Hip replacement: landmark surgery in modern medical history.
Total hip replacement (THR) is most often performed to treat end-stage symptomatic osteoarthritis. Patients typically present with increasing pain, restricted mobility and stiffness. In this procedure, the femoral head and part of the femoral neck are excised. The acetabulum is enlarged and an acetabular cup is inserted. The femoral head is replaced by a femoral component, the stem of which is inserted into the medullary canal of the femur. The components can be either cemented in place or press-fit (cementless). The THR concept was popularised by Sir John Charnley in the 1960s and although, over half a century of development has resulted in incremental improvements, the procedure is not dramatically different from the one he described. However, over the last two decades there have been significant changes in the types of bearing surfaces used. Metal on polyethylene continues to be the workhorse for the majority of cases. In the young and active, bearing surfaces with low wear rate are increasingly used. Since the early 1960s, THR has played an important role in alleviating pain and restoring mobility to millions of people. The cost-effectiveness of THR in treating advanced osteoarthritis makes it one of the most successful of all surgical interventions.


Differential effects of countermovement magnitude and volitional effort on vertical jumping.
The importance of vertical jumping in sport and rehabilitative medicine is widely recognized. Despite the ample use of jump tests to assess neuromuscular function, the differential effects of muscular activation (volitional effort) and strategy (countermovement magnitude) on jumping performance have not been studied. The present study aimed to investigate the differential effects of countermovement magnitude and volitional effort on vertical jump performance. Ten male participants performed a total of 60 countermovement jumps each with three different countermovement knee angles (50, 70 and 90°) and four effort levels (25, 50, 75 and 100% of maximal effort). Kinematics and Kinetics were recorded using Vicon System together with a force platform. Electromyography of four muscles was recorded. Results show that countermovement magnitude and volitional effort both affect jump performance. These effects were synergistic for jump height (P < 0.001), but antagonistic for peak ground reaction force (P < 0.001). Interestingly, peak jump mechanical power was affected by volitional effort, implying an increase from 31.26 W/kg at 25% to 41.68 W/kg at 100% of volitional effort, but no countermovement magnitude effect was observed for 100% of volitional effort. This suggests that the apparent paradox of larger ground reaction forces in sub-maximal as compared to maximal jumps is due to the different jump strategies. Moreover, these results are relevant for jumping mechanography as a clinical tool, suggesting that peak power can be used to assess neuromuscular performance even when countermovement magnitude varies as a result of age or pathology.


Are there indirect fitness benefits of female extra-pair reproduction? Lifetime reproductive success of within-pair and extra-pair offspring.
The forces driving extra-pair reproduction by socially monogamous females, and the resulting genetic polyandry, remain unclear. A testable prediction of the hypothesis that extra-pair reproduction partly reflects indirect selection on females is that extra-pair young (EPY) will be fitter than their within-pair young (WPY) maternal half-siblings. This prediction has not been comprehensively tested in a wild population, requiring data on the lifetime reproductive success (LRS) of maternal half-sib EPY and WPY. We used 17 years of genetic parentage data from song sparrows, Melospiza melodia, to compare the LRS of hatched EPY and WPY maternal half-siblings measured as their lifetime number of hatched offspring, recruited offspring, and hatched grandoffspring. EPY hatchlings were not significantly fitter than WPY hatchlings for any of three measures of LRS. Furthermore, opposite to prediction, EPY hatchlings tended to have lower LRS than their maternal half-sibling WPY hatchlings on average. EPY also tended to be less likely to survive to hatch than their maternal half-sibling WPY. Taken together, these results fail to support one key hypothesis explaining the evolution of genetic polyandry by socially monogamous females and suggest there may be weak indirect selection against female extra-pair reproduction in song sparrows.


Development of a new test system to determine penetration of multi-walled carbon nanotubes through filtering facepiece respirators.
Carbon nanotubes (CNTs) are currently used in numerous industrial and biomedical applications. Recent studies suggest that workers may be at risk of adverse health effects if they are exposed to CNTs. A National Institute for Occupational Safety and Health (NIOSH) survey of the carbonaceous nanomaterial industry found that 77% of the companies used respiratory protection. Elastomeric half-mask respirators and filtering facepiece respirators (FFRs) are commonly used. Although numerous respirator filtration studies have been done with surrogate engineered nanoparticles, such as sodium chloride, penetration data from engineered nanoparticles such as CNTs are lacking. The aims of this study were to develop a new CNT aerosol respirator testing system and to determine multi-walled CNT (MWCNT) penetration through FFRs. A custom-designed CNT aerosol respirator testing system (CNT-ARTS) was developed which was capable of producing a sufficient amount of airborne MWCNTs for testing of high efficiency FFRs. The size distribution of airborne MWCNTs was 20-10,000 nm, with 99% of the particles between 25 and 2840 nm. The count median diameter (CMD) was 209 nm with a geometric standard deviation (GSD) of 1.98. This particle size range is similar to those found in some work environments (particles ≤6000 nm). The penetration of MWCNTs through six tested FFR models at two constant flow rates of 30 and 85 LPM was determined. Penetration at 85 LPM (0.58-2.04% for N95, 0.15-0.32% for N99, and 0.007-0.009% for P100 FFRs) was greater compared with the values at 30 LPM (0.28-1.79% for N95, 0.10-0.24% for N99, and 0.005-0.006% for P100 FFRs). The most penetrating particle size through all six tested FFR models was found to be in the range of 25-130 nm and 35-200 nm for the 30-LPM and 85-LPM flow rates, respectively.


Marketing foods to children through product packaging: prolific, unhealthy and misleading.
To investigate marketing techniques used on the packaging of child-oriented products sold through supermarkets. Food and beverage products which met criteria for 'marketed to children' were recorded as child-oriented. The products were analysed for food categories, nutritional value, and type and extent of marketing techniques used. A major supermarket chain in Adelaide, South Australia. Child-oriented food and beverage products. One hundred and fifty-seven discrete products were marketed to children via product packaging; most (75·2 %) represented non-core foods, being high in fat or sugar. Many marketing techniques (more than sixteen unique marketing techniques) were used to promote child-oriented food products. Claims about health and nutrition were found on 55·5 % of non-core foods. A median of 6·43 marketing techniques per product was found. The high volume and power of marketing non-core foods to children via product packaging in supermarkets should be of concern to policy makers wanting to improve children's diet for their health and to tackle childhood obesity. Claims about health or nutrition on non-core foods deserve urgent attention owing to their potential to mislead and confuse child and adult consumers.


Affective contingencies in the affiliative domain: Physiological assessment, associations with the affiliation motive, and prediction of behavior.
According to classical motive disposition theory, individuals differ in their propensity to derive pleasure from affiliative experiences. This propensity is considered a core process underlying the affiliation motive and a pervasive cause of motivated behavior. In this study, we tested these assumptions. We presented participants with positive affiliative stimuli and used electromyography to record changes in facial muscular activity that are indicative of subtle smiling. We were thus able to physiologically measure positive affect following affiliative cues. Individual differences in these affective contingencies were internally consistent and temporally stable. They converged with affiliation motive self- and informant reports and picture story exercise scores, indicating that they are partly accessible to the self, observable to outsiders, and overlap with implicit systems. Finally, they predicted affiliative behavior in terms of situation selection and modification across a wide variety of contexts (i.e., in daily life, the laboratory, and an online social network). These findings corroborate the long-held assumption that affective contingencies represent a motivational core aspect of affiliation.


The effects of nutritional interventions on recurrence in survivors of colorectal adenomas and cancer: a systematic review of randomised controlled trials.
Nutrition and dietary supplementation may modulate outcomes in colorectal cancer (CRC) survivors. However, no recent systematic review has focused on randomised controlled trials (RCTs). The aim of this systematic review was to examine the effects of nutritional RCTs in survivors of colorectal adenomas and cancer. Medline, Embase, Scopus, Web of Science and the Cochrane Library were searched to identify research between April 2006 and January 2014. The primary outcomes were colorectal adenoma and cancer recurrence. Each included study was assessed for risk of bias. A meta-analysis using a random-effects model was performed, in which two or more RCTs investigated the same dietary intervention. Eight completed RCTs, all in colorectal adenoma survivors, were identified, with four investigating the effect of folic acid. A meta-analysis of the four folic acid RCTs showed no statistically significant effect of folic acid on colorectal adenoma recurrence (relative risks=0.93; 95% confidence interval: 0.69, 1.25). The impact of the remaining completed RCTs, investigating antioxidant supplementation, green tea extract, prebiotic fibre and phytooestrogens/insoluble fibre, could not be reliably estimated because of the limited number and heterogeneity of the interventions. In addition, three heterogeneous ongoing RCTs were identified, investigating green tea (n=1) and eicosapentaenoic acid (n=1) in colorectal adenoma survivors and dietary modifications (n=1) in CRC survivors in remission. Overall, this systematic review highlights the need for further research, especially in CRC survivors, as we identified no completed and only one ongoing RCT in this population.


Stress and worry in the 2020 coronavirus pandemic: relationships to trust and compliance with preventive measures across 48 countries in the COVIDiSTRESS global survey.
The COVIDiSTRESS global survey collects data on early human responses to the 2020 COVID-19 pandemic from 173 429 respondents in 48 countries. The open science study was co-designed by an international consortium of researchers to investigate how psychological responses differ across countries and cultures, and how this has impacted behaviour, coping and trust in government efforts to slow the spread of the virus. Starting in March 2020, COVIDiSTRESS leveraged the convenience of unpaid online recruitment to generate public data. The objective of the present analysis is to understand relationships between psychological responses in the early months of global coronavirus restrictions and help understand how different government measures succeed or fail in changing public behaviour. There were variations between and within countries. Although Western Europeans registered as more concerned over COVID-19, more stressed, and having slightly more trust in the governments' efforts, there was no clear geographical pattern in compliance with behavioural measures. Detailed plots illustrating between-countries differences are provided. Using both traditional and Bayesian analyses, we found that individuals who worried about getting sick worked harder to protect themselves and others. However, concern about the coronavirus itself did not account for all of the variances in experienced stress during the early months of COVID-19 restrictions. More alarmingly, such stress was associated with less compliance. Further, those most concerned over the coronavirus trusted in government measures primarily where policies were strict. While concern over a disease is a source of mental distress, other factors including strictness of protective measures, social support and personal lockdown conditions must also be taken into consideration to fully appreciate the psychological impact of COVID-19 and to understand why some people fail to follow behavioural guidelines intended to protect themselves and others from infection. The Stage 1 manuscript associated with this submission received in-principle acceptance (IPA) on 18 May 2020. Following IPA, the accepted Stage 1 version of the manuscript was preregistered on the Open Science Framework at https://osf.io/g2t3b. This preregistration was performed prior to data analysis.


Modulation of Ca2+ oscillation and melatonin secretion by BKCa channel activity in rat pinealocytes.
The pineal glands regulate circadian rhythm through the synthesis and secretion of melatonin. The stimulation of nicotinic acetylcholine receptor due to parasympathetic nerve activity causes an increase in intracellular Ca(2+) concentration and eventually downregulates melatonin production. Our previous report shows that rat pinealocytes have spontaneous and nicotine-induced Ca(2+) oscillations that are evoked by membrane depolarization followed by Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCCs). These Ca(2+) oscillations are supposed to contribute to the inhibitory mechanism of melatonin secretion. Here we examined the involvement of large-conductance Ca(2+)-activated K(+) (BKCa) channel conductance on the regulation of Ca(2+) oscillation and melatonin production in rat pinealocytes. Spontaneous Ca(2+) oscillations were markedly enhanced by BKCa channel blockers (1 μM paxilline or 100 nM iberiotoxin). Nicotine (100 μM)-induced Ca(2+) oscillations were also augmented by paxilline. In contrast, spontaneous Ca(2+) oscillations were abolished by BKCa channel opener [3 μM 12,14-dichlorodehydroabietic acid (diCl-DHAA)]. Under whole cell voltage-clamp configurations, depolarization-elicited outward currents were significantly activated by diCl-DHAA and blocked by paxilline. Expression analyses revealed that the α and β3 subunits of BKCa channel were highly expressed in rat pinealocytes. Importantly, the activity of BKCa channels modulated melatonin secretion from whole pineal gland of the rat. Taken together, BKCa channel activation attenuates these Ca(2+) oscillations due to depolarization-synchronized Ca(2+) influx through VDCCs and results in a recovery of reduced melatonin secretion during parasympathetic nerve activity. BKCa channels may play a physiological role for melatonin production via a negative-feedback mechanism.


Five-Year Experience: Reflective Writing in a Preclinical End-of-Life Care Curriculum.
This paper examines the use of reflective writing in a preclinical end-of-life curriculum including comparison of the role and outcomes of out-of-class (OC) versus in-class (IC) writing. Learners were required to complete one-page essays on their experiences and concerns about death and dying after attending a series of end-of-life care lectures. From 2002-2005, essays were completed OC and in 2006 and 2007 essays were completed during the first ten minutes of small group discussion sessions. Essays were collected and analyzed for salient themes. Between 2002-2007, reflection essays were gathered from 829 learners, including 522 OC essays and 307 IC essays. Essay analysis identified four major themes of student concerns related to caring for dying patients, as well as student reactions to specific curricular components and to the use of reflection. IC essays were shorter and less polished than OC essays but utilized a wider variety of formats including poems and bulleted lists. IC essays tended to react to lecture content immediately preceding the writing exercise whereas OC varied in curricular components upon which they focused. OC essays have the advantage of giving learners more time to choose subject matter, whereas IC essays provide a structured time in which to actively reflect. Both formats served as catalysts for small group discussions. Writing exercises can effectively provide an important opportunity and motivation for learners to reflect on past experiences and future expectations related to providing end-of-life care.


Carbon Nanotube and Asbestos Exposures Induce Overlapping but Distinct Profiles of Lung Pathology in Non-Swiss Albino CF-1 Mice.
Carbon nanotubes (CNTs) are emerging as important occupational and environmental toxicants owing to their increasing prevalence and potential to be inhaled as airborne particles. CNTs are a concern because of their similarities to asbestos, which include fibrous morphology, high aspect ratio, and biopersistence. Limitations in research models have made it difficult to experimentally ascertain the risk of CNT exposures to humans and whether these may lead to lung diseases classically associated with asbestos, such as mesothelioma and fibrosis. In this study, we sought to comprehensively compare profiles of lung pathology in mice following repeated exposures to multiwall CNTs or crocidolite asbestos (CA). We show that both exposures resulted in granulomatous inflammation and increased interstitial collagen; CA exposures caused predominantly bronchoalveolar hyperplasia, whereas CNT exposures caused alveolar hyperplasia of type II pneumocytes (T2Ps). T2Ps isolated from CNT-exposed lungs were found to have upregulated proinflammatory genes, including interleukin 1ß (IL-1ß), in contrast to those from CA exposed. Immunostaining in tissue showed that while both toxicants increased IL-1ß protein expression in lung cells, T2P-specific IL-1ß increases were greater following CNT exposure. These results suggest related but distinct mechanisms of action by CNTs versus asbestos which may lead to different outcomes in the 2 exposure types.


Dynamic Cross-Linking of Polymeric Binders Based on Host-Guest Interactions for Silicon Anodes in Lithium Ion Batteries.
We report supramolecular cross-linking of polymer binders via dynamic host-guest interactions between hyperbranched β-cyclodextrin polymer and a dendritic gallic acid cross-linker incorporating six adamantane units for high-capacity silicon anodes. Calorimetric analysis in the solution phase indicates that the given host-guest complexation is a highly spontaneous and enthalpically driven process. These findings are further verified by carrying out gelation experiments in both aqueous and organic media. The dynamic cross-linking process enables intimate silicon-binder interaction, structural stability of electrode film, and controlled electrode-electrolyte interface, yielding enhanced cycling performance. Control experiments using both α, γ-CDp with different cavity sizes and a guest molecule incorporating a single adamantane unit verified that the enhanced cycle life originates from the host-guest interaction between β-cyclodextrin and adamantane. The impact of the dynamic cross-linking is maximized at an optimal stoichiometry between the two components. Importantly, the present investigation proves that the molecular-level tuning of the host-guest interactions can be translated directly to the cycling performance of silicon anodes.


Cryo-EM structures of PI3Kα reveal conformational changes during inhibition and activation.
Phosphoinositide 3-kinases (PI3Ks) are lipid kinases essential for growth and metabolism. Their aberrant activation is associated with many types of cancers. Here we used single-particle cryoelectron microscopy (cryo-EM) to determine three distinct conformations of full-length PI3Kα (p110α-p85α): the unliganded heterodimer PI3Kα, PI3Kα bound to the p110α-specific inhibitor BYL-719, and PI3Kα exposed to an activating phosphopeptide. The cryo-EM structures of unbound and of BYL-719-bound PI3Kα are in general accord with published crystal structures. Local deviations are presented and discussed. BYL-719 stabilizes the structure of PI3Kα, but three regions of low-resolution extra density remain and are provisionally assigned to the cSH2, BH, and SH3 domains of p85. One of the extra density regions is in contact with the kinase domain blocking access to the catalytic site. This conformational change indicates that the effects of BYL-719 on PI3Kα activity extend beyond competition with adenosine triphosphate (ATP). In unliganded PI3Kα, the DFG motif occurs in the "in" and "out" positions. In BYL-719-bound PI3Kα, only the DFG-in position, corresponding to the active conformation of the kinase, was observed. The phosphopeptide-bound structure of PI3Kα is composed of a stable core resolved at 3.8 Å. It contains all p110α domains except the adaptor-binding domain (ABD). The p85α domains, linked to the core through the ABD, are no longer resolved, implying that the phosphopeptide activates PI3Kα by fully releasing the niSH2 domain from binding to p110α. The structures presented here show the basal form of the full-length PI3Kα dimer and document conformational changes related to the activated and inhibited states.


High intensity interval running enhances measures of physical fitness but not metabolic measures of cardiovascular disease risk in healthy adolescents.
With accumulating evidence suggesting that CVD has its origins in childhood, the purpose of this study was to examine whether a high intensity training (HIT) intervention could enhance the CVD risk profile of secondary school aged adolescents in a time efficient manner. Participants in the study were adolescent school children (64 boys, 25 girls, 16.7 ± 0.6 years). The intervention group (30 boys, 12 girls) performed three weekly exercise sessions over 7 weeks with each session consisting of either four to six repeats of maximal sprint running within a 20 m area with 30 s recovery. The control group were instructed to continue their normal behaviour. All participants had indices of obesity, blood pressure and nine biochemical risk markers for cardiovascular disease recorded as well as four physical performance measures at baseline and post-intervention. Feedback was provided through informal discussion throughout the intervention period as well as post-intervention focus groups. Statistical differences between and within groups were determined by use of paired samples t-tests and ANCOVA. Significant enhancements (P ≤ 0.05) in vertical jump performance, 10 m sprint speed and cardiorespiratory fitness was evident in the intervention group whereas a significant decrease in both agility and vertical jump performance was evident in the control group. Participants in the intervention group also experienced a significant decrease in systolic blood pressure post-intervention. Limited changes occurred with respect to the biochemical markers although both groups did experience a significant increase in LDL post-intervention whilst the control group experienced a significant decrease in total cholesterol. No apparent differences were evident between groups post intervention for any of the biochemical markers. Feedback indicated that participants endorsed the use of the intervention as an effective means of exercise. Our results demonstrate that high intensity exercise interventions may be used in the school setting for adolescents as a means of improving measures of physical fitness. Further investigations involving a larger cohort of participants, taken from different schools, is recommended. NCT01027156.


A model of wound-healing angiogenesis in soft tissue.
Angiogenesis, or blood vessel growth, is a critical step in the wound-healing process, involving the chemotactic response of blood vessel endothelial cells to macrophage-derived factors produced in the wound space. In this article, we formulate a system of partial differential equations that model the evolution of the capillary-tip endothelial cells, macrophage-derived chemoattractants, and the new blood vessels during the tissue repair process. Chemotaxis is incorporated as a dominant feature of the model, driving the wave-like ingrowth of the wound-healing unit. The resulting model admits traveling wave solutions that exhibit many of the features characteristic of wound healing in soft tissue. The steady propagation of the healing unit through the wound space, the development of a dense band of fine, tipped capillaries near the leading edge of the wound-healing unit (the brush-border effect), and an elevated vessel density associated with newly healed wounds, prior to vascular remodeling, are all discernible from numerical simulations of the full model. Numerical simulations mimic not only the normal progression of wound healing but also the potential for some wounds to fail to heal. Through the development and analysis of a simplified model, insight is gained into how the balance between chemotaxis, tip proliferation, and tip death affects the structure and speed of propagation of the healing unit. Further, expressions defining the healed vessel density and the wavespeed in terms of known parameters lead naturally to the identification of a maximum wavespeed for the wound-healing process and to bounds on the healed vessel density. The implications of these results for wound-healing management are also discussed.


Deficiency in Th2 cytokine responses exacerbate orthopoxvirus infection.
Ectromelia virus (ECTV) causes mousepox in mice, a disease very similar to smallpox in humans. ECTV and variola virus (VARV), the agent of smallpox, are closely related orthopoxviruses. Mousepox is an excellent small animal model to study the genetic and immunologic basis for resistance and susceptibility of humans to smallpox. Resistance to mousepox is dependent on a strong polarized type 1 immune response, associated with robust natural killer (NK) cell, cytotoxic T lymphocyte (CTL) and gamma interferon (IFN-γ) responses. In contrast, ECTV-susceptible mice generate a type 2 response, associated with weak NK cell, CTL and IFN-γ responses but robust IL-4 responses. Nonetheless, susceptible strains infected with mutant ECTV lacking virus-encoded IFN-γ binding protein (vIFN-γbp) (ECTV-IFN-γbpΔ) control virus replication through generation of type 1 response. Since the IL-4/IL-13/STAT-6 signaling pathways polarize type 2/T helper 2 (Th2) responses with a corresponding suppression of IFN-γ production, we investigated whether the combined absence of vIFN-γbp, and one or more host genes involved in Th2 response development, influence generation of protective immunity. Most mutant mouse strains infected with wild-type (WT) virus succumbed to disease more rapidly than WT animals. Conversely, the disease outcome was significantly improved in WT mice infected with ECTV-IFN-γbpΔ but absence of IL-4/IL-13/STAT-6 signaling pathways did not provide any added advantage. Deficiency in IL-13 or STAT-6 resulted in defective CTL responses, higher mortality rates and accelerated deaths. Deficiencies in IL-4/IL-13/STAT-6 signaling pathways significantly reduced the numbers of IFN-γ producing CD4 and CD8 T cells, indicating an absence of a switch to a Th1-like response. Factors contributing to susceptibility or resistance to mousepox are far more complex than a balance between Th1 and Th2 responses.


Taura syndrome virus loads in Litopenaeus vannamei hemolymph following infection are related to differential mortality.
Taura syndrome is an economically important disease that can cause catastrophic losses of farmed shrimp. Without effective treatments for Taura syndrome virus (TSV), one approach to managing the problem is to selectively breed shrimp populations with increased disease resistance. To better understand why some shrimp can survive exposure to TSV, information is needed on how viral loads progress and persist following infection. Data reported here show that mortalities occurring mostly within 1 wk of infection are associated with high viral titers, and titers as high as 10(8.7) genome copies per microl hemolymph can persist for up to 3 wk in survivors. Thereafter, and up to approximately 9 wk post-exposure, most surviving shrimp remain chronically infected with TSV loads ranging from 10(4) to 10(8) genome copies per microl hemolymph. Challenging shrimp from families with varying TSV resistance showed that in shrimp from less resistant families, the TSV load in hemolymph increased earlier and reached higher peaks than in shrimp from more resistant families. Although TSV loads in moribund shrimp from families differing in resistance did not differ significantly, infection loads among survivors were lower in shrimp from more resistant families. Taken together, the data suggest that lethal infection loads can occur in both more and less susceptible shrimp and that survivors represent shrimp in which viral expansion is better contained.


Uniparental genetic heritage of belarusians: encounter of rare middle eastern matrilineages with a central European mitochondrial DNA pool.
Ethnic Belarusians make up more than 80% of the nine and half million people inhabiting the Republic of Belarus. Belarusians together with Ukrainians and Russians represent the East Slavic linguistic group, largest both in numbers and territory, inhabiting East Europe alongside Baltic-, Finno-Permic- and Turkic-speaking people. Till date, only a limited number of low resolution genetic studies have been performed on this population. Therefore, with the phylogeographic analysis of 565 Y-chromosomes and 267 mitochondrial DNAs from six well covered geographic sub-regions of Belarus we strove to complement the existing genetic profile of eastern Europeans. Our results reveal that around 80% of the paternal Belarusian gene pool is composed of R1a, I2a and N1c Y-chromosome haplogroups - a profile which is very similar to the two other eastern European populations - Ukrainians and Russians. The maternal Belarusian gene pool encompasses a full range of West Eurasian haplogroups and agrees well with the genetic structure of central-east European populations. Our data attest that latitudinal gradients characterize the variation of the uniparentally transmitted gene pools of modern Belarusians. In particular, the Y-chromosome reflects movements of people in central-east Europe, starting probably as early as the beginning of the Holocene. Furthermore, the matrilineal legacy of Belarusians retains two rare mitochondrial DNA haplogroups, N1a3 and N3, whose phylogeographies were explored in detail after de novo sequencing of 20 and 13 complete mitogenomes, respectively, from all over Eurasia. Our phylogeographic analyses reveal that two mitochondrial DNA lineages, N3 and N1a3, both of Middle Eastern origin, might mark distinct events of matrilineal gene flow to Europe: during the mid-Holocene period and around the Pleistocene-Holocene transition, respectively.


Association between maternal anaemia and postpartum depression in an urban sample of pregnant women in Iran.
The aim of this prospective study was to determine the relationship between anaemia during pregnancy and postpartum depression. Two hundred eighty-one non-anaemic mothers with singleton and low-risk pregnancy and no history of antidepressant-use were studied. Demographic and reproductive data at week 20 were obtained. Mothers were followed up and haemoglobin (Hb) was checked at delivery. Iranian version of Edinburgh Postpartum Depression Scale (EPDS) was completed 4-6 weeks after delivery. Mean age of the mothers was 26.6+/-4 years. The prevalence of postpartum depression according to EPDS was 5.5%. Binary logistic regression analysis showed that Hb <11 g/dL at delivery would increase the chance of postpartum depression (OR 4.64; 95% CI 1.33-16.08). The results show that diagnosis and treatment of physiologic factors, especially anaemia, would reduce the risk of postpartum depression.


Biological markers in noninvasive brain stimulation trials in major depressive disorder: a systematic review.
The therapeutic effects of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation in patients with major depression have shown promising results; however, there is a lack of mechanistic studies using biological markers (BMs) as an outcome. Therefore, our aim was to review noninvasive brain stimulation trials in depression using BMs. The following databases were used for our systematic review: MEDLINE, Web of Science, Cochrane, and SCIELO. We examined articles published before November 2012 that used TMS and transcranial direct current stimulation as an intervention for depression and had BM as an outcome measure. The search was limited to human studies written in English. Of 1234 potential articles, 52 articles were included. Only studies using TMS were found. Biological markers included immune and endocrine serum markers, neuroimaging techniques, and electrophysiological outcomes. In 12 articles (21.4%), end point BM measurements were not significantly associated with clinical outcomes. All studies reached significant results in the main clinical rating scales. Biological marker outcomes were used as predictors of response, to understand mechanisms of TMS, and as a surrogate of safety. Functional magnetic resonance imaging, single-photon emission computed tomography, positron emission tomography, magnetic resonance spectroscopy, cortical excitability, and brain-derived neurotrophic factor consistently showed positive results. Brain-derived neurotrophic factor was the best predictor of patients' likeliness to respond. These initial results are promising; however, all studies investigating BMs are small, used heterogeneous samples, and did not take into account confounders such as age, sex, or family history. Based on our findings, we recommend further studies to validate BMs in noninvasive brain stimulation trials in MDD.


Accurate and rapid 3D printing of microfluidic devices using wavelength selection on a DLP printer.
The use of microfluidics on synchrotron X-ray beamlines represents an advanced sample preparation and delivery platform for state-of-the-art X-ray characterization of micro-samples. The recent developments of 3D printing technologies have opened possibilities for rapid fabrication of complex microfluidic devices. One of the major challenges in 3D printing of microfluidic devices using a digital light processing (DLP) desktop printer is that the static liquid resin trapped in the channels, once the "ceiling" is printed, still receives small doses of light through the subsequently printed layers. This easily triggers partial polymerisation of the resin which impedes its flushing out of the channels after completion of the printing session. We show here that it is possible to gain better control over the resin polymerisation and improve the quality of the microfluidic devices by efficiently reducing the penetration depth of the UV LED light through wavelength selection combined with a careful choice of absorber and photo-initiator materials. We produced and tested several structures using a slightly modified desktop printer at 385 nm wavelength with 37 × 37 μm2 pixel resolution at a printed layer thickness of 25 μm. The structures include particle filters, mixers, droplet generators and droplet storage traps with features below 100 μm. We demonstrate crystallisation of model inorganic and organic compounds in trapped droplets and assess the feasibility of in-device X-ray diffraction experiments. This research opens the path for the use of 3D printed microfluidic devices on X-ray beamlines.


Secondary measures of access to abortion services in the United States, 2011 and 2012: gestational age limits, cost, and harassment.
Aspects of U.S. clinical abortion service provision such as gestational age limits, charges for abortion services, and anti-abortion harassment can impact the accessibility of abortion; this study documents changes in these measures between 2008 and 2012. In 2012 and 2013, we surveyed all known abortion-providing facilities in the United States (n = 1,720). This study summarizes information obtained about gestational age limits, charges, and exposure to anti-abortion harassment among clinics; response rates for relevant items ranged from 54% (gestational limits) to 80% (exposure to harassment). Weights were constructed to compensate for nonresponding facilities. We also examine the distribution of abortions and abortion facilities by region. Almost all abortion facilities (95%) offered abortions at 8 weeks' gestation; 72% did so at 12 weeks, 34% at 20 weeks, and 16% at 24 weeks in 2012. In 2011 and 2012, the median charge for a surgical abortion at 10 weeks gestation was $495, and $500 for an early medication abortion, compared with $503 and $524 (adjusted for inflation) in 2009. In 2011, 84% of clinics experienced at least one form of harassment, only slightly higher than found in 2009. Hospitals and physicians' offices accounted for a substantially smaller proportion of facilities in the Midwest and South. Clinics in the Midwest and South were exposed to more harassment than their counterparts in the Northeast and West. Although there was a substantial decline in abortion incidence between 2008 and 2011, the secondary measures of abortion access examined in this study changed little during this time period.


High Frequency of Recurrent Falls Among Prefrail and Frail Women With and Without HIV.
Frailty may occur at younger ages among HIV+ populations. We evaluated associations of the frailty status with self-reported single and recurrent falls in the Women's Interagency HIV Study (WIHS). The frailty status was defined using the Fried Frailty Phenotype (FFP) among 897 HIV+ and 392 HIV- women; median age 53 years. Women were classified as robust (FFP 0), prefrail (FFP 1-2), and frail (FFP 3-5). Stepwise logistic regression models adjusting for the HIV status and study site were fit to evaluate associations of the FFP with self-reported single (1 vs. 0) and recurrent falls (≥2 vs. 0) over the prior 12 months. HIV+ women were less likely to be frail (9% vs. 14% vs. P = 0.009), but frequency of falls did not differ by the HIV status. In multivariate analyses, recurrent falls were more common among prefrail [adjusted odds ratio (AOR) 2.23, 95% confidence interval (CI): 1.40 to 3.57, P = 0.0008] and frail (AOR 3.61, 95% CI: 1.90 to 6.89, P < 0.0001) than robust women. Among HIV+ women, single (AOR 2.88, 95% CI: 1.16 to 7.20, P = 0.023) and recurrent falls (AOR 3.50, 95% CI: 1.24 to 9.88, P = 0.018) were more common among those who were frail; recurrent, but not single falls, were more common among prefrail than robust HIV+ women (AOR 2.00, 95% CI: 1.03 to 3.91, P = 0.042). HIV+ women were less likely to be frail. Compared with robust women, prefrail and frail women with and without HIV were more likely to experience single or recurrent falls within a 12-month period. Additional studies are needed to develop interventions that decrease development of frailty and reduce risk of recurrent falls among HIV+ women.


Brightness field distributions of microlens arrays using micro molding.
This study describes the brightness field distributions of microlens arrays fabricated by micro injection molding (μIM) and micro injection-compression molding (μICM). The process for fabricating microlens arrays used room-temperature imprint lithography, photoresist reflow, electroforming, μIM, μICM, and optical properties measurement. Analytical results indicate that the brightness field distribution of the molded microlens arrays generated by μICM is better than those made using μIM. Our results further demonstrate that mold temperature is the most important processing parameter for brightness field distribution of molded microlens arrays made by μIM or μICM.


Thymic Hyperplasia Associated with Graves' Disease in a 10-year-old Boy.
Thymic hyperplasia associated with Graves' disease is rarely reported in children, although it is not uncommon in adults. Occasionally, an enlarged thymus presents as an anterior mediastinal mass on a radiographic examination. Such patients often undergo invasive procedures such as a thymus biopsy or thymectomy because of suspected malignancy. However, an enlarged thymus with Graves' disease is known to shrink after treatment with antithyroid drugs. Therefore, recognition of this benign course would avoid unnecessary surgical resection. This report presents the case of a 10-yr-old boy with Graves' disease complicated with an anterior mediastinal mass. Computed tomography showed a homogenous mass with no invasion into the surrounding tissue. A gallium-67 scintigraphy showed no abnormal uptake. Shrinkage of the mass after treatment with an antithyroid drug (methyl-mercaptoimidazole) supported the diagnosis of thymic hyperplasia with Graves' disease. This case report illustrates two important points. First, pediatricians should be aware that thymic hyperplasia can coexist with Graves' disease, even in children. Second, close radiographic assessment would support a diagnosis of thymic hyperplasia and eliminate invasive diagnostic procedures.


Organizing actions of neurosteroids in the Purkinje neuron.
It is becoming clear that steroids can be synthesized de novo by the brain of vertebrates. Such steroids synthesized de novo in the brain, as well as other areas of the nervous system, are called neurosteroids. To understand neurosteroid actions in the brain, we need data on the specific biosynthesis in particular sites of the brain at particular times. Therefore our studies for this exciting area of neuroscience research have focused on the biosynthesis and action of neurosteroids in the identified neurosteroidogenic cells underlying important brain functions. We have demonstrated that the Purkinje cell, a typical cerebellar neuron, is a major site for neurosteroid formation in the brain. This neuron actively synthesizes progesterone and estradiol de novo from cholesterol only during neonatal life, when cerebellar cortical formation occurs dramatically. This is the first observation of neuronal neurosteroidogenesis in the brain. Subsequently the actions of progesterone and estradiol during cerebellar development have become clear by a series of our studies using an excellent Purkinje cellular model. These neurosteroids promote dendritic growth, spinogenesis and synaptogenesis via each receptor in the Purkinje cell. Here we summarize the advances made in our understanding of organizing actions of neurosteroids in the Purkinje cell, an important brain neuron.


Oral lichen planus (OLP), oral lichenoid lesions (OLL), oral dysplasia, and oral cancer: retrospective analysis of clinicopathological data from 2002-2011.
This 10-year retrospective study analyzed the incidence of malignant transformation of oral lichen planus (OLP). The study also included dysplasia and oral lichenoid lesion (OLL) in the initial biopsy as a potential differential diagnosis. A total of 692 scalpel biopsies were taken from 542 patients (207 [38.2%] men and 335 [61.8%] women). Clinical and histopathological parameters were analyzed. The parameters gender (p = 0.022) and smoking behavior (p < 0.001) were significantly associated with the severity of diagnosis. Mucosal lesions with an ulcerative appearance (p = 0.006) and those located on the floor of the mouth (p < 0.001) showed significantly higher degrees of dysplasia or were diagnosed as oral squamous cell carcinoma (OSCC). Smoking and joint disease appeared to be significant risk factors. Treatment with tretinoin in different concentrations (0.005-0.02%) significantly improved diagnosis. Twelve patients (8 female, 4 male) showed malignant transformation to OSCC within an average period of 1.58 years. The malignant transformation rate (MTR) was higher for OLL (4.4%) than OLP (1.2%). If the first biopsy showed intraepithelial neoplasia, the risk of developing OSCC increased (by 3.5% for squamous intraepithelial neoplasia (SIN) II and by 6.7% for SIN III). Although we cannot rule out that OLP is a premalignant oral condition, we can confirm that OLP had the lowest MTR of all diagnoses.


Negotiating jurisdictional boundaries in response to new genetic possibilities in breast cancer care: The creation of an 'oncogenetic taskscape'.
Changes in the nature and structure of healthcare pathways have implications for healthcare professionals' jurisdictional boundaries. The introduction of treatment focused BRCA1 and 2 genetic testing (TFGT) for newly diagnosed patients with breast cancer offers a contemporary example of pathway change brought about by technological advancements in gene testing and clinical evidence, and reflects the cultural shift towards genomics. Forming part of an ethnographically informed study of patient and practitioner experiences of TFGT at a UK teaching hospital, this paper focuses on the impact of a proposal to pilot a mainstreamed TFGT pathway on healthcare professionals' negotiations of professional jurisdiction. Based upon semi-structured interviews (n = 19) with breast surgeons, medical oncologists and members of the genetics team, alongside observations of breast multidisciplinary team meetings, during the time leading up to the implementation of the pilot, we describe how clinicians responded to the anticipated changes associated with mainstreaming. Interviews suggest that mainstreaming the breast cancer pathway, and the associated jurisdictional reconfigurations, had advocates as well as detractors. Medical oncologists championed the plans, viewing this adaptation in care provision and their professional role as a logical next step. Breast surgeons, however, regarded mainstreaming as an unfeasible expansion of their workload and questioned the relevance of TFGT to their clinical practice. The genetics team, who introduced the pilot, appeared cautiously optimistic about the potential changes. Drawing on sociological understandings of the negotiation of professional jurisdictions our work contributes a timely, micro-level examination of the responses among clinicians as they worked to renegotiate professional boundaries in response to the innovative application of treatment-focused BRCA testing in cancer care - a local and dynamic process which we refer to as an 'oncogenetic taskscape in the making'.


Comparison of trends in the quantity and variety of Science Citation Index (SCI) literature on human pathogens between China and the United States.
The proportion of pathogenic microorganisms in the microbial world is relatively small, while their threat to human health, economic development and social stability is severe. The quantity and variation of Science Citation Index (SCI) literature related to pathogenic microorganisms may reflect the level of relevant research and the degree of attention. Here we compared trends in the quantity and variety of SCI literature relating to certain important pathogenic microorganisms published by scientists from United States and China from 1996 to 2010 by searching the Science Citation Index database. The pathogenic microorganisms in this study comprise two categories of pathogens: Bacillus anthracis, Yersinia pestis, Francisella tularensis, Ebola virus, Burkholderia pseudomallei, which belong to biodefense-associated pathogens (BDAPs) and the human immunodeficiency virus (HIV), SARS coronavirus, hepatitis B virus (HBV), Mycobacterium tuberculosis, influenza virus, which belong to the commonly encountered health-threatening pathogens. Our results showed that the United States (US) published much more SCI literature on these pathogens than China. Furthermore, literature on BDAPs published by scientists from the US has increased sharply since 2002. However, the numbers of literature relating to CEHTPs from China has demonstrated a gradual increase from 1996 to 2010. Research into pathogenic microorganisms requires three balance to be achieved: investment in BDAP and CEHTP studies; basic and applied research; a faster pace of research into pathogens and fulfilling biosafety and biosecurity requirements.


Ascorbic acid: new role of an age-old micronutrient in the management of periodontal disease in older adults.
To review the new role of an age-old micronutrient - ascorbic acid - in the management of periodontal disease. Articles pertaining to the topic were searched in PubMed and other search engines from year 1974 to April 2014 with the following key words: "ascorbic acid," "ascorbate," "vitamin C," "periodontal disease," "gingivitis," "periodontitis," "anti-oxidants" and "elderly." Balanced nutrition is an essential factor in the elderly. Modification of nutritional requirement is important to overcome the effect of an unbalanced diet in older individuals as a result of several external and internal host-associated factors. Micronutrient requirements as aging advances could change, and require due attention. Ascorbic acid and its relationship with periodontal disease are very well known. However, recent changes in the concept of understanding the pathogenicity has led to a new path of therapeutic intervention with ascorbic acid in many chronic diseases. Oxidative stress with its associated burden might alter the disease process. In the era of "periodontal medicine," the impact of remote tissue changes on systemic disease has to be taken into serious consideration. Deficiency of nutritional impact on the host, with micronutrient vitamin C detailed in this review with sources, absorption, interaction and its relationship with systemic disease, and thereby the impact on periodontal disease. Ascorbic acid plays an important role in the aging process, and in the maintenance of periodontal health in the elderly.


Interaction between microbiota and immunity in health and disease.
The interplay between the commensal microbiota and the mammalian immune system development and function includes multifold interactions in homeostasis and disease. The microbiome plays critical roles in the training and development of major components of the host's innate and adaptive immune system, while the immune system orchestrates the maintenance of key features of host-microbe symbiosis. In a genetically susceptible host, imbalances in microbiota-immunity interactions under defined environmental contexts are believed to contribute to the pathogenesis of a multitude of immune-mediated disorders. Here, we review features of microbiome-immunity crosstalk and their roles in health and disease, while providing examples of molecular mechanisms orchestrating these interactions in the intestine and extra-intestinal organs. We highlight aspects of the current knowledge, challenges and limitations in achieving causal understanding of host immune-microbiome interactions, as well as their impact on immune-mediated diseases, and discuss how these insights may translate towards future development of microbiome-targeted therapeutic interventions.


Atomic force microscopy of DNA and bacteriophage in air, water and propanol: the role of adhesion forces.
We have developed a chemical treatment for the mica surface which allows biopolymers to be held in place for atomic force microscopy, even under water, using conventional, untreated force sensing tips. We illustrate the procedure with images of lambda DNA and fd phage. The phage adheres well enough to permit in situ imaging of the adsorption process in water. These experiments yield a mean length for the phage of 883 +/- 72 nm. This compares with a measured length of 883 +/- 33 nm when the phage are imaged after drying following adsorption from water, showing that the effect of dehydration is quite small. Adhesion forces between the force sensing tip and the substrate and the sensing tip and the biomolecules are very different in the three media (air, water and propanol). The apparent height of the phage and the width and height of the DNA depends upon these adhesion forces quite strongly. In contrast, changing the Hookean spring force exerted by the scanning tip makes little difference. These results suggest that the chemical factors involved in adhesion can dominate atomic force images and that the composition of the scanning tip is at least as important a factor as its geometry.


An evaluation of the clinical and cost-effectiveness of pulmonary artery catheters in patient management in intensive care: a systematic review and a randomised controlled trial.
To evaluate the clinical and cost-effectiveness of managing critically ill patients in adult, general intensive care with or without pulmonary artery catheters (PACs). An open, multi-centre, randomised controlled trial with economic evaluation (cost-utility and cost-effectiveness analysis). The setting was general (mixed medical/surgical) intensive care units (ICUs) in the UK admitting adults. Adult patients in participating ICUs deemed by the responsible treating clinician to require management with a PAC. These were insertion of a PAC and subsequent clinical management, at the discretion of the responsible treating clinicians, using data derived from the PAC. The control group were managed without a PAC but with the option of using alternative cardiac output monitoring devices. The main outcome measure was hospital mortality. Secondary outcome measures were length of stay in the ICU, length of stay in an acute hospital and organ-days of support in the ICU. For the economic evaluation, the main outcome measure was quality-adjusted life-years (QALYs) and the secondary outcome measure was hospital mortality. Sixty-five ICUs in the UK participated. Of these, 43 (66%) used alternative cardiac output monitoring devices in control group patients. A total of 1263 patients were identified as being eligible for the trial. Of these, 1041 (82.4%) were randomised and allocated to management with (n = 519) or without (n = 522) a PAC. There were no losses to follow-up. However, 27 patients (13 in the PAC group and 14 in the control group) were withdrawn from the trial because either the patient withdrew consent on recovering mental competency or the relatives withdrew agreement following randomisation. Data on 1014 patients were included in the analysis. Participants in the two groups had similar baseline characteristics. There was no difference in hospital mortality for patients managed with (68.4%) or without (65.7%) a PAC. The adjusted hazard ratio (PAC versus no PAC) was 1.09 [95% confidence interval (CI) 0.94 to 1.27]. There was no difference in the median length of stay in ICU, the median length of stay in an acute hospital or mean organ-days of support in ICU between the two groups. The economic evaluation found that the expected cost per QALY gained from the withdrawal of PAC was 2985 pounds. The expected cost per life gained from the withdrawal of PAC was 22,038 pounds. Clinical management of critically ill patients with a PAC, as currently practised in the UK, neither improves hospital survival for adult, general intensive care patients nor reduces length of stay in hospital. The lack of demonstrable benefit from a device previously believed to be beneficial could be explained by statistical chance, by misinterpretation of PAC-derived data, by ineffective treatment strategies based on data correctly interpreted using the current paradigm or by subsequent inaction following insertion of the device. It is also possible that detailed data on haemodynamics, however used, cannot modify the disease process sufficiently to influence disease outcome. The economic evaluation, using decision analysis techniques rather than conventional hypothesis testing, suggests that the withdrawal of the PAC from routine clinical practice in the NHS would be considered cost-effective in the current decision-making climate, and might result in lives or life-years being saved at modest cost. With the declining use of PACs in the UK and the findings of this report indicating no overall benefit from management with a PAC, it should now be possible to examine protocolised management with a PAC in selected groups of critically ill patients against appropriate controls, something that was difficult while PACs were the considered standard of care.


In vivo rat pancreatic acinar cell function during supramaximal stimulation with caerulein.
Infusion of a supramaximal dose of caerulein results in acute interstitial pancreatitis in rats. We report studies of in vivo pancreatic acinar cell function during the initial 3.5 h of supramaximal stimulation with caerulein (5 micrograms X kg-1 X h-1). Amino acid [( 3H]phenylalanine) uptake was not altered, and there was no change in the rate or extent of protein synthesis or in intracellular transport of in vivo pulse-labeled proteins from microsome to zymogen granule-enriched fractions. However, the discharge of labeled protein was markedly inhibited. Radioautographic studies indicated that the pulse-labeled proteins retained in the gland were not located extracellularly but had accumulated within acinar cells, with a preferential distribution at the cell apex (presumably in zymogen granules) and in large vacuoles that form within the cell during hyperstimulation. Supramaximal stimulation with caerulein also caused increasing amounts of amylase and labeled proteins to be recovered in the postmicrosomal fraction. These findings suggest that supramaximal stimulation causes digestive enzymes to become localized in organelles that are fragile and subject to disruption during tissue homogenization. These organelles may be the vacuoles noted in morphological studies and believed to represent immature condensing vacuoles and/or crinophagic vacuoles.


Characterization of the antibodies to p62 nucleoporin in primary biliary cirrhosis using human recombinant antigen.
Reactivity of sera from patients with primary biliary cirrhosis (PBC) with a 60 kDa component of nuclear pore complexes (NPCs), purified by affinity chromatography on wheat-germ agglutinin (WGA)-Sepharose, was previously detected. Recently, clinical significance of the anti-NPC antibodies in PBC became evident. In the light of recent reports, indicating the correlation of the anti-NPC antibodies with severity and progression of the disease, the characterization of the reactive antigens is becoming essential in the clinical management of patients with PBC. Since accurate autoantibody detection represents one of the fundamental requirements for a reliable testing, we have generated a human recombinant p62 protein and validated an immunoprecipitation assay for the detection of anti-p62. We also demonstrated that the generated human recombinant p62 nucleoporin was modified by N-acetylglucosamine residues. More than 50% of tested PBC sera precipitated (35)S-radioactively labeled p62 recombinant nucleoporin and 40% recognized this recombinant antigen by immunoblotting. We compared the reactivity of PBC sera with rat and human nucleoporin. The incidence of anti-p62 nucleoporin positive PBC sera increased by 15% when human recombinant antigen was used. The titer of autoantibodies in p62-positive PBC samples strongly varied. Preadsorption of the PBC sera with p62 recombinant protein completely abolished their reactivity with the antigen. In conclusion, this study unequivocally proves that autoantibodies reacting with the 60 kDa component of NPCs target p62 nucleoporin and, more importantly, provide a better antigen source for future evaluations of the clinical role of anti-p62 in PBC.


Multidisciplinary baseline assessment of homosexual men with and without human immunodeficiency virus infection. I. Overview of study design.
Although much is known about the virus believed by most experts to be the cause of the acquired immunodeficiency syndrome and about its pathogenic actions, major areas of ignorance remain. Among these are the reasons for the varying time between infection with human immunodeficiency virus and development of acquired immunodeficiency syndrome, the relationship between neurologic and medical aspects of the disease, the time course of neuropsychological findings, and the prevalence of psychiatric morbidity. We assessed 124 homosexual men who were positive for human immunodeficiency virus and 84 who were negative for the virus. In this article we describe the study design, method of recruitment, and medical and demographic characteristics of the cohort, which will be followed up for 5 years.


Comparative retinal morphology of the platypus.
The purpose of this study is to identify evolutionary origin and fate of anatomic features of the duck-billed platypus eye. Eyes from the duck-billed platypus and four key evolutionary basal vertebrates (Pacific hagfish, north hemisphere sea lamprey, and Australian and South American lungfishes) were prepared for light microscopy. In addition to a standard panel of stains, tissues were immunostained against a variety of rod and cone opsins. Finally, published opsin sequences of platypus and several other vertebrate species were aligned and compared with immunohistochemical results. A complete scleral cartilage similar to that seen in birds, reptiles and amphibians encloses the platypus eye. This feature is present in sharks and rays, and in extant relatives of tetrapods, the lungfishes. The choroid lacks a tapetum. The retina is largely avascular and is rod-dominated, with a minority of red- and blue- cone immunoreactive photoreceptors. Like marsupials and many nonmammalian vertebrates, cones contain clear inner segment droplets. Double cones were present, a feature not found in eutherian mammals or marsupials. Evaluation of opsins indicates that red and blue immunoreactive cone opsins, but not rhodopsin, are present in the most basal of the extant species examined, the Pacific hagfish. Rhodopsin appears in the Australian and South American lungfishes, establishing emergence of this pigment in an extant relative of tetrapods. Unlike eyes of eutherian mammals, the platypus eye has retained morphologic features present in early tetrapods such as amphibians and their evolutionarily basal sister group, the lungfishes. These include scleral cartilage, double cones and cone droplets. In the platypus, as in other mammals, rod rhodopsin is the predominant photoreceptor pigment, at expense of the cone system.


Bayesian isotonic regression and trend analysis.
In many applications, the mean of a response variable can be assumed to be a nondecreasing function of a continuous predictor, controlling for covariates. In such cases, interest often focuses on estimating the regression function, while also assessing evidence of an association. This article proposes a new framework for Bayesian isotonic regression and order-restricted inference. Approximating the regression function with a high-dimensional piecewise linear model, the nondecreasing constraint is incorporated through a prior distribution for the slopes consisting of a product mixture of point masses (accounting for flat regions) and truncated normal densities. To borrow information across the intervals and smooth the curve, the prior is formulated as a latent autoregressive normal process. This structure facilitates efficient posterior computation, since the full conditional distributions of the parameters have simple conjugate forms. Point and interval estimates of the regression function and posterior probabilities of an association for different regions of the predictor can be estimated from a single MCMC run. Generalizations to categorical outcomes and multiple predictors are described, and the approach is applied to an epidemiology application.


Identification of a metaplastic cell lineage associated with human gastric adenocarcinoma.
Metaplastic cell lineages arising in response to chronic injury are precursors for the evolution of dysplasia and adenocarcinoma. Although a subtype of intestinal metaplasia has been associated with gastric adenocarcinoma, the link between this lineage and the evolution of gastric adenocarcinoma has remained unclear. Wang et al (1998) have reported that an aberrant metaplastic cell lineage with morphological characteristics similar to Brunner's glands of the duodenum develops in the fundic mucosa of mice infected with Helicobacter felis. This metaplastic lineage expresses the trefoil peptide spasmolytic polypeptide (SP). Given the epidemiological association of Helicobacter species infection with gastric cancer, we hypothesized that this SP-expressing metaplastic (SPEM) lineage may represent a precursor to or appear commensurate with gastric adenocarcinoma. The SPEM lineage was present in 68% of fundic biopsies from patients with fundic Helicobacterpylori-associated gastritis, but was absent in biopsies of fundic mucosa from patients without H. pylori infection. In a review of archival samples from 22 resected gastric adenocarcinomas, we found the SPEM lineage in 91% of cases, typically located in mucosa adjacent to the carcinoma or areas of dysplasia. Importantly, 59% of resections showed SP immunoreactivity within dysplastic cells. These data indicate a strong association of the SPEM lineage with both chronic H. pylori infection and gastric adenocarcinoma.


Weak chaos and the "melting transition" in a confined microplasma system.
We present results demonstrating the occurrence of changes in the collective dynamics of a Hamiltonian system which describes a confined microplasma characterized by long-range Coulomb interactions. In its lower energy regime, we first detect macroscopically the transition from a "crystallinelike" to a "liquidlike" behavior, which we call the "melting transition." We then proceed to study this transition using a microscopic chaos indicator called the smaller alignment index (SALI), which utilizes two deviation vectors in the tangent dynamics of the flow and is nearly constant for ordered (quasiperiodic) orbits, while it decays exponentially to zero for chaotic orbits as exp[-(lambda(1)-lambda(2))t], where lambda(1)>lambda(2)>0 are the two largest Lyapunov exponents. During the melting phase, SALI exhibits a peculiar stairlike decay to zero, reminiscent of "sticky" orbits of Hamiltonian systems near the boundaries of resonance islands. This alerts us to the importance of the Deltalambda=lambda(1)-lambda(2) variations in that regime and helps us identify the energy range over which "melting" occurs as a multistage diffusion process through weakly chaotic layers in the phase space of the microplasma. Additional evidence supporting further the above findings is given by examining the GALI(k) indices, which generalize SALI (=GALI(2)) to the case of k>2 deviation vectors and depend on the complete spectrum of Lyapunov exponents of the tangent flow about the reference orbit.


Sex differences in common Marmosets (Callithrix jacchus) in response to an unfamiliar food task.
There is a growing body of information on sex differences in callitrichid behaviour that includes the animals' performance in food tasks. For example, both reproductive and non-reproductive adult females have been found to be more successful than adult males in solving food tasks. In this study ten adult male and ten adult female common marmosets (Callithrix jacchus), housed individually, were tested with an unfamiliar task that involved the extraction of an embedded food. The task was to open a plastic canister that contained a raisin; the open end was covered with parchment paper. Each marmoset was given 15 trials in three blocks of 5 consecutive days. We measured the latency for each animal to open the lid and get the raisin--by one of five strategies that spontaneously emerged. The females learned the task faster and more efficiently than males; all the females opened the canister on day 1, for instance, in contrast to seven of the males on the same day. Females also progressively decreased the time that they took to open the tube. The final latency on day 15, for instance, was significantly shorter for the females. These results are consistent with relevant literature for callitrichids and cannot be accounted for in terms of differences in mental abilities, strength, hand morphology, or energy requirements. Further investigation is necessary to clarify the reasons for these differences.


Bis(imino)pyridine cobalt-catalyzed dehydrogenative silylation of alkenes: scope, mechanism, and origins of selective allylsilane formation.
The aryl-substituted bis(imino)pyridine cobalt methyl complex, ((Mes)PDI)CoCH3 ((Mes)PDI = 2,6-(2,4,6-Me3C6H2-N═CMe)2C5H3N), promotes the catalytic dehydrogenative silylation of linear α-olefins to selectively form the corresponding allylsilanes with commercially relevant tertiary silanes such as (Me3SiO)2MeSiH and (EtO)3SiH. Dehydrogenative silylation of internal olefins such as cis- and trans-4-octene also exclusively produces the allylsilane with the silicon located at the terminus of the hydrocarbon chain, resulting in a highly selective base-metal-catalyzed method for the remote functionalization of C-H bonds with retention of unsaturation. The cobalt-catalyzed reactions also enable inexpensive α-olefins to serve as functional equivalents of the more valuable α, ω-dienes and offer a unique method for the cross-linking of silicone fluids with well-defined carbon spacers. Stoichiometric experiments and deuterium labeling studies support activation of the cobalt alkyl precursor to form a putative cobalt silyl, which undergoes 2,1-insertion of the alkene followed by selective β-hydrogen elimination from the carbon distal from the large tertiary silyl group and accounts for the observed selectivity for allylsilane formation.


The path from anti Parkinson drug selegiline and rasagiline to multifunctional neuroprotective anti Alzheimer drugs ladostigil and m30.
The therapeutic use of enzyme inhibitors in treatment of neurodegenerative diseases has its origin in the anti Parkinson action of the selective monoamine oxidase (MAO) B inhibitor, l-deprenyl (selegiline ), a failed anti depressant in 1975. This led to further development of MAO- A and B, catechol-O-methyltansferase and cholinestrerase inhibitors as anti Parkinson and Alzheimer drugs. One of the main reasons for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB) is degeneration of cholinergic cortical neurones and synaptic plasticity. This led to a correlation that similar to Parkinson's Disease (PD), cholinesterase inhibitors (ChEI) may also have therapeutic activity in AD. Significant percentage of AD and DLB subjects also nigrostriatal dopaminergic, locus ceruleous noradrenergic and raphe nucleus serotoninergic neurones. The present ChEI anti AD drugs have limited symptomatic activity and devoid of neuroprotective property that is needed for disease modifying action. It is becoming clear that there are no magic bullets for neurodegenerative disorders and shut gun approach is needed either as polypharmacology or drugs with multiple activity at different target sites in the CNS. The complex pathology of AD as well as cascade of events that leads to the neurodegenerative process has led us to develop several multifunctional neuroprotective drugs with several CNS targets with possible disease modifying activity. Employing the pharamcophore of our antiparkinson drug rasagiline (Azilect, Agilect, N-propagrgyl-1R-aminoindan) we have developed a novel multifunctional neuroprotective drug, ladostigil [TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate)], with both cholinesterase-butyrylesterase (Ch-BuE) and brain selective monoamine-oxidase (MAO) AB inhibitory activities possessing the neuroprotective-neurescue propargyl moiety, as potential treatment of AD and DLB and PD with dementias. Since brain MAO and iron increase in AD, PD and ageing, that could lead to iron dependent oxidative stress neurodegeneration, we have developed another series of multifunctional drugs (M30 HLA-20 series) which are brain permeable iron chelators- brain selective MAO inhibitors and possess the propargyl neuroprotective moiety. These series of drugs have the ability of regulating and processing APP (amyloid precursor protein) and reducing Abeta peptide, since APP is a metaloprotein, with an iron responsive element 5d'UTR similar to transferring and ferritin.


Human CD34+ CD133+ hematopoietic stem cells cultured with growth factors including Angptl5 efficiently engraft adult NOD-SCID Il2rγ-/- (NSG) mice.
Increasing demand for human hematopoietic stem cells (HSCs) in clinical and research applications necessitates expansion of HSCs in vitro. Before these cells can be used they must be carefully evaluated to assess their stem cell activity. Here, we expanded cord blood CD34(+) CD133(+) cells in a defined medium containing angiopoietin like 5 and insulin-like growth factor binding protein 2 and evaluated the cells for stem cell activity in NOD-SCID Il2rg(-/-) (NSG) mice by multi-lineage engraftment, long term reconstitution, limiting dilution and serial reconstitution. The phenotype of expanded cells was characterized by flow cytometry during the course of expansion and following engraftment in mice. We show that the SCID repopulating activity resides in the CD34(+) CD133(+) fraction of expanded cells and that CD34(+) CD133(+) cell number correlates with SCID repopulating activity before and after culture. The expanded cells mediate long-term hematopoiesis and serial reconstitution in NSG mice. Furthermore, they efficiently reconstitute not only neonate but also adult NSG recipients, generating human blood cell populations similar to those reported in mice reconstituted with uncultured human HSCs. These findings suggest an expansion of long term HSCs in our culture and show that expression of CD34 and CD133 serves as a marker for HSC activity in human cord blood cell cultures. The ability to expand human HSCs in vitro should facilitate clinical use of HSCs and large-scale construction of humanized mice from the same donor for research applications.


Detection of Vibrio cholerae O1 and O139 in environmental waters of rural Bangladesh: a flow-cytometry-based field trial.
Presence of Vibrio cholerae serogroups O1 and O139 in the waters of the rural area of Matlab, Bangladesh, was investigated with quantitative measurements performed with a portable flow cytometer. The relevance of this work relates to the testing of a field-adapted measurement protocol that might prove useful for cholera epidemic surveillance and for validation of mathematical models. Water samples were collected from different water bodies that constitute the hydrological system of the region, a well-known endemic area for cholera. Water was retrieved from ponds, river waters, and irrigation canals during an inter-epidemic time period. Each sample was filtered and analysed with a flow cytometer for a fast determination of V. cholerae cells contained in those environments. More specifically, samples were treated with O1- and O139-specific antibodies, which allowed precise flow-cytometry-based concentration measurements. Both serogroups were present in the environmental waters with a consistent dominance of V. cholerae O1. These results extend earlier studies where V. cholerae O1 and O139 were mostly detected during times of cholera epidemics using standard culturing techniques. Furthermore, our results confirm that an important fraction of the ponds' host populations of V. cholerae are able to self-sustain even when cholera cases are scarce. Those contaminated ponds may constitute a natural reservoir for cholera endemicity in the Matlab region. Correlations of V. cholerae concentrations with environmental factors and the spatial distribution of V. cholerae populations are also discussed.


First evidence of cholinesterase-like activity in Basidiomycota.
Cholinesterases (ChE), the enzymes whose primary function is the hydrolysis of choline esters, are widely expressed throughout the nature. Although they have already been found in plants and microorganisms, including ascomycete fungi, this study is the first report of ChE-like activity in fungi of the phylum Basidiomycota. This activity was detected in almost a quarter of the 45 tested aqueous fungal extracts. The ability of these extracts to hydrolyse acetylthiocholine was about ten times stronger than the hydrolytic activity towards butyrylthiocholine and propionylthiocholine. In-gel detection of ChE-like activity with acetylthiocholine indicated a great variability in the characteristics of these enzymes which are not characterized as vertebrate-like based on (i) differences in inhibition by excess substrate, (ii) susceptibility to different vertebrate acetylcholinesterase and butyrylcholinesterase inhibitors, and (iii) a lack of orthologs using phylogenetic analysis. Limited inhibition by single inhibitors and multiple activity bands using in-gel detection indicate the presence of several ChE-like enzymes in these aqueous extracts. We also observed inhibitory activity of the same aqueous mushroom extracts against insect acetylcholinesterase in 10 of the 45 samples tested; activity was independent of the presence of ChE-like activity in extracts. Both ChE-like activities with different substrates and the ability of extracts to inhibit insect acetylcholinesterase were not restricted to any fungal family but were rather present across all included Basidiomycota families. This study can serve as a platform for further research regarding ChE activity in mushrooms.


The organizational dynamics enabling patient portal impacts upon organizational performance and patient health: a qualitative study of Kaiser Permanente.
Patient portals may lead to enhanced disease management, health plan retention, changes in channel utilization, and lower environmental waste. However, despite growing research on patient portals and their effects, our understanding of the organizational dynamics that explain how effects come about is limited. This paper uses qualitative methods to advance our understanding of the organizational dynamics that influence the impact of a patient portal on organizational performance and patient health. The study setting is Kaiser Permanente, the world's largest not-for-profit integrated delivery system, which has been using a portal for over ten years. We interviewed eighteen physician leaders and executives particularly knowledgeable about the portal to learn about how they believe the patient portal works and what organizational factors affect its workings. Our analytical framework centered on two research questions. (1) How does the patient portal impact care delivery to produce the documented effects?; and (2) What are the important organizational factors that influence the patient portal's development? We identify five ways in which the patient portal may impact care delivery to produce reported effects. First, the portal's ability to ease access to services improves some patients' satisfaction as well as changes the way patients seek care. Second, the transparency and activation of information enable some patients to better manage their care. Third, care management may also be improved through augmented patient-physician interaction. This augmented interaction may also increase the 'stickiness' of some patients to their providers. Forth, a similar effect may be triggered by a closer connection between Kaiser Permanente and patients, which may reduce the likelihood that patients will switch health plans. Finally, the portal may induce efficiencies in physician workflow and administrative tasks, stimulating certain operational savings and deeper involvement of patients in medical decisions. Moreover, our analysis illuminated seven organizational factors of particular importance to the portal's development--and thereby ability to impact care delivery: alignment with financial incentives, synergy with existing IT infrastructure and operations, physician-led governance, inclusive decision making and knowledge sharing, regional flexibility to implementation, continuous innovation, and emphasis on patient-centered design. These findings show how organizational dynamics enable the patient portal to affect care delivery by summoning organization-wide support for and use of a portal that meets patient needs.


A computational physiology approach to personalized treatment models: the beneficial effects of slow breathing on the human cardiovascular system.
Heart rate variability biofeedback intervention involves slow breathing at a rate of ∼6 breaths/min (resonance breathing) to maximize respiratory and baroreflex effects on heart period oscillations. This intervention has wide-ranging clinical benefits and is gaining empirical support as an adjunct therapy for biobehavioral disorders, including asthma and depression. Yet, little is known about the system-level cardiovascular changes that occur during resonance breathing or the extent to which individuals differ in cardiovascular benefit. This study used a computational physiology approach to dynamically model the human cardiovascular system at rest and during resonance breathing. Noninvasive measurements of heart period, beat-to-beat systolic and diastolic blood pressure, and respiration period were obtained from 24 healthy young men and women. A model with respiration as input was parameterized to better understand how the cardiovascular processes that control variability in heart period and blood pressure change from rest to resonance breathing. The cost function used in model calibration corresponded to the difference between the experimental data and model outputs. A good match was observed between the data and model outputs (heart period, blood pressure, and corresponding power spectral densities). Significant improvements in several modeled cardiovascular functions (e.g., blood flow to internal organs, sensitivity of the sympathetic component of the baroreflex, ventricular elastance) were observed during resonance breathing. Individual differences in the magnitude and nature of these dynamic responses suggest that computational physiology may be clinically useful for tailoring heart rate variability biofeedback interventions for the needs of individual patients.


PhenX RISING: real world implementation and sharing of PhenX measures.
The purpose of this manuscript is to describe the PhenX RISING network and the site experiences in the implementation of PhenX measures into ongoing population-based genomic studies. Eighty PhenX measures were implemented across the seven PhenX RISING groups, thirty-three of which were used at more than two sites, allowing for cross-site collaboration. Each site used between four and 37 individual measures and five of the sites are validating the PhenX measures through comparison with other study measures. Self-administered and computer-based administration modes are being evaluated at several sites which required changes to the original PhenX Toolkit protocols. A network-wide data use agreement was developed to facilitate data sharing and collaboration. PhenX Toolkit measures have been collected for more than 17,000 participants across the PhenX RISING network. The process of implementation provided information that was used to improve the PhenX Toolkit. The Toolkit was revised to allow researchers to select self- or interviewer administration when creating the data collection worksheets and ranges of specimens necessary to run biological assays has been added to the Toolkit. The PhenX RISING network has demonstrated that the PhenX Toolkit measures can be implemented successfully in ongoing genomic studies. The next step will be to conduct gene/environment studies.


Antiretroviral therapy (ART) for treating HIV infection in ART-eligible pregnant women.
This systematic review focuses on antiretroviral therapy (ART) for treating human immunodeficiency virus (HIV) infection in ART-eligible pregnant women. Mother-to-child transmission (MTCT) is the primary means by which children worldwide acquire HIV infection. MTCT occurs during three major timepoints during pregnancy and the postpartum period: in utero, intrapartum, and during breastfeeding. Strategies to reduce MTCT focus on these periods of exposure and include maternal and infant use of ART, caesarean section before onset of labour or rupture of membranes, and complete avoidance of breastfeeding. Where these combined interventions are available, the risk of MTCT is as low as 1-2%. Thus, ART used among mothers who require treatment of HIV for their own health also plays a significant role in decreasing MTCT.This review is one in a series of systematic reviews performed in preparation for the revision of the 2006 World Health Organization (WHO) Guidelines regarding "Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants" and "Antiretroviral therapy (ART) for HIV Infections in Adults and Adolescents." The findings from these reviews were discussed with experts, key stakeholders, and country representatives at the 2009 WHO guideline review meeting. The resulting WHO 2009 "rapid advice" preliminary guidance on adult and adolescent ART now recommends lifelong treatment for all adults with HIV infection and CD4 counts <350 cells/mm(3). These recommendations also apply to pregnant women who are HIV-infected and they place a high value on early ART to benefit the mother's own health (WHO 2009). The "rapid advice" preliminary guidance also aims to minimize side effects for mothers and their infants (WHO 2009). Our objective was to assess the current literature regarding the treatment of HIV infection in pregnant women who are clinically or immunologically eligible for ART. This review includes an evaluation of the optimal time to start therapy in relation to the woman's laboratory parameters and/or gestational age. It also includes an analysis of which specific antiretroviral medications to start in women who are not yet on ART and which agents to continue in women who are already on ART. In June 2009, electronic searches were undertaken in these databases: Cochrane's "CENTRAL," EMBASE, PubMed, LILACS, and Web of Science/Web of Social Science. Hand searches were performed of the reference lists of all pertinent reviews and studies identified. Abstracts from relevant conferences were searched. Experts in the field were contacted to locate additional studies. The search strategy was iterative. We selected randomized controlled trials and observational studies that evaluated pregnant women with HIV infection who were eligible for ART according to criteria defined by the WHO guideline review committee. Studies were included in the systematic review when a comparison group was clearly defined and where the intervention comprised triple ART. For a study to be considered, each medication in the ART regimen needed to be clearly described. Two authors independently assessed the selected studies for relevance and inclusion. Relevant data was then extracted from included studies, and the risk of bias assessed. In each included study, the relative risk (RR) for the intervention versus the comparison group was calculated for each outcome, as appropriate, with 95% confidence intervals (CIs). To our knowledge, there are no randomized controlled trials or observational studies that address the optimal time to start antiretroviral drugs in ART-eligible pregnant women in relation to the woman's laboratory parameters and/or gestational age. The medications to continue in ART-eligible pregnant women who are already receiving ART also have not been evaluated systematically in the current literature. The long-term mortality of HIV-positive pregnant women on ART for their own health, and the long-term virologic or clinical efficacy of ART in treating them, has not been evaluated in randomized clinical trials. In this review, surrogate outcomes for long-term mortality and virologic and clinical efficacy (e.g. MTCT and infant HIV transmission or death) were evaluated to determine the efficacy of specific antiretroviral regimens to start in women who are not yet on ART.Three randomized controlled trials and six observational studies were selected. No studies addressed comparative maternal mortality, which regimens to continue in women already on ART, or the laboratory parameters and gestational age at which to start therapy. The use of zidovudine (AZT), lamivudine (3TC) and lopinavir/ritonavir (LPV-r) starting at 28-36 weeks gestation in a breastfeeding population reduced infant HIV-transmission or death at 12 months compared to a short-course regimen (RR 0.64, 95% CI: 0.44-0.92) (deVincenzi, 2009). Starting AZT, 3TC, and nevirapine (NVP) at 34 weeks in a mixed-feeding population reduced infant HIV-transmission or death at 7 months compared to a short-course regimen (RR 0.39, 95% CI: 0.12-0.85) (Bae, 2008).In the Mma Bana study (a randomized controlled trial in a breastfeeding population) there was no difference in MTCT at six months between the AZT/3TC/LPV-r and AZT, 3TC, and abacavir (ABC) arms (RR 0.17, 95% CI: 0.02-1.44) (Shapiro, 2009). Both regimens also showed 92-95% efficacy in virologic suppression at delivery and during the breastfeeding period. In the Kesho Bora study there was a significant difference in MTCT at 12 months between breastfeeding women who initiated AZT/3TC/LPV-r starting between 28 and 36 weeks and those receiving a short course regimen (RR 0.58, 95% CI: 0.34-0.97) (deVincenzi, 2009). MTCT also decreased significantly when AZT/3TC/NVP was compared with a short-course regimen at seven months in a feeding intervention study (RR 0.15, 95% CI: 0.04-0.62) (Bae, 2008) and 12 months in a population where either exclusive breastfeeding or replacement feeding was encouraged (RR 0.14, CI: 0.04-0.47) (Ekouevi, 2008).In the Mma Bana study, there was increased risk of prematurity among infants born to women receiving AZT/3TC/LPV-r (RR 1.52, CI: 1.07- 2.17) compared with AZT/3TC/ABC (Shapiro, 2009). Ekouevi 2008 showed higher rates of infant low birth weight on AZT/3TC/NVP started at 24 weeks compared to a short course regimen started between 32 and 36 weeks (RR 1.81, 95% CI: 1.09- 3.0). Tonwe-Gold 2007 showed an increase in maternal severe adverse events among the women receiving AZT/3TC/NVP compared with a short-course regimen (RR 25.33, CI 1.49- 340.51). In ART-eligible pregnant women with HIV infection, ART is a safe and effective means of providing maternal virologic suppression, decreasing infant mortality, and reducing MTCT. Specifically, AZT/3TC/NVP, AZT/3TC/LPV-r, and AZT/3TC/ABC have been shown to decrease MTCT. More research is needed regarding the use of specific regimens and their maternal and infant side-effect profiles.


High Specific Power Dual-Metal-Ion Rechargeable Microbatteries Based on LiMn2O4 and Zinc for Miniaturized Applications.
Miniaturized rechargeable batteries with high specific power are required for substitution of the large sized primary batteries currently prevalent in integrated systems since important implications in dimensions and power are expected in future miniaturized applications. Commercially available secondary microbatteries are based on lithium metal which suffers from several well-known safety and manufacturing issues and low specific power when compared to (super) capacitors. A high specific power and novel dual-metal-ion microbattery based on LiMn2O4, zinc, and an aqueous electrolyte is presented in this work. Specific power densities similar to the ones exhibited by typical electrochemical supercapacitors (3400 W kg-1) while maintaining specific energies in the range of typical Li-ion batteries are measured (∼100 Wh kg-1). Excellent stability with very limited degradation (99.94% capacity retention per cycle) after 300 cycles is also presented. All of these features, together with the intrinsically safe nature of the technology, allow anticipation of this alternative micro power source to have high impact, particularly in the high demand field of newly miniaturized applications.


SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery.
Since the publication of the Society for Immunotherapy of Cancer's (SITC) original cancer immunotherapy biomarkers resource document, there have been remarkable breakthroughs in cancer immunotherapy, in particular the development and approval of immune checkpoint inhibitors, engineered cellular therapies, and tumor vaccines to unleash antitumor immune activity. The most notable feature of these breakthroughs is the achievement of durable clinical responses in some patients, enabling long-term survival. These durable responses have been noted in tumor types that were not previously considered immunotherapy-sensitive, suggesting that all patients with cancer may have the potential to benefit from immunotherapy. However, a persistent challenge in the field is the fact that only a minority of patients respond to immunotherapy, especially those therapies that rely on endogenous immune activation such as checkpoint inhibitors and vaccination due to the complex and heterogeneous immune escape mechanisms which can develop in each patient. Therefore, the development of robust biomarkers for each immunotherapy strategy, enabling rational patient selection and the design of precise combination therapies, is key for the continued success and improvement of immunotherapy. In this document, we summarize and update established biomarkers, guidelines, and regulatory considerations for clinical immune biomarker development, discuss well-known and novel technologies for biomarker discovery and validation, and provide tools and resources that can be used by the biomarker research community to facilitate the continued development of immuno-oncology and aid in the goal of durable responses in all patients.


From caging to Rouse dynamics in polymer melts with intramolecular barriers: a critical test of the mode coupling theory.
By means of computer simulations and solution of the equations of the mode coupling theory (MCT), we investigate the role of the intramolecular barriers on several dynamic aspects of nonentangled polymers. The investigated dynamic range extends from the caging regime characteristic of glass-formers to the relaxation of the chain Rouse modes. We review our recent work on this question, provide new results, and critically discuss the limitations of the theory. Solutions of the MCT for the structural relaxation reproduce qualitative trends of simulations for weak and moderate barriers. However, a progressive discrepancy is revealed as the limit of stiff chains is approached. This disagreement does not seem related with dynamic heterogeneities, which indeed are not enhanced by increasing barrier strength. It is not connected either with the breakdown of the convolution approximation for three-point static correlations, which retains its validity for stiff chains. These findings suggest the need of an improvement of the MCT equations for polymer melts. Concerning the relaxation of the chain degrees of freedom, MCT provides a microscopic basis for time scales from chain reorientation down to the caging regime. It rationalizes, from first principles, the observed deviations from the Rouse model on increasing the barrier strength. These include anomalous scaling of relaxation times, long-time plateaux, and nonmonotonous wavelength dependence of the mode correlators.


Diagnosis of Persistent Infection in Prosthetic Two-Stage Exchange: Evaluation of the Effect of Sonication on Antibiotic Release from Bone Cement Spacers.
Introduction : When treating periprosthetic joint infection with a two-stage procedure, antibiotic-impregnated spacers can be used in the interval between prosthetic removal and reimplantation. In our experience, cultures of sonicated spacers are most often negative. The objective of the study was to assess whether that sonication causes an elution of antibiotics, leading to elevated antibiotic concentrations in the sonication fluid inhibiting bacterial growth and thus causing false-negative cultures. Methods : A prospective monocentric study was performed from September 2014 to March 2016. Inclusion criteria were a two-stage procedure for prosthetic infection and agreement of the patient to participate in the study. Spacers were made of gentamicin-containing cement to which tobramycin and vancomycin were added. Antibiotic concentrations in the sonication fluid were determined by mass-spectometry (LC-MS). Results : 30 patients were identified (15 hip and 14 knee and 1 ankle arthroplasties). No cases of culture positive sonicated spacer fluid were observed in our serie. In the sonication fluid median concentrations of 13.2µg/ml, 392 µg/ml and 16.6 µg/ml were detected for vancomycin, tobramycin and gentamicin, respectively. According to the European Committee on antimicrobial susceptibility testing (EUCAST), these concentrations released from cement spacer during sonication are higher than the minimal inhibitory concentrations (MICs) for most bacteria relevant in prosthetic joint infections. Conclusion: Spacer sonication cultures remained sterile in all of our cases. Elevated concentrations of antibiotics released during sonication could explain partly negative-cultured sonicated spacers. Indeed, the absence of antibiotic free interval during the two-stages can also contribute to false-negative spacers sonicated cultures.


X-ray Diffraction Studies of Echinoderm Plates.
X-ray diffraction studies confirm that, with few exceptions, each skeletal element of echtinoderms is a single crystal of magnesium-rich calcite and that a relation exists between the shape of the element and the crystallographic a- and c-axes. The exceptions incluide the teeth of echinoids, and the calcareous ring as well as the anal teeth of holothurians. The tubercles of an echinoid plate begin their growth as parts of the single crystal of the plate; under the mechanical action of the spines that are attached to them, they become partly polycrystalline, as shown by scanning electron microscopy and by x-ray powder diffraction. The interface between inorganic crystalline and organic amorphous matter in the skeletal element appears to be the first example reported in nature of a periodic mninimal suirface.