How Prefrail Older People Living Alone Perceive Information and Communications Technology and What They Would Ask a Robot for: Qualitative Study.
In the last decade, the family system has changed significantly. Although in the past, older people used to live with their children, nowadays, they cannot always depend on assistance of their relatives. Many older people wish to remain as independent as possible while remaining in their homes, even when living alone. To do so, there are many tasks that they must perform to maintain their independence in everyday life, and above all, their well-being. Information and communications technology (ICT), particularly robotics and domotics, could play a pivotal role in aging, especially in contemporary society, where relatives are not always able to accurately and constantly assist the older person. The aim of this study was to understand the needs, preferences, and views on ICT of some prefrail older people who live alone. In particular, we wanted to explore their attitude toward a hypothetical caregiver robot and the functions they would ask for. We designed a qualitative study based on an interpretative phenomenological approach. A total of 50 potential participants were purposively recruited in a big town in Northern Italy and were administered the Fried scale (to assess the participants' frailty) and the Mini-Mental State Examination (to evaluate the older person's capacity to comprehend the interview questions). In total, 25 prefrail older people who lived alone participated in an individual semistructured interview, lasting approximately 45 min each. Overall, 3 researchers independently analyzed the interviews transcripts, identifying meaning units, which were later grouped in clustering of themes, and finally in emergent themes. Constant triangulation among researchers and their reflective attitude assured trustiness. From this study, it emerged that a number of interviewees who were currently using ICT (ie, smartphones) did not own a computer in the past, or did not receive higher education, or were not all young older people (aged 65-74 years). Furthermore, we found that among the older people who described their relationship with ICT as negative, many used it in everyday life. Referring to robotics, the interviewees appeared quite open-minded. In particular, robots were considered suitable for housekeeping, for monitoring older people's health and accidental falls, and for entertainment. Older people's use and attitudes toward ICT does not always seem to be related to previous experiences with technological devices, higher education, or lower age. Furthermore, many participants in this study were able to use ICT, even if they did not always acknowledge it. Moreover, many interviewees appeared to be open-minded toward technological devices, even toward robots. Therefore, proposing new advanced technology to a group of prefrail people, who are self-sufficient and can live alone at home, seems to be feasible.


Expression of interleukin-6 is suppressed by inhibition of voltage-sensitive Na+/Ca2+ channels after cerebral ischemia.
Expression of interleukin-6 (IL-6), a neurotrophic cytokine, is up-regulated after cerebral ischemia, but the underlying mechanism of the up-regulation remains unclear. NS-7 is a novel blocker of voltage-sensitive Ca2+ and Na+ channels and is known to reduce cerebral damage by ischemia. The present study was undertaken to examine the association between increases in intracellular Ca2+ concentration induced by membrane depolarization and IL-6 induction. IL-6 expression in rat brain was investigated by immunohistochemistry and Western blot analysis following 3.5-48 h of reperfusion after 1.5 h of occlusion of the middle cerebral artery. NS-7 (1 mg/kg; NS-7 group) or saline (saline group) was injected i.v. 5 min after the start of reperfusion. The saline group showed clear IL-6 expression in various cortical regions, which peaked at 24 h of reperfusion. By contrast, IL-6 expression was significantly suppressed in the NS-7 group throughout the reperfusion period. Microglia activation was also reduced in the NS-7 group. These findings suggest that IL-6 expression may be up-regulated by the increased intracellular Ca2+ concentration triggered by membrane depolarization after cerebral ischemia.


Moral Decision Making: From Bentham to Veil of Ignorance via Perspective Taking Accessibility.
Making morally sensitive decisions and evaluations pervade many human everyday activities. Philosophers, economists, psychologists and behavioural scientists researching such decision-making typically explore the principles, processes and predictors that constitute human moral decision-making. Crucially, very little research has explored the theoretical and methodological development (supported by empirical evidence) of utilitarian theories of moral decision-making. Accordingly, in this critical review article, we invite the reader on a moral journey from Jeremy Bentham's utilitarianism to the veil of ignorance reasoning, via a recent theoretical proposal emphasising utilitarian moral behaviour-perspective-taking accessibility (PT accessibility). PT accessibility research revealed that providing participants with access to all situational perspectives in moral scenarios, eliminates (previously reported in the literature) inconsistency between their moral judgements and choices. Moreover, in contrast to any previous theoretical and methodological accounts, moral scenarios/tasks with full PT accessibility provide the participants with unbiased even odds (neither risk averse nor risk seeking) and impartiality. We conclude that the proposed by Martin et al. PT Accessibility (a new type of veil of ignorance with even odds that do not trigger self-interest, risk related preferences or decision biases) is necessary in order to measure humans' prosocial utilitarian behaviour and promote its societal benefits.


Autocratisation and universal health coverage: synthetic control study.
To assess the relation between autocratisation-substantial decreases in democratic traits (free and fair elections, freedom of civil and political association, and freedom of expression)-and countries' population health outcomes and progress toward universal health coverage (UHC). Synthetic control analysis. Global sample of countries for all years from 1989 to 2019, split into two categories: 17 treatment countries that started autocratising during 2000 to 2010, and 119 control countries that never autocratised from 1989 to 2019. The treatment countries comprised low and middle income nations and represent all world regions except North America and western Europe. A weighted combination of control countries was used to construct synthetic controls for each treatment country. This statistical method is especially well suited to population level studies when random assignment is infeasible and sufficiently similar comparators are not available. The method was originally developed in economics and political science to assess the impact of policies and events, and it is now increasingly used in epidemiology. HIV-free life expectancy at age 5 years, UHC effective coverage index (0-100 point scale), and out-of-pocket spending on health per capita. All outcome variables are for the period 1989 to 2019. Autocratising countries underperformed for all three outcome variables in the 10 years after the onset of autocratisation, despite some improvements in life expectancy, UHC effective coverage index, and out-of-pocket spending on health. On average, HIV-free life expectancy at age 5 years increased by 2.2% (from 64.7 to 66.1 years) during the 10 years after the onset of autocratisation. This study estimated that it would have increased by 3.5% (95% confidence interval 3.3% to 3.6%, P<0.001) (from 64.7 to 66.9 years) in the absence of autocratisation. On average, the UHC effective coverage index increased by 11.9% (from 42.5 to 47.6 points) during the 10 years after the onset of autocratisation. This study estimated that it would have increased by 20.2% (95% confidence interval 19.6% to 21.2%, P<0.001) (from 42.5 to 51.1 points) in the absence of autocratisation. Finally, on average, out-of-pocket spending on health per capita increased by 10.0% (from $4.00 (£3.1; €3.4) to $4.4, log transformed) during the 10 years after the onset of autocratisation. This study estimated that it would have increased by only 4.4% (95% confidence interval 3.9% to 4.6%, P<0.001) (from $4.0 to $4.2, log transformed) in the absence of autocratisation. Autocratising countries had worse than estimated life expectancy, effective health service coverage, and levels of out-of-pocket spending on health. These results suggest that the noticeable increase in the number of countries that are experiencing democratic erosion in recent years is hindering population health gains and progress toward UHC. Global health institutions will need to adjust their policy recommendations and activities to obtain the best possible results in those countries with a diminishing democratic incentive to provide quality healthcare to populations.


Glucocorticoid use and ischemia-reperfusion injury in laparoscopic liver resection: Randomized controlled trial.
Laparoscopic liver resection (LLR) is increasingly carried out worldwide. However, there are concerns regarding ischemia-reperfusion injury caused by pneumoperitoneum and the Pringle maneuver. It is not clear whether perioperative use of glucocorticoids lowers the risk of ischemia-reperfusion hepatic injury in LLR as has been reported for open liver resection. The aim of the present study was to investigate the role of perioperative glucocorticoid use in improving hepatic function and surgical outcomes after LLR. In this double-blind, randomized controlled trial (UMIN000013823), we enrolled 130 patients who presented to our institution for LLR between April 2014 and October 2018. Six patients were excluded, resulting in 124 patients being randomized to either the glucocorticoid or the control group. Preoperatively, patients in the glucocorticoid group received 500 mg methylprednisolone in saline solution, patients in the control group saline solution only. Surgical outcomes and blood parameters were compared between the two groups. The Pringle maneuver could not be carried out in 24 patients, resulting in 50 patients in each group being included in the analysis. Postoperatively, total, direct and indirect bilirubin, and C-reactive protein and interleukin-6 levels were significantly lower, albumin levels were significantly higher, and prothrombin time was significantly shorter in the glucocorticoid than in the control group. Surgical outcomes were not significantly different between the groups. This first report on preoperative glucocorticoid use in LLR showed that it significantly improved postoperative liver function and thus might enhance the safety of LLR.


Assembly of the TLR2/6 transmembrane domains is essential for activation and is a target for prevention of sepsis.
TLR2, together with TLR1 and TLR6, is essential for detecting lipopeptides and bacterial cell wall components such as lipoteichoic acid from Gram-positive bacteria. In this study, we report that transmembrane domain (TMD)-derived peptides from TLR2 and TLR6 specifically inhibit TLR2 activation. Secretion of the cytokines TNF-α and IL-6 by cultured macrophages (RAW264.7 cell line) was inhibited by these peptides in response to TLR2 activation by lipoteichoic acid (TLR2/6 activator) or palmitoyl (3)-Cys-Ser-Lys(4)-OH (TLR2/1 activator) but not by LPS (TLR4 activator). Extensive biophysical and biochemical assays, combined with GALLEX experiments, show that these peptides heterodimerize with their complementary TMDs on their reciprocal protein. These results suggest that TLR2/6/1 TMD assembly is essential for activating this complex. Importantly, when administered to mice inflicted by TLR2, but not TLR4-driven lethal inflammation, a selected peptide rescued 60% of these septic mice, showing potent in vivo inhibition of TNF-α and IL-6 secretion. Furthermore, this peptide also showed high protection in a whole bacteria model. Owing to the importance of TLR2 regulation under a variety of pathological conditions, compounds that can fine-tune this activity are of great importance.


CSSSCL: a python package that uses combined sequence similarity scores for accurate taxonomic classification of long and short sequence reads.
Sequence comparison of genetic material between known and unknown organisms plays a crucial role in genomics, metagenomics and phylogenetic analysis. The emerging long-read sequencing technologies can now produce reads of tens of kilobases in length that promise a more accurate assessment of their origin. To facilitate the classification of long and short DNA sequences, we have developed a Python package that implements a new sequence classification model that we have demonstrated to improve the classification accuracy when compared with other state of the art classification methods. For the purpose of validation, and to demonstrate its usefulness, we test the combined sequence similarity score classifier (CSSSCL) using three different datasets, including a metagenomic dataset composed of short reads. Package's source code and test datasets are available under the GPLv3 license at https://github.com/oicr-ibc/cssscl. firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Unified terminology for cestode microtriches: a proposal from the International Workshops on Cestode Systematics in 2002-2008.
Terminology for microtriches, the surface features both unique to and ubiquitous among cestodes, is standardised based on discussions that occurred at the International Workshops on Cestode Systematics in Storrs, Connecticut, USA in 2002, in Ceské Budejovice, Czech Republic in 2005 and in Smolenice, Slovakia in 2008. The following terms were endorsed for the components of individual microtriches: The distal, electron-dense portion is the cap, the proximal more electron-lucent region is the base. These two elements are separated from one another by the baseplate. The base is composed of, among other elements, microfilaments. The cap is composed of cap tubules. The electron-lucent central portion of the base is referred to as the core. The core may be surrounded by an electron-dense tunic. The entire microthrix is bounded by a plasma membrane, the external layer of which is referred to as the glycocalyx. Two distinct sizes of microtriches are recognised: those < or = 200 nm in basal width, termed filitriches, and those >200 nm in basal width, termed spinitriches. Filitriches are considered to occur in three lengths: papilliform (< or = 2 times as long as wide), acicular (2-6 times as long as wide), and capilliform (>6 times as long as wide). In instances in which filitriches appear to be doubled at their base, the modifier duplicated is used. Spinitriches are much more variable in form. At present a total of 25 spinithrix shapes are recognised. These consist of 13 in which the width greatly exceeds the thickness (i.e., bifid, bifurcate, cordate, gladiate, hamulate, lanceolate, lineate, lingulate, palmate, pectinate, spathulate, trifid, and trifurcate), and 12 in which width and thickness are approximately equal (i.e., chelate, clavate, columnar, coniform, costate, cyrillionate, hastate, rostrate, scolopate, stellate, trullate, and uncinate). Spiniform microtriches can bear marginal (serrate) and/or dorsoventral (gongylate) elaborations; they can also bear apical features (aristate). The latter two modifiers should be used only if the features are present. The terminology to describe the overall form of a spinithrix should be used in the following order: tip, margins, shape. Each type of microthrix variation is defined and illustrated with one or more scanning electron micrographs. An indication of the taxa in which each of the microthrix forms is found is also provided.


Assets and Challenges to Recruiting and Engaging Families in a Childhood Obesity Treatment Research Trial: Insights From Academic Partners, Community Partners, and Study Participants.
Background: There is need for the childhood obesity treatment literature to identify effective recruitment and engagement strategies for rural communities that are more likely to lack supportive infrastructure for healthy lifestyles and clinical research relative to their urban counterparts. This community case study examines recruitment and engagement strategies from a comparative effectiveness research (CER) trial of two family-based childhood obesity (FBCO) treatment interventions conducted in a medically underserved, rural region. Guided by a Community Based Participatory Research (CBPR) and systems-based approach, the primary aim was to analyze interviews from academic partners, community partners, and parent study participants for recruitment and engagement assets, challenges, and lessons learned. Methods: Over the 3-year lifespan of the study, researchers conducted 288 interviews with Community Advisory Board members (n = 14), Parent Advisory Team members (n = 7), and study participants (n = 100). Using an inductive-deductive approach, interviews were broadly coded for recruitment and engagement assets, challenges, and recommendations; analyzed for descriptive sub-coding; and organized into stakeholder/organization and participant level themes. Codes were analyzed aggregately across time and examined for differences among stakeholders and parent study participants. Results: Adherence to CBPR principles and development of strong community partnerships facilitated recruitment and engagement; however, variability in recruitment and engagement success impacted partner confidence, threatened outcome validity, and required additional resources. Specifically, assets and challenges emerged around eight key needs. Three were at the stakeholder/organization level: (1) readiness of stakeholders to conduct CBPR research, (2) development of sustainable referral protocols, and (3) development of participant engagement systems. The remaining five were at the participant level: (1) comfort and trust with research, (2) awareness and understanding of the study, (3) intervention accessibility, (4) intervention acceptability, and (5) target population readiness. Future recommendations included conducting readiness assessments and awareness campaigns, piloting and evaluating recruitment and engagement strategies, identifying participant barriers to engagement and finding a priori solutions, and fostering stakeholder leadership to develop sustainable protocols. Conclusion: Collective findings from multiple perspectives demonstrate the need for multi-leveled approaches focusing on infrastructure supports and strategies to improve stakeholder and participant awareness of, and capacity for, recruiting and engaging medically underserved, rural families in a FBCO CER trial.


Co-produced natural ketolides methymycin and pikromycin inhibit bacterial growth by preventing synthesis of a limited number of proteins.
Antibiotics methymycin (MTM) and pikromycin (PKM), co-produced by Streptomyces venezuelae, represent minimalist macrolide protein synthesis inhibitors. Unlike other macrolides, which carry several side chains, a single desosamine sugar is attached to the macrolactone ring of MTM and PKM. In addition, the macrolactone scaffold of MTM is smaller than in other macrolides. The unusual structure of MTM and PKM and their simultaneous secretion by S. venezuelae bring about the possibility that two compounds would bind to distinct ribosomal sites. However, by combining genetic, biochemical and crystallographic studies, we demonstrate that MTM and PKM inhibit translation by binding to overlapping sites in the ribosomal exit tunnel. Strikingly, while MTM and PKM readily arrest the growth of bacteria, ∼40% of cellular proteins continue to be synthesized even at saturating concentrations of the drugs. Gel electrophoretic analysis shows that compared to other ribosomal antibiotics, MTM and PKM prevent synthesis of a smaller number of cellular polypeptides illustrating a unique mode of action of these antibiotics.


Biosynthetic chlorination of the piperazate residue in kutzneride biosynthesis by KthP.
Kutznerides 2 and 8 of the cyclic hexadepsipeptide family of antifungal natural products from the soil actinomycete Kutzneria sp. 744 contain two sets of chlorinated residues, a 6,7-dichlorohexahydropyrroloindole moiety derived from dichlorotryptophan and a 5-chloropiperazate moiety, as well as a methylcyclopropylglycine residue that may arise from isoleucine via a cryptic chlorination pathway. Previous studies identified KtzD, KtzQ, and KtzR as three halogenases in the kutzneride pathway but left no candidate for installing the C5 chlorine on piperazate. On the basis of analysis of the complete genome sequence of Kutzneria, we now identify a fourth halogenase in the pathway whose gene is separated from the defined kutzneride cluster by 12 open reading frames. KthP (kutzneride halogenase for piperazate) is a mononuclear nonheme iron halogenase that acts on the piperazyl ring tethered by a thioester linkage to the holo forms of thiolation domains. MS analysis of the protein-bound product confirmed chlorination of the piperazate framework from the (3S)- but not the (3R)-piperazyl-S-pantetheinyl thiolation proteins. After thioesterase-mediated release, nuclear magnetic resonance was used to assign the free imino acid as (3S,5S)-5-chloropiperazate, distinct from the 3S,5R stereoisomer reported in the mature kutznerides. These results demonstrate that a fourth halogenase, KthP, is active in the kutzneride biosynthetic pathway and suggest further processing of the (3S,5S)-5-chloropiperazate during subsequent incorporation into the kutzneride depsipeptide frameworks.


How subvisible particles become invisible-relevance of the refractive index for protein particle analysis.
The aim of the present study was to quantitatively assess the relevance of transparency and refractive index (RI) on protein particle analysis by the light-based techniques light obscuration (LO) and Micro-Flow Imaging (MFI). A novel method for determining the RI of protein particles was developed and provided an RI of 1.41 for protein particles from two different proteins. An increased RI of the formulation by high protein concentration and/or sugars at pharmaceutically relevant levels was shown to lead to a significant underestimation of the subvisible particle concentration determined by LO and MFI. An RI match even caused particles to become "invisible" for the system, that is, not detectable anymore by LO and MFI. To determine the influence of formulation RI on particle measurements, we suggest the use of polytetrafluoroethylene (PTFE) particles to test a specific formulation for RI effects. In case of RI influences, we recommend also using a light-independent technique such as resonant mass measurement (RMM) (Archimedes) for subvisible particle analysis in protein formulations.


Addressing drought tolerance in maize by transcriptional profiling and mapping.
In order to unravel the genetic architecture underlying plant response to drought, we adopted an integrated approach, combining transcript profiling and quantitative trait loci (QTL) mapping. In fact, improving plant tolerance to water stress is an important, but, at the same time, a difficult task, since plant tolerance is the result of many complex mechanisms acting at different levels of plant organization, and its genetic basis is largely unknown. The phenotypic data, concerning yield components and flowering time, of a population of 142 maize Recombinant Inbred Lines (RILs), grown under well watered conditions or under water stress, were submitted to linkage analysis to detect drought-tolerance QTLs. Thirty genomic regions containing 50 significant QTLs distributed on nine chromosomes were identified. At the same time, a customized targeted oligoarray was used to monitor the expression levels of 1,000 genes, representative of the immature maize kernel transcriptome. Using this DNA array we compared transcripts from 10 days after pollination kernels of two susceptible and two drought tolerant genotypes (extracted from our RILs) grown under control and water stress field conditions. Two hundred and fifty-two genes were significantly affected by stress in at least one genotype. From a set of these, 49 new molecular markers were developed. By mapping most of them and by in silico mapping other regulated sequences, 88 differentially expressed genes were localized onto our linkage map, which, added to the existing 186 markers, brought their total number on the map to 274. Twenty-two of the 88 differentially expressed genes mapped in the same chromosomal segments harbouring QTLs for tolerance, thus representing candidate genes for further functional studies.


Diethyldithiocarbamate injection induces transient oxidative stress in goldfish tissues.
The effects of intraperitoneal injection of diethyldithiocarbamate (DDC) on free radical processes were examined in brain, liver and kidney of goldfish (Carassius auratus). Levels of oxidatively modified lipids and proteins as well as the activities of antioxidant and associated enzymes were measured. Intraperitoneal injection of DDC at a concentration of 0.01 mg/g wet mass decreased SOD activities by about 30-50% after 48 and 168 h compared to corresponding sham-injected values. This treatment resulted in transient oxidative stress. Lipid peroxide content increased after DDC injection at all time points in the kidney, after 48 h in the liver and was elevated in most experimental groups in the brain. Thiobarbituric-acid reactive substances (end products of lipid peroxidation) rose within the first 48 h after injection, but returned to initial levels after 168 h. Two other indices of oxidative stress were also transiently modified: protein carbonyl levels in the brain and kidney increased 24h post-injection, and the low-molecular mass thiol content was reduced over the same period in all tissues examined. Activities of catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, and glucose-6-phosphate dehydrogenase showed differential responses to DDC treatment that rebounded by 168 h post-injection. Glutathione peroxidase activities were reduced by 60, 45 and 65% in the brain, liver and kidney, respectively, after 24h but rebounded thereafter. After 48 h post-injection with DDC significant decreases were also seen in liver and kidney catalase, GST activities in all three tissues, and kidney GR and G6PDH activities. In some cases, catalase, GST, GR and G6PDH activities transiently increased after 24 h. It was concluded that DDC injection depleted SOD and simultaneously stimulated lipid peroxidation, but did not require compensatory enhancement of other enzymatic defenses. Different actions of the superoxide anion in cellular metabolism and possible consequences of the impairment of superoxide dismutase are discussed.


Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys.
Zika virus (ZIKV) is responsible for a major ongoing epidemic in the Americas and has been causally associated with fetal microcephaly. The development of a safe and effective ZIKV vaccine is therefore an urgent global health priority. Here we demonstrate that three different vaccine platforms protect against ZIKV challenge in rhesus monkeys. A purified inactivated virus vaccine induced ZIKV-specific neutralizing antibodies and completely protected monkeys against ZIKV strains from both Brazil and Puerto Rico. Purified immunoglobulin from vaccinated monkeys also conferred passive protection in adoptive transfer studies. A plasmid DNA vaccine and a single-shot recombinant rhesus adenovirus serotype 52 vector vaccine, both expressing ZIKV premembrane and envelope, also elicited neutralizing antibodies and completely protected monkeys against ZIKV challenge. These data support the rapid clinical development of ZIKV vaccines for humans.


An update on the use of biologic therapies in the management of uveitis in Behçet's disease: a comprehensive review.
: Behçet's disease (BD) is a systemic vasculitis characterised by a relapsing remitting course, affecting multiple organ systems. In the eye, it is a cause of potentially blinding inflammation in the form of uveitis. Management of uveitis in BD often requires the use of systemic immunosuppression, in order to reduce disease activity and prevent accumulation of irreversible damage. Whilst corticosteroids remain the mainstay of treatment, long-term use is limited by the development of adrenocorticotrophic side effects. There has therefore been significant interest in the use of corticosteroid-sparing immunosuppressive agents, and more recently, biologic therapies. Recent publications have demonstrated biologic therapy to have beneficial effects both on overall disease control, and quality of life for patients with BD. Widespread use of such agents is however limited, partly by the lack of high quality research evidence, and partly by the prohibitive cost of biologic treatments. In this review, we discuss the most recent research investigating the use of biologic therapy in uveitis due to BD, with consideration of health economics and quality of life outcomes.


Wanderlust kinetics and variable Ca(2+)-sensitivity of dSlo [correction of Drosophila], a large conductance CA(2+)-activated K+ channel, expressed in oocytes.
Cloned large conductance Ca2+-activated K+ channels (BK or maxi-K+ channels) from Drosophila (dSlo) were expressed in Xenopus oocytes and studied in excised membrane patches with the patch-clamp technique. Both a natural variant and a mutant that eliminated a putative cyclic AMP-dependent protein kinase phosphorylation site exhibited large, slow fluctuations in open probability with time. These fluctuations, termed "wanderlust kinetics," occurred with a time course of tens of seconds to minutes and had kinetic properties inconsistent with simple gating models. Wanderlust kinetics was still observed in the presence of 5mM caffeine or 50 nM thapsigargin, or when the Ca2+ buffering capacity of the solution was increased by the addition of 5 mM HEDTA, suggesting that the wanderlust kinetics did not arise from Ca2+ release from caffeine and thapsigargin sensitive internal stores in the excised patch. The slow changes in kinetics associated with wanderlust kinetics could be generated with a discrete-state Markov model with transitions among three or more kinetic modes with different levels of open probability. To average out the wanderlust kinetics, large amounts of data were analyzed and demonstrated up to a threefold difference in the [Ca2+]i required for an open probability of 0.5 among channels expressed from the same injected mRNA. These findings indicate that cloned dSlo channels in excised patches from Xenopus oocytes can exhibit large variability in gating properties, both within a single channel and among channels.


The Exercise is Medicine Global Health Initiative: a 2014 update.
A third of the world's population does not engage in recommended levels of physical activity (PA), leading to substantial health and economic burdens. The healthcare sector offers a variety of resources that can help counsel, refer and deliver PA promotion programmes for purposes of primordial, primary, secondary and tertiary prevention. Substantial evidence already exists in support of multipronged PA counselling, prescription and referral strategies, in particular those linking healthcare and community-based resources. The Exercise is Medicine (EIM) initiative was introduced in 2007 to advance the implementation of evidence-based strategies to elevate the status of PA in healthcare. In this article, we describe the evolution and global expansion of the EIM initiative, its components, their implementation, an evaluation framework and future initiative activities. Until now, EIM has a presence in 39 countries with EIM Regional Centers established in North America, Latin America, Europe, Africa, Southeast Asia, China and Australasia. The EIM Global Health Initiative is transitioning from its initial phase of infrastructure and awareness building to a phase of programme implementation, with an emphasis in low-to-middle income countries, where 80% of deaths due to non-communicable diseases already occur, but where a large gap in research and implementation of PA strategies exists. Broad implementation of PA counselling and referral systems, as clinical practice standard of care, has the potential to improve PA at the population level by complementing and leveraging other efforts and to contribute to achieving global targets for the reduction of inactivity and related morbidity and mortality.


A clustering of injury behaviors.
Alcohol is a well-known risk factor for injury. A number of other behaviors are also associated with injury risk. We hypothesized that risky drinking would be associated with other high risk behaviors, thereby delineating a need for behavioral interventions in addition to alcohol. A consecutive sample of trauma patients was interviewed for drinking and risky behaviors including seat belt use, helmet use, and driving behaviors. The Alcohol Use Disorders Identification Test was used to screen for risky drinking and risky behavior questions were taken from validated questionnaires. Behaviors were ranked on a Likert scale ranging from a low to a high likelihood of the behavior or assessed the frequency of behavior in the past 30 days. An Alcohol Use Disorders Identification Test score of 8 or more was considered risky drinking for adults age 21 to 64, and 4 or more for ages 16 to 20 and over 65. Risky and nonrisky drinkers were compared on behavior risk items. A p value of less than 0.05 was considered significant. One hundred sixty patients (mean age, 36.8 years, 72% men,) were interviewed. Risky drinkers were more likely to drive after consuming alcohol, ride with drinking drivers, tailgate, weave in and out of traffic, and make angry gestures at other drivers (all p < 0.05). Risky drinkers were less likely to wear motorcycle helmets. However, risky drinkers were no more or less likely to talk on the cell phone while driving, to use seatbelts, or use turn signals. Although number of lifetime vehicle crashes were similar, risky drinkers were more likely to have been the party at fault for the crash (mean 1.09 vs. 0.64, p = 0.03). Factors other than alcohol increase injury risk in problem drinkers. Injury prevention programs performing alcohol interventions should consider including behavioral interventions along with alcohol reduction strategies. New screening and intervention programs should be developed for injury behaviors that increase risk but are not alcohol related.


Is hypothermia in the victim of major trauma protective or harmful? A randomized, prospective study.
The purpose of this randomized, prospective clinical trial was to determine whether hypothermia during resuscitation is protective or harmful to critically injured trauma patients. Hypothermia has both protective and harmful clinical effects. Retrospective studies show higher mortality in patients with hypothermia; however, hypothermia is more common in more severely injured patients, which makes it difficult to determine whether hypothermia contributes to mortality independently of injury severity. There are no randomized, prospective treatment studies to assess hypothermia's impact as an independent variable. Fifty-seven hypothermic (T < or = 34.5 C), critically injured patients requiring a pulmonary artery catheter were randomized to a rapid rewarming protocol using continuous arteriovenous rewarming (CAVR) or to a standard rewarming (SR) control group. The primary outcome of interest was first 24-hour blood product and fluid resuscitation requirements. Other comparative analyses included coagulation assays, hemodynamic and oxygen transport measurements, length of stay, and mortality. The two groups were well matched for demographic and injury severity characteristics. CAVR rewarmed significantly faster than did SR (p < 0.01), producing two groups with different amounts of hypothermia exposure. The patients who underwent CAVR required less fluid during resuscitation to the same hemodynamic goals (24,702 mL vs. 32,540 mL, p = 0.05) and were significantly more likely to rewarm (p = 0.002). Only 2 (7%) of 29 patients who underwent CAVR failed to warm to 36 C and both died, whereas 12 (43%) of 28 patients who underwent SR failed to reach 36 C, and all 12 died. Patients who underwent CAVR had significantly less early mortality (p = 0.047). Hypothermia increases fluid requirements and independently increases acute mortality after major trauma.


Charge Transport and Observation of Persistent Photoconductivity in Tl6SeI4 Single Crystals.
The chalcohalide compound Tl6SeI4 is a promising wide-bandgap semiconductor for efficient hard radiation detection at room temperature due to its high density, average atomic number and mobility-lifetime product. However, the nature of its charge transport kinetics, especially the role of defects in recombination, has not been examined in detail. To determine the charge transport kinetics in Tl6SeI4 single crystals, electrical conductivity and photoinduced current transient spectroscopy were measured over the temperature range 105-330 K. These measurements reveal the existence of multiple defect states with energy levels in the range 0.10-0.90 eV, within the bandgap of Tl6SeI4. Large persistent photoconductivity (PPC) is observed at low temperature that shows strong thermal quenching at 160 K. The quenching of PPC is described using a configuration coordinate model involving a deep level donor state, which is tentatively attributed to the presence of iodine vacancies or Si interstitial impurities.


The missing link--the role of primary care in global health.
This chapter provides an overview of the role of primary care in the context of global health. Universal health coverage is a key priority for WHO and its member states, and provision of accessible and safe primary care is recognised as essential to meet this important international policy goal. Nevertheless, more than three decades after Alma Ata, the provision of primary health care remains inadequate, indicating that primary care has not received the priority it deserves, in many parts of the world. This is despite the proven health benefits that result from access to comprehensive primary health care. We highlight some examples of good practice and discuss the relevance of primary care in the context of health equity and cost-effectiveness. Challenges that influence the success of primary care include the availability of a qualified workforce, financing and system design and quality assurance and patient safety.


Azimuthal Correlations within Exclusive Dijets with Large Momentum Transfer in Photon-Lead Collisions.
The structure of nucleons is multidimensional and depends on the transverse momenta, spatial geometry, and polarization of the constituent partons. Such a structure can be studied using high-energy photons produced in ultraperipheral heavy-ion collisions. The first measurement of the azimuthal angular correlations of exclusively produced events with two jets in photon-lead interactions at large momentum transfer is presented, a process that is considered to be sensitive to the underlying nuclear gluon polarization. This study uses a data sample of ultraperipheral lead-lead collisions at sqrt[s_{NN}]=5.02 TeV, corresponding to an integrated luminosity of 0.38 nb^{-1}, collected with the CMS experiment at the LHC. The measured second harmonic of the correlation between the sum and difference of the two jet transverse momentum vectors is found to be positive, and rising, as the dijet transverse momentum increases. A well-tuned model that has been successful at describing a wide range of proton scattering data from the HERA experiments fails to describe the observed correlations, suggesting the presence of gluon polarization effects.


Network analysis identifies a putative role for the PPAR and type 1 interferon pathways in glucocorticoid actions in asthmatics.
Asthma is a chronic inflammatory airway disease influenced by genetic and environmental factors that affects ~300 million people worldwide, leading to ~250,000 deaths annually. Glucocorticoids (GCs) are well-known therapeutics that are used extensively to suppress airway inflammation in asthmatics. The airway epithelium plays an important role in the initiation and modulation of the inflammatory response. While the role of GCs in disease management is well understood, few studies have examined the holistic effects on the airway epithelium. Gene expression data were used to generate a co-transcriptional network, which was interrogated to identify modules of functionally related genes. In parallel, expression data were mapped to the human protein-protein interaction (PPI) network in order to identify modules with differentially expressed genes. A common pathways approach was applied to highlight genes and pathways functionally relevant and significantly altered following GC treatment. Co-transcriptional network analysis identified pathways involved in inflammatory processes in the epithelium of asthmatics, including the Toll-like receptor (TLR) and PPAR signaling pathways. Analysis of the PPI network identified RXRA, PPARGC1A, STAT1 and IRF9, among others genes, as differentially expressed. Common pathways analysis highlighted TLR and PPAR signaling pathways, providing a link between general inflammatory processes and the actions of GCs. Promoter analysis identified genes regulated by the glucocorticoid receptor (GCR) and PPAR pathways as well as highlighted the interferon pathway as a target of GCs. Network analyses identified known genes and pathways associated with inflammatory processes in the airway epithelium of asthmatics. This workflow illustrated a hypothesis generating experimental design that integrated multiple analysis methods to produce a weight-of-evidence based approach upon which future focused studies can be designed. In this case, results suggested a mechanism whereby GCs repress TLR-mediated interferon production via upregulation of the PPAR signaling pathway. These results highlight the role of interferons in asthma and their potential as targets of future therapeutic efforts.


Warm-up Practices in Elite Boxing Athletes: Impact on Power Output.
Cunniffe, B, Ellison, M, Loosemore, M, and Cardinale, M. Warm-up practices in elite boxing athletes: Iimpact on power output. J Strength Cond Res 31(1): 95-105, 2017-This study evaluated the performance impact of routine warm-up strategies in elite Olympic amateur boxing athletes and physiological implications of the time gap (GAP) between warm-up and boxing activity. Six male boxers were assessed while performing standardized prefight warm-up routines. Core and skin temperature measurements (Tcore and Tskin), heart rate, and upper- and lower-body power output (PO) were assessed before and after warm-up, during a 25-minutes GAP and after 3 × 2 minutes rounds of sparring. Reflected temperature (Tc) was also determined using high-resolution thermal images at fixed time-points to explore avenues for heat loss. Despite individual differences in warm-up duration (range 7.4-18.5 minutes), increases in Tcore and Tskin occurred (p ≤ 0.05). Corresponding increases (4.8%; p ≤ 0.05) in countermovement jump (CMJ) height and upward-rightward shifts in upper-body force-velocity and power-velocity curves were observed. Athletes remained inactive during the 25-minutes GAP with a gradual and significant increase in Tc occurring by the end of GAP suggesting the likelihood of heat loss. Decreases in CMJ height and upper-body PO were observed after 15 minutes and 25 minutes GAP (p ≤ 0.05). By the end of GAP period, all performance variables had returned to pre-warm-up values. Results suggest routine warm-ups undertaken by elite boxers have acute effects on power-generating capacity. Gradual decreases in performance variables are evident with inactivity and seem related to alterations in body temperature. Considering the constraints of major competitions and time spent in air conditioned holding areas before fights, practitioners should be aware of the potential of nullifying the warm-up effects.


Intracellular injection of heparin and polyamines. Effects on phototransduction in limulus ventral photoreceptors.
Heparin is thought to inhibit InsP3 binding to receptors involved in the intracellular release of Ca2+. Injection of heparin into Limulus ventral photoreceptors to high intracellular concentrations reduces the amplitude and slows the rate of rise of voltage-clamp currents induced by brief flashes, tends to make the responses to long flashes more "square," and tends to block the light-induced rise in [Ca2+]i detected by arsenazo III. In these ways, intracellular heparin mimics the effects of high concentrations of intracellular BAPTA or EGTA. In addition, the effects of heparin are attenuated by prior injection of BAPTA to high intracellular concentrations. Neomycin and spermine are thought to inhibit phospholipase C activity. Injections of spermine or neomycin to low intracellular concentrations largely mimic the effects of intracellular heparin. These findings suggest that the predominant effect of polyamines is to inhibit light-induced production of InsP3 by phospholipase C activity and thereby reduce the light-induced increase in [Ca2+]i. Our findings suggest that excitation can proceed in the absence of InsP3-induced increases in [Ca2+]i, but (a) the gain and speed of transduction are reduced and (b) adaptation is largely blocked.


In vitro labeling and gold activation autoradiography for determination of labeling index and DNA synthesis times of solid tumors.
In vitro labeling and gold activation autoradiography were used to determine the [3H]thymidine ([3H]TdR)-labeling indices and DNA synthesis times for C3H/He spontaneous mammary tumors. Three variations of the [3H]TdR, [14C]thymidine ([14C]TdR) double-labeling method, together with double-emulsion autoradiography, were used to determine the DNA synthesis times (TS). Tumors labeled totally in vivo (in vivo-in vivo method) and tumors labeled with [3H]TdR in vivo and subsequently labeled with [14C]TdR in vitro showed similar TS values. DNA synthesis times for tumors determined totally in vitro by double labeling (in vitro-in vitro method) were significantly longer than those observed in vivo; however, identical samples subjected to Hypaque-Ficoll gradient separation after double labeling showed TS's similar to those found in vivo. Furthermore, the interval between [3H]TdR and [14C]TdR administration had no effect on TS estimates in vitro. Gold activation autoradiography was used in the present experiments to reduce autoradiographic exposure times. This method, together with in vitro labeling, permits [3H]TdR labeling index and TS determinations after 6-hr and 7-day exposures, respectively.


Ethics of mobile phone surveys to monitor non-communicable disease risk factors in low- and middle-income countries: A global stakeholder survey.
Active public health surveillance has traditionally been carried out through face-to-face household surveys or contact with providers, which can be time and resource intensive. The increasing ubiquity of mobile phones and availability of phone survey platforms provide an opportunity to explore the use of mobile phone surveys (MPS) for active disease and risk factor surveillance, including for non-communicable diseases (NCDs). Scholars are increasingly examining the ethics implications of mobile health (mHealth), but few have focused on the ethics of mHealth in low- and middle-income countries (LMICs), and even fewer on mHealth for active surveillance. Given that little is known about ethics-related attitudes and practices of stakeholders invested in the conduct and oversight of mHealth in LMICs, we undertook a cross-sectional global stakeholder survey of ethics-related issues implicated by active observational MPS, with a contextual frame of monitoring NCD risk factors in LMICs. We analyse these findings with an organising focus on ethical issues that arise before, during and after conduct of an MPS including defining the activity; anticipating harms and benefits; obtaining consent; data ownership, access, and use; and ensuring sustainability. Finally, we present a set of empirical, conceptual, and normative considerations that arise from this analysis and merit further consideration.


Systemic and regional hemodynamic effects of dietary calcium supplementation in mineralocorticoid hypertension.
This study was undertaken to determine the systemic and regional hemodynamic effects of long-term dietary calcium supplementation in mineralocorticoid (DOC)-salt hypertension. Systemic and regional hemodynamic measurements were determined by the radioactive microsphere technique in conscious and unrestrained rats (kidneys intact) with DOC-salt-induced hypertension that were pair-fed either a normal calcium (0.6% by weight, n = 12) or a calcium-supplemented (high-calcium) diet (2.5% by weight, n = 12). After 7 to 8 weeks, there were no differences in weight, heart rate, or cardiac output between the two groups. In contrast, the high-calcium rats had a significantly lower mean blood pressure (125 +/- 4 mm Hg, mean +/- SEM) than the normal calcium rats (143 +/- 5 mm Hg); this finding appeared to result predominantly from a reduction in total peripheral resistance. The high-calcium rats had a higher renal blood flow (7.8 +/- 0.5% vs. 6.2 +/- 0.4% cardiac output; p less than 0.05) and lower renal (14.3 +/- 1 vs. 19.3 +/- 2 mm Hg/min/ml/g tissue; p less than 0.05) and jejunal vascular resistance than did the normal calcium rats. Two additional identical groups of normal calcium-and high-calcium-DOC-salt rats (n = 12 each) were also studied. In these rats, serum-ionized calcium decreased significantly (p less than 0.05) from baseline in both groups. Urinary sodium increased in both groups but did not differ significantly. In conclusion, dietary calcium supplementation attenuates the rise in peripheral vascular resistance that accompanies DOC-salt hypertension. This attenuated resistance appears to be relatively selective and is noted particularly in the renal vasculature.


Display of functional proteins on supramolecular peptide nanofibrils using a split-protein strategy.
The display of functional proteins on self-assembled peptide nanofibrils is challenging since the steric bulk of proteins attached to simple self-assembling peptides often impedes incorporation into nanofibrils. Herein is described a split-protein strategy to tether functional proteins to preassembled peptide nanofibrils. In this strategy, a short affinity motif peptide derived from a split protein system is appended to a self-assembly motif (the amphipathic Ac-(FKFE)2-NH2 peptide) to form an affinity-assembly fusion peptide. The small size of the affinity motif allows the affinity-assembly fusion peptide to be readily incorporated into peptide nanofibrils that display the affinity motif when the affinity-assembly peptide is coassembled with Ac-(FKFE)2-NH2. Introduction of the split-protein that is complementary to the affinity motif to the assembled nanofibrils results in efficient, multivalent attachment of functional proteins to the peptide nanofibrils. This strategy is demonstrated with two split-protein systems, ribonuclease S' (RNase S') and split green fluorescent protein (GFP).


Combining sonodynamic therapy with chemoradiation for the treatment of pancreatic cancer.
Treatment options for patients with pancreatic cancer are limited and survival prospects have barely changed over the past 4 decades. Chemoradiation treatment (CRT) has been used as neoadjuvant therapy in patients with borderline resectable disease to reduce tumour burden and increase the proportion of patients eligible for surgery. Antimetabolite drugs such as gemcitabine and 5-fluorouracil are known to sensitise pancreatic tumours to radiation treatment. Likewise, photodynamic therapy (PDT) has also been shown to enhance the effect of radiation therapy. However, PDT is limited to treating superficial lesions due to the attenuation of light by tissue. The ability of the related technique, sonodynamic therapy (SDT), to enhance CRT was investigated in two murine models of pancreatic cancer (PSN-1 and BxPC-3) in this study. SDT uses low intensity ultrasound to activate an otherwise non-toxic sensitiser, generating toxic levels of reactive oxygen species (ROS) locally. It is applicable to greater target depths than PDT due to the ability of ultrasound to propagate further than light in tissue. Both CRT and the combination of CRT plus SDT delayed tumour growth in the two tumour models. In the PSN-1 model, but not the BxPC-3 model, the combination treatment caused an increase in survival relative to CRT alone (p = 0.038). The improvement in survival conferred by the addition of SDT in this model may be related to differences in tumour architecture between the two models. MRI and US images showed that PSN-1 tumours were less well perfused and vascularised than BxPC-3 tumours. This poor vascularisation may explain why PSN-1 tumours were more susceptible to the effects of vascular damage exerted by SDT treatment.


Multi-objective four-dimensional vehicle motion planning in large dynamic environments.
This paper presents Multi-Step A∗ (MSA∗), a search algorithm based on A∗ for multi-objective 4-D vehicle motion planning (three spatial and one time dimensions). The research is principally motivated by the need for offline and online motion planning for autonomous unmanned aerial vehicles (UAVs). For UAVs operating in large dynamic uncertain 4-D environments, the motion plan consists of a sequence of connected linear tracks (or trajectory segments). The track angle and velocity are important parameters that are often restricted by assumptions and a grid geometry in conventional motion planners. Many existing planners also fail to incorporate multiple decision criteria and constraints such as wind, fuel, dynamic obstacles, and the rules of the air. It is shown that MSA∗ finds a cost optimal solution using variable length, angle, and velocity trajectory segments. These segments are approximated with a grid-based cell sequence that provides an inherent tolerance to uncertainty. The computational efficiency is achieved by using variable successor operators to create a multiresolution memory-efficient lattice sampling structure. The simulation studies on the UAV flight planning problem show that MSA∗ meets the time constraints of online replanning and finds paths of equivalent cost but in a quarter of the time (on average) of a vector neighborhood-based A∗.


Separate and combined effects of a 10-d exposure to hypoxia and inactivity on oxidative function in vivo and mitochondrial respiration ex vivo in humans.
An integrative evaluation of oxidative metabolism was carried out in 9 healthy young men (age, 24.1 ± 1.7 yr mean ± SD) before (CTRL) and after a 10-day horizontal bed rest carried out in normoxia (N-BR) or hypoxia (H-BR, FiO2 = 0.147). H-BR was designed to simulate planetary habitats. Pulmonary O2 uptake (V̇o2) and vastus lateralis fractional O2 extraction (changes in deoxygenated hemoglobin+myoglobin concentration, Δ[deoxy(Hb+Mb)] evaluated using near-infrared spectroscopy) were evaluated in normoxia and during an incremental cycle ergometer (CE) and one-leg knee extension (KE) exercise (aimed at reducing cardiovascular constraints to oxidative function). Mitochondrial respiration was evaluated ex vivo by high-resolution respirometry in permeabilized vastus lateralis fibers. During CE V̇o2peak and Δ[deoxy(Hb+Mb)]peak were lower (P < 0.05) after both N-BR and H-BR than during CTRL; during KE the variables were lower after N-BR but not after H-BR. During CE the overshoot of Δ[deoxy(Hb+Mb)] during constant work rate exercise was greater in N-BR and H-BR than CTRL, whereas during KE a significant difference vs. CTRL was observed only after N-BR. Maximal mitochondrial respiration determined ex vivo was not affected by either intervention. In N-BR, a significant impairment of oxidative metabolism occurred downstream of central cardiovascular O2 delivery and upstream of mitochondrial function, possibly at the level of the intramuscular matching between O2 supply and utilization and peripheral O2 diffusion. Superposition of hypoxia on bed rest did not aggravate, and partially reversed, the impairment of muscle oxidative function in vivo induced by bed rest. The effects of longer exposures will have to be determined.


In vitro Cytotoxicity and Apoptotic Assay in HT-29 Cell Line Using Ficus hispida Linn: Leaves Extract.
Ficus hispida Linn. (Family Moraceae), well-known beneficial medicinal shrub, has been traditionally used for the treatment of various diseases such as leukoderma. The aim of the present study is to investigate the efficacy of F. hispida ethanolic leaves extract for antiproliferative, apoptotic, cell cycle blockade, and wound healing. F. hispida leaves extract was treated with colorectal adenocarcinoma cancer cell line HT29 for 24 h with control. The cells were treated at varying concentration ranges of 15, 31, 62, 125, and 250 μg/ml each The cytotoxicity effect of leaves extract was studied by 3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyltetrazolium bromide assay and their anticancer activity was further evaluated using cell cycle analysis and wound scratch assay. The end antiproliferative result showed that HT-29 cell viability decreases in a concentration-dependent manner and the growth inhibitory effect (IC50) values are obtained at a concentration of 125 μg. The increase in number of apoptotic cell was observed after treating HT-29 cells with the sample in double-staining methods. G0/G1 phase of the cell cycle was significantly blocked by the test sample followed by the G2/M phase in a negligible manner. In vitro cell wound closure or contracture was not significant when compared the sample against control group. F. hispida Linn. ethanolic leaves extract had shown to possess excellent cytotoxic effect through inducing apoptosis, especially causing cell cycle arrest at the G0/G1 phase. The experiment tries to evaluate the effectiveness of F. hispida leaves extract as an antiproliferative, apoptotic, cell cycle inhibitor and wound healing agent. Results showed that F. hispida Linn extract own cytotoxic property by inducing apoptosis through cell cycle arrest. Abbreviations used: HT 29: Human adenocarcinoma colorectal cell line; PBS: Phosphate Buffered Saline; FBS: Fetal Bovine Serum; DMEM: Dulbecco's Modified Eagles Medium; MTT: 3 [4, 5 dimethylthiazol 2 yl] 2, 5 diphenyltetrazolium bromide; NCCS: National Centre for Cell Sciences; DMSO: DiMethyl SulfOxide; PI: Propidium Iodide; AO: Acridine Orange;EB: Ethidium Bromide; IC: Inhibitory Concentration.


Utilizing Crowdsourced Data for Studies of Cycling and Air Pollution Exposure: A Case Study Using Strava Data.
With the development of information and communications technology, user-generated content and crowdsourced data are playing a large role in studies of transport and public health. Recently, Strava, a popular website and mobile app dedicated to tracking athletic activity (cycling and running), began offering a data service called Strava Metro, designed to help transportation researchers and urban planners to improve infrastructure for cyclists and pedestrians. Strava Metro data has the potential to promote studies of cycling and health by indicating where commuting and non-commuting cycling activities are at a large spatial scale (street level and intersection level). The assessment of spatially varying effects of air pollution during active travel (cycling or walking) might benefit from Strava Metro data, as a variation in air pollution levels within a city would be expected. In this paper, to explore the potential of Strava Metro data in research of active travel and health, we investigate spatial patterns of non-commuting cycling activities and associations between cycling purpose (commuting and non-commuting) and air pollution exposure at a large scale. Additionally, we attempt to estimate the number of non-commuting cycling trips according to environmental characteristics that may help identify cycling behavior. Researchers who are undertaking studies relating to cycling purpose could benefit from this approach in their use of cycling trip data sets that lack trip purpose. We use the Strava Metro Nodes data from Glasgow, United Kingdom in an empirical study. Empirical results reveal some findings that (1) when compared with commuting cycling activities, non-commuting cycling activities are more likely to be located in outskirts of the city; (2) spatially speaking, cyclists riding for recreation and other purposes are more likely to be exposed to relatively low levels of air pollution than cyclists riding for commuting; and (3) the method for estimating of the number of non-commuting cycling activities works well in this study. The results highlight: (1) a need for policymakers to consider how to improve cycling infrastructure and road safety in outskirts of cities; and (2) a possible way of estimating the number of non-commuting cycling activities when the trip purpose of cycling data is unknown.


Age-friendliness of living environments from the older person's viewpoint: development of the Age-Friendly Environment Assessment Tool.
according to the World Health Organisation, the role of the environment for older adults is to maintain and facilitate independence and promote quality of life. However, measures that examine the environment in terms of its potential impact on older people are either oriented towards specific aspects of the environment, specifically designed for community-level assessment rather than individually oriented, or are unwieldy for everyday use. this article describes the development and validation of the Age-Friendly Environment Assessment Tool (AFEAT), assessing whether individual function and frailty impact on perceptions of environmental age-friendliness. The extent to which such perceptions may have moderate impacts of frailty on outcomes such as need for care support, quality of life and loneliness is examined. a total of 132 participants aged 58-96 were recruited from retirement villages and local communities in the Midlands of the UK. Participants completed the AFEAT, and a series of measures designed to assess frailty and assessments of quality of life, loneliness and perceptions of functional limitations. internal reliability assessment indicated that the AFEAT possesses a Cronbach's Alpha score of 0.745. The AFEAT significantly predicted quality of life and loneliness, accounting for 17.1% and 5.8% of variance respectively, indicating high concurrent and predictive validity. Furthermore, the AFEAT moderated the predictive strength of frailty in predicting the amount of formal care an individual receives, but not quality of life or loneliness. the AFEAT is a valid and reliable tool, and analyses highlight the need for an individual-oriented Age-Friendly environment tool.


Predicting benign course and prolonged illness in lower respiratory tract infections: a 13 European country study.
Clinicians and patients are often uncertain about the likely clinical course of community-acquired lower respiratory tract infection (LRTI) in individual patients. We therefore set out to develop a prediction rule to identify patients at risk of prolonged illness and those with a benign course. We determined which signs and symptoms predicted prolonged illness (moderately bad symptoms lasting >3 weeks after consultation) in 2690 adults presenting in primary care with LRTI in 13 European countries by using multilevel modelling. 212 (8.1%) patients experienced prolonged illness. Illness that had lasted >5 days at the time of presentation, >1 episode of cough in the preceding year, chronic use of inhaled pulmonary medication and diarrhoea independently predicted prolonged illness. Applying a rule based on these four variables, 3% of the patients with ≤ 1 variable present (n = 955, 37%) had prolonged illness. Patients with all four variables present had a 30% chance of prolonged illness (n = 71, 3%). Most patients with acute cough (>90%) recover within 3 weeks. A prediction rule containing four clinical items had predictive value for the risk of prolonged illness, but given its imprecision, appeared to have little clinical utility. Patients should be reassured that they are most likely to recover within three weeks and advised to re-consult if their symptoms persist beyond that period.


Alkali-aided protein extraction of chicken dark meat: composition and stability to lipid oxidation of the recovered proteins.
Chicken dark meat has been considered as a major underused commodity due to the increasing demand for further-processed breast meat products. One option to increase the utilization of chicken dark meat is to extract myofibrillar proteins and separate them from fat and pigments to enhance their application for the preparation of further-processed meat products. The objective of the current study was to determine the effect of pH, in the range of 10.5 to 12.0, on the alkaline solubilization process of chicken dark meat. Aspects studied were the effect of the alkali-aided process on protein content, lipid composition, lipid oxidation, and color characteristics of the extracted meat. Each experiment and each assay were done at least in triplicate. Lipid content of the extracted meat showed a 50% reduction compared with the chicken dark meat. Neutral lipids were reduced by 61.51%, whereas polar lipids were not affected by the alkali treatments. There was a higher amount of TBA reactive substances observed in the extracted meat compared with chicken dark meat, indicating that extracted meat was more susceptible to oxidation. Long-chain polyunsaturated fatty acids (22:4n-6, 20:3n-3, 20:5n-3, 22:5n-3, and 22:6n-3), which were detected only in the polar lipids, were responsible for increasing lipid oxidation susceptibility of extracted meat compared with chicken dark meat. Alkali-aided extraction of chicken dark meat lightened the color of the meat. The redness, yellowness, and total heme pigments in extracted meat significantly decreased by 83, 11, and 53%, respectively, compared with chicken dark meat. Even though this process did not remove polar lipids, based on our early findings, the extracted meat had considerable physicochemical and textural properties for product preparation compared with those of raw dark meat. Hence, alkali recovery of protein can be considered a potentially useful method to increase the utilization of dark chicken meat.


The Effectiveness and Safety of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer Patients With Stage III/IV: A Multicenter Study.
Immune checkpoint inhibitors (ICIs) have been approved to treat patients with various cancer types, including lung cancer, in many countries. This study aims to investigate the effectiveness and safety of ICIs under different treatment conditions of non-small cell lung cancer patients. A population-based retrospective cohort study was conducted using the electronic health records of three medical centers in Taiwan. From January 01, 2016, to November 30, 2018, a total of 91 ICIs and 300 traditional chemotherapy users who had undergone stage III and IV lung cancer treatment were included in the study. We performed the randomized matched pair design by selecting a Chemotherapy subject for each ICI patient in the sample population. All subjects were monitored from the date of taking ICIs or chemotherapy drugs until the event of death, loss to follow-up, or were occurred with any defined adverse events. Kaplan-Meier estimators and cox proportional hazard regression models were used to compute the overall survival, efficacy, and safety of the ICIs group. The median overall survival (OS) in the ICI and Chemo groups after matching was 11.2 months and 10.5 months, respectively. However, the results showed no significant OS differences between ICIs and chemo groups for both before and after matching (HR,1.30; 95%CI, 0.68-2.46; p=0.428 before matching and HR,0.96; 95CI%, 0.64-1.44; p=0.838 after matching). We observed that with the higher amount of PD-L1, the length of the patients' overall survival was (positive vs. negative PD-L1, HR,0.21; 95%CI, 0.05-0.80; p=0.022). The incidences of serious adverse drug events above grade 3 in the ICIs and traditional chemo groups were 12.7% and 21.5%, respectively. We also found that the number of AEs was less in ICIs than in the Chemo group, and the AEs that occurred after treatments were observed earlier in the ICIs compared to the Chemo group. ICIs drugs were observed to be safer than traditional chemotherapy as they had a lower risk of serious adverse drug events. It is necessary to pay attention to immune-related side effects and provide appropriate treatment. Furthermore, the patient's physical status and PD-L1 test can be used to evaluate the clinical effectiveness of ICIs.


Blood plasma levels of deoxynivalenol and its de-epoxy metabolite in broilers after a single oral dose of the toxin.
To evaluate the transfer of deoxynivalenol (DON) and its de-epoxy metabolite (de-epoxy-DON) in the plasma of chicken, mashed oats naturally contaminated with 9.5 mg DON/kg were fed to four broilers (35 days age) at a dose of 20 g/bird. Blood samples were then collected from two birds at 1 h, 3 h, and 5 h post-feeding, while from the other two birds at 2 h, 4 h, and 6 h post-feeding. Analysis of DON and de-epoxy-DON was carried out by using liquid chromatography-tandem mass spectrometry after clean-up with immunoaffinity columns. At 1 h, 3 h, and 5 h post-feeding, the average values of plasma DON were 0.35 ng/ml, 0.20 ng/ml, and 0.15 ng/ml, respectively. The corresponding average values of de-epoxy-DON at these time points were 0.70 ng/ml, 0.80 ng/ml, and 0.25 ng/ml, respectively. The sum of DON and de-epoxy-DON appearing in the plasma at 1 h post-feeding in these birds was estimated to be 0.044% of the total DON fed. At 2 h, 4 h, and 6 h post-feeding, the average values of plasma DON were 0.85 ng/ml, 0.45 ng/ml, and 0.30 ng/ml. De-epoxy-DON could not be detected in the birds sampled at 2 h, 4 h, and 6 h post-feeding. The total amount of DON appearing in the plasma at 2 h post-feeding in these birds was estimated to be 0.036% of the DON fed. These data show that the absorption rate of DON is very low in broilers and that there is also a rapid transformation, and clearance from plasma. Furthermore, there appeared to be individual variability in the capacity of birds to de-epoxidise DON.


Glycoprotein-180 deficiency: genetics and abnormal neutrophil activation.
Neutrophil function was studied in a patient with polymorphonuclear leukocyte (PMN) glycoprotein-180 deficiency and in her parents. PMNs of the patient had abnormal chemotaxis, phagocytosis, adherence, surface charge, and membrane-associated events of activation. Selective defects to C3b, immunoglobulin G (IgG), phorbol myristate acetate (PMA) and N-formyl-methionyl-leucyl-phenylalanine (FMLP) are described, although C3b receptor density was normal. The parents were found to have abnormal adherence to nylon-wool fibers, abnormal transmembrane potential depolarization with PMA, and reduced amounts of glycoprotein-180 in their PMNs. These studies provide further evidence that the oxidative burst has several different pathways for activation. They demonstrate that the absence of a single PMN surface glycoprotein is associated with a broad spectrum of PMN functional abnormalities. Finally, the observations made in the parents support an autosomal recessive mode of inheritance.


Cause-specific mortality in women with breast cancer in situ.
The long-term mortality remains unknown in women diagnosed with breast cancer in situ (BCIS). Here, we assessed the cause-specific mortality in BCIS patients. This population-based cohort study included 12,243 women diagnosed with BCIS in Sweden between 1980 and 2011. Patients were followed until death, emigration, or 31 December 2013, whichever came first. The 30-year cumulative incidence of breast cancer-specific mortality was 6.3%, which is considerably lower than 49.7% observed for other-cause mortality. Women diagnosed with BCIS were more likely to die from breast cancer (standardized mortality ratio [SMR], 3.85; 95% CI, 3.47-4.27) but less likely to die from cardiovascular disease (SMR, 0.88; 95% CI, 0.82-0.95) than women in the general population. Specifically, the SMRs for breast cancer-specific mortality decreased over time from 5.19 (95% CI, 3.95-6.81) among BCIS diagnosed during 1980-1989 to 3.03 (95% CI, 2.35-3.91) among those diagnosed during 2000-2011. Furthermore, higher risk of death from other causes was seen among those with older age at BCIS diagnosis, lower levels of education, nulliparity, higher Charlson Comorbidity Index, and being hospitalized before BCIS diagnosis; whereas, lower risk of death from breast cancer was seen among BCIS diagnosed in the later time period and those with younger age at first birth. We conclude that most women diagnosed with BCIS die from causes other than breast cancer, which highlights the need for actions not only to reduce nonbreast cancer mortality but also to identify patient where extensive curative BCIS treatment is not adding to survival.


Exploring approaches for predictive cancer patient digital twins: Opportunities for collaboration and innovation.
We are rapidly approaching a future in which cancer patient digital twins will reach their potential to predict cancer prevention, diagnosis, and treatment in individual patients. This will be realized based on advances in high performance computing, computational modeling, and an expanding repertoire of observational data across multiple scales and modalities. In 2020, the US National Cancer Institute, and the US Department of Energy, through a trans-disciplinary research community at the intersection of advanced computing and cancer research, initiated team science collaborative projects to explore the development and implementation of predictive Cancer Patient Digital Twins. Several diverse pilot projects were launched to provide key insights into important features of this emerging landscape and to determine the requirements for the development and adoption of cancer patient digital twins. Projects included exploring approaches to using a large cohort of digital twins to perform deep phenotyping and plan treatments at the individual level, prototyping self-learning digital twin platforms, using adaptive digital twin approaches to monitor treatment response and resistance, developing methods to integrate and fuse data and observations across multiple scales, and personalizing treatment based on cancer type. Collectively these efforts have yielded increased insights into the opportunities and challenges facing cancer patient digital twin approaches and helped define a path forward. Given the rapidly growing interest in patient digital twins, this manuscript provides a valuable early progress report of several CPDT pilot projects commenced in common, their overall aims, early progress, lessons learned and future directions that will increasingly involve the broader research community.


Cultural and health beliefs of pregnant women in Zambia regarding pregnancy and child birth.
Health beliefs related to pregnancy and childbirth exist in various cultures globally. Healthcare practitioners need to be aware of these beliefs so as to contextualise their practice in their communities. To explore the health beliefs regarding pregnancy and childbirth of women attending the antenatal clinic at Chawama Health Center in Lusaka Zambia. This was a descriptive, cross-sectional survey of women attending antenatal care(n = 294) who were selected by systematic sampling. A researcher-administered questionnaire was used for data collection. Results indicated that women attending antenatal care at Chawama Clinic held certain beliefs relating to diet, behaviour and the use of medicinal herbs during pregnancy and post-delivery. The main beliefs on diet related to a balanced diet, eating of eggs, okra, bones, offal, sugar cane, alcohol consumption and salt intake. The main beliefs on behaviour related to commencement of antenatal care, daily activities, quarrels, bad rituals, infidelity and the use of condoms during pregnancy. The main beliefs on the use of medicinal herbs were on their use to expedite the delivery process, to assist in difficult deliveries and for body cleansing following a miscarriage. Women attending antenatal care at the Chawama Clinic hold a number of beliefs regarding pregnancy and childbirth. Those beliefs that are of benefit to the patients should be encouraged with scientific explanations, whilst those posing a health risk should be discouraged respectfully.


Forming a ruthenium isomerisation catalyst from Grubbs II: a DFT study.
A DFT investigation into the mechanism for the decomposition of Grubbs 2nd generation pre-catalyst (2) in the presence of methanol, is presented. Gibbs free energy profiles for decomposition of the pre-catalyst (2) via two possible mechanisms were computed. We predict that decomposition following tricyclohexylphosphane dissociation is most favoured compared to direct decomposition of the pre-catalyst (2). However, depending on the reaction conditions, an on-pathway mechanism may be competitive with ruthenium hydride formation.


A molecular signature of tissues with pacemaker activity in the heart and upper urinary tract involves coexpressed hyperpolarization-activated cation and T-type Ca2+ channels.
Renal pacemakers set the origin and frequency of the smooth muscle contractions that propel wastes from the kidney to the bladder. Although congenital defects impairing this peristalsis are a leading cause of pediatric renal failure, the mechanisms underlying renal pacemaker activity remain unknown. Using ratiometric optical mapping and video microscopy, we discovered that hyperpolarization-activated cation (HCN) channel block with the specific anatagonist ZD7288 (30 μm; IC50) abolished the pacemaker depolarizations that initiate murine upper urinary tract peristalsis. Optical mapping and immunohistochemistry indicate that pacemaker potentials are generated by cells expressing HCN isoform-3, and that HCN3(+) cells are coupled to definitive smooth muscle via gap junctions. Furthermore, we demonstrate that HCN3(+) cells coexpress T-type Ca(2+) (TTC) channels and that TTC channel inhibition with R(-)efonidipine or NNC55-0396 decreased contractile frequency in a dose-dependent manner. Collectively, these data demonstrate that HCN3(+)/TTC(+) cells are the pacemakers that set the origin and rate of upper urinary tract peristalsis. These results reveal a conserved mechanism controlling autorhythmicity in 2 distinct muscle types, as HCN and TTC channels also mediate cardiac pacemaker activity. Moreover, these findings have translational applications, including the development of novel diagnostics to detect fetal urinary tract motility defects prior to renal damage.-Hurtado, R., Bub, G., Herzlinger, D. A molecular signature of tissues with pacemaker activity in the heart and upper urinary tract involves coexpressed hyperpolarization-activated cation and T-type Ca(2+) channels.


Rearrangement of the Extracellular Domain/Extracellular Loop 1 Interface Is Critical for Thyrotropin Receptor Activation.
The thyroid stimulating hormone receptor (TSHR) is a G protein-coupled receptor (GPCR) with a characteristic large extracellular domain (ECD). TSHR activation is initiated by binding of the hormone ligand TSH to the ECD. How the extracellular binding event triggers the conformational changes in the transmembrane domain (TMD) necessary for intracellular G protein activation is poorly understood. To gain insight in this process, the knowledge on the relative positioning of ECD and TMD and the conformation of the linker region at the interface of ECD and TMD are of particular importance. To generate a structural model for the TSHR we applied an integrated structural biology approach combining computational techniques with experimental data. Chemical cross-linking followed by mass spectrometry yielded 17 unique distance restraints within the ECD of the TSHR, its ligand TSH, and the hormone-receptor complex. These structural restraints generally confirm the expected binding mode of TSH to the ECD as well as the general fold of the domains and were used to guide homology modeling of the ECD. Functional characterization of TSHR mutants confirms the previously suggested close proximity of Ser-281 and Ile-486 within the TSHR. Rigidifying this contact permanently with a disulfide bridge disrupts ligand-induced receptor activation and indicates that rearrangement of the ECD/extracellular loop 1 (ECL1) interface is a critical step in receptor activation. The experimentally verified contact of Ser-281 (ECD) and Ile-486 (TMD) was subsequently utilized in docking homology models of the ECD and the TMD to create a full-length model of a glycoprotein hormone receptor.


Mitochondrial protein content and in vivo synthesis rates in skeletal muscle from critically ill rats.
1. Recently we reported decreased activities of two mitochondrial marker enzymes (citrate synthase and cytochrome c oxidase) in skeletal muscle from a rat model of critical illness (zymosan injection). In the present study we investigated (i) whether these decreases in enzyme activity reflect a reduction in mitochondrial content and (ii) whether this potential reduction in mitochondrial content was the result of decreased mitochondrial protein synthesis rates. 2. Mitochondrial protein content was calculated from the activities of cytochrome c oxidase in whole-muscle homogenates and purified mitochondria. Synthesis rates of mitochondrial protein in vivo were studied by measuring the incorporation of [3H]phenylalanine into mitochondrial protein using the flooding dose technique. 3. Mitochondrial protein content was reduced to 54% of that measured in the pair-fed rats and to 71% of that measured in control rats fed ad libitum 2 days after the zymosan treatment. The decreased mitochondrial protein content observed 2 days after zymosan challenge was preceded by a reduced rate of synthesis of mitochondrial protein 16h after treatment. Both changes were of greater magnitude than the general muscle wasting and the decreased rate of synthesis of mixed protein observed in the zymosan-treated rats. 4. We conclude that the acute phase of critical illness in zymosan-treated rats is characterized by a substantial reduction in muscle mitochondria that is at least in part caused by a decreased rate of synthesis of mitochondrial protein. This derangement in mitochondrial protein metabolism may be related to the impaired muscle function observed during and after critical illness.


A multisensory cortical network for understanding speech in noise.
In noisy environments, listeners tend to hear a speaker's voice yet struggle to understand what is said. The most effective way to improve intelligibility in such conditions is to watch the speaker's mouth movements. Here we identify the neural networks that distinguish understanding from merely hearing speech, and determine how the brain applies visual information to improve intelligibility. Using functional magnetic resonance imaging, we show that understanding speech-in-noise is supported by a network of brain areas including the left superior parietal lobule, the motor/premotor cortex, and the left anterior superior temporal sulcus (STS), a likely apex of the acoustic processing hierarchy. Multisensory integration likely improves comprehension through improved communication between the left temporal-occipital boundary, the left medial-temporal lobe, and the left STS. This demonstrates how the brain uses information from multiple modalities to improve speech comprehension in naturalistic, acoustically adverse conditions.


Long-term results after fluoroscopy-guided closure of patent foramen ovale for secondary prevention of paradoxical embolism.
To carry out long-term follow-up after percutaneous closure of patent foramen ovale (PFO) in patients with cryptogenic stroke. Prospective cohort study. Single tertiary care centre. 525 consecutive patients (mean (SD) age 51 (12) years; 56% male). Percutaneous PFO closure without intraprocedural echocardiography. Freedom from recurrent embolic events. A mean (SD) of 1.7 (1.0) clinically apparent embolic events occurred for each patient, and 186 patients (35%) had >1 event. An atrial septal aneurysm was associated with the PFO in 161 patients (31%). All patients were followed up prospectively for up to 11 years. The implantation procedure failed in two patients (0.4%). There were 13 procedural complications (2.5%) without any long-term sequelae. Contrast transoesophageal echocardiography at 6 months showed complete closure in 86% of patients, and a minimal, moderate or large residual shunt in 9%, 3% and 2%, respectively. Patients with small occluders (<30 mm; n = 429) had fewer residual shunts (small 11% vs large 27%; p<0.001). During a mean (SD) follow-up of 2.9 (2.2) years (median 2.3 years; total 1534 patient-years), six ischaemic strokes, nine transient ischaemic attacks (TIAs) and two peripheral emboli occurred. Freedom from recurrent stroke, TIA, or peripheral embolism was 98% at 1 year, 97% at 2 years and 96% at 5 and 10 years, respectively. A residual shunt (hazard ratio = 3.4; 95% CI 1.3 to 9.2) was a risk factor for recurrence. This study attests to the long-term safety and efficacy of percutaneous PFO closure guided by fluoroscopy only for secondary prevention of paradoxical embolism in a large cohort of consecutive patients.


Ascorbate concentration in tissues from normal and buphthalmic rabbits.
Previous studies show a progressive lowering of ascorbate concentration in the aqueous humor from rabbits with hereditary buphthalmus, depending on the severity of the buphthalmus. In this study, the ascorbate concentration of different tissues from age-matched adult buphthalmic and control rabbits were analyzed to determine whether a defect of ascorbate transport occurs in a variety of tissues from rabbits with hereditary buphthalmus. Our results showed that ascorbate changes were observed only in ocular tissues. The lowering of ascorbate concentration occurs only in lens and cornea, which depend on the aqueous humor to deliver ascorbate from the blood. The tissues that derive ascorbate directly from the blood, such as the ciliary body-iris and retina of buphthalmic eyes, have normal ascorbate concentration. It has been postulated that ascorbate is oxidized in the ciliary body-iris to facilitate its transport across the epithelium. A defect in the buphthalmic eyes to oxidize ascorbate could be the primary cause of lowering ascorbate concentration in the aqueous humor.


Stents versus coronary-artery bypass grafting for left main coronary artery disease.
Several studies have compared the treatment effects of coronary stenting and coronary-artery bypass grafting (CABG). However, there are limited data regarding the long-term outcomes of these two interventions for patients with unprotected left main coronary artery disease. We evaluated 1102 patients with unprotected left main coronary artery disease who underwent stent implantation and 1138 patients who underwent CABG in Korea between January 2000 and June 2006. We compared adverse outcomes (death; a composite outcome of death, Q-wave myocardial infarction, or stroke; and target-vessel revascularization) with the use of propensity-score matching in the overall cohort and in separate subgroups according to type of stent. In the overall matched cohort, there was no significant difference between the stenting and CABG groups in the risk of death (hazard ratio for the stenting group, 1.18; 95% confidence interval [CI], 0.77 to 1.80) or the risk of the composite outcome (hazard ratio for the stenting group, 1.10; 95% CI, 0.75 to 1.62). The rates of target-vessel revascularization were significantly higher in the group that received stents than in the group that underwent CABG (hazard ratio, 4.76; 95% CI, 2.80 to 8.11). Comparisons of the group that received bare-metal stents with the group that underwent CABG and of the group that received drug-eluting stents with the group that underwent CABG produced similar results, although there was a trend toward higher rates of death and the composite end point in the group that received drug-eluting stents. In a cohort of patients with unprotected left main coronary artery disease, we found no significant difference in rates of death or of the composite end point of death, Q-wave myocardial infarction, or stroke between patients receiving stents and those undergoing CABG. However, stenting, even with drug-eluting stents, was associated with higher rates of target-vessel revascularization than was CABG.


Detecting the role of individual species for overyielding in experimental grassland communities composed of potentially dominant species.
Several studies have shown that the contribution of individual species to the positive relationship between species richness and community biomass production cannot be easily predicted from species monocultures. Here, we used a biodiversity experiment with a pool of nine potentially dominant grassland species to relate the species richness-productivity relationship to responses in density, size and aboveground allocation patterns of individual species. Aboveground community biomass increased strongly with the transition from monocultures to two-species mixtures but only slightly with the transition from two- to nine-species mixtures. Tripartite partitioning showed that the strong increase shown by the former was due to trait-independent complementarity effects, while the slight increase shown by the latter was due to dominance effects. Trait-dependent complementarity effects depended on species composition. Relative yield total (RYT) was greater than 1 (RYT>1) in mixtures but did not increase with species richness, which is consistent with the constant complementarity effect. The relative yield (RY) of only one species, Arrhenatherum elatius, continually increased with species richness, while those of the other species studied decreased with species richness or varied among different species compositions within richness levels. High observed/expected RYs (RYo/RYe>1) of individual species were mainly due to increased module densities, whereas low observed/expected RYs (RYo/RYe<1) were due to more pronounced decreases in module density (species with stoloniferous or creeping growth) or module size (species with clearly-defined plant individuals). The trade-off between module density and size, typical for plant populations under the law of constant final yield, was compensated among species. The positive trait-independent complementarity effect could be explained by an increase in community module density, which reached a maximum at low species richness. In contrast, the increasing dominance effect was attributable to the species-specific ability, in particular that of A. elatius, to increase module size, while intrinsic growth limitations led to a suppression of the remaining species in many mixtures.


The Role of the Immune System in Metabolic Health and Disease.
In addition to the immune system's traditional roles of conferring anti-infectious and anti-neoplastic protection, it has been recently implicated in the regulation of systemic metabolic homeostasis. This cross-talk between the immune and the metabolic systems is pivotal in promoting "metabolic health" throughout the life of an organism and plays fundamental roles in its adaptation to ever-changing environmental makeups and nutritional availability. Perturbations in this intricate immune-metabolic cross-talk contribute to the tendency to develop altered metabolic states that may culminate in metabolic disorders such as malnutrition, obesity, type 2 diabetes mellitus (T2DM), and other features of the metabolic syndrome. Regulators of immune-metabolic interactions include host genetics, nutritional status, and the intestinal microbiome. In this Perspective, we highlight current understanding of immune-metabolism interactions, illustrate differences among individuals and between populations in this respect, and point toward future avenues of research possibly enabling immune harnessing as means of personalized treatment for common metabolic disorders.


Assessing the use of artificial substrates to monitor Gambierdiscus populations in the Florida Keys.
Four distinct coastal locations were sampled on a monthly basis near Long Key (Florida Keys, USA) over a 13-month period to study Gambierdiscus population dynamics on different substrates, including four macrophyte species (Dictyota spp., Halimeda spp., Laurencia spp., and Thalassia testudinum) and three artificial substrates (polyvinyl chloride (PVC) tiles, burlap, and fiberglass window screen). Cell densities of Gambierdiscus were generally lower on Dictyota versus Halimeda and Laurencia. Cell densities of Gambierdiscus were significantly correlated among macrophyte hosts in 54% of the comparisons, and between macrophyte hosts and artificial substrates in 72% of the comparisons. Predictive slopes determined from regression analyses between cell densities on artificial substrates and macrophyte hosts indicated that, on an areal basis, fewer cells were present on macrophytes versus artificial substrates (cells cm-2) and that slope variation (error) among the different macrophytes and sites ranged from 5% to 200%, averaging 61% overall. As the data required log-transformation prior to analyses, this level of error translates into two-orders of magnitude in range of estimation of the overall average abundance of Gambierdiscus cells on macrophytes (135 cells g-1 wet weight); 20-2690 cells g-1 ww. The lack of consistent correlation among Gambierdiscus cell densities on macrophytes versus artificial substrates, coupled with the high level of error associated with the predictive slope estimations, indicates that extreme caution should be taken when interpreting the data garnered from artificial substrate deployments, and that such deployments should be thoroughly vetted prior to routine use for monitoring purposes.


Linkage analysis of peripheral neurofibromatosis (Von Recklinghausen disease) and chromosome 19 markers linked to myotonic dystrophy.
Three chromosome 19 markers known to be linked to myotonic dystrophy have been studied in nine families with peripheral neurofibromatosis (Von Recklinghausen's disease). Clear evidence against linkage has been found for all three markers, excluding the peripheral neurofibromatosis gene from the myotonic dystrophy region of chromosome 19. Previous reports of co-inheritance of the two disorders in families cannot therefore be explained on the basis of close genetic linkage between the loci.


Damage of collagen and elastic fibres by borrelia burgdorferi - known and new clinical and histopathological aspects.
Lyme Borreliosis, or Lyme's disease, manifests itself in numerous skin conditions. Therapeutic intervention should be initiated as soon as a clinical diagnosis of erythema migrans is made. The histopathology of some of the skin conditions associated with Lyme Borreliosis is characterised by structural changes to collagen, and sometimes also elastic fibres. These conditions include morphea, lichen sclerosus et atrophicus and acrodermatitis chronica atrophicans. More recently, further skin conditions have been identified by the new microscopic investigation technique of focus floating microscopy: granuloma annulare, necrobiosis lipoidica, necrobiotic xanthogranuloma, erythema annulare centrifugum, interstitial granulomatous dermatitis, cutaneous sarcoidosis and lymphocytic infiltration; these conditions also sometimes cause changes in the connective tissue. In the case of ligaments and tendons, collagen and elastic fibres predominate structurally. They are also the structures that are targeted by Borrelia. The resultant functional disorders have previously only rarely been associated with Borreliosis in clinical practice. Ligamentopathies and tendinopathies, spontaneous ruptures of tendons after slight strain, dislocation of vertebrae and an accumulation of prolapsed intervertebral discs as well as ossification of tendon insertions can be viewed in this light.


A Cost Analysis of Hospitalizations for Infections Related to Injection Drug Use at a County Safety-Net Hospital in Miami, Florida.
Infections related to injection drug use are common. Harm reduction strategies such as syringe exchange programs and skin care clinics aim to prevent these infections in injection drug users (IDUs). Syringe exchange programs are currently prohibited by law in Florida. The goal of this study was to estimate the mortality and cost of injection drug use-related bacterial infections over a 12-month period to the county safety-net hospital in Miami, Florida. Additionally, the prevalence of HIV and hepatitis C virus among this cohort of hospitalized IDUs was estimated. IDUs discharged from Jackson Memorial Hospital were identified using the International Classification of Diseases, Ninth Revision, codes for illicit drug abuse and endocarditis, bacteremia or sepsis, osteomyelitis and skin and soft tissue infections (SSTIs). 349 IDUs were identified for chart abstraction and 92% were either uninsured or had publicly funded insurance. SSTIs, the most common infection, were reported in 64% of IDUs. HIV seroprevalence was 17%. Seventeen patients (4.9%) died during their hospitalization. The total cost for treatment for injection drug use-related infections to Jackson Memorial Hospital over the 12-month period was $11.4 million. Injection drug use-related bacterial infections represent a significant morbidity for IDUs in Miami-Dade County and a substantial financial cost to the county hospital. Strategies aimed at reducing risk of infections associated with injection drug use could decrease morbidity and the cost associated with these common, yet preventable infections.