHC class II alleles had greater apparent survival, and resistance to malaria infection was associated with the presence of a particular MHC class II allele. Thus, extrapair mating may provide female warblers with immunity genes that are related to parasite resistance, survival, and the expression of a male ornament, consistent with good genes models of sexual selection.


Preventive effects of a traditional Chinese formulation, Chaihu-jia-Longgu-Muli-tang, on intimal thickening of carotid artery injured by balloon endothelial denudation in rats.
We report here that the traditional Chinese formulation, Chaihu-jia-Longgu-Muli-tang (CLM), significantly inhibited the increase in intimal thickening in rat carotid artery injured by balloon endothelial denudation, which mimics many aspects of restenosis after percutaneous coronary intervention (PCI) in humans. CLM, Saiko-ka-Ryukotsu-Borei-to in Japanese, is commonly prescribed for symptoms accompanying hypertension and atherosclerosis in Japanese Kampo medical care. CLM administered orally 1 week before and 1, 4 and 8 weeks after balloon injury inhibited the increase in intimal area, intimal/medial ratio and stenosis ratio. To our knowledge, this is the first report demonstrating inhibitory effects of a traditional Chinese formulation on intimal thickening of carotid artery after balloon injury. It is worth noting that CLM maintained its inhibitory effect up to 8 weeks after balloon injury. The reduction in intimal thickening by CLM could have resulted from inhibition of intimal smooth muscle cell proliferation, which was assessed by immuno-histochemical analysis using monoclonal antibody against proliferating cell nuclear antigen. Therefore, CLM may be a favourable candidate for prevention of restenosis after PCI. Moreover CLM may have a therapeutic value in the prevention of atherosclerosis, because restenosis after PCI is considered to be an accelerated atherosclerosis.


Atorvastatin modulates matrix metalloproteinase expression, activity, and signaling in abdominal aortic aneurysms.
Statins may reduce abdominal aortic aneurysm (AAA) progression. We sought to measure how atorvastatin (AT) treatment might modulate matrix metalloproteinase (MMP) expression and/or activity in human AAA. Tissue from human AAAs at surgical repair was obtained from patients who were either not on statins (NST, n = 19) or treated with AT (n = 19). Immunoblots measured expression and zymography measured activity. Expression of most proteins was greater in the central compared with distal AAA region. Matrix metalloproteinase 1, MMP2, MMP3, MMP9, Tissue Inhibitor of Metalloproteinase (TIMP2), TIMP3, TIMP4, or total Sma Mothers Against Decapentaplegia (SMAD2) expression did not differ with treatment. There was a trend toward reduced MMP8 and TIMP1 expression and MMP2 zymographic activity in the AT-treatment group. In contrast, AT-treated samples had significantly reduced MMP13 (P = .02), latent-transforming growth factor (TGF)-beta (P = .02), and phospho-SMAD2 (P = .029) expression than NST-treated samples. We conclude that the AT-mediated decrease in MMP expression and activity reduces TGF-beta signaling in the central region of human AAAs.


Quantitative Live Single-cell Mass Spectrometry with Spatial Evaluation by Three-Dimensional Holographic and Tomographic Laser Microscopy.
The locations and volumes of the contents of a single HepG2 cell were visualized under three-dimensional (3D) holographic and tomographic (HT) laser microscopy, colored by refractive index, not staining. After trapping the specific area of a target cell in a nanospray tip, quantification was performed by live single-cell mass spectrometry. Comparison of the HepG2 cells' before and after 3D-HT images allowed the inference of the precise volume and original location of the trapped cell contents. The total amount of a trapped molecule was estimated. The images also revealed morphological changes in the cell structure caused by the manipulation.


Simulation of Ligand Transport in Receptors Using CaverDock.
Interactions between enzymes and small molecules lie in the center of many fundamental biochemical processes. Their analysis using molecular dynamics simulations have high computational demands, geometric approaches fail to consider chemical forces, and molecular docking offers only static information. Recently, we proposed to combine molecular docking and geometric approaches in an application called CaverDock. CaverDock is discretizing enzyme tunnel into discs, iteratively docking with restraints into one disc after another and searching for a trajectory of the ligand passing through the tunnel. Here, we focus on the practical side of its usage describing the whole method: from getting the application, and processing the data through a workflow, to interpreting the results. Moreover, we shared the best practices, recommended how to solve the most common issues, and demonstrated its application on three use cases.


Hospitalists' Needs Assessment and Perceived Barriers in Wound Care Management: A Quality Improvement Project.
The purpose of this quality improvement project was to determine hospitalists' knowledge, practices, and perspectives related to management of pressure injuries and neuropathic/diabetic foot complications (having a foot ulcer or subsequent development of a foot infection because of a foot ulcer). We also sought to identify resources for and knowledge-based barriers to management of these wounds. This quality improvement effort targeted an interdisciplinary group of 55 hospitalists in internal medicine that consisted of 8 nurse practitioners, 10 physician assistants, and 38 physicians. The site of this initiative was the Johns Hopkins Bayview Medical Center, a 342-bed academic hospital located in the mid-Atlantic United States (Baltimore Maryland). The first phase of our quality improvement project comprised an online survey to identify hospitalists' knowledge, practices, and opinions on inpatient management of pressure injuries and diabetic foot complications. The second phase involved semistructured focus groups attended by hospitalists to identify resource gaps and barriers inferred by survey results. Twenty-nine of 55 (52%) hospitalists responded to the survey; 72% indicated no formal training in wound care. Over 90% had little to no confidence in management of pressure injuries and diabetic foot complications. In a separate ranking section of the survey, respondents selected lack of knowledge/confidence 12 of 29 (41.3%) and resources 9 of 29 (31.0%) as number 1 barriers to wound care. Managing patients with obesity was identified as a second major barrier from 10 of 29 selected options (34.5%). Eighteen of 55 (33%) hospitalists attended focus group sessions acknowledging barriers to wound care that included provider education, information technology, system factors, and interprofessional engagement. Attendees welcomed additional educational and ancillary resource support.


The dynamin-related GTPase Opa1 is required for glucose-stimulated ATP production in pancreatic beta cells.
Previous studies using in vitro cell culture systems have shown the role of the dynamin-related GTPase Opa1 in apoptosis prevention and mitochondrial DNA (mtDNA) maintenance. However, it remains to be tested whether these functions of Opa1 are physiologically important in vivo in mammals. Here, using the Cre-loxP system, we deleted mouse Opa1 in pancreatic beta cells, in which glucose-stimulated ATP production in mitochondria plays a key role in insulin secretion. Beta cells lacking Opa1 maintained normal copy numbers of mtDNA; however, the amount and activity of electron transport chain complex IV were significantly decreased, leading to impaired glucose-stimulated ATP production and insulin secretion. In addition, in Opa1-null beta cells, cell proliferation was impaired, whereas apoptosis was not promoted. Consequently, mice lacking Opa1 in beta cells develop hyperglycemia. The data suggest that the function of Opa1 in the maintenance of the electron transport chain is physiologically relevant in beta cells.


Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction.
Myocardial infarction (MI) results in the generation of dead cells in the infarcted area. These cells are swiftly removed by phagocytes to minimize inflammation and limit expansion of the damaged area. However, the types of cells and molecules responsible for the engulfment of dead cells in the infarcted area remain largely unknown. In this study, we demonstrated that cardiac myofibroblasts, which execute tissue fibrosis by producing extracellular matrix proteins, efficiently engulf dead cells. Furthermore, we identified a population of cardiac myofibroblasts that appears in the heart after MI in humans and mice. We found that these cardiac myofibroblasts secrete milk fat globule-epidermal growth factor 8 (MFG-E8), which promotes apoptotic engulfment, and determined that serum response factor is important for MFG-E8 production in myofibroblasts. Following MFG-E8-mediated engulfment of apoptotic cells, myofibroblasts acquired antiinflammatory properties. MFG-E8 deficiency in mice led to the accumulation of unengulfed dead cells after MI, resulting in exacerbated inflammatory responses and a substantial decrease in survival. Moreover, MFG-E8 administration into infarcted hearts restored cardiac function and morphology. MFG-E8-producing myofibroblasts mainly originated from resident cardiac fibroblasts and cells that underwent endothelial-mesenchymal transition in the heart. Together, our results reveal previously unrecognized roles of myofibroblasts in regulating apoptotic engulfment and a fundamental importance of these cells in recovery from MI.


Addressing location uncertainties in GPS-based activity monitoring: A methodological framework.
Location uncertainty has been a major barrier in information mining from location data. Although the development of electronic and telecommunication equipment has led to an increased amount and refined resolution of data about individuals' spatio-temporal trajectories, the potential of such data, especially in the context of environmental health studies, has not been fully realized due to the lack of methodology that addresses location uncertainties. This article describes a methodological framework for deriving information about people's continuous activities from individual-collected Global Positioning System (GPS) data, which is vital for a variety of environmental health studies. This framework is composed of two major methods that address critical issues at different stages of GPS data processing: (1) a fuzzy classification method for distinguishing activity patterns; and (2) a scale-adaptive method for refining activity locations and outdoor/indoor environments. Evaluation of this framework based on smartphone-collected GPS data indicates that it is robust to location errors and is able to generate useful information about individuals' life trajectories.


Unsymmetrical difunctionalization of cyclooctadiene under continuous flow conditions: expanding the scope of ring opening metathesis polymerization.
Functionalized cyclooctenes (FCOEs) are important monomers in ring-opening metathesis polymerization (ROMP). Herein, a new library of disubstituted FCOEs bearing adjacent heteroatoms were synthesized and applied in ROMP. To address the issues associated with the handling of the reactive thienyl chloride intermediate, a two-step continuous flow method has been developed to prepare 5-thio-6-chlorocyclooctene compounds from abundant cyclooctadiene starting materials. These newly synthesized FCOE monomers were subsequently polymerized through ROMP, giving rise to a range of functionalized polymers with high molecular weights. Furthermore, we demonstrated that the thermal properties of these polymers could be fine-tuned by changing the functional groups in the FCOE monomers. We expect that this functionalization-polymerization strategy will enable the preparation of a range of polymeric materials with complex structures.


Cytolethal Distending Toxin Enhances Radiosensitivity in Prostate Cancer Cells by Regulating Autophagy.
Cytolethal distending toxin (CDT) produced by Campylobacter jejuni contains three subunits: CdtA, CdtB, and CdtC. Among these three toxin subunits, CdtB is the toxic moiety of CDT with DNase I activity, resulting in DNA double-strand breaks (DSB) and, consequently, cell cycle arrest at the G2/M stage and apoptosis. Radiation therapy is an effective modality for the treatment of localized prostate cancer (PCa). However, patients often develop radioresistance. Owing to its particular biochemical properties, we previously employed CdtB as a therapeutic agent for sensitizing radioresistant PCa cells to ionizing radiation (IR). In this study, we further demonstrated that CDT suppresses the IR-induced autophagy pathway in PCa cells by attenuating c-Myc expression and therefore sensitizes PCa cells to radiation. We further showed that CDT prevents the formation of autophagosomes via decreased high-mobility group box 1 (HMGB1) expression and the inhibition of acidic vesicular organelle (AVO) formation, which are associated with enhanced radiosensitivity in PCa cells. The results of this study reveal the detailed mechanism of CDT for the treatment of radioresistant PCa.


Evaluation of dental panoramic radiographic findings in edentulous jaws: A retrospective study of 743 patients "Radiographic features in edentulous jaws".
The aim of this study was to determine the frequency of significant panoramic radiographic findings and eventual treatment requirements before conventional or implant supported prosthetic treatment in asymptomatic edentulous patients. A total of 743 asymptomatic edentulous patients were retrospectively evaluated using a digital panoramic system. We analyzed the radiographic findings, including impacted teeth, retained root fragments, foreign bodies, severe atrophy of the posterior maxillary alveolar bone, mucous retention cysts, soft tissue calcifications and radiopaque-radiolucent conditions. Four-hundred-eighty-seven (65.6%) patients had no radiographic finding. A total of 331 radiographic findings were detected in 256 (34%) patients. In 52.9% (n=175) of these conditions, surgical treatment was required before application of implant-supported fixed prosthesis. However, before application of conventional removable prosthesis surgical treatment was required for 6% (n=20) of these conditions. The edentulous patients who will have implant placement for implant-supported fixed prosthesis can frequently require additional surgical procedures to eliminate pathological conditions.


Fuzzy decision tree to classify complex fractionated atrial electrograms.
Catheter ablation has emerged as an effective treatment strategy for atrial fibrillation (AF) in recent years. During AF, complex fractionated atrial electrograms (CFAE) can be recorded and are known to be a potential target for ablation. Automatic algorithms have been developed to simplify CFAE detection, but they are often based on a single descriptor or a set of descriptors in combination with sharp decision classifiers. However, these methods do not reflect the progressive transition between CFAE classes. The aim of this study was to develop an automatic classification algorithm, which combines the information of a complete set of descriptors and allows for progressive and transparent decisions. We designed a method to automatically analyze CFAE based on a set of descriptors representing various aspects, such as shape, amplitude and temporal characteristics. A fuzzy decision tree (FDT) was trained and evaluated on 429 predefined electrograms. CFAE were classified into four subgroups with a correct rate of 81±3%. Electrograms with continuous activity were detected with a correct rate of 100%. In addition, a percentage of certainty is given for each electrogram to enable a comprehensive and transparent decision. The proposed FDT is able to classify CFAE with respect to their progressive transition and may allow objective and reproducible CFAE interpretation for clinical use.


Early management of craniosynostosis using endoscopic-assisted strip craniectomies and cranial orthotic molding therapy.
To assess the safety, efficacy, and results of the early treatment of infants with craniosynostosis using minimally invasive endoscopic strip craniectomies and postoperative helmet molding therapy. A total of 100 patients with documented diagnosis of craniosynostosis were prospectively studied and treated with endoscopic strip craniectomies. A total of 106 stenosed sutures were operated on with the following distribution: 61 sagittal, 23 coronal, 18 metopic, and 4 lambdoid sutures. Sixty-three patients were treated under 16 weeks of age. After surgery, all patients were treated with custom-made molding helmets for up to 7 months. Follow-up ranged between 4 months and 50 months. All patients underwent the surgical procedures successfully and without complications. The mean surgical operative time was 52.7 minutes. The mean estimated blood loss was 26.2 mL; only 1 patient underwent intraoperative blood transfusion, and 10 patients had a non- life-threatening postoperative blood transfusion. All but 3 patients were discharged on the first postoperative day. There were no infections, dural sinus tears, cerebrospinal fluid leaks, or neurologic injuries, and there were no significant complications related to the use of helmet therapy. Most patients have achieved or are in the process of reaching normalization of their craniofacial deformities. The results indicate that the early treatment of craniosynostosis with minimally invasive endoscopic strip craniectomies is a safe, efficacious, and valuable therapeutic alternative to the current extensive surgical treatment modalities. The significantly less blood loss, need for blood transfusions, and length of stay and decreased costs make this procedure an excellent early option for treating infants who present with craniosynostosis.


MRI-based age prediction using hidden Markov models.
Cortical thinning and intracortical gray matter volume losses are widely observed in normal ageing, while the decreasing rate of the volume loss in subjects with neurodegenerative disorders such as Alzheimer's disease is reported to be faster than the average speed. Therefore, neurodegenerative disease is considered as accelerated ageing. Accurate detection of accelerated ageing based on the magnetic resonance imaging (MRI) of the brain is a relatively new direction of research in computational neuroscience as it has the potential to offer positive clinical outcome through early intervention. In order to capture the faster structural alterations in the brain with ageing, we propose in this paper a computational approach for modelling the MRI-based structure of the brain using the framework of hidden Markov models, which can be utilized for age prediction. Experiments were carried out on healthy subjects to validate its accuracy and its robustness. The results have shown its ability of predicting the brain age with an average normalized age-gap error of two to three years, which is superior to several recently developed methods for brain age prediction.


Dynamic imaging of a capillary-gravity wave in shallow water using amplitude variations of eigenbeams.
Dynamic acoustic imaging of a surface wave propagating at an air-water interface is a complex task that is investigated here at the laboratory scale through an ultrasonic experiment in a shallow water waveguide. Using a double beamforming algorithm between two source-receiver arrays, the authors isolate and identify each multi-reverberated eigenbeam that interacts with the air-water and bottom interfaces. The waveguide transfer matrix is recorded 100 times per second while a low-amplitude gravity wave is generated by laser-induced breakdown at the middle of the waveguide, just above the water surface. The controlled, and therefore repeatable, breakdown results in a blast wave that interacts with the air-water interface, which creates ripples at the surface that propagate in both directions. The amplitude perturbations of each ultrasonic eigenbeam are measured during the propagation of the gravity-capillary wave. Inversion of the surface deformation is performed from the amplitude variations of the eigenbeams using a diffraction-based sensitivity kernel approach. The accurate ultrasonic imaging of the displacement of the air-water interface is compared to simultaneous measurements with an optical camera, which provides independent validation.


Ticagrelor with aspirin or alone in high-risk patients after coronary intervention: Rationale and design of the TWILIGHT study.
Dual antiplatelet therapy (DAPT) is necessary to prevent thrombosis yet increases bleeding after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Antiplatelet monotherapy with a potent P2Y12 receptor antagonist may reduce bleeding while maintaining anti thrombotic efficacy compared with conventional DAPT. TWILIGHT is a randomized, double-blind placebo-controlled trial evaluating the comparative efficacy and safety of antiplatelet monotherapy versus DAPT in up to 9000 high-risk patients undergoing PCI with DES. Upon enrollment after successful PCI, all patients will be treated with open label low-dose aspirin (81-100 mg daily) plus ticagrelor (90 mg twice daily) for 3 months. Event-free patients will then be randomized in a double-blind fashion to low-dose aspirin versus matching placebo with continuation of open-label ticagrelor for an additional 12 months. The primary hypothesis is that a strategy of ticagrelor monotherapy will be superior with respect to the primary endpoint of bleeding academic research consortium type 2, 3 or 5, while maintaining non-inferiority for ischemic events compared with ticagrelor plus ASA. TWILIGHT is the largest study to date that is specifically designed and powered to demonstrate reductions in bleeding with ticagrelor monotherapy versus ticagrelor plus ASA beyond 3 months post-procedure in a high-risk PCI population treated with DES. The trial will provide novel insights with respect to the potential role of ticagrelor monotherapy as an alternative for long-term platelet inhibition in a broad population of patients undergoing PCI with DES.


End-of-life care in nursing home settings: do race or age matter?
One-quarter of all U.S. chronic-disease deaths occur in nursing homes, yet few studies examine palliative care quality in these settings. This study tests whether racial and/or age-based differences in end-of-life care exist in these institutional settings. We abstracted residents' charts (N = 1133) in 12 nursing homes. Researchers collected data on indicators of palliative care in two domains of care--advance care planning and pain management--and on residents' demographic and health status variables. Analyses tested for differences by race and age. White residents were more likely than minorities to have DNR orders (69.5% vs. 37.3%), living wills (39% vs. 5%), and health care proxies (36.2% vs. 11.8%; p < .001 for each). Advance directives were highly and positively correlated with age. In-depth advance care planning discussions between residents, families, and health care providers were rare for all residents, irrespective of demographic characteristics. Nursing staff considered older residents to have milder and less frequent pain than younger residents. We found no disparities in pain management based on race. To the extent that advance care planning improves care at the end of life, racial minorities in nursing homes are disadvantaged compared to their white fellow residents. Focusing on in-depth discussions of values and goals of care can improve palliative care for all residents and may help to ameliorate racial disparities in end-of-life care. Staff should consider residents of all ages as appropriate recipients of advance care planning efforts and should be cognizant of the fact that individuals of all ages can experience pain. Nursing homes may do a better job than other health care institutions in eliminating racial disparities in pain management.


Bladder dysfunction in hereditary spastic paraplegia: what to expect?
Hereditary spastic paraplegia (HSP) comprises a group of rare neurodegenerative disorders characterised by progressive spasticity and hyperreflexia of the legs. Neurogenic bladder dysfunction is a well recognised problem in patients with HSP but it has not yet been described systematically in the literature. The aim of this study was to provide an evidential overview of the ways in which urinary dysfunction presents in HSP. 49 patients with HSP were included and underwent evaluation. A history was followed by a semi-structured interview and, in those patients who consented, measurement of residual volume of urine (PVR) and urodynamic evaluation. 38 subjects (77.6%) reported some type of urinary symptom. Subjective complaints of bladder problems showed a correlation with verified urinary dysfunction. There were no significant differences in the occurrence of urinary disturbances between the pure and complex forms of HSP. The most frequent symptoms were incontinence (69.4%), hesitancy (59.2%), increased frequency of micturition (55.1%) and urgency (51.0%). Incomplete bladder emptying was the rarest (36.7%). The most common combination of symptoms was to have all of them (14.3%). Incomplete bladder emptying as a complaint was associated with an increased risk of PVR. Women had a higher risk of increased voiding frequency. To our knowledge, this work is the first systematic and disease oriented overview of neurogenic bladder disturbances in patients with HSP. Our results may be useful to the clinicians who work with HSP patients, allowing them to make appropriate screening and management decisions.


A non-invasive, quantitative study of broadband spectral responses in human visual cortex.
Currently, non-invasive methods for studying the human brain do not routinely and reliably measure spike-rate-dependent signals, independent of responses such as hemodynamic coupling (fMRI) and subthreshold neuronal synchrony (oscillations and event-related potentials). In contrast, invasive methods-microelectrode recordings and electrocorticography (ECoG)-have recently measured broadband power elevation in field potentials (~50-200 Hz) as a proxy for locally averaged spike rates. Here, we sought to detect and quantify stimulus-related broadband responses using magnetoencephalography (MEG). Extracranial measurements like MEG and EEG have multiple global noise sources and relatively low signal-to-noise ratios; moreover high frequency artifacts from eye movements can be confounded with stimulus design and mistaken for signals originating from brain activity. For these reasons, we developed an automated denoising technique that helps reveal the broadband signal of interest. Subjects viewed 12-Hz contrast-reversing patterns in the left, right, or bilateral visual field. Sensor time series were separated into evoked (12-Hz amplitude) and broadband components (60-150 Hz). In all subjects, denoised broadband responses were reliably measured in sensors over occipital cortex, even in trials without microsaccades. The broadband pattern was stimulus-dependent, with greater power contralateral to the stimulus. Because we obtain reliable broadband estimates with short experiments (~20 minutes), and with sufficient signal-to-noise to distinguish responses to different stimuli, we conclude that MEG broadband signals, denoised with our method, offer a practical, non-invasive means for characterizing spike-rate-dependent neural activity for addressing scientific questions about human brain function.