Limited hybridization between Quercus lobata and Quercus douglasii (Fagaceae) in a mixed stand in central coastal California.
Many oak species are interfertile, and morphological and genetic evidence for hybridization is widespread. Here we use DNA microsatellite markers to characterize hybridization between two closely related oak species in a mixed stand in central coastal California, Quercus lobata (valley oak) and Q. douglasii (blue oak) (Fagaceae). Genotypes from four microsatellite loci indicate that many alleles are shared between the two species. However, each species harbors unique alleles, and allele frequencies differ significantly. A Bayesian analysis of genetic structure in the stand identified two highly differentiated genetic clusters, essentially corresponding to species assignment based on morphology. Data from the four loci were sufficient to assign all 135 trees to one of the two species. In addition, five putative hybrid individuals having intermediate morphologies could be assigned genetically to one or the other species, and all but one had low probability of hybrid ancestry. Overally, only six (4.6%) trees showed >0.05 probability of hybrid ancestry, in all cases their probabilities for nonhybrid ancestry were substantially higher. We conclude that adult hybrids of Q. douglasii × Q. lobata are rare at this site and plasticity in morphological characters may lead to overestimates of hybridization among Quercus species.


Training community-based treatment providers to implement contingency management for opioid addiction: Time to and frequency of adoption.
Contingency management (CM) is a well-established treatment for opioid use, yet its adoption remains low in community clinics. This manuscript presents a secondary analysis of a study comparing a comprehensive implementation strategy (Science to Service Laboratory; SSL) to didactic training-as-usual (TAU) as a means of implementing CM across a multi-site opioid use disorder program. Hypotheses predicted that providers who received the SSL implementation strategy would 1) adopt CM faster and 2) deliver CM more frequently than TAU providers. In addition, we examined whether the effect of implementation strategy varied as a function of a set of theory-driven moderators, guided by the Consolidated Framework for Implementation Research: perceived intervention characteristics, perceived organizational climate, and provider characteristics (i.e., race/ethnicity, gender). Sixty providers (39 SSL, 21 TAU) across 15 clinics (7 SSL, 8 TAU) completed a comprehensive set of measures at baseline and reported biweekly on CM use for 52 weeks. All participants received didactic CM training; SSL clinics received 9 months of enhanced training, including access to an external coach, an in-house innovation champion, and a collaborative learning community. Discrete-time survival analysis found that SSL providers more quickly adopted CM; provider characteristics (i.e., race/ethnicity) emerged as the sole moderator of time to adoption. Negative binomial regression revealed that SSL providers also delivered CM more frequently than TAU providers. Frequency of CM adoption was moderated by provider (i.e., gender and race/ethnicity) and intervention characteristics (i.e., compatibility). Implications for implementation strategies for community-based training are discussed.


Granulocyte-macrophage colony-stimulating factor, interleukin-2, and interleukin-12 synergize with calcium ionophore to enhance dendritic cell function.
The authors previously showed that monocytes treated with calcium ionophore (CI) acquire characteristics of mature dendritic cells (DC) in part through a calcineurin-dependent pathway. In this study, the authors evaluated the ability of granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-2 (IL-2), and interleukin-12 (IL-12) alone or in combination with CI to induce DC characteristics in peripheral blood monocytes. Monocytes obtained by leukapheresis and countercurrent centrifugal elutriation were cultured with calcium, cytokines, or both, profiled by flow cytometry, and assessed for antigen uptake and sensitization of autologous CD8+ T cells to antigen. Monocytes treated with the combination of GM-CSF, IL-2, and IL-12 resulted in immunophenotypic and antigen uptake profiles typical of immature DC, including loss of surface CD14 expression, de novo low-level expression of B7.1, negligible CD83 expression, marked enhancement of CD40 and ICAM-1, and high major histocompatibility complex class I and II levels. A high level of antigen uptake by macro-pinocytosis was observed. In contrast, CI treatment significantly up-regulates B7.1, B7.2, CD40, CD54, and CD83 and substantially down-regulates CD14 and macro-pinocytosis, a profile consistent with mature DC. Many CI-induced modulations, but none resulting from cytokine treatment alone, were inhibited by the calcineurin phosphatase inhibitor cyclosporin A. Compared with monocytes treated with CI alone, combined treatment of monocytes with GM-CSF, IL-2, IL-12, and CI augmented B7.1 and CD83 expression and enhanced sensitization of autologous CD8+ T cells to melanoma-antigen-derived peptides. These results suggest that several independent pathways of DC activation can cooperatively enhance the function of monocyte-derived DC.


Neuropsychiatric Traits Associated with Refractory Impulse Control Disorder in Parkinson's Disease.
Impulse control disorder (ICD) in Parkinson's disease (PD) is a critical nonmotor symptom with personality or neuropsychiatric traits contributing to ICD. This study aimed to identify predictive traits for persistent or paradoxical aggravation of ICD after dopamine agonist substitution therapy for ICD in PD. We conducted a case-control study using a database of a multicenter intervention trial for ICD in PD. The poor-outcome group was defined by showing paradoxical increases in ICD behaviors after the substitution of dopamine agonists with levodopa. We analyzed the pre-intervention personality traits associated with the poor outcome and also evaluated the risk traits for refractory ICD using a receiver-operating characteristic (ROC) curve analysis. The poor-outcome group showed higher levels of anger expression (p =0.007) and obsessive-compulsive traits (p =0.009) compared with the good-outcome group at the pre-intervention state. In the ROC curve analysis, the Obsessive-Compulsive Inventory showed the highest area under the curve with 80.0% sensitivity and 74.3% specificity in discriminating against the poor-outcome group. Our results suggest that assessment of obsessive compulsiveness may be useful for predicting the refractoriness of ICD behaviors in planning an interventional treatment for ICD in PD.


Hydraulic "fracking": are surface water impacts an ecological concern?
Use of high-volume hydraulic fracturing (HVHF) in unconventional reservoirs to recover previously inaccessible oil and natural gas is rapidly expanding in North America and elsewhere. Although hydraulic fracturing has been practiced for decades, the advent of more technologically advanced horizontal drilling coupled with improved slickwater chemical formulations has allowed extensive natural gas and oil deposits to be recovered from shale formations. Millions of liters of local groundwaters are utilized to generate extensive fracture networks within these low-permeability reservoirs, allowing extraction of the trapped hydrocarbons. Although the technology is relatively standardized, the geographies and related policies and regulations guiding these operations vary markedly. Some ecosystems are more at risk from these operations than others because of either their sensitivities or the manner in which the HVHF operations are conducted. Generally, the closer geographical proximity of the susceptible ecosystem to a drilling site or a location of related industrial processes, the higher the risk of that ecosystem being impacted by the operation. The associated construction of roads, power grids, pipelines, well pads, and water-extraction systems along with increased truck traffic are common to virtually all HVHF operations. These operations may result in increased erosion and sedimentation, increased risk to aquatic ecosystems from chemical spills or runoff, habitat fragmentation, loss of stream riparian zones, altered biogeochemical cycling, and reduction of available surface and hyporheic water volumes because of withdrawal-induced lowering of local groundwater levels. The potential risks to surface waters from HVHF operations are similar in many ways to those resulting from agriculture, silviculture, mining, and urban development. Indeed, groundwater extraction associated with agriculture is perhaps a larger concern in the long term in some regions. Understanding the ecological impacts of these anthropogenic activities provides useful information for evaluations of potential HVHF hazards. Geographic information system-based modeling combined with strategic site monitoring has provided insights into the relative importance of these and other ecoregion and land-use factors in discerning potential HVHF impacts. Recent findings suggest that proper siting and operational controls along with strategic monitoring can reduce the potential for risks to aquatic ecosystems. Nevertheless, inadequate data exist to predict ecological risk at this time. The authors suggest considering the plausibility of surface water hazards associated with the various HVHF operations in terms of the ecological context and in the context of relevant anthropogenic activities.


Complicated septic cervical and lumbar discitis.
A 69-year-old lady presented with back pain for 5 days associated with spiking temperatures, lower limb weakness and urinary retention. Urgent MRI showed discitis at the disc between cervical vertebra seven (C7), thoracic vertebra one (T1) and lumbar vertebra three and four (L3-4), associated dural inflammation, stenosis of the cervical spinal canal and cervical cord oedema at the level of C3. No definite epidural abscess was seen. She was transferred to the spinal unit for observation. Following transfer she rapidly developed respiratory compromise and required emergency spinal decompression later that day.


First Report of Tomato spotted wilt virus on Pepper in Montenegro.
In April 2009, chlorotic and necrotic ring spots, chlorotic line patterns, and stunting were observed on greenhouse-grown pepper plants in the vicinity of Podgorica, Montenegro. Disease symptom incidence was estimated at 40%. Symptomatic leaves were tested for the presence of Tomato spotted wilt virus (TSWV) with a commercial double-antibody sandwich (DAS)-ELISA diagnostic kit (Bioreba AG, Reinach, Switzerland). Commercial positive and negative controls were included in each ELISA. TSWV was detected serologically in 33 of 75 pepper samples. The virus was mechanically transmitted from ELISA-positive pepper samples to Nicotiana tabacum cv. Samsun using chilled 0.05 M phosphate buffer (pH 7) containing 0.1% sodium sulfite (1). Inoculated test plants produced chlorotic and necrotic concentric rings and necrotic spots, consistent with symptoms caused by TSWV on N. tabacum. For further confirmation of TSWV infection, reverse transcription (RT)-PCR was performed with the One-Step RT-PCR Kit (Qiagen, Hilden, Germany) using three sets of primers: S70-for/S890-rev (2) and S574-for/S1433-rev (3), both specific to the nonstructural (NSs) gene; and S1983-for/S2767-rev (2), specific to the nucleocapsid protein (N) gene. Total RNAs from naturally infected pepper and symptomatic N. tabacum cv. Samsun plants were extracted with the RNeasy Plant Mini Kit (Qiagen, Hilden, Germany). Total RNAs obtained from the Italian isolate of TSWV (GenBank Accession No. DQ398945) and healthy tobacco plants were used as positive and negative controls, respectively. The expected sizes of the RT-PCR products (820, 859, and 784 bp) were amplified from symptomatic pepper samples but not from healthy tissues. The PCR product obtained from isolate Is-344 using primers specific to N gene was purified by a QIAquick PCR Purification Kit (Qiagen), cloned into the pGEM-T Easy Vector (Promega, Madison, WI) and sequenced in both directions using the same primer pair as in RT-PCR. The sequences amplified with the two primer pairs specific to the NSs gene were obtained by direct sequencing (Bio-Fab Research Srl, Pomezia, Italy) and joined using MEGA4 software. Sequence analysis of the complete N gene (777 bp; GenBank Accession No. GU369717) revealed that the TSWV isolate originating from Montenegro shared 98.2 to 99.7% nucleotide identity (98.1 to 100% amino acid identities) with corresponding TSWV sequences deposited in GenBank. The Montenegrin isolate Is-344 was most closely related to Italian isolates from tomato (GU369725) and eggplant (GU369720). The partial (1,257 bp) nucleotide sequence of NSs gene (GU369737) showed 96 to 99.8% nucleotide identity (96.9 to 100% amino acid identity) with previously reported TSWV sequences, and in this case the highest identity was with French isolates from tomato (FR692835) and lettuce (FR692831). To our knowledge, this is the first report on the occurrence of TSWV in Montenegro. Data of this study sheds light on the importance of further survey studies and inspections of TSWV-susceptible crops cultivated in Montenegro. References: (1) Anonymous. OEPP/EPPO Bull. 29:465, 1999. (2) W. P. Qiu et al. Virology 244:186, 1998. (3) M. Tsompana et al. Mol. Ecol. 14:53, 2005.


Environmental DNA from Seawater Samples Correlate with Trawl Catches of Subarctic, Deepwater Fishes.
Remote polar and deepwater fish faunas are under pressure from ongoing climate change and increasing fishing effort. However, these fish communities are difficult to monitor for logistic and financial reasons. Currently, monitoring of marine fishes largely relies on invasive techniques such as bottom trawling, and on official reporting of global catches, which can be unreliable. Thus, there is need for alternative and non-invasive techniques for qualitative and quantitative oceanic fish surveys. Here we report environmental DNA (eDNA) metabarcoding of seawater samples from continental slope depths in Southwest Greenland. We collected seawater samples at depths of 188-918 m and compared seawater eDNA to catch data from trawling. We used Illumina sequencing of PCR products to demonstrate that eDNA reads show equivalence to fishing catch data obtained from trawling. Twenty-six families were found with both trawling and eDNA, while three families were found only with eDNA and two families were found only with trawling. Key commercial fish species for Greenland were the most abundant species in both eDNA reads and biomass catch, and interpolation of eDNA abundances between sampling sites showed good correspondence with catch sizes. Environmental DNA sequence reads from the fish assemblages correlated with biomass and abundance data obtained from trawling. Interestingly, the Greenland shark (Somniosus microcephalus) showed high abundance of eDNA reads despite only a single specimen being caught, demonstrating the relevance of the eDNA approach for large species that can probably avoid bottom trawls in most cases. Quantitative detection of marine fish using eDNA remains to be tested further to ascertain whether this technique is able to yield credible results for routine application in fisheries. Nevertheless, our study demonstrates that eDNA reads can be used as a qualitative and quantitative proxy for marine fish assemblages in deepwater oceanic habitats. This relates directly to applied fisheries as well as to monitoring effects of ongoing climate change on marine biodiversity-especially in polar ecosystems.


Study of human neurovegetative and hematologic effects of environmental low-frequency (50-Hz) electromagnetic fields produced by transformers.
A survey of neurovegetative and hematologic disorders was conducted in a population (n = 13) exposed occupationally to environmental electromagnetic fields; the population was matched with 13 control subjects. The exposed subjects worked at least 8 h/d for 1-5 y in premises located above transformers and high-tension cables, and the subjects were submitted to low-frequency electromagnetic fields (i.e., 50 Hz) of 0.2 microT-6.6 microT. The subjects were matched with respect to socioeconomic category, sex, and age with a control population of subjects that worked in premises outside of the immediate vicinity of transformers or high-tension cables. The exposed population had a significant increase in degree of certain neurovegetative disorders (i.e., physical fatigue, psychical asthenia, lipothymia, decreased libido, melancholy, depressive tendency, and irritability). In addition, the population experienced a significant fall in total lymphocytes and CD4, CD3, and CD2 lymphocytes, as well as a rise in NK cells. Leukopenia and neutropenia were also observed in two persons permanently exposed to doses of 1.2-6.6 microT. The disorders disappeared when exposure stopped, and they reappeared on reexposure.


Association between the findings of metachronous secondary primary malignancies and the number of Lugol-voiding lesions.
This study was designed to evaluate the relation between dysplastic squamous epithelium in the esophageal mucosa and the development of metachronous secondary primary malignancies (mSPM) other than esophagus after endoscopic resection (ER) in patients with early esophageal squamous cell carcinoma (SCC). We studied 330 patients with early esophageal SCC who underwent ER as a post hoc analysis of a prospective multicenter cohort study (UMIN Clinical Trials Registry ID UMIN000001676). Lugol-voiding lesions (LVL) were graded into 3 categories (A = no lesion; B = 1 to 9 lesions; C ≥ 10 lesions). The following variables were studied: (i) the incidences of mSPM other than esophagus; (ii) the standardized incidence ratios (SIRs) of mSPM; (iii) the cumulative incidence and total number of mSPM other than esophagus; and (iv) predictors of mSPM other than esophagus on analysis with a multivariate Cox proportional-hazards model. After a median follow-up of 46.6 months, mSPM other than esophagus was diagnosed in a total of 73 patients (90 lesions). Among the 106 patients in group C, 37 patients had mSPM (51 lesions), including head and neck cancer in 14 patients (24 lesions) and gastric cancer in 12 patients (16 lesions). The SIR of mSPM was 3.61 in this study subjects. An increase in the LVL grade (A to B to C) was associated with a progressive increase in the cumulative incidence rate of mSPM other than esophagus (P = 0.017 for A vs. C, P = 0.023 for B vs. C). An increase in the LVL grade (A to B to C) was also associated with a progressive increase in the total number of mSPM other than esophagus per 100 person-years (primary events, relative risk [RR] = 1.66 and 3.24 for grades B and C, respectively, vs. A, P = 0.002 for trend; all events, RR = 1.81 and 4.66 for grades B and C, respectively, vs. A, P < 0.0001 for trend). LVL grade C was a strong predictor of mSPM other than esophagus (RR = 3.41 for A vs. C). LVL grade may be a useful predictor of the risk of mSPM other than esophagus after ER in patients with early esophageal SCC.


Is comfrey root more than toxic pyrrolizidine alkaloids? Salvianolic acids among antioxidant polyphenols in comfrey (Symphytum officinale L.) roots.
Comfrey root preparations are used for the external treatment of joint distortions and myalgia, due to its analgesic and anti-inflammatory properties. Up to date, key activity-determining constituents of comfrey root extracts have not been completely elucidated. Therefore, we applied different approaches to further characterize a comfrey root extract (65% ethanol). The phenolic profile of comfrey root sample was characterized by HPLC-DAD-QTOF-MS/MS. Rosmarinic acid was identified as main phenolic constituent (7.55 mg/g extract). Moreover, trimers and tetramers of caffeic acid (isomers of salvianolic acid A, B and C) were identified and quantified for the first time in comfrey root. In addition, pyrrolizidine alkaloids were evaluated by HPLC-QQQ-MS/MS and acetylintermedine, acetyllycopsamine and their N-oxides were determined as major pyrrolizidine alkaloids in the comfrey root sample. Lastly, the antioxidant activity was determined using four assays: DPPH and ABTS radicals scavenging assays, reducing power assay and 15-lipoxygenase inhibition assay. Comfrey root extract exhibited significant antioxidant activities when compared to known antioxidants. Thus, comfrey root is an important source of phenolic compounds endowed with antioxidant activity which may contribute to the overall bioactivity of Symphytum preparations.


Hostility, social support, and ambulatory cardiovascular activity.
The present study compared ambulatory blood pressure in male and female subjects preselected for high and low hostility levels and investigated interpersonal daily stress as a possible mediational mechanism. Ambulatory blood pressure and heart rate were measured in 48 male and female students previously classified as high or low on the Cook-Medley Hostility (Ho) Scale. Subjects wore an ambulatory monitor for a working day and also completed measures of perceived social support, daily interpersonal stress, and health behavior information. Results indicated that subjects scoring high on the Ho scale had higher mean levels of ambulatory systolic blood pressure than low Ho subjects, even when controlling for traditional risk factors, such as cigarette smoking. High Ho subjects also reported greater daily interpersonal stress and less social support than low Ho subjects. Perceived interpersonal stress partially accounted for the relationship between hostility and blood pressure. Subjects high in hostility showed greater mean ambulatory systolic blood pressure levels. Consistent with the transactional model of hostility and health, the relationship between hostility and blood pressure appears to be partially accounted for by the daily experience of interpersonal stress.


Sources of funding for Nobel Prize-winning work: public or private?
Funding is important for scientists' work and may contribute to exceptional research outcomes. We analyzed the funding sources reported in the landmark scientific papers of Nobel Prize winners. Between 2000 and 2008, 70 Nobel laureates won recognition in medicine, physics, and chemistry. Sixty five (70%) of the 93 selected papers related to the Nobel-awarded work reported some funding source including U.S. government sources in 53 (82%), non-U.S. government sources in 19 (29%), and nongovernment sources in 33 (51%). A substantial portion of this exceptional work was unfunded. We contacted Nobel laureates whose landmark papers reported no funding. Thirteen Nobel laureates responded and offered their insights about the funding process and difficulties inherent in funding. Overall, very diverse sources amounting to a total of 64 different listed sponsors supported Nobel-related work. A few public institutions, in particular the U.S. National Institutes of Health (with n=26 funded papers) and the National Science Foundation (with n=17 papers), stood out for their successful record for funding exceptional research. However, Nobel-level work arose even from completely unfunded research, especially when institutions offered a protected environment for dedicated scientists.


Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation.
The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries.


Synthetic and mechanistic aspects of sulfonyl migrations.
Over the past 20 years reports of sulfonyl migrations have appeared, frequently described as 'unusual' and 'unexpected'. This comprehensive review compiles, for the first time, sulfonyl migrations reported over the last 20 years including formal 1,2-, 1,3-, 1,4-, 1,5-, 1,6- and 1,7-sulfonyl shifts, occurring through either radical or polar processes, either inter- or intramolecularly. Discussion of the sulfonyl migrations is structured according to reaction type, i.e. nitrogen-carbon, nitrogen-oxygen, nitrogen-nitrogen, oxygen-carbon (including anionic and non-anionic thia-Fries rearrangements), oxygen-oxygen and carbon-carbon migrations. Discussion of the underlying mechanisms for the migrations is included, with particular attention afforded to the principal techniques utilised for their elucidation, namely isotopic-labelling, crossover experiments, density functional theory calculations and electron paramagnetic resonance spectroscopy amongst others.


Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54.
We have recently described a molecular gatekeeper of the hypothalamic-pituitary-gonadal axis with the observation that G protein-coupled receptor 54 (GPR54) is required in mice and men for the pubertal onset of pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion to occur. In the present study, we investigate the possible central mode of action of GPR54 and kisspeptin ligand. First, we show that GPR54 transcripts are colocalized with gonadotropin-releasing hormone (GnRH) neurons in the mouse hypothalamus, suggesting that kisspeptin, the GPR54 ligand, may act directly on these neurons. Next, we show that GnRH neurons seem anatomically normal in gpr54-/- mice, and that they show projections to the median eminence, which demonstrates that the hypogonadism in gpr54-/- mice is not due to an abnormal migration of GnRH neurons (as occurs with KAL1 mutations), but that it is more likely due to a lack of GnRH release or absence of GnRH neuron stimulation. We also show that levels of kisspeptin injected i.p., which stimulate robust LH and FSH release in wild-type mice, have no effect in gpr54-/- mice, and therefore that kisspeptin acts directly and uniquely by means of GPR54 signaling for this function. Finally, we demonstrate by direct measurement, that the central administration of kisspeptin intracerebroventricularly in sheep produces a dramatic release of GnRH into the cerebrospinal fluid, with a parallel rise in serum LH, demonstrating that a key action of kisspeptin on the hypothalamo-pituitary-gonadal axis occurs directly at the level of GnRH release. The localization and GnRH release effects of kisspeptin thus define GPR54 as a major control point in the reproductive axis and suggest kisspeptin to be a neurohormonal effector.


Airways obstruction among older construction and trade workers at Department of Energy nuclear sites.
A study of chronic obstructive pulmonary disease (COPD) among 7,579 current and former workers participating in medical screening programs at Department of Energy (DOE) nuclear weapons facilities through September 2008 was undertaken. Participants provided a detailed work and exposure history and underwent a respiratory examination that included a respiratory history, respiratory symptoms, a posterior-anterior (P-A) chest radiograph classified by International Labour Office (ILO) criteria, and spirometry. Statistical models were developed to generate group-level exposure estimates that were used in multivariate logistic regression analyses to explore the risk of COPD in relation to exposures to asbestos, silica, cement dust, welding, paints, solvents, and dusts/fumes from paint removal. Risk for COPD in the study population was compared to risk for COPD in the general US population as determined in National Health and Nutrition Examination Survey (NHANES III). The age-standardized prevalence ratio of COPD among DOE workers compared to all NHANES III data was 1.3. Internal analyses found the odds ratio of COPD to range from 1.6 to 3.1 by trade after adjustment for age, race, sex, smoking, and duration of DOE employment. Statistically significant associations were observed for COPD and exposures to asbestos, silica, welding, cement dusts, and some tasks associated with exposures to paints, solvents, and removal of paints. Our study of construction workers employed at DOE sites demonstrated increased COPD risk due to occupational exposures and was able to identify specific exposures increasing risk. This study provides additional support for prevention of both smoking and occupational exposures to reduce the burden of COPD among construction workers.


Untreated villages and factors associated with the absence of Community-Directed Treatment with Ivermectin (CDTI) in DRC.
The African Programme for Onchocerciasis Control (APOC), the main objective of which was the Community-Directed Treatment with Ivermectin (CDTI), was closed by the end of 2015. The purpose of this study was to describe untreated villages in DRC and to assess the factors associated with the absence of CDTI in endemic villages, between 2001 and 2014. This retrospective study was descriptive. Several annual technical reports of the National Onchocerciasis Task Force (NOTF) and national technical reports of CDTI projects were analysed; 21 projects implemented to control the disease were considered, representing the coverage of 42,778 endemic villages. Data were collected over a 3 month-period, between October and December 2016. Only 15,700 endemic villages were not treated through an annual CDT with Mectizan, i.e. 36.7%. The population at risk totalled 29,712,381 individuals and 7,681,995 of them were not treated, i.e. 25.9%. Eight projects recorded high proportions of untreated villages, i.e. 7,100 endemic entities (16.6%). Factors independently associated with non-treatment were the fear of serious side effects (adjusted OR: 10.6; 95% CI: 4.5-27.7), supply impaired by insecurity (adjusted OR: 15.9; 95% CI: 6.7-41.4) and geographical inaccessibility (adjusted OR: 19; 95% CI: 6.9-63.9). After 15 CDTI-cycles in DRC, the mean geographical coverage and therapeutic coverage rates reached 63.3% and 74.1%, respectively. The 2025 target of onchocerciasis eradication, as advocated by APOC, will not be reached. Untreated areas are partly responsible for such results. Many weaknesses persist in the National Program for Onchocerciasis Control (NPOC) and new strategies of disease control should be investigated.


Chicken skin virome analyzed by high-throughput sequencing shows a composition highly different from human skin.
Recent studies show that human skin at homeostasis is a complex ecosystem whose virome include circular DNA viruses, especially papillomaviruses and polyomaviruses. To determine the chicken skin virome in comparison with human skin virome, a chicken swabs pool sample from fifteen indoor healthy chickens of five genetic backgrounds was examined for the presence of DNA viruses by high-throughput sequencing (HTS). The results indicate a predominance of herpesviruses from the Mardivirus genus, coming from either vaccinal origin or presumably asymptomatic infection. Despite the high sensitivity of the HTS method used herein to detect small circular DNA viruses, we did not detect any papillomaviruses, polyomaviruses, or circoviruses, indicating that these viruses may not be resident of the chicken skin. The results suggest that the turkey herpesvirus is a resident of chicken skin in vaccinated chickens. This study indicates major differences between the skin viromes of chickens and humans. The origin of this difference remains to be further studied in relation with skin physiology, environment, or virus population dynamics.


An Injectable Hydrogel Prepared Using a PEG/Vitamin E Copolymer Facilitating Aqueous-Driven Gelation.
Hydrogels have been widely explored for biomedical applications, with injectable hydrogels being of particular interest for their ability to precisely deliver drugs and cells to targets. Although these hydrogels have demonstrated satisfactory properties in many cases, challenges still remain for commercialization. In this paper, we describe a simple injectable hydrogel based on poly(ethylene glycol) (PEG) and a vitamin E (Ve) methacrylate copolymer prepared via simple free radical polymerization and delivered in a solution of low molecular weight PEG and Ve as the solvent instead of water. The hydrogel formed immediately in an aqueous environment with a controllable gelation time. The driving force for gelation is attributed to the self-assembly of hydrophobic Ve residues upon exposure to water to form a physically cross-linked polymer network via polymer chain rearrangement and subsequent phase separation, a spontaneous process with water uptake. The hydrogels can be customized to give the desired water content, mechanical strength, and drug release kinetics simply by formulating the PEGMA-co-Ve polymer with an appropriate solvent mixture or by varying the molecular weight of the polymer. The hydrogels exhibited no significant cytotoxicity in vitro using fibroblasts and good tissue compatibility in the eye and when injected subcutaneously. These polymers thus have the potential to be used in a variety of applications where injection of a drug or cell containing depot would be desirable.


Topically applied minocycline microspheres: why it works.
This article presents the results of a single-arm, open-label, multicenter clinical trial of the topical use of sustained-release minocycline hydrochloride (HCl) microspheres as an adjunct to scaling and root planing. The objective of this study was to evaluate the long-term safety and efficacy of the subgingival application of resorbable minocycline microspheres as an adjunct to scaling and root planing in the treatment of chronic periodontitis. The primary outcome measures were the reduction in probing pocket depth at 9- and 12-month evaluations, and the percent of bleeding upon probing. A total of 173 patients with moderate-to-severe chronic periodontitis were enrolled in this multicenter clinical trial. All patients received full-mouth scaling and root planing plus minocycline microspheres in all periodontal pockets that probed > or = 5 mm. All sites treated at baseline and any new sites > or = 5 mm again received minocycline microspheres at 3- and 6-month follow-up appointments with no further scaling and root planing. Significant improvements in all clinical parameters measured were found at all time points (1, 3, 6, 9 and 12 months). The product was found to be well-tolerated by patients, safe, and easy to deliver. Scaling and root planing with the topical application of minocycline microspheres appeared to give better results than would have been expected with scaling and root planing alone.


A randomized trial of an acid-peptic disease management program in a managed care environment.
To study the effectiveness of a disease management program for patients with acid-related disorders. A cluster-randomized clinical trial of 406 patients comparing a disease management program with "usual practice." Enrolled patients included those presenting with new dyspepsia and chronic users of antisecretory drugs in 8 geographically separate physician offices associated with the Orlando Health Care Group. There were 35 providers in the intervention group and 48 in the control group. The disease management program included evidence-based practice guidelines implemented by using physician champions, academic detailing, and multidisciplinary teams. Processes of care, patient symptoms, quality of life, costs, and work days lost were measured 6 months after patient enrollment. Compared with usual practice, disease management was associated with improvements in Helicobacter pylori testing (61% vs 9%; P = .001), use of recommended H pylori treatment regimens (96% vs 10%; P = .001), and discontinuation rates of proton pump therapy after treatment (70% vs 36%; P = .04). There were few differences in patient quality of life or symptoms between the 2 study groups. Disease management resulted in fewer days of antisecretory therapy (71.7 vs 88.1 days; P = .02) but no difference in total costs. This disease management program for patients with acid-related disorders led to improved processes of care. The effectiveness of such a program in other settings requires further study.


Two separate UV-B radiation wavelength regions control expression of different molecular markers in Arabidopsis thaliana.
Fluence-response curves were obtained at nine wavelengths in the interval 280-360 nm for mRNA transcripts of four molecular markers induced by ultraviolet-B (UV-B) radiation in Arabidopsis thaliana (L.) Heynh.: CHS (encoding chalcone synthase), PDX1.3 (encoding an enzyme involved in formation of pyridoxine), MEB5.2 (encoding a protein with unknown function but which is strongly upregulated by UV-B), and LHCB1*3 (encoding a chlorophyll a/b binding protein). Intact Arabidopsis plants were irradiated for 3 h using a high intensity deuterium radiation source and narrow bandwith filters without supplementary PAR. The results obtained suggest the existence of two distinct UV-B signal responses: one sensitive between 300 and 310 nm and the other sensitive around 280-290 nm. Among the investigated molecular markers, CHS and PDX1.3 were regulated through the chromophore absorbing around 300 nm, whereas MEB5.2 and LHCB1*3 were regulated through the chromophore absorbing at 280-290 nm. The results obtained show that at least two signal transduction pathways exist that regulate gene expression as a result of absorption of UV-B radiation in plants.


Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study.
To determine if maintenance rituximab (MR) after standard chemotherapy improves progression-free survival (PFS) in advanced-stage indolent lymphoma. Patients with stage III-IV indolent lymphoma with responding or stable disease after cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy were stratified by initial tumor burden, residual disease after CVP (minimal or gross), and histology, and randomly assigned to observation (OBS) or MR 375 mg/m(2) once per week for 4 weeks every 6 months for 2 years. PFS was the primary end point. Three hundred eleven (282 with follicular lymphoma) evaluable patients who received CVP were randomly assigned to OBS (n = 158) or MR (n = 153). Best response improved in 22% MR versus 7% OBS patients (P = .00006). Toxicity was minimal in both study arms. Three-year PFS after random assignment was 68% MR versus 33% OBS (hazard ratio [HR] = 0.4; P = 4.4 x 10(-10) [all patients]) and 64% MR v 33% OBS (HR = 0.4; P = 9.2 x 10(-8) [patients with follicular lymphoma]). There was an advantage for MR regardless of Follicular Lymphoma International Prognostic Index score, tumor burden, residual disease, or histology. In multivariate analysis of MR patients, minimal disease after CVP was a favorable prognostic factor. OS at 3 years was 92% MR versus 86% OBS (HR = 0.6; log-rank one-sided P = .05) and, among patients with follicular lymphoma, OS was 91% MR versus 86% (HR = 0.6; log-rank one-sided P = .08). A trend favoring MR was observed among patients with high tumor burden (log-rank one-sided P = .03). The E1496 study provides the first phase III data in untreated indolent lymphoma that MR after chemotherapy significantly prolongs PFS.


First Human Implantation of a Bioresorbable Polymer Scaffold for Acute Traumatic Spinal Cord Injury: A Clinical Pilot Study for Safety and Feasibility.
A porous bioresorbable polymer scaffold has previously been tested in preclinical animal models of spinal cord contusion injury to promote appositional healing, spare white matter, decrease posttraumatic cysts, and normalize intraparenchymal tissue pressure. This is the first report of its human implantation in a spinal cord injury patient during a pilot study testing the safety and feasibility of this technique (ClinicalTrials.gov Identifier: NCT02138110). A 25-year-old man had a T11-12 fracture dislocation sustained in a motocross accident that resulted in a T11 American Spinal Injury Association Impairment Scale (AIS) grade A traumatic spinal cord injury. He was treated with acute surgical decompression and spinal fixation with fusion, and enrolled in the spinal scaffold study. A 2 × 10 mm bioresorbable scaffold was placed in the spinal cord parenchyma at T12. The scaffold was implanted directly into the traumatic cavity within the spinal cord through a dorsal root entry zone myelotomy at the caudal extent of the contused area. By 3 months, his neurological examination improved to an L1 AIS grade C incomplete injury. At 6-month postoperative follow-up, there were no procedural complications or apparent safety issues related to the scaffold implantation. Although longer-term follow-up and investigation are required, this case demonstrates that a polymer scaffold can be safely implanted into an acutely contused spinal cord. This is the first human surgical implantation, and future outcomes of other patients in this clinical trial will better elucidate the safety and possible efficacy profile of the scaffold. AIS, American Spinal Injury Association Impairment ScaleSCI, spinal cord injurytSCI, traumatic spinal cord injury.


DNA polymorphism among Fusarium oxysporum f.sp. elaeidis populations from oil palm, using a repeated and dispersed sequence "Palm".
A worldwide collection, of 76 F. oxysporum f.sp. elaeidis isolates (Foe), and of 21 F. oxysporum isolates from the soil of several palm grove was analysed by RFLP. As a probe, we used a random DNA fragment (probe 46) from a genomic library of a Foe isolate. This probe contains two different types of sequence, one being repeated and dispersed in the genome "Palm", the other being a single-copy sequence. All F. oxysporum isolates from the palm-grove soils were non-pathogenic to oil palm. They all had a simple restriction pattern with one band homologous to the single-copy sequence of probe 46. All Foe isolates were pathogenic to oil palm and they all had complex patterns due to hybridization with "Palm". This repetitive sequence reveals that Foe isolates are distinct from the other F. oxysporum palm-grove soils isolates. The sequence can reliably discriminate pathogenic from non-pathogenic oil palm isolates. Based on DNA fingerprint similarities, Foe populations were divided into ten groups consisting of isolates with the same geographic origin. Isolates from Brazil and Ecuador were an exception to that rule as they had the same restriction pattern as a few isolates from the Ivory Coast, suggesting they may originated from Africa.


Detection of pulmonary emboli with 99mTc-labeled anti-D-dimer (DI-80B3)Fab' fragments (ThromboView).
We report a new method to diagnose acute pulmonary embolism (PE) by single photon emission computerized tomography (SPECT) after administration of (99m)Tc-labeled anti-D-dimer (DI-80B3) monoclonal antibody Fab' fragments. This novel technique provides an additional approach to diagnosing PE in patients for whom other methods are nondiagnostic or contraindicated. We performed a prospective, multicenter study to investigate the sensitivity and specificity of (99m)Tc-DI-80B3/SPECT in patients with suspected acute PE. Subjects with a moderate to high clinical probability of PE or a positive D-dimer test underwent a PE-protocol contrast-enhanced multidetector thoracic computed tomography (CT) scan as well as (99m)Tc-DI-80B3/SPECT (0.5 mg (99m)Tc-DI-80B3 intravenously followed by a thoracic SPECT 2.5 h later). Separate and independent adjudication committees, blinded to clinical data and other test results, interpreted the (99m)Tc-DI-80B3/SPECT scans (PE detected as foci of abnormally increased (99m)Tc uptake) and the thoracic CT scans using Prospective Investigation of Pulmonary Embolism Diagnosis II criteria. Of the 52 patients who were enrolled and completed both tests, 42 had both evaluable SPECT scans and thoracic CT scans. Using the criterion standard (thoracic CT scan) there were 21 patients with PE and 21 without. (99m)Tc-DI-80B3/SPECT had a sensitivity of 76.2% (95% confidence interval, 52.8-91.8%) and a specificity of 90.5% (95% confidence interval, 69.8-98.8%). Treatment-related serious adverse events did not occur. (99m)Tc-DI-80B3/SPECT was sensitive and specific for acute PE in subjects with moderate to high clinical probability of PE or a positive D-dimer test. (99m)Tc-DI-80B3/SPECT demonstrated an acceptable safety profile and avoids exposure to contrast.


Crystal structure of human adenovirus at 3.5 A resolution.
Rational development of adenovirus vectors for therapeutic gene transfer is hampered by the lack of accurate structural information. Here, we report the x-ray structure at 3.5 angstrom resolution of the 150-megadalton adenovirus capsid containing nearly 1 million amino acids. We describe interactions between the major capsid protein (hexon) and several accessory molecules that stabilize the capsid. The virus structure also reveals an altered association between the penton base and the trimeric fiber protein, perhaps reflecting an early event in cell entry. The high-resolution structure provides a substantial advance toward understanding the assembly and cell entry mechanisms of a large double-stranded DNA virus and provides new opportunities for improving adenovirus-mediated gene transfer.


Oncoplastic Breast-Conserving Surgery: Can We Reduce Rates of Mastectomy and Chemotherapy Use in Patients with Traditional Indications for Mastectomy?
Traditional indications for mastectomy include multiple ipsilateral lesions and/or disease spanning ≥ 5 cm. Neoadjuvant chemotherapy increases breast conservation but does not improve survival. We hypothesized that oncoplastic breast-conserving surgery (OPS) may allow for breast conservation while providing full staging and tumor profiling information to guide systemic therapy decisions, thereby permitting more judicious chemotherapy use. This was an observational cohort of patients with invasive breast cancer with multiple lesions and/or disease spanning ≥ 5 cm who underwent OPS from 2012 to 2018. Clinicopathologic features, mastectomy rate, chemotherapy use, and recurrence were evaluated. Overall, 100 patients were identified. Average disease span was 62.8 ± 20.1 mm, with an average of 2.9 lesions (range 1-13). 'No ink on tumor' was achieved at the index operation in 80 patients; 13 patients underwent completion mastectomy to achieve adequate margins. Eighty-one patients completed radiation therapy. Breast conservation was possible in 50/58 (86%) patients who did not receive chemotherapy. Forty-two patients received chemotherapy (8 neoadjuvant, 34 adjuvant), of whom 37 (88%) achieved breast conservation. Twenty-six patients with high-risk features received adjuvant chemotherapy. Oncotype DX testing demonstrated the need for chemotherapy in an additional eight patients. After a median follow-up of 40 months, four patients had a local recurrence, including two who declined radiation therapy. OPS can facilitate breast conservation in most patients with traditional indications for mastectomy. Additionally, OPS may reduce unnecessary chemotherapy, especially in patients who qualify for Oncotype DX testing. Further study evaluating long-term oncologic and cosmetic outcomes is warranted.


Ethnic variation in personality disorder: evaluation of 6 years of hospital admissions.
Aims and methodThere is limited evidence on ethnic differences in personality disorder prevalence rates. We compared rates of people with personality disorder admitted to hospital in East London from 2007 to 2013. Of all people admitted to hospital, 9.7% had a personality disorder diagnosis. The admission rate for personality disorder has increased each year. Compared with White subjects, personality disorder was significantly less prevalent among Black and other minority ethnic (BME) groups. Personality disorder was diagnosed in 20% of forensic, 11% of general adult, 8% of adolescent and 2% of old-age in-patients.Clinical implicationsThe increasing number of personality disorder diagnoses year on year indicates the increasing impact of personality disorder on in-patient services. It is important to identify and appropriately manage patients with a personality disorder diagnosis due to the significant strain they place on resources. The reasons for fewer admissions of BME patients may reflect alternative service use, a truly lower prevalence rate or under-detection.Declaration of interestNone.


Unsteady penetration of a target by a liquid jet.
It is widely acknowledged that ceramic armor experiences an unsteady penetration response: an impacting projectile may erode on the surface of a ceramic target without substantial penetration for a significant amount of time and then suddenly start to penetrate the target. Although known for more than four decades, this phenomenon, commonly referred to as dwell, remains largely unexplained. Here, we use scaled analog experiments with a low-speed water jet and a soft, translucent target material to investigate dwell. The transient target response, in terms of depth of penetration and impact force, is captured using a high-speed camera in combination with a piezoelectric force sensor. We observe the phenomenon of dwell using a soft (noncracking) target material. The results show that the penetration rate increases when the flow of the impacting water jet is reversed due to the deformation of the jet-target interface--this reversal is also associated with an increase in the force exerted by the jet on the target. Creep penetration experiments with a constant indentation force did not show an increase in the penetration rate, confirming that flow reversal is the cause of the unsteady penetration rate. Our results suggest that dwell can occur in a ductile noncracking target due to flow reversal. This phenomenon of flow reversal is rather widespread and present in a wide range of impact situations, including water-jet cutting, needleless injection, and deposit removal via a fluid jet.


Lifespan of restriction-modification systems critically affects avoidance of their recognition sites in host genomes.
Avoidance of palindromic recognition sites of Type II restriction-modification (R-M) systems was shown for many R-M systems in dozens of prokaryotic genomes. However the phenomenon has not been investigated systematically for all presently available genomes and annotated R-M systems. We have studied all known recognition sites in thousands of prokaryotic genomes and found factors that influence their avoidance. Only Type II R-M systems consisting of independently acting endonuclease and methyltransferase (called 'orthodox' here) cause avoidance of their sites, both palindromic and asymmetric, in corresponding prokaryotic genomes; the avoidance takes place for ~ 50 % of 1774 studied cases. It is known that prokaryotes can acquire and lose R-M systems. Thus it is possible to talk about the lifespan of an R-M system in a genome. We have shown that the recognition site avoidance correlates with the lifespan of R-M systems. The sites of orthodox R-M systems that are encoded in host genomes for a long time are avoided more often (up to 100 % in certain cohorts) than the sites of recently acquired ones. We also found cases of site avoidance in absence of the corresponding R-M systems in the genome. An analysis of closely related bacteria shows that such avoidance can be a trace of lost R-M systems. Sites of Type I, IIС/G, IIM, III, and IV R-M systems are not avoided in vast majority of cases. The avoidance of orthodox Type II R-M system recognition sites in prokaryotic genomes is a widespread phenomenon. Presence of an R-M system without an underrepresentation of its site may indicate that the R-M system was acquired recently. At the same time, a significant underrepresentation of a site may be a sign of presence of the corresponding R-M system in this organism or in its ancestors for a long time. The drastic difference between site avoidance for orthodox Type II R-M systems and R-M systems of other types can be explained by a higher rate of specificity changes or a less self-toxicity of the latter.


Processing of artificial visual feedback in the walking fruit fly Drosophila melanogaster.
A computerized 360 degrees panorama allowed us to suppress most of the locomotion-induced visual feedback of a freely walking fly without neutralizing its mechanosensory system ('virtual open-loop' conditions). This novel paradigm achieves control over the fly's visual input by continuously evaluating its actual position and orientation. In experiments with natural visual feedback (closed-loop conditions), the optomotor turning induced by horizontal pattern motion in freely walking Drosophila melanogaster increased with the contrast and brightness of the stimulus. Conspicuously striped patterns were followed with variable speed but often without significant overall slippage. Using standard open-loop conditions in stationary walking flies and virtual open-loop or closed-loop conditions in freely walking flies, we compared horizontal turning induced by either horizontal or vertical motion of appropriately oriented rhombic figures. We found (i) that horizontal displacements and the horizontal-motion illusion induced by vertical displacements of the oblique edges of the rhombic figures elicited equivalent open-loop turning responses; (ii) that locomotion-induced visual feedback from the vertical edges of the rhombic figures in a stationary horizontal position diminished the closed-loop turning elicited by vertical displacements to only one-fifth of the response to horizontal displacements; and (iii) that virtual open-loop responses of mobile flies and open-loop responses of immobilized flies were equivalent in spite of delays of up to 0.1 s in the generation of the virtual stimulus. Horizontal compensatory turning upon vertical displacements of oblique edges is quantitatively consistent with the direction-selective summation of signals from an array of elementary motion detectors for the horizontal stimulus components within their narrow receptive fields. A compensation of the aperture-induced ambiguity can be excluded under these conditions. However, locomotion-induced visual feedback greatly diminished the horizontal-motion illusion in a freely walking fly. The illusion was used to assay the quality of open-loop simulation in the new paradigm.


Clinical and Echocardiographic Factors Associated With New-Onset Atrial Fibrillation in Heart Failure - Subanalysis of the WARCEF Trial.
Heart failure (HF) patients have a high incidence of new-onset AF. Given the adverse prognostic influence of AF in HF, identifying patients at high risk of developing AF is important. The incidence and factors associated with new-onset AF were investigated in patients in sinus rhythm with reduced LVEF enrolled in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial. Analyses involved clinical factors alone (n=2,219), and clinical plus echocardiographic findings (n=1,125). During 3.5±1.8 years of follow-up, 212 patients (9.6% of total cohort) developed AF. In both samples, new-onset AF was associated with age, male sex, White race, and IHD. Among echocardiographic variables, only LAD predicted AF. On multivariate Cox modeling, age (HR, 1.02; 95% CI: 1.00-1.03, P=0.008), IHD (HR, 1.37; 95% CI: 1.02-1.84, P=0.036) and LAD (HR, 1.48; 95% CI: 1.15-1.91, P=0.003) remained associated with AF onset. Patients with IHD, LAD>4.5 cm and age>50 years had a 2.5-fold higher risk of AF than patients without any of these characteristics (HR, 2.52; 95% CI: 1.72-3.69, P<0.0001). Age, IHD and LAD independently predict new-onset AF in HF patients in sinus rhythm, at younger age and smaller LAD than generally believed. This information may be useful to risk-stratify HF patients for AF development, allowing close monitoring and possibly early detection. (Circ J 2016; 80: 619-626).


In vitro characterization of a calcium sulfate/PLLA composite for use as a bone graft material.
A study was conducted to characterize the dissolution, morphology, and chemical composition of a calcium sulfate/poly (L-lactic acid) (CS/PLLA) composite material before and after immersion in simulated body fluid (SBF). Twelve groups of experimental samples were prepared by coating CS pellets 1, 2, 3, or 4 times with one of three concentrations of a PLLA solution and wrapping them in mesh; CS pellets for use as controls were similarly prepared but not coated. The PLLA coating added from 1 to 22% to the weight of experimental pellets; scanning electron microscopy revealed that the coating thickness ranged from 2 to 50 microm depending on the concentration of the coating solution and the number of coatings. All samples were immersed in SBF for up to 97 days. After immersion, the experimental coatings thinned out, small cracks and holes formed in the coating, and the coating became roughened. Mean dissolution rates for each of the 12 CS/PLLA groups were significantly lower than those of uncoated CS pellets; among CS/PLLA groups, dissolution rates varied according to concentration of the coating solution and number of coatings. The half-life of pure CS pellets was 19 days whereas the half-life of CS/PLLA composite pellets ranged from 30 to 70 days. X-ray microprobe analysis of experimental pellets after immersion in SBF revealed that mineralization occurred in the CS portion of these pellets as well as on the coating; most of the mineral was calcium phosphate, most of which was on the coating. Further studies will be required to confirm this composite's promise as a clinically effective osteoconductive material.


[Assessment of neonatal hyperbilirubinemia using a transcutaneous bilirubinometry].
The purpose of the study is to investigate the relationship between total serum bilirubin(TSB) and transcutaneous bilirubinometry(TcB) in neonates with jaundice. TcB from various sites(forehead, sternum, abdomen, buttock, hand, dorsalis-pedia) was measured using a JM-102 in a total of 102 neonate, 42 female and 60 male, with the mean 37.5 gestational week and the mean 2,903 gram of birth weight, as well as TSB from capillary punctures. The mean bilirubin was 11.73 in serum, 20.55 on the forehead, 17.23 on the sternum, 16.19 on the abdomen, 18.22 on the buttock, 15.83 on the hand and 15.49 on the dorsalis-pedia. The relationship between TSB and TcBs were formulated by simple regression with 0.406 < r < 0.668(p <.000). A higher relationship was revealed between TSB and TCB at the forehead in infants of full-term, ABO incompatibility, and Hb greater than 16 mg/dl(r = 0.725, 0.790, and 0.717, retrospectively). Phototherapy altered the measurement of TcB per site. TcB on the forehead is a reliable, noninvasive and convenient measurement of TSB in normal infants(Institutions need to establish quantitative equations representing the specific relationship between TSB and TCB according to the hemodynamic problems of infants such as ABO incompatibility, or low Hb).


The role of inheritance in the development of adolescent varicoceles.
The prevalence of varicoceles is estimated to be 15% in the general population but is nearly 35% among men with primary infertility and increases by 10% with each decade of life. Studies among adults infer a higher rate of varicoceles among first-degree relatives of patients with varicoceles. However, these studies do not consider the presence of varicoceles, or other venous abnormalities, at the time of desired paternity in first-degree relatives of adolescent patients. Our aim was to document the prevalence of varicoceles and varicose veins among first-degree relatives of pediatric patients diagnosed with varicoceles. A series of 884 patients between the ages of 17 and 22 diagnosed with a varicocele were contacted and of the responders, permission was asked to discuss family history. Each patient underwent a telephone survey regarding the presence of a varicocele in the father prior to achieving paternity, the presence of a varicocele in brothers in childhood, or varicose veins in the father and mother prior to achieving pregnancy. If a varicocele or varicose vein was present, a history of intervention was surveyed. Descriptive statistics were performed to assess overall prevalence of varicocele and varicose veins in first-degree relatives. Chi-squared and logistic regression analyses were performed. In total, 152 patients (17.2%) responded and 139 (91.4%) consented to the telephone survey (mean age 19.5±1.84 years old). Overall, 12.9% of fathers had varicoceles and 8.6% of fathers underwent surgical intervention. Among siblings, 18 individuals had a varicocele and 5.6% of siblings with varicocele required intervention. Varicose veins were diagnosed in 7.9% of fathers and 25.2% of mothers; 8.6% of mothers underwent intervention. Surveillance was employed in 76.3% of patients, and surgery undertaken 21.6%. Patients with grade 2 or 3 varicoceles were more likely to have a father with a varicocele than those with grade 1 varicocele (P=0.037). Patients with grade 2 varicocele were more likely to have a father who required varicocele surgery than grade 1 (P=0.019). There was no statistical association of adolescent varicocele and varicose veins in first degree relatives (P=0.306). This series shows that while a father's prevalence is similar to that of the general population, higher grade varicoceles were associated with a higher prevalence of varicoceles and surgical ligation. This suggests the existence of a hereditary predisposition to high grade varicoceles. Furthermore, varicocele is not associated with varicose veins in first degree relatives.


CD36 is differentially expressed on B cell subsets during development and in responses to antigen.
Of a number of mAbs made by immunization with sort-purified marginal zone (MZ) B cells, one was shown to recognize the mouse scavenger receptor CD36. Although CD36 is expressed by most resting MZ B cells and not by follicular and B1 B cells, it is rapidly induced on follicular B cells in vitro following TLR and CD40 stimulation. In response to T-independent and T-dependent Ag challenge, we found that CD36 was expressed on IgM+ plasma cells, but down-regulated on isotype-switched plasma cells in vivo. Although development, localization, and phenotype of MZ B cells in CD36-/- mice appeared normal, there was a minor block in the transitional stages of mature B cell development. In both primary and secondary Ab responses to heat-killed Streptococcus pneumoniae (R36A strain), both phosphoryl choline (PC)-specific IgM and IgG levels in CD36-/- mice were slightly reduced compared with wild-type mice. In addition, mice deficient in both TLR2 and CD36 produced significantly reduced levels of anti-PC IgG titers than those of single gene-deficient mice, suggesting that they may cooperate in an anti-PC Ab response. Collectively, these results show that CD36 does not affect the development of B cells, but modulates both primary and secondary anti-PC Ab responses during S. pneumoniae infection similarly to TLR2.


Sortase B, a new class of sortase in Listeria monocytogenes.
Sortases are transamidases that covalently link proteins to the peptidoglycan of gram-positive bacteria. The genome of the pathogenic bacterium Listeria monocytogenes encodes two sortases genes, srtA and srtB. The srtA gene product anchors internalin and some other LPXTG-containing proteins to the listerial surface. Here, we focus on the role of the second sortase, SrtB. Whereas SrtA acts on most of the proteins in the peptidoglycan fraction, SrtB appears to target minor amounts of surface polypeptides. We identified one of the SrtB-anchored proteins as the virulence factor SvpA, a surface-exposed protein which does not contain the LPXTG motif. Therefore, as in Staphylococcus aureus, the listerial SrtB represents a second class of sortase in L. monocytogenes, involved in the attachment of a subset of proteins to the cell wall, most likely by recognizing an NXZTN sorting motif. The DeltasrtB mutant strain does not have defects in bacterial entry, growth, or motility in tissue-cultured cells and does not show attenuated virulence in mice. SrtB-mediated anchoring could therefore be required to anchor surface proteins involved in the adaptation of this microorganism to different environmental conditions.


Reinforcement Learning for Bioretrosynthesis.
Metabolic engineering aims to produce chemicals of interest from living organisms, to advance toward greener chemistry. Despite efforts, the research and development process is still long and costly, and efficient computational design tools are required to explore the chemical biosynthetic space. Here, we propose to explore the bioretrosynthesis space using an artificial intelligence based approach relying on the Monte Carlo Tree Search reinforcement learning method, guided by chemical similarity. We implement this method in RetroPath RL, an open-source and modular command line tool. We validate it on a golden data set of 20 manually curated experimental pathways as well as on a larger data set of 152 successful metabolic engineering projects. Moreover, we provide a novel feature that suggests potential media supplements to complement the enzymatic synthesis plan.


Recommendations for treatment of hospital-acquired and ventilator-associated pneumonia: review of recent international guidelines.
Recently published guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia are reviewed for recommendations regarding diagnosis and antimicrobial therapy to assess the implications for development of future clinical trials. Despite some differences (mostly related to likely pathogens), there is a general agreement about the recommended approach to management. All of the reviewed guidelines invariably recommend early, appropriate antimicrobial therapy and avoidance of excessive antimicrobials by deescalation of therapy on the basis of microbiological culture results and the clinical response of the patient. Developers of future clinical trials will need to be mindful of these recommendations to maintain best practice care for each investigator.


Possibility of corrector plate tuning of x-ray focusing.
Schemes for focusing a hard x-ray beam to a small spot are described. The theoretical minimum spot size, assuming perfect mirror shape, is shown to be 4 nm FWHM, independent of x-ray wavelength. This is less than the 10 nm previously said to be the minimum achievable diffraction-limited x-ray spot size. While providing the penetrating power only possible with x rays, this approaches the resolution needed to image individual atoms or atomic layers. However, the perfect mirror assumption is physically unrealistic. This paper discusses the compensation of mirror shape errors by a corrector plate and shows that the tolerances for corrector plate shape are far looser than are tolerances for mirror shape. The full eventual success of achieving theoretical minimum resolution will require mirror shape precision considerably better than has been achieved at this time, though far looser than would be required for simpleminded paraboloidal focusing. Two variants of the scheme, subject to the same mathematical treatment, are described. (i) The "corrector plate" name is copied from the similarly functioning element of the same name in a Schmidt camera. The focusing is achieved using glancing, yet coherent, reflection from a high-Z paraboloidal mirror. The strategy is to obtain dominant focusing from reflection and to compensate with weak refractive focusing. The reflective focusing is strong and achromatic but insufficiently accurate. The refractive focusing is weak and chromatic but highly accurate. The corrector plate improves resolution the way eyeglasses help a person to see. It can, for example, be "fitted" the same trial-and-error way an optometrist establishes a prescription for glasses. Dimensional tolerances for the compensator are far looser than would be needed for a mirror to achieve the same resolution. Unlike compound refractive lenses, attenuation will be small, at least for wavelengths longer than 1 A, because the compensation layer is thin. (ii) For this variant, the corrector plate is a washer-shaped refractive or Fresnel lens, and the mirror is (theoretically) a perfect cone. All focusing is provided by the lens. Even though the cone provides no focusing, it improves the resolution by increasing the numerical aperture of the device. Compared to a paraboloidal shape, it is assumed that the conical shape can be more accurately fabricated. Of the two variants, only the first variant is, in principle, capable of achieving the theoretical minimum resolution. Configurations are suggested, in both case (i) and case (ii), that use currently possible construction precisions to produce resolutions better than have been achieved to date. However, both results will remain well above the theoretical minimum until fabrication techniques have been developed that provide greater precision than is possible at this time.


Viewing the body after bereavement due to a traumatic death: qualitative study in the UK.
Whether bereaved relatives should be encouraged to view the body after a traumatic death is uncertain. This analysis of narrative interviews interprets people's accounts of why and how they decided whether to view the body and their emotional reactions to this, immediately and at a later stage. In depth interviews with qualitative analysis. A maximum variation sample of 80 people bereaved because of suicide or other traumatic death. Most people were interviewed in their homes. For those who had the option, decisions about seeing the body varied. Some wanted someone else to identify the body, because they feared how it might look or preferred to remember their relative as they had been in life. Those who had wanted to see the body gave various reasons beyond the need to check identity. Some felt they ought to see the body. Others felt that the body had not lost its social identity, so wanted to make sure the loved one was "being cared for" or to say goodbye. Some people wanted to touch the body, in privacy, but the coroner sometimes allowed this only after the postmortem examination, which made relatives feel that the body had become police property. Seeing the body brought home the reality of death; it could be shocking or distressing, but, in this sample, few who did so said they regretted it. Even after a traumatic death, relatives should have the opportunity to view the body, and time to decide which family member, if any, should identify remains. Officials should prepare relatives for what they might see, and explain any legal reasons why the body cannot be touched. Guidelines for professional practice must be sensitive to the needs and preferences of people bereaved by traumatic death. The way that relatives refer to the body can be a strong indication for professionals about whether the person who died retains a social identity for the bereaved.


REV1 and DNA polymerase zeta in DNA interstrand crosslink repair.
DNA interstrand crosslinks (ICLs) are covalent linkages between two strands of DNA, and their presence interferes with essential metabolic processes such as transcription and replication. These lesions are extremely toxic, and their repair is essential for genome stability and cell survival. In this review, we will discuss how the removal of ICLs requires interplay between multiple genome maintenance pathways and can occur in the absence of replication (replication-independent ICL repair) or during S phase (replication-coupled ICL repair), the latter being the predominant pathway used in mammalian cells. It is now well recognized that translesion DNA synthesis (TLS), especially through the activities of REV1 and DNA polymerase zeta (Polζ), is necessary for both ICL repair pathways operating throughout the cell cycle. Recent studies suggest that the convergence of two replication forks upon an ICL initiates a cascade of events including unhooking of the lesion through the actions of structure-specific endonucleases, thereby creating a DNA double-stranded break (DSB). TLS across the unhooked lesion is necessary for restoring the sister chromatid before homologous recombination repair. Biochemical and genetic studies implicate REV1 and Polζ as being essential for performing lesion bypass across the unhooked crosslink, and this step appears to be important for subsequent events to repair the intermediate DSB. The potential role of Fanconi anemia pathway in the regulation of REV1 and Polζ-dependent TLS and the involvement of additional polymerases, including DNA polymerases kappa, nu, and theta, in the repair of ICLs is also discussed in this review.


Hydrogen bonding and electron transfer between dimetal paddlewheel compounds containing pendant 2-pyridone functional groups.
The compounds M2(TiPB)3(HDON) (TiPB = 2,4,6-triisopropylbenzoic acid; H2DON = 2,7-dihdroxy-1,8-napthyridine; M = Mo (1a) or W (1b)) and Mo2(TiPB)2(O2CCH2Cl)(HDON) (1c) which contain a pendant 2-pyridone functional group have been prepared. These compounds are capable of forming self-complementary hydrogen bonds, resulting in the formation of "dimers of dimers" ([1a-c]2) in CH2Cl2 solutions. Electrochemical studies reveal two successive one-electron redox processes for [1a-c]2 in CH2Cl2 solutions that correspond to successive oxidations of the dimetal core, indicating stabilization of the mixed-valence state. Only small changes in the value of Kc are observed upon changing the ancillary ligand or metal, implying that proton coupled mixed valency is responsible for the stabilization. Dimethylsulfoxide (DMSO) disrupts the hydrogen bonding interactions in these compounds, and a single oxidation process is observed in DMSO which shifts to lower potential as the number of HDON ligands increases. Further substitution of carboxylate ligands with HDON leads to the formation of Mo2(TiPB)2(HDON)2 (2) and Mo2(HDON)4 (3), which adopt trans-1,1 and cis-2,2 regioisomers in the solid-state. (1)H NMR spectroscopy indicates that there are at least two regioisomers present in solution for both compounds. The lowest energy transition in the electronic absorption spectra of these compounds corresponds to a M2-δ → HDON-π* transition. The electrochemical, spectroscopic and structural results were rationalized with the aid of density functional theory (DFT) calculations.


A Review of Roof Harvested Rainwater in Australia.
To address concern regarding water sustainability, the Australian Federal Government and many state governments have implemented regulatory mechanisms and incentives to support households to purchase and install rainwater harvesting systems. This has led to an increase in rainwater harvesting in regional and urban Australia. This review examines the implementation of the regulatory mechanisms across Australia. In addition, the literature investigating the potential health consequences of rainwater consumption in Australia was explored. Studies demonstrated that although trace metals such as arsenic, cadmium, chromium, lead, and iron were present in Australian rainwater, these metallic elements were generally found below the health limit guideline, except in high industrial areas. In addition, pathogenic or indicator microorganisms that include, but are not limited to, Escherichia coli, total and faecal coliforms, Campylobacter, Salmonella, Legionella, Pseudomonas, Cryptosporidium, Enterococci, Giardia, Aeromonas, and Mycobacterium avium Complex (MAC) have been detected in rainwater collected in Australia. However, epidemiological evidence suggests that drinking rainwater does not increase the risk of gastrointestinal disease. It was also identified that there is a need for further research investigating the potential for rainwater to be a source of infection for opportunistic pathogens.


Interaction of Salmonella paratyphi A and Schistosoma mansoni in hamsters.
It has previously been shown that Salmonella paratyphi A associates with adult Schistosoma mansoni worms in animal models and in patients with schistosomiasis, resulting in Salmonella infections that are difficult to manage unless the helminthic parasite is eliminated. In the present study, characteristics of this association were explored. In vitro, fresh serum, but not heat-inactivated (56 degree C, 30 minutes) serum, from normal hamsters (NH) and schistosome-infected hamsters (SIH) equally inhibited bacterial growth. When either group of animals was given S. paratyphi A intracardially, there was a decline in recoverable bacteria in the blood for 3 days, but after the third day, the number of bacteria increased in SIH whereas NH blood became sterile. Co-cultivation of S. paratyphi A in Earle's medium with live worms yielded more bacterial growth than occurred in the medium without worms, suggesting that nutritional factors are involved in the relationship. An intimate association in vivo of bacteria and trematodes was confirmed by culturing Salmonella from both worm surfaces and homogenized worms, with more bacteria being recovered from female worms. Although the bacterial infection induced a significant hepatic shift of adult worms in SIH, oogram analyses were normal and no lethal effect of bacteria on worms was noted.


Bioactive compounds of Crocus sativus L. and their semi-synthetic derivatives as promising anti-Helicobacter pylori, anti-malarial and anti-leishmanial agents.
Crocus sativus L. is known in herbal medicine for the various pharmacological effects of its components, but no data are found in literature about its biological properties toward Helicobacter pylori, Plasmodium spp. and Leishmania spp. In this work, the potential anti-bacterial and anti-parasitic effects of crocin and safranal, two important bioactive components in C. sativus, were explored, and also some semi-synthetic derivatives of safranal were tested in order to establish which modifications in the chemical structure could improve the biological activity. According to our promising results, we virtually screened our compounds by means of molecular modeling studies against the main H. pylori enzymes in order to unravel their putative mechanism of action.


A Pichia biosensor for high-throughput analyses of compounds that can influence mosquito behavior.
Mosquitoes utilize their sense of smell to locate prey and feed on their blood. Repellents interfere with the biochemical cascades that detect odors. Consequently, repellants are highly effective and resource-efficient alternatives for controlling the spread of mosquito-borne illnesses. Unfortunately, the discovery of repellents is slow, laborious, and error-prone. To this end, we have taken a giant stride toward improving the speed and accuracy of repellant discovery by constructing a prototypical whole-cell biosensor for accurate detection of mosquito behavior-modifying compounds such as repellants. As a proof-of-concept, we genetically engineered Pichia pastoris to express the olfactory receptor co-receptor (Orco) of Anopheles gambiae mosquitoes. This transmembrane protein behaves like a cationic channel upon activation by stimulatory odorants. When the engineered Pichia cells are cultured in calcium-containing Hank's buffer, induction of the medium with a stimulatory odorant results in an influx of calcium ions into the cells, and the stimulatory effect is quantifiable using the calcium-sequestering fluorescent dye, fluo-4-acetoxymethyl ester. Moreover, the stimulatory effect can be titrated by adjusting either the concentration of calcium ions in the medium or the level of induction of the stimulatory odorant. Subsequent exposure of the activated Pichia cells to a repellant molecule inhibits the stimulatory effect and quenches the fluorescent signal, also in a titratable manner. Significantly, the modular architecture of the biosensor allows easy and efficient expansion of its detection range by co-expressing Orco with other olfactory receptors. The high-throughput assay is also compatible with robotic screening infrastructure, and our development represents a paradigm change for the discovery of mosquito repellants.


Retinoic acid and meiosis induction in adult versus embryonic gonads of medaka.
In vertebrates, one of the first recognizable sex differences in embryos is the onset of meiosis, known to be regulated by retinoic acid (RA) in mammals. We investigated in medaka a possible meiotic function of RA during the embryonic sex determination (SD) period and in mature gonads. We found RA mediated transcriptional activation in germ cells of both sexes much earlier than the SD stage, however, no such activity during the critical stages of SD. In adults, expression of the RA metabolizing enzymes indicates sexually dimorphic RA levels. In testis, RA acts directly in Sertoli, Leydig and pre-meiotic germ cells. In ovaries, RA transcriptional activity is highest in meiotic oocytes. Our results show that RA plays an important role in meiosis induction and gametogenesis in adult medaka but contrary to common expectations, not for initiating the first meiosis in female germ cells at the SD stage.


Tension of red blood cell membrane in simple shear flow.
When a red blood cell (RBC) is subjected to an external flow, it is deformed by the hydrodynamic forces acting on its membrane. The resulting elastic tensions in the membrane play a key role in mechanotransduction and govern its rupture in the case of hemolysis. In this study, we analyze the motion and deformation of an RBC in a simple shear flow and the resulting elastic tensions on the membrane. The large deformation of the red blood cell is modelled by coupling a finite element method to solve the membrane mechanics and a boundary element method to solve the flows of the internal and external liquids. Depending on the capillary number Ca, ratio of the viscous to elastic forces, we observe three kinds of RBC motion: tumbling at low Ca, swinging at larger Ca, and breathing at the transitions. In the swinging regime, the region of the high principal tensions periodically oscillates, whereas that of the high isotropic tensions is almost unchanged. Due to the strain-hardening property of the membrane, the deformation is limited but the membrane tension increases monotonically with the capillary number. We have quantitatively compared our numerical results with former experimental results. It indicates that a membrane isotropic tension O(10{-6} N/m) is high enough for molecular release from RBCs and that the typical maximum membrane principal tension for haemolysis would be O(10{-4} N/m). These findings are useful to clarify not only the membrane rupture but also the mechanotransduction of RBCs.


Artificial Metalloproteins with Dinuclear Iron-Hydroxido Centers.
Dinuclear iron centers with a bridging hydroxido or oxido ligand form active sites within a variety of metalloproteins. A key feature of these sites is the ability of the protein to control the structures around the Fe centers, which leads to entatic states that are essential for function. To simulate this controlled environment, artificial proteins have been engineered using biotin-streptavidin (Sav) technology in which Fe complexes from adjacent subunits can assemble to form [FeIII-(μ-OH)-FeIII] cores. The assembly process is promoted by the site-specific localization of the Fe complexes within a subunit through the designed mutation of a tyrosinate side chain to coordinate the Fe centers. An important outcome is that the Sav host can regulate the Fe···Fe separation, which is known to be important for function in natural metalloproteins. Spectroscopic and structural studies from X-ray diffraction methods revealed uncommonly long Fe···Fe separations that change by less than 0.3 Å upon the binding of additional bridging ligands. The structural constraints imposed by the protein host on the di-Fe cores are unique and create examples of active sites having entatic states within engineered artificial metalloproteins.


Environmental enrichment: effects on spatial memory and hippocampal CREB immunoreactivity.
Environmental enrichment has been shown to improve performance in tests of spatial memory, induce neurogenesis in the hippocampus, enhance survival of newly formed granule cells, and inhibit spontaneous apoptosis. Although neuroplasticity of the mammalian brain declines with age, recent evidence suggests that the adult brain exhibits significant plasticity in response to environmental stimulation. The present study was designed to evaluate the effect of environmental enrichment on spatial memory and on immunoreactivity to cAMP response element binding protein (CREB) from the hippocampus. C57/BL/6 mice were trained in a Morris water maze after exposure to an enriched environment, either from 35 to 94 days or from 100 to 159 days of age. Hippocampal tissue from representative animals was later analyzed by Western blot for CREB immunoreactivity. Results indicate that environmental enrichment (particularly during the earlier period) improved performance on the Morris water maze and tended to increase immunoreactivity to CREB in the hippocampus. Social interaction by itself did not result in significant differences in navigational performance. Results with regard to social interaction and CREB immunoreactivity were mixed. Results are discussed in terms of evaluating the construct of enrichment, the correlation of CREB transcription and behavior change, and the importance of the developmental period for enrichment.


Inspiratory and skeletal muscle strength and endurance and diaphragmatic activation in patients with chronic airflow limitation.
To determine whether patients with chronic airflow limitation have a specific alteration in skeletal muscle performance, the strength and endurance of inspiratory and limb muscles were compared in 11 patients with chronic airflow limitation and 11 control subjects during maximal voluntary contractions. Peak inspiratory pressure at observed functional residual capacity (FRC) was significantly less in the patients than in the control subjects (mean 72 (SD 25) v 93 (21) cm H2O), though only two patients had low maximal pressures across a wide volume range. Maximal voluntary torque of the elbow flexor muscles was also reduced in the patients but the difference was not significant (60 (17) v 72 (18) Nm). During the endurance sequence of 18 maximal voluntary contractions (10 s duration, 5 s rest interval) the decline in peak and average force was less for the inspiratory muscles than for the elbow flexors in both groups. Inspiratory muscle endurance was slightly greater in the patients with chronic airflow limitation than in the control subjects, whereas limb muscle endurance was slightly impaired in the patients. In three patients with chronic airflow limitation, two of whom had low maximal inspiratory pressures at FRC, the ability to drive the diaphragm voluntarily was examined by stimulating the phrenic nerves during maximal inspiratory efforts. Each patient was capable of full activation of the diaphragm during the maximal inspiratory efforts. These results suggest that the relative preservation of inspiratory muscle performance in patients with chronic airflow limitation may be an adaptive response to respiratory "loading."


Quantitative Comparison of Effects of Dofetilide, Sotalol, Quinidine, and Verapamil between Human Ex vivo Trabeculae and In silico Ventricular Models Incorporating Inter-Individual Action Potential Variability.
Background:In silico modeling could soon become a mainstream method of pro-arrhythmic risk assessment in drug development. However, a lack of human-specific data and appropriate modeling techniques has previously prevented quantitative comparison of drug effects between in silico models and recordings from human cardiac preparations. Here, we directly compare changes in repolarization biomarkers caused by dofetilide, dl-sotalol, quinidine, and verapamil, between in silico populations of human ventricular cell models and ex vivo human ventricular trabeculae. Methods and Results:Ex vivo recordings from human ventricular trabeculae in control conditions were used to develop populations of in silico human ventricular cell models that integrated intra- and inter-individual variability in action potential (AP) biomarker values. Models were based on the O'Hara-Rudy ventricular cardiomyocyte model, but integrated experimental AP variability through variation in underlying ionic conductances. Changes to AP duration, triangulation and early after-depolarization occurrence from application of the four drugs at multiple concentrations and pacing frequencies were compared between simulations and experiments. To assess the impact of variability in IC50 measurements, and the effects of including state-dependent drug binding dynamics, each drug simulation was repeated with two different IC50 datasets, and with both the original O'Hara-Rudy hERG model and a recently published state-dependent model of hERG and hERG block. For the selective hERG blockers dofetilide and sotalol, simulation predictions of AP prolongation and repolarization abnormality occurrence showed overall good agreement with experiments. However, for multichannel blockers quinidine and verapamil, simulations were not in agreement with experiments across all IC50 datasets and IKr block models tested. Quinidine simulations resulted in overprolonged APs and high incidence of repolarization abnormalities, which were not observed in experiments. Verapamil simulations showed substantial AP prolongation while experiments showed mild AP shortening. Conclusions: Results for dofetilide and sotalol show good agreement between experiments and simulations for selective compounds, however lack of agreement from simulations of quinidine and verapamil suggest further work is needed to understand the more complex electrophysiological effects of these multichannel blocking drugs.


Accelerometer-determined physical activity, mobility disability, and health.
We have a limited understanding of the objectively-determined physical activity levels among those with mobility limitations. Further, the association between objectively-measured physical activity and biomarkers among those with mobility limitations is relatively unknown. Therefore, the primary objectives of this study were to compare accelerometer-determined physical activity levels among those with and without mobility limitations and determine if greater participation in physical activity was associated with more favorable health outcomes among those with mobility disability. Data from the 2003-2006 NHANES were used. Mobility limitation status was self-reported; accelerometer-measured estimates of sedentary, light, and moderate-to-vigorous physical activity (MVPA) were determined; and blood samples were taken to measure various biomarkers. In general, adults with mobility limitations, compared to those without, engaged in more sedentary behavior and less light-intensity physical activity and MVPA. Adults with mobility limitations, had a higher BMI, waist circumference, C-reactive protein, white blood cells, neutrophil levels, triglycerides, glucose, HbA1C and homocysteine levels. If an adult were to increase their sedentary behavior by 60-min, their rate ratio for chronic disease would be expected to increase by a factor of 1.04. Similarly, for an increase of 60-min in light-intensity physical activity, the rate ratio for chronic disease would be expected to decrease by a factor of 0.95. MVPA was also significantly associated with chronic disease (RR: 0.91; 95% CI: 0.85-0.97). Minimizing sedentary behavior and increasing physical activity (even light-intensity) among those with mobility limitations may help to improve health outcomes.


Effects of electromyostimulation training and volleyball practice on jumping ability.
The aim of this study was to investigate the influence of a 4-week electromyostimulation (EMS) training program on the vertical jump performance of 12 volleyball players. EMS sessions were incorporated into volleyball sessions 3 times weekly. EMS consisted of 20-22 concomitant stimulations of the knee extensor and plantar flexor muscles and lasted approximately 12 minutes. No significant changes were observed after EMS training for squat jump (SJ) and counter movement jump (CMJ) performance, while the mean height and the mean power maintained during 15 seconds of consecutive CMJs significantly increased by approximately 4% (p < 0.05). Ten days after the end of EMS training, the jumping height significantly (p < 0.05) increased compared with baseline also for single jumps (SJ +6.5%, CMJ +5.4%). When the aim of EMS resistance training is to enhance vertical jump ability, sport-specific workouts following EMS would enable the central nervous system to optimize the control to neuromuscular properties.


Interactive use of online health resources: a comparison of consumer and professional questions.
To understand how consumer questions on online resources differ from questions asked by professionals, and how such consumer questions differ across resources. Ten online question corpora, 5 consumer and 5 professional, with a combined total of over 40 000 questions, were analyzed using a variety of natural language processing techniques. These techniques analyze questions at the lexical, syntactic, and semantic levels, exposing differences in both form and content. Consumer questions tend to be longer than professional questions, more closely resemble open-domain language, and focus far more on medical problems. Consumers ask more sub-questions, provide far more background information, and ask different types of questions than professionals. Furthermore, there is substantial variance of these factors between the different consumer corpora. The form of consumer questions is highly dependent upon the individual online resource, especially in the amount of background information provided. Professionals, on the other hand, provide very little background information and often ask much shorter questions. The content of consumer questions is also highly dependent upon the resource. While professional questions commonly discuss treatments and tests, consumer questions focus disproportionately on symptoms and diseases. Further, consumers place far more emphasis on certain types of health problems (eg, sexual health). Websites for consumers to submit health questions are a popular online resource filling important gaps in consumer health information. By analyzing how consumers write questions on these resources, we can better understand these gaps and create solutions for improving information access.This article is part of the Special Focus on Person-Generated Health and Wellness Data, which published in the May 2016 issue, Volume 23, Issue 3.


On-Board Real-Time Trajectory Planning for Fixed Wing Unmanned Aerial Vehicles in Extreme Environments.
A team from the University of Bristol have developed a method of operating fixed wing Unmanned Aerial Vehicles (UAVs) at long-range and high-altitude over Volcán de Fuego in Guatemala for the purposes of volcanic monitoring and ash-sampling. Conventionally, the mission plans must be carefully designed prior to flight, to cope with altitude gains in excess of 3000 m, reaching 9 km from the ground control station and 4500 m above mean sea level. This means the climb route cannot be modified mid-flight. At these scales, atmospheric conditions change over the course of a flight and so a real-time trajectory planner (RTTP) is desirable, calculating a route on-board the aircraft. This paper presents an RTTP based around a genetic algorithm optimisation running on a Raspberry Pi 3 B+, the first of its kind to be flown on-board a UAV. Four flights are presented, each having calculated a new and valid trajectory on-board, from the ground control station to the summit region of Volcań de Fuego. The RTTP flights are shown to have approximately equivalent efficiency characteristics to conventionally planned missions. This technology is promising for the future of long-range UAV operations and further development is likely to see significant energy and efficiency savings.


Efficacy of probiotic in perennial allergic rhinitis under five year children: A randomized controlled trial.
To determine the efficacy of probiotic (Lactobacillus Paracasei, LP-33) and compare it with cetirizine for the treatment of perennial allergic rhinitis in under five year's children. The randomised clinical trial was conducted at Kharadar General Hospital, Karachi, from Dec 2016 to Nov 2017. Children aged 6 to 60 months, clinically presented with allergic rhinitis were included in the study. Total 212 children, randomized into intervention group A (received probiotic LP-33) and control group B (received cetirizine) for six weeks, were included in the analysis. Baseline allergic rhinitis symptoms (rhinorrhea, sneezing, nasal blocking, coughing, feeding & sleeping difficulties) were assessed after two and six weeks follow up and correlated both groups by using Pearson chi-square test. A p value of <0.05 were considered statistically significant. Total 212 children were analysed, out of them 113 (53.3%) were male. Mean age of study participant was 26 ± 16.64 months and mean body weight was 10.1 ± 3.26 Kg. More than 95% cases have shown significant improvement in their baseline symptoms (rhinorrhea, sneezing, nasal blocking, coughing, feeding difficulties and sleeping difficulties) in both intervention (L-33 Probiotic) and control (Cetirizine) groups. Statistically there was no difference in effectiveness of probiotic and cetirizine treatment for perennial allergic rhinitis (P > 0.05). Probiotic (LP-33) was equally effective as cetirizine in under five year's children for the treatment of perennial allergic rhinitis. Probiotic has additional benefit to treat allergic rhinitis without causing any major side effect in children reported by the study.