Automated integration of structural, biological and metabolic similarities to improve read-across.
Read-across (RAX) is a popular data-gap filling technique that uses category and analogue approaches to predict toxicological endpoints for a target. Despite its increasing relevance, RAX relies on human expert judgement and lacks a reproducible and automated protocol. It also only relies on structural similarity for identifying the analogues, while other aspects are often neglected. In this paper, we propose an automated procedure for the selection of analogues for data gap-filling. Analogues were identified with a decision algorithm that integrates three similarity metrics, each considering different toxicologically relevant aspects (i.e., structural, biological and metabolic similarity). Structural filters based on the presence of maximum common substructures (MCS) and common functional groups were applied to narrow the chemical space for the analogues search. The procedure has been implemented as a workflow in KNIME and is freely available. The workflow provides informative tabular and graphical outputs to support toxicologists and risk assessors in drawing conclusion based on the RAX approach. The procedure has been validated for its predictive power on two datasets related to high-tier in vivo toxicological endpoints, i.e. human hepatotoxicity and drug-induced liver injury (DILI). The validation results gave good accuracy values (i.e., up to 0.79 for the binary hepatotoxicity classification and up to 0.67 for the three-class DILI classification) that were higher than those returned by RAX based on the sole use of structural similarity. Results confirmed the suitability of the procedure as a source of data to support regulatory decision-making.


Coherent control of a single electron spin with electric fields.
Manipulation of single spins is essential for spin-based quantum information processing. Electrical control instead of magnetic control is particularly appealing for this purpose, because electric fields are easy to generate locally on-chip. We experimentally realized coherent control of a single-electron spin in a quantum dot using an oscillating electric field generated by a local gate. The electric field induced coherent transitions (Rabi oscillations) between spin-up and spin-down with 90 degrees rotations as fast as approximately 55 nanoseconds. Our analysis indicated that the electrically induced spin transitions were mediated by the spin-orbit interaction. Taken together with the recently demonstrated coherent exchange of two neighboring spins, our results establish the feasibility of fully electrical manipulation of spin qubits.


Culture and immortalization of pancreatic ductal epithelial cells.
Some populations of the epithelial cells from the duct and ductular network of the mammalian pancreas have been isolated and maintained in vitro for up to 3 mo. These cells express many of the surface factors that are unique to them in vivo. They also retain significant drug- and carcinogen-metabolizing capacity in vitro. In this chapter we review the progression of the methods for the isolation, culture and maintenance in vitro for these cells from the earliest when only duct/ductular fragments were obtainable to the current ones which provide epithelial cells. The critical steps in the isolation process are identified and strategies are provided to facilitate these steps. These include the selection of tissue digestive enzymes, the importance of extensive mincing before culture and the importance of roles of some co-factors used in the culture medium.


Physiological, biochemical and transcriptional analysis of onion bulbs during storage.
During the transition from endo-dormancy to eco-dormancy and subsequent growth, the onion bulb undergoes the transition from sink organ to source, to sustain cell division in the meristematic tissue. The mechanisms controlling these processes are not fully understood. Here, a detailed analysis of whole onion bulb physiological, biochemical and transcriptional changes in response to sprouting is reported, enabling a better knowledge of the mechanisms regulating post-harvest onion sprout development. Biochemical and physiological analyses were conducted on different cultivars ('Wellington', 'Sherpa' and 'Red Baron') grown at different sites over 3 years, cured at different temperatures (20, 24 and 28 °C) and stored under different regimes (1, 3, 6 and 6 → 1 °C). In addition, the first onion oligonucleotide microarray was developed to determine differential gene expression in onion during curing and storage, so that transcriptional changes could support biochemical and physiological analyses. There were greater transcriptional differences between samples at harvest and before sprouting than between the samples taken before and after sprouting, with some significant changes occurring during the relatively short curing period. These changes are likely to represent the transition from endo-dormancy to sprout suppression, and suggest that endo-dormancy is a relatively short period ending just after curing. Principal component analysis of biochemical and physiological data identified the ratio of monosaccharides (fructose and glucose) to disaccharide (sucrose), along with the concentration of zeatin riboside, as important factors in discriminating between sprouting and pre-sprouting bulbs. These detailed analyses provide novel insights into key regulatory triggers for sprout dormancy release in onion bulbs and provide the potential for the development of biochemical or transcriptional markers for sprout initiation. Evidence presented herein also suggests there is no detrimental effect on bulb storage life and quality caused by curing at 20 °C, producing a considerable saving in energy and costs.


Confirmed case of encephalitis caused by Murray Valley encephalitis virus infection in a horse.
A 5-year-old Australian stock horse in Monto, Queensland, Australia, developed neurological signs and was euthanized after a 6-day course of illness. Histological examination of the brain and spinal cord revealed moderate to severe subacute, nonsuppurative encephalomyelitis. Sections of spinal cord stained positively in immunohistochemistry with a flavivirus-specific monoclonal antibody. Reverse transcription polymerase chain reaction assay targeting the envelope gene of flavivirus yielded positive results from brain, spinal cord, cerebrospinal fluid, and facial nerve. A flavivirus was isolated from the cerebrum and spinal cord. Nucleotide sequences obtained from amplicons from both tissues and virus isolated in cell culture were compared with those in GenBank and had 96-98% identity with Murray Valley encephalitis virus. The partial envelope gene sequence of the viral isolate clustered into genotype 1 and was most closely related to a previous Queensland isolate.


Determinants for the effectiveness of implementing an occupational therapy intervention in routine dementia care.
A multifaceted implementation (MFI) strategy was used to implement an evidence-based occupational therapy program for people with dementia (COTiD program). This strategy was successful in increasing the number of referrals, but not in improving occupational therapists' (OTs) adherence. Therefore, a process evaluation was conducted to identify factors that influenced the effectiveness of the MFI strategy. A mixed-method approach of qualitative and quantitative research was used to evaluate the implementation process. The MFI strategy as planned and as executed were reported and evaluated based on the framework of Hulscher et al. (2003; 2006). Data on OTs attitudes and expected barriers were collected at baseline from 94 OTs using a 19-item questionnaire. Data on the experiences were collected after finishing the implementation using focus groups with OTs and telephone interviews with physicians and managers. For quantitative data, frequencies and correlations were calculated and qualitative data were analyzed using inductive content analysis. The implementation strategy as executed had a stronger focus than planned on increasing OTs promotional skills due to an initial lack of referrals. This resulted in less attention for increasing OTs' skills in using the COTiD program as initially intended. At baseline, OTs had a positive attitude toward the program, however, 75% did not feel experienced enough and only 14.3% felt competent in using the program. Focus groups and interviews revealed various determinants that influenced implementation. Most managers were positive about the program. However, the degree of operational support of managers for OTs regarding the implementation was not always adequate. Managers stated that a well-defined place for occupational therapy within the dementia care network was lacking although this was perceived necessary for successful implementation. Several physicians perceived psychosocial interventions not to be in their area of expertise or not their responsibility. All professionals perceived inter-professional collaboration to be a facilitator for effective implementation, and general practitioners were perceived as key partners in this collaboration. However, collaboration was not always optimal. OTs indicated that increasing the referral rate was most effective when promoting OT via other disciplines within a physician's network. Our data suggests that a first step in successful implementation should be to make sure that individual and organizational barriers are resolved. In addition, implementation should be network-based and encourage inter-professional collaboration. Initial promotion of COTiD should focus on physicians that have a positive attitude toward non-pharmacological interventions.


Travelers with immune-mediated inflammatory diseases: are they different?
Patients with immune-mediated inflammatory diseases (IMIDs) increasingly benefit from improved health due to new therapeutic regimens allowing increasing numbers of such patients to travel overseas. This study aims to assess the proportion of IMID travelers seeking advice at the Travel Clinic of the University of Zurich, Switzerland, and to determine whether demographics, travel, and vaccination patterns differ between IMID- and non-IMID travelers. Pre-travel visits and differences between IMID- and non-IMID travelers were assessed; logistic regression was used to adjust for confounders. Among 22,584 travelers who visited the Zurich Travel Clinic in a 25-month period, 1.8% suffered from an IMID, with gastroenterological and rheumatic conditions being the most common; 34.2% were using immunosuppressive or immunomodulatory medication. The reasons for travel and the destinations did not differ between IMID- and non-IMID travelers, Thailand and India being the most common destinations. IMID travelers stayed less often for longer than 1 month abroad and traveled less frequently on a low budget. Inactivated vaccines were similarly administered to both groups, while live vaccines were given half as often to IMID travelers. The increasing numbers of IMID patients, many using immunosuppressive or immunomodulatory therapy, show similar travel patterns as non-IMID travelers. Thus, they are exposed to the same travel health risks, vaccine-preventable infections being one among them. Particularly, in view of the fact that live attenuated vaccines are less often administered to IMID patients more data are needed on the safety and immunogenicity of vaccines and on travel-specific risks to be able to offer evidence-based pre-travel health advice.


Does the variable-stiffness colonoscope makes colonoscopy easier? A meta-analysis of the efficacy of the variable stiffness colonoscope compared with the standard adult colonoscope.
The variable-stiffness colonoscope (VSC) appears to have advantages over the standard adult colonoscope (SAC), although data are conflicting. To provide a comprehensive up-to-date review, we conducted a meta-analysis to compare the efficacies of the VSC and SAC. Electronic databases, including PubMed, EMBASE, the Cochrane library and the Science Citation Index, were searched to retrieve relevant trials. In addition, meeting abstracts and the reference lists of retrieved articles were reviewed for further relevant studies. Eight randomized controlled trials (RCTs), enrolling a total of 2033 patients, were included in the meta-analysis. There was no significant heterogeneity among these studies. The cecal intubation rate was higher with the use of VSC (RR = 1.03, 95% CI 1.01 to 1.06, 8 RCTs). The VSC was also associated with fewer position changes made during colonoscopy. Time to cecal intubation was similar with VSC and SAC (WMD -0.54, 95% CI -1.40 to 0.32) but shorter in subgroup analysis with the use of VSC (WMD = -1.36, 95% CI -2.29 to -0.43). Sedation dose used with the two types of instruments showed no evidence of differences either. For all trials, only patients were blinded because of the nature of the interventions. Use of the VSC significantly improved the cecal intubation rate and reduced ancillary maneuvers made during the procedure. Cecal intubation time was similar for the two colonoscope types over all trials, whereas a shortened time with the use of the adult VSC was seen in subgroup analysis.


Season, equipment, and job function related to gastrointestinal problems in waste collectors.
Informal reports have suggested that work as a waste collector entails exposures that cause gastrointestinal symptoms--such as nausea and diarrhoea. This study explores this hypothesis by correlating data on the type of waste collected, the persons' job function, the equipment used, and the times of the week and the year of reported nausea and diarrhoea. 1747 male waste collectors and a control group for comparison of 1111 male municipality workers answered a questionnaire on work environment, work related exposure, and health status. In a multivariate analysis collection of organic and residual waste (prevalence proportion ratio (PPR) 1.45) and mixed household waste (PPR 1.43) were associated with reported nausea and so was the job loader (PPR 1.51). More symptoms were reported in the summer. Multivariate analysis of diarrhoea showed that the job front runner was associated with reported diarrhoea (PPR 1.22) and so was the job loader (PPR 1.26). More symptoms occurred in the summer. The workers stated that the gastrointestinal symptoms were related to the smell of rotten waste. This may support the hypothesis that microbial compounds were the causal agents. The gastrointestinal symptoms were associated with the job of waste collector and moreover the symptoms predominantly occurred in the summer.


Prognostic value of different CT measurements in early therapy response evaluation in patients with metastatic colorectal cancer.
Patients with advanced stage colorectal carcinoma (CRC) display hepatic metastases on initial staging in up to 20% of cases. The effectiveness of chemotherapy is generally evaluated by computed tomography (CT) imaging using standardized criteria (RECIST). However, RECIST is not always optimal, and other criteria have been shown to correlate with pathologic response and overall survival. The aim of this study was to evaluate the prognostic value of different CT measurement for response assessment after initiation of chemotherapy in patients with synchronous colorectal cancer liver metastases. Fifty-five patients with CRC and synchronous hepatic metastases were evaluated retrospectively at 2 academic centers. Different size, volume, ratio and attenuation parameters were determined at baseline and after 3 cycles of chemotherapy. The prognostic value of baseline measurements and of the change between baseline and second measurements was analyzed using Kaplan-Meier estimates. Median time to progression was 279 days, median overall survival was 704 days. In this selective patient population, neither a significant prognostic value of initial baseline CT parameters nor a prognostic value of the change between the first and the second CT measurements was found. Initial morphological response assessment using different CT measurements has no prognostic value concerning time to progression or overall survival in patients with synchronous colorectal liver metastases.


Characterization of kinin receptors on human synovial cells and upregulation of receptor number by interleukin-1.
Bradykinin has been implicated in the pathogenesis of inflammatory arthritis by virtue of its potent proinflammatory properties. We have previously shown bradykinin to be a potent stimulus for the release of prostanoids from interleukin-1 (IL-1)-treated, but not untreated, human synovial cells. We hypothesize that one mechanism by which IL-1 induces responsiveness to bradykinin is by upregulation of number or affinity of kinin receptors on human synovial cells. We performed [3H]bradykinin binding studies in intact human synovial tissue and in cultured human synovial cells. Specific, saturable [3H]bradykinin binding sites in intact synovia were identified by autoradiographic localization and were present in much higher density in rheumatoid, than in osteoarthritis, synovia. In untreated human synovial cells in culture, a single (B2) class of kinin binding sites with a Kd of 2.3 nM and Bmax of 58 +/- 9 fmol/10(6) cells was demonstrated. In matched experiments, IL-1 treatment enhanced specific [3H]bradykinin binding 1.5- to 2.0-fold above that observed in untreated cells. This enhancement was attributable to an increase in Bmax (53 +/- 4 vs. 105 +/- 24 fmol/10(6) cells in untreated and IL-1-treated cells, respectively), rather than an alteration in Kd (1.7 and 1.4 nM, respectively). The potencies of a series of kinin analogs and antagonists and unrelated peptides in displacing [3H]bradykinin from IL-1-treated cells correlated well with their abilities to induce prostanoid release. These studies provide novel information regarding the nature of kinin receptors in intact human synovia and in cultured human synovial cells, their regulation by IL-1 and their role in IL-1-treated cells in kinin-mediated prostaglandin E2 production.


Cholesterol, primary and secondary prevention, and all-cause mortality.
Clinical trials of cholesterol lowering in apparently healthy persons (primary prevention) and in persons with known coronary disease (secondary prevention) routinely show a decrease in the incidence of nonfatal and fatal coronary events. Primary prevention trials, however, generally have failed to show a beneficial effect of cholesterol lowering on total mortality, because of both low overall death rates and a disturbingly high number of deaths from noncoronary causes in the treatment groups. Studies of secondary prevention give more clear-cut evidence of benefit. The rate of death from coronary heart disease is extremely high in these studies, overwhelming the rates for other causes of death. Thus, a possible increase in noncoronary deaths is of much less concern in secondary prevention studies. A possible link between cholesterol lowering and noncoronary causes of death should be explored using dose-response analyses of existing data sets, in both individual studies and aggregate meta-analysis; such analyses should be similar to those that have been done to study the relation between cholesterol lowering and coronary events. These analyses would greatly assist us in developing safe, efficacious ways to prevent coronary heart disease.


Electrophysiological measures of language processing in bilinguals.
The aim of the present study was to investigate how multiple languages are represented in the human brain. Event-related brain potentials (ERPs) were recorded from right-handed polyglots and monolinguals during a task involving silent reading. The participants in the experiment were nine Italian monolinguals and nine Italian/Slovenian bilinguals of a Slovenian minority in Trieste; the bilinguals, highly fluent in both languages, had spoken both languages since birth. The stimuli were terminal words that would correctly complete a short, meaningful, previously shown sentence, or else were semantically or syntactically incorrect. The task consisted in deciding whether the sentences were well formed or not, giving the response by pressing a button. Both groups read the same set of 200 Italian sentences to compare the linguistic processing, while the bilinguals also received a set of 200 Slovenian sentences, comparable in complexity and length, to compare the processing of the two languages within the group. For the bilinguals, the ERP results revealed a strong, left-sided activation, reflected by the N1 component, of the occipitotemporal regions dedicated to orthographic processing, with a latency of about 150 msec for Slovenian words, but bilateral activation of the same areas for Italian words, which was also displayed by topographical mapping. In monolinguals, semantic error produced a long-lasting negative response (N2 and N4) that was greater over the right hemisphere, whereas syntactic error activated mostly the left hemisphere. Conversely, in the bilinguals, semantic incongruence resulted in greater response over the left hemisphere than over the right. In this group, the P615 syntactical error responses were of equal amplitude on both hemispheres for Italian words and greater on the right side for Slovenian words. The present findings support the view that there are interand intrahemispheric brain activation asymmetries when monolingual and bilingual speakers comprehend written language. The fact that the bilingual speakers in the present study were highly fluent and had acquired both languages in early infancy suggests that the brain activation patterns do not depend on the age of acquisition or the fluency level, as in the case of late, not-so-proficient L2 language learners, but on the functional organization of the bilinguals' brain due to polyglotism and based on brain plasticity.


Prediction of biodiversity hotspots in the Anthropocene: The case of veteran oaks.
Over the past centuries, humans have transformed large parts of the biosphere, and there is a growing need to understand and predict the distribution of biodiversity hotspots influenced by the presence of humans. Our basic hypothesis is that human influence in the Anthropocene is ubiquitous, and we predict that biodiversity hot spot modeling can be improved by addressing three challenges raised by the increasing ecological influence of humans: (i) anthropogenically modified responses to individual ecological factors, (ii) fundamentally different processes and predictors in landscape types shaped by different land use histories and (iii) a multitude and complexity of natural and anthropogenic processes that may require many predictors and even multiple models in different landscape types. We modeled the occurrence of veteran oaks in Norway, and found, in accordance with our basic hypothesis and predictions, that humans influence the distribution of veteran oaks throughout its range, but in different ways in forests and open landscapes. In forests, geographical and topographic variables related to the oak niche are still important, but the occurrence of veteran oaks is shifted toward steeper slopes, where logging is difficult. In open landscapes, land cover variables are more important, and veteran oaks are more common toward the north than expected from the fundamental oak niche. In both landscape types, multiple predictor variables representing ecological and human-influenced processes were needed to build a good model, and several models performed almost equally well. Models accounting for the different anthropogenic influences on landscape structure and processes consistently performed better than models based exclusively on natural biogeographical and ecological predictors. Thus, our results for veteran oaks clearly illustrate the challenges to distribution modeling raised by the ubiquitous influence of humans, even in a moderately populated region, but also show that predictions can be improved by explicitly addressing these anthropogenic complexities.


Reducing obesity: motivating action while not blaming the victim.
The rise in obesity in the United States may slow or even reverse the long-term trend of increasing life expectancy. Like many risk factors for disease, obesity results from behavior and shows a social gradient. Especially among women, obesity is more common among lower-income individuals, those with less education, and some ethnic/racial minorities. This article examines the underlying assumptions and implications for policy and the interventions of the two predominant models used to explain the causes of obesity and also suggests a synthesis that avoids "blaming the victim" while acknowledging the role of individuals' health behaviors in weight maintenance. (1) The medical model focuses primarily on treatment, addressing individuals' personal behaviors as the cause of their obesity. An underlying assumption is that as independent agents, individuals make informed choices. Interventions are providing information and motivating individuals to modify their behaviors. (2) The public health model concentrates more on prevention and sees the roots of obesity in an obesogenic environment awash in influences that lead individuals to engage in health-damaging behaviors. Interventions are modifying environmental forces through social policies. (3) There is a tension between empowering individuals to manage their weight through diet and exercise and blaming them for failure to do so. Patterns of obesity by race/ethnicity and socioeconomic status highlight this tension. (4) Environments differ in their health-promoting resources; for example, poorer communities have fewer supermarkets, more fast-food outlets, and fewer accessible and safe recreational opportunities. A social justice perspective facilitates a synthesis of both models. This article proposes the concept of "behavioral justice" to convey the principle that individuals are responsible for engaging in health-promoting behaviors but should be held accountable only when they have adequate resources to do so. This perspective maintains both individuals' control and accountability for behaviors and society's responsibility to provide health-promoting environments.


Influence of microsatellite instability and KRAS and BRAF mutations on lymph node harvest in stage I-III colon cancers.
Lymph node (LN) harvest is influenced by several factors, including tumor genetics. Microsatellite instability (MSI) is associated with improved node harvest, but the association to other genetic factors is largely unknown. Research methods included a prospective series of stage I-III colon cancer patients undergoing ex vivo sentinel-node sampling. The presence of MSI, KRAS mutations in codons 12 and 13, and BRAF V600E mutations was analyzed. Uni- and multivariate regression models for node sampling were adjusted for clinical, pathological and molecular features. Of 204 patients, 67% had an adequate harvest (≥ 12 nodes). Adequate harvest was highest in patients whose tumors exhibited MSI (79%; odds ratio [OR] 2.5, 95% confidence interval [CI] 1.2-4.9; P = 0.007) or were located in the proximal colon (73%; 2.8, 1.5-5.3; P = 0.002). In multiple linear regression, MSI was a significant predictor of the total LN count (P = 0.02). Total node count was highest for cancers with MSI and no KRAS/BRAF mutations. The independent association between MSI and a high LN count persisted for stage I and II cancers (P = 0.04). Tumor location in the proximal colon was the only significant predictor of an adequate LN harvest (adjusted OR 2.4, 95% CI 1.2-4.9; P = 0.01). An increase in the total number of nodes harvested was not associated with an increase in nodal metastasis. In conclusion, number of nodes harvested is highest for cancers of the proximal colon and with MSI. The nodal harvest associated with MSI is influenced by BRAF and KRAS genotypes, even for cancers of proximal location. Mechanisms behind the molecular diversity and node yield should be further explored.


Hyoid motion during swallowing: factors affecting forward and upward displacement.
During swallowing, the hyoid bone is described as moving first upward, then forward, then returning to the starting position. This study examined hyoid motion during swallowing of chewed solids and liquids. Barium videofluorography (VFG) was performed on 12 healthy volunteers eating 8-cc portions of various solid foods and drinking liquid. Hyoid position was measured frame-by-frame for 88 swallows relative to the occlusal plane of the upper teeth. The hyoid bone moved both upward and forward during swallowing, but upward displacement was sometimes very small. There was no correlation between the amplitudes of hyoid upward and forward displacements. The amplitude of upward displacement was highly variable, smaller for liquids than for solid foods (p <0.001), and, for solid foods, larger for the first swallow than for the second swallow (p = 0.02). The amplitude of forward displacement did not differ significantly between liquids and solids or between first and second swallows. We conclude that upward displacement of the hyoid bone in swallowing is related primarily to events in the oral cavity, while its forward displacement is related to pharyngeal processes, especially the opening of the upper esophageal sphincter.


Characterization of a UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase with an unusual lectin domain from the platyhelminth parasite Echinococcus granulosus.
As part of a general project aimed at elucidating the initiation of mucin-type O-glycosylation in helminth parasites, we have characterized a novel ppGalNAc-T (UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase) from the cestode Echinococcus granulosus (Eg-ppGalNAc-T1). A full-length cDNA was isolated from a library of the tissue-dwelling larval stage of the parasite, and found to code for a 654-amino-acid protein containing all the structural features of ppGalNAc-Ts. Functional characterization of a recombinant protein lacking the transmembrane domain showed maximal activity at 28 degrees C, in the range 6.5-7.5 pH units and in the presence of Cu2+. In addition, it transferred GalNAc to a broad range of substrate peptides, derived from human mucins and O-glycosylated parasite proteins, including acceptors containing only serine or only threonine residues. Interestingly, the C-terminal region of Eg-ppGalNAc-T1 bears a highly unusual lectin domain, considerably longer than the one from other members of the family, and including only one of the three ricin B repeats generally present in ppGalNAc-Ts. Furthermore, a search for conserved domains within the protein C-terminus identified a fragment showing similarity to a recently defined domain, specialized in the binding of organic phosphates (CYTH). The role of the lectin domain in the determination of the substrate specificity of these enzymes suggests that Eg-ppGalNAc-T1 would be involved in the glycosylation of a special type of substrate. Analysis of the tissue distribution by in situ hybridization and immunohistochemistry revealed that this transferase is expressed in the hydatid cyst wall and the subtegumental region of larval worms. Therefore it could participate in the biosynthesis of O-glycosylated parasite proteins exposed at the interface between E. granulosus and its hosts.


Histologic assessment of ligament vascularity and synovitis in dogs with cranial cruciate ligament disease.
To assess the relationship between histologic degeneration of cranial cruciate ligaments (CCLs) and severity of synovitis and ligament vascularity. CCL and synovium from 59 stifle joints (53 dogs). CCL and synovium specimens were obtained from stifle joints of juvenile (15 joints; 12 dogs) and adult (25 joints; 22 dogs) dogs with intact CCLs and dogs with CCL rupture (rCCL; 19 joints; 19 dogs). Vascular density and degenerative changes of the CCL core region and severity of synovitis were semiquantitatively evaluated. Relationships were analyzed by use of a random effects model to account for correlated specimens. Mean ± SD modified Bonar scores (scale, 0 to 9) of adults (4.85 ± 0.44) and dogs with rCCL (5.69 ± 0.49) were significantly higher than scores of juveniles (1.13 ± 0.55). Vascularity scores (scale, 0 to 3) were significantly higher for juveniles (3.00 ± 0.24) than for adults (1.53 ± 0.27) and dogs with rCCL (0.78 ± 0.23). Synovitis scores were not significantly different among groups. There was a significant negative relationship between modified Bonar scores and vascularity scores for juveniles and adults and for adults and dogs with rCCL when controlling for age, but there was not a significant relationship between modified Bonar scores and synovitis scores. There was a significant relationship between modified Bonar scores and body weight of adults. Poor blood supply to the core region could be an important underlying condition for spontaneous degeneration of the CCL in at-risk dogs.


A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy.
Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.


Transformers in medical imaging: A survey.
Following unprecedented success on the natural language tasks, Transformers have been successfully applied to several computer vision problems, achieving state-of-the-art results and prompting researchers to reconsider the supremacy of convolutional neural networks (CNNs) as de facto operators. Capitalizing on these advances in computer vision, the medical imaging field has also witnessed growing interest for Transformers that can capture global context compared to CNNs with local receptive fields. Inspired from this transition, in this survey, we attempt to provide a comprehensive review of the applications of Transformers in medical imaging covering various aspects, ranging from recently proposed architectural designs to unsolved issues. Specifically, we survey the use of Transformers in medical image segmentation, detection, classification, restoration, synthesis, registration, clinical report generation, and other tasks. In particular, for each of these applications, we develop taxonomy, identify application-specific challenges as well as provide insights to solve them, and highlight recent trends. Further, we provide a critical discussion of the field's current state as a whole, including the identification of key challenges, open problems, and outlining promising future directions. We hope this survey will ignite further interest in the community and provide researchers with an up-to-date reference regarding applications of Transformer models in medical imaging. Finally, to cope with the rapid development in this field, we intend to regularly update the relevant latest papers and their open-source implementations at https://github.com/fahadshamshad/awesome-transformers-in-medical-imaging.


Temperature-sensitive yeast mutants defective in meiotic recombination and replication.
A system is described for isolating temperature-sensitive mutants of Saccharomyces cerevisiae with defects in early meiotic events. We used an otherwise haploid strain disomic (n+1) for chromosome III, and heteroallelic at the leucine-2 locus. Meiotic development was initiated by exposure of the strain to acetate sporulation medium, and monitored by the appearance of leucine-independent intragenic recombinants. Mutant isolation was based on the recovery of thermally induced defects in recombination. The temperature-sensitive characteristic was included to allow eventual characterizations of the temporal period during meiosis when each gene performs its essential function. Following mutagenesis with either ethyl methane sulfonate or nitrosoguanidine individual clones were tested at 34 degrees and 24 degrees for acetate-induced recombination. Starting with 2700 clones, derived from cells that survived mutagenic treatment, we isolated 48 strains with thermally induced lesions in recombination. In the majority of mutants premeiotic replication occurred normally, or nearly normally, at the restrictive temperature, indicating that the meiotic cycle was initiated and that there was a defect in an event required for intragenic recombination. We also detected mutants where the thermally induced lesion in recombination resulted from temperature-sensitive premeiotic DNA synthesis.


Children Use Wealth Cues to Evaluate Others.
Wealth differences between individuals are ubiquitous in modern society, and often serve as the basis for biased social evaluations among adults. The present research probed whether children use cues that are commonly associated with wealth differences in society to guide their consideration of others. In Study 1, 4-5-year-old participants from diverse racial backgrounds expressed preferences for children who were paired with high-wealth cues; White children in Study 1 also matched high-wealth stimuli with White faces. Study 2 conceptually replicated the preference effect from Study 1, and showed that young children (4-6 years) also use material wealth indicators to guide their inferences about people's relative standing in other domains (i.e., competence and popularity). Study 3 revealed that children (5-9 years) use a broad range of wealth cues to guide their evaluations of, and actions toward, unfamiliar people. Further, biased responses were not attenuated among children whose families were lower in socioeconomic status. Often overlooked by those who study children's attitudes and stereotypes, social class markers appear to influence evaluations, inferences, and behavior early in development.


RecFOR proteins are essential for Pol V-mediated translesion synthesis and mutagenesis.
When the replication fork moves through the template DNA containing lesions, daughter-strand gaps are formed opposite lesion sites. These gaps are subsequently filled-in either by translesion synthesis (TLS) or by homologous recombination. RecA filaments formed within these gaps are key intermediates for both of the gap-filling pathways. For instance, Pol V, the major lesion bypass polymerase in Escherichia coli, requires a functional interaction with the tip of the RecA filament. Here, we show that all three recombination mediator proteins RecFOR are needed to build a functionally competent RecA filament that supports efficient Pol V-mediated TLS in the presence of ssDNA-binding protein (SSB). A positive contribution of RecF protein to Pol V lesion bypass is demonstrated. When Pol III and Pol V are both present, Pol III imparts a negative effect on Pol V-mediated lesion bypass that is counteracted by the combined action of RecFOR and SSB. Mutations in recF, recO or recR gene abolish induced mutagenesis in E. coli.


Interdigital athlete's foot. The interaction of dermatophytes and resident bacteria.
Quantitative cultures in 140 cases of interdigital "athlete's foot" established the following clinical-microbiological correlations. In 39 cases of mild, scaling, relatively asymptomatic variety, fungi were recovered in 84% of cases. As the disease progressed to maceration, hyperkeratosis, and increased symptoms, recovery of fungi fell to 55% in moderately symptomatic and to 36% in severe cases. Symptomatic cases had increasing numbers of resident aerobic organisms, particularly large colony diphtheroids. Experimental manipulations of the interspace microflora in volunteers, monitored with quantitative cultures, demonstrated that symptomatic, macerated, hyperkeratotic process results from an overgrowth of resident organisms if the stratum corneum barrier is damaged by preexisting fungi, while overgrowth of the same organisms in normal, fungus-free interspaces does not produce lesions. These experiments support the conclusion that athlete's foot represents a continuum from a relatively asymptomatic, scaling eruption produced by fungi to a symptomatic, macerated, hyperkeratotic variety that is caused by an overgrowth of bacteria.


An autologous in situ tumor vaccination approach for hepatocellular carcinoma. 1. Flt3 ligand gene transfer increases antitumor effects of a radio-inducible suicide gene therapy in an ectopic tumor model.
Hepatocellular carcinoma (HCC) often presents as a diffuse or multifocal tumor making it difficult to control by surgery or radiation. Radio-inducible herpes simplex virus thymidine kinase (HSV-TK) gene therapy has been shown to enhance local tumor control after radiation therapy (RT), while limiting the expression of the transgene in the irradiated tumor tissues. To prevent liver tumor recurrence and control systemic disease while limiting the potential bystander toxicity of HSV-TK therapy, we proposed to stimulate endogenous dendritic cell (DC) proliferation with systemic adenovirus Flt3 ligand (Adeno-Flt3L) gene therapy, followed by primary tumor radiation therapy combined with a radio-inducible HSV-TK gene therapy. We hypothesized that adenovirus-expressing Flt3L gene therapy will stimulate DC proliferation, allowing the upregulated DCs to locally harness tumor antigens released from HSV-TK/RT-treated HCC cells, thereby converting irradiated tumors to an autologous in situ tumor vaccine in mice with primary liver tumors. To test this hypothesis, an expression vector of HSV-TK was constructed under the control of a radio-inducible promoter early-growth response (Egr-TK) and a recombinant adenovirus-expressing human Flt3L was constructed. The Adeno-Flt3L [10(9) plaque forming units (pfu)] was administered intravenously on days 1 and 8 after radiation therapy. The murine hepatoma cell line (BNL1ME) was stably transfected by Egr-TK or Egr-Null (encoding no therapeutic gene). Palpable tumors in BALB/c mice were treated with a localized dose of 25 Gy of radiation followed by ganciclovir (GCV, 100 mg/kg, 14 days). Four treatment cohorts were compared: Egr-Null/GCV + RT + Adeno-LacZ; Egr-Null/GCV + RT + Adeno-Flt3L; Egr-TK/GCV + RT + Adeno-LacZ; and Egr-TK/GCV + RT + Adeno-Flt3L. There was no primary tumor regression in the Egr-Null tumors after radiation therapy alone. In contrast, Egr-TK tumors had nearly complete tumor regression for 3 weeks after radiation therapy (P < 0.01), however, long-term follow-up demonstrated primary tumor recurrence and death secondary to pulmonary metastasis. Flt3L expression was confirmed by serum bioassay (mean = 88 ng/mL) in these animals and Western blotting of tissue culture medium in Adeno-Flt3L-infected BaF/huFlt3L cells. Radiation therapy with Adeno-Flt3L gene therapy effectively retarded primary tumor growth when compared to radiation therapy alone. The trimodality therapy (Egr-TK/GCV + RT + Adeno-Flt3L) was the most efficacious with 40% complete tumor regression (>100 days) and <20% pulmonary metastases, indicating the development of sustained antitumor immune response. These studies provide a rationale for triple modality therapies with radiation-inducible HSV-TK gene therapy and Adeno-Flt3L when used in combination with primary tumor radiation therapy for improved local and systemic control of HCC.


Knowing how to navigate: mechanisms of semaphorin signaling in the nervous system.
Neuronal connections are made during embryonic development with astonishing precision to ultimately form the physical basis for the central nervous system's main capacity: information processing. Over the past few decades, much has been learned about the general principles of axon guidance. A key finding to emerge is that extracellular cues play decisive roles in establishing the connections. One family of such cues, the semaphorin proteins, was first identified as repellents for navigating axons during brain wiring. Recent studies have implicated these molecules in many other processes of neuronal development, including axonal fasciculation, target selection, neuronal migration, and dendritic guidance, as well as in the remodeling and repair of the adult nervous system. It appears that responding neuronal processes sense these semaphorin signals by a family of transmembrane molecules, namely the plexins, even though neuropilins were also found to be required for mediating the interaction between plexins and class 3 semaphorins. Our understanding of the intracellular signaling machinery linking the receptors to the cytoskeleton machinery is still incomplete, but several molecules have been implicated in mediating or modulating semaphorin-induced responses. Adding to the complexity of semaphorin biology, new findings implicate semaphorins in functioning not only as signaling ligands, but also as signal-transducing receptors. Thus, semaphorins may serve as important probes for exploring the mechanisms of intercellular communication during the development and function of the nervous system.


Carotid plaque rather than intima-media thickness as a predictor of recurrent vascular events in patients with acute ischemic stroke.
To investigate the impacts of carotid plaque and intima-media thickness (IMT) on future vascular events (VEs) in the patients with acute ischemic stroke. A total of 479 consecutive Korean patients with acute ischemic stroke were divided into 2 groups according to development of VEs; VE group (65.4 ± 10.9 years) vs no VE group (62.8 ± 13.2 years). VEs were defined as the development of recurrent stroke, coronary events, peripheral arterial disease, and death. Clinical, laboratory, and imaging findings were compared between the groups. During 105.5 ± 29.0 months of follow up, VEs were developed in 142 patients (29.6%). In univariate analysis, VEs were significantly associated with age, gender, diabetes, renal function, lipid levels, left ventricular function, carotid plaque or IMT. In multivariate analysis, the presence of carotid plaque, diabetes, renal function and male gender were independent predictors of future VEs in the patients with ischemic stroke, but carotid IMT was not a predictor of future VEs. Event free survival was significantly lower in patients with carotid plaque than without carotid plaque on Kaplan-Meier analysis (log rank p < 0.001). The present study demonstrated that diabetes, impaired renal function, male gender, and the presence of carotid plaque rather than IMT were independent predictors of future VEs in Korean patients with acute ischemic stroke. Active medical management and careful monitoring for the development of recurrent VEs are strongly recommended in patients with acute ischemic stroke and carotid plaque.


Structure of Sr-substituted photosystem II at 2.1 A resolution and its implications in the mechanism of water oxidation.
Oxygen-evolving complex of photosystem II (PSII) is a tetra-manganese calcium penta-oxygenic cluster (Mn4CaO5) catalyzing light-induced water oxidation through several intermediate states (S-states) by a mechanism that is not fully understood. To elucidate the roles of Ca(2+) in this cluster and the possible location of water substrates in this process, we crystallized Sr(2+)-substituted PSII from Thermosynechococcus vulcanus, analyzed its crystal structure at a resolution of 2.1 Å, and compared it with the 1.9 Å structure of native PSII. Our analysis showed that the position of Sr was moved toward the outside of the cubane structure of the Mn4CaO5-cluster relative to that of Ca(2+), resulting in a general elongation of the bond distances between Sr and its surrounding atoms compared with the corresponding distances in the Ca-containing cluster. In particular, we identified an apparent elongation in the bond distance between Sr and one of the two terminal water ligands of Ca(2+), W3, whereas that of the Sr-W4 distance was not much changed. This result may contribute to the decrease of oxygen evolution upon Sr(2+)-substitution, and suggests a weak binding and rather mobile nature of this particular water molecule (W3), which in turn implies the possible involvement of this water molecule as a substrate in the O-O bond formation. In addition, the PsbY subunit, which was absent in the 1.9 Å structure of native PSII, was found in the Sr-PSII structure.


Flow cytometry data analysis: comparing large multivariate data sets using classification trees.
This paper describes a method to compare flow cytometry data sets, which typically contain 50,000 six-parameter measurements each. By this method, the data points in two such data sets are divided into subpopulations using a binary classification tree generated from the data. The chi 2 test is then used to establish the homogeneity of the two data sets based on how their data are distributed across these subpopulations. Preliminary results indicate that this comparison method is sufficiently sensitive to detect differences between flow cytometry data sets that are too subtle for human investigators to notice.


Kinetic study of heterogeneous reaction of deliquesced NaCl particles with gaseous HNO3 using particle-on-substrate stagnation flow reactor approach.
Heterogeneous reaction kinetics of gaseous nitric acid with deliquesced sodium chloride particles NaCl(aq) + HNO3(g) --> NaNO3(aq) + HCl(g) were investigated with a novel particle-on-substrate stagnation flow reactor (PS-SFR) approach under conditions, including particle size, relative humidity, and reaction time, directly relevant to the atmospheric chemistry of sea salt particles. Particles deposited onto an electron microscopy grid substrate were exposed to the reacting gas at atmospheric pressure and room temperature by impingement via a stagnation flow inside the reactor. The reactor design and choice of flow parameters were guided by computational fluid dynamics to ensure uniformity of the diffusion flux to all particles undergoing reaction. The reaction kinetics was followed by observing chloride depletion in the particles by computer-controlled scanning electron microscopy with energy-dispersive X-ray analysis (CCSEM/EDX). The validity of the current approach was examined first by conducting experiments with median dry particle diameter D(p) = 0.82 microm, 80% relative humidity, particle loading densities 4 x 10(4) <or= N(s) <or= 7 x 10(6) cm(-2) and free stream HNO3 concentrations 2, 7, and 22 ppb. Upon deliquescence the droplet diameter D(d) approximately doubles. The apparent, pseudo-first-order rate constant determined in these experiments varied with particle loading and HNO3 concentration in a manner consistent with a diffusion-kinetic analysis reported earlier (Laskin, A.; Wang, H.; Robertson, W. H.; Cowin, J. P.; Ezell, M. J.; Finlayson-Pitts, B. J. J. Phys. Chem. A 2006, 110, 10619). The intrinsic, second-order rate constant was obtained as kII = 5.7 x 10(-15) cm3 molecule(-1) s(-1) in the limit of zero particle loading and by assuming that the substrate is inert to HNO3. Under this loading condition the experimental, net reaction uptake coefficient was found to be gamma(net) = 0.11 with an uncertainty factor of 3. Additional experiments examined the variations of HNO3 uptake on pure NaCl, a sea salt-like mixture of NaCl and MgCl2 (Mg-to-Cl molar ratio of 0.114) and real sea salt particles as a function of relative humidity. Results show behavior of the uptake coefficient to be similar for all three types of salt particles with D(p) approximately 0.9 miccrom over the relative humidity range 20-80%. Gaseous HNO3 uptake coefficient peaks around a relative humidity of 55%, with gamma(net) well over 0.2 for sea salt. Below the efflorescence relative humidity the uptake coefficient declines with decreasing RH for all three sea salt types, and it does so without exhibiting a sudden shutoff of reactivity. The uptake of HNO3 on sea salt particles was more rapid than that on the mixture of NaCl and MgCl2, and uptake on both sea salt and sea salt-like mixture was faster than on pure NaCl. The uptake of HNO3 on deliquesced, pure NaCl particles was also examined over the particle size range of 0.57 <or= D(p) <or= 1.7 microm (1.1 <or= D(d) <or= 3.4 microm) under a constant relative humidity of 80%. The uptake coefficient decreases monotonically with an increase in particle size. Application of a resistance model of reaction kinetics and reactant diffusion over a single particle suggests that, over the range of particle size studied, the uptake is largely controlled by gaseous reactant diffusion from the free stream to the particle surface. In addition, a combined consideration of uptake coefficients obtained in the present study and those previously reported for substantially smaller droplets (D(d) approximately 0.1 microm) (Saul, T. D.; Tolocka, M. P.; Johnston, M. V. J. Phys. Chem. A 2006, 110, 7614) suggests that the peak reactivity occurs at a droplet diameter of approximately 0.7 microm, which is immediately below the size at which sea salt aerosols begin to notably contribute to light scattering.


A litmus test for exploitation: James Stacey Taylor's stakes and kidneys.
James Stacy Taylor advances a thorough argument for the legalization of markets in current (live) human kidneys. The market is seemly the most abhorrent type of market, a market where the least well-off sell part of their body to the most well off. Though rigorously defended overall, his arguments concerning exploitation are thin. I examine a number of prominent bioethicists' account of exploitation: most importantly, Ruth Sample's exploitation as degradation. I do so in the context of Taylor's argument, with the aim of buttressing Taylor's position that a regulated kidney market is morally allowable. I argue that Sample fails to provide normative grounds consistent with her claim that exploitation is wrong. I then reformulate her account for consistency and plausibility. Still, this seemingly more plausible view does not show that Taylor's regulated kidney market is prohibitively exploitative of impoverished persons. I tack into place one more piece of support for Taylor's conclusion. (wc. 148).


Fine scale mapping of a genetic locus for conditioned fear.
Fear conditioning is one of a number of models for investigating the genetic basis of individual variation in emotion and learning. Genetic mapping using crosses between strains of laboratory mice has identified a locus on chromosome one that appears to influence not only variation in conditioned fear, but also in other validated tests of fear-related behaviour, (including the open-field and the elevated-plus maze), suggesting that the rodent locus may act in ways consistent with how a locus influencing susceptibility to anxiety in humans is believed to operate. Here we use high-resolution mapping in genetically heterogeneous mice to show that a quantitative trait locus influencing conditioned fear can be separated from loci influencing open-field activity. Mapping in two different heterogeneous stocks, the Boulder and Northport HS, gave similar map locations for open-field activity at two positions on the current mouse physical map, one at 162 Mb on chromosome one (negative log P-value 5.4) the other at 173 Mb (negative log P-value 4.8), while mapping of contextual conditioned fear in the Boulder HS identified a locus at 170 Mb (negative log P-value 5.4). Estimates of the 95% confidence intervals show that the locations do not overlap. The region containing a gene or genes that influence variation in conditioned fear is approximately 1 megabase in size and contains only one gene of known function, a pre-B cell leukaemia factor.


Coregulation of voltage-dependent kinetics of Na(+) and K(+) currents in electric organ.
The electric organ cells of Sternopygus generate action potentials whose durations vary over a fourfold range. This variation in action potential duration is the basis for individual variation in a communication signal. Thus, action potential duration must be precisely regulated in these cells. We had observed previously that the inactivation kinetics of the electrocyte Na(+) current show systematic individual variation. In this study, using a two-electrode voltage clamp, we found that the voltage-dependent activation and deactivation kinetics of the delayed rectifying K(+) current in these cells covary in a graded and predictable manner across fish. Furthermore, when Na(+) and K(+) currents were recorded in the same cell, their voltage-dependent kinetics were highly correlated. This finding illustrates an unprecedented degree of coregulation of voltage-dependent properties in two molecularly distinct ionic channels. Such a coregulation of ionic channels is uniquely observable in a cell specialized to generate individual differences in electrical activity and in which the results of biophysical control mechanisms are evident in behaving animals. We propose that the precise coregulation of the voltage-dependent kinetics of multiple ionic currents may be a general mechanism for regulation of membrane excitability.


[The development of a linear function for stratifying the risk of hospital mortality in acute myocardial infarct].
In spite of conventional treatment in a Coronary Unit, there is a group of patients with acute myocardial infarction who present a high mortality index. A more aggressive attitude (coronariography, angioplasty, and/or emergency coronary bypass) could improve the prognosis in some of these patients but can only be performed in a limited number of centers. In the present work, we have reviewed data obtained from the Emergency Room on 167 patients diagnosed of myocardial infarction. The variables that were correlated to mortality were: age, heart rate, blood pressure, presence of rales, radiologic heart failure cardiomegaly, ventricular extrasystoles in ECG and delay in arrival to hospital. We obtain a lineal function (z = 24.6 X1 - 0.4 X2 + 0.2 X3 + 11) which combining ventricular extrasystoles, diastolic arterial pressure, and heart rate permits to differentiate three risk groups: low, medium and high, associated to hospital mortality rates of 5.7, 36.4 and 83.3%. We suggest the use of a function of this type to select those patients who should be sent to a hospital with facilities for emergency coronary surgery.


DECIMER-hand-drawn molecule images dataset.
The translation of images of chemical structures into machine-readable representations of the depicted molecules is known as optical chemical structure recognition (OCSR). There has been a lot of progress over the last three decades in this field, but the development of systems for the recognition of complex hand-drawn structure depictions is still at the beginning. Currently, there is no data for the systematic evaluation of OCSR methods on hand-drawn structures available. Here we present DECIMER - Hand-drawn molecule images, a standardised, openly available benchmark dataset of 5088 hand-drawn depictions of diversely picked chemical structures. Every structure depiction in the dataset is mapped to a machine-readable representation of the underlying molecule. The dataset is openly available and published under the CC-BY 4.0 licence which applies very few limitations. We hope that it will contribute to the further development of the field.


Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs.
Crohn's disease and ulcerative colitis (the inflammatory bowel diseases) have a strong genetic component. Although over 20 putative susceptibility loci have been identified by individual genome scans, the majority of these loci have not been replicated. Many individual studies are at the lower limit of acceptable power for complex disease linkage analysis. Genome scan meta-analysis (GSMA), by use of sample sizes an order of magnitude greater than individual linkage studies, has increased power to detect novel loci, may confirm or refute regions detected in smaller individual studies, and enables regions to be prioritized for further gene identification efforts. Genome scan data (markers, significance scores) were obtained from 10 separate studies and meta-analysis was performed using the GSMA method. These studies comprised 1952 inflammatory bowel disease, 1068 Crohn's disease and 457 ulcerative colitis affected relative pairs. Study results were divided into 34 cM chromosomal bins, ranked, weighted by study size, summed across studies and bin-by-bin significance obtained by simulation. A region on chromosome 6p (containing the HLA) met genome wide significance for inflammatory bowel disease. Loci meeting suggestive significance for inflammatory bowel disease were 2q, 3q, 5q, 7q and 16 (NOD2/CARD15 region); Crohn's disease, 2q, 3q, 6p, 16 (NOD2/CARD15 region), 17q, 19p; and ulcerative colitis, 2q. Clustering of adjacent bins was observed for chromosomes 6p, 16, 19p. The meta-analysis has identified novel loci and prioritized genomic regions for further gene identification studies.


CSF biomarker variability in the Alzheimer's Association quality control program.
The cerebrospinal fluid (CSF) biomarkers amyloid beta 1-42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1-42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.


Cost-effectiveness of Community-Based Minigrants to Increase Physical Activity in Youth.
American youth are insufficiently active, and minigrant programs have been developed to facilitate implementation of evidence-based interventions in communities. However, little is known about the cost-effectiveness of targeted minigrant programs for the implementation of physical activity (PA) promoting strategies for youth. To determine the cost-effectiveness of a minigrant program to increase PA among youth. Twenty community grantees were pair-matched and randomized to receive funding at the beginning of year 1 (2010-2011) or year 2 (2011-2012) to implement interventions to increase PA in youth. Costs were calculated by examining financial reports provided by the granting organization and grantees. Twenty counties in North Carolina. A random sample of approximately 800 fourth- to eighth-grade youth (per year) from the approximately 6100 youth served by the 20 community-based interventions. Cost-effectiveness ratios (CERs) were calculated at the county and project levels to determine the cost per child-minute of moderate-to-vigorous PA (MVPA) increased by wave. Analyses were conducted utilizing cost data from 20 community grantees and accelerometer-derived PA from the participating youth. Of the 20 participating counties, 18 counties displayed increased youth MVPA between at least 2 waves of observation. Of those 18 counties, the CER (US dollars/MVPA minutes per day) ranged from $0.02 to $1.86 (n = 13) in intervention year 1, $0.02 to $6.19 (n = 15) in intervention year 2, and $0.02 to $0.58 (n = 17) across both years. If utilized to implement effectual behavior change strategies, minigrants can be a cost-effective means of increasing children's MVPA, with a low monetary cost per minute of MVPA.


Immunocontraception in Eastern gray squirrels (Sciurus carolinensis): morphologic changes in reproductive organs.
Eastern gray squirrels (EGS) (Sciurus carolinensis) damage trees through bark stripping or gnawing due to territorial marking or agonistic gnawing behavior in concert with higher densities. This study was conducted to determine the effects of a contraceptive vaccine on EGS and its reproductive organ histology. Free-ranging urban EGS were vaccinated with the immunocontraceptive GonaCon. All EGS were > or = 6 mo of age as determined by a combination of pelage characteristics and body weights. The vaccine was administered by injection at a dosage rate of 0.4 ml containing 400 microg of GnRH-mollusk protein conjugate i.m. in the thigh to 33 EGS (17 male [m], 16 female [f]) in trapping session 1 (TS1), 23 (14 m, 9 f) in trapping session 2 (TS2), and 11 (8 m, 3 f) in trapping session 3 (TS3). A sham injection containing 0.4 ml saline-AdjuVac was given as control to 22 EGS (16 m, 6 f) in TS1, 20 (12 m, 8 f) in TS2, and 8 (4 m, 4 f) in TS3. In the last trapping session (TS4), 35 EGS (16 treated, 19 control) were killed for necropsy to evaluate histologic changes in testes and ovaries. Treated EGS males had testicular, prostatic, and epididymal atrophy compared with control EGS males. The tubuli seminiferi and prostatic glandular lumen of treated EGS males were atrophic, and the epididymal lumen contained no sperm cells. No histologic changes were observed in treated EGS females; however, females likely were not collected when changes due to GonaCon would have been observed. There were no observable histologic differences in the pituitary gland of treated and control EGS. There were no statistically significant differences in either testosterone or progesterone concentrations between control and treated EGS. Although there were no serious side effects to the vaccine, six EGS developed injection site abscesses. GonaCon may be a potential tool for EGS population control.


SCM, a novel M-like protein from Streptococcus canis, binds (mini)-plasminogen with high affinity and facilitates bacterial transmigration.
Streptococcus canis is an important zoonotic pathogen capable of causing serious invasive diseases in domestic animals and humans. In the present paper we report the binding of human plasminogen to S. canis and the recruitment of proteolytically active plasmin on its surface. The binding receptor for plasminogen was identified as a novel M-like protein designated SCM (S. canis M-like protein). SPR (surface plasmon resonance) analyses, radioactive dot-blot analyses and heterologous expression on the surface of Streptococcus gordonii confirmed the plasminogen-binding capability of SCM. The binding domain was located within the N-terminus of SCM, which specifically bound to the C-terminal part of plasminogen (mini-plasminogen) comprising kringle domain 5 and the catalytic domain. In the presence of urokinase, SCM mediated plasminogen activation on the bacterial surface that was inhibited by serine protease inhibitors and lysine amino acid analogues. Surface-bound plasmin effectively degraded purified fibrinogen as well as fibrin clots, resulting in the dissolution of fibrin thrombi. Electron microscopic illustration and time-lapse imaging demonstrated bacterial transmigration through fibrinous thrombi. The present study has led, for the first time, to the identification of SCM as a novel receptor for (mini)-plasminogen mediating the fibrinolytic activity of S. canis.


Development and User Evaluation of a Smartphone-Based System to Assess Range of Motion of Wrist Joint.
Measuring range of motion (ROM) in the wrist joint is an essential part of hand and wrist functional evaluations, especially before and after surgery. However, accurate measurements require experience and time. To reduce patient and surgeon burdens related to ROM measurement, a smartphone-based system, which enables participants to measure the ROM of the wrist joint semiautomatically using self-taken pictures on a smartphone, was developed and evaluated in this study. In the developed system, participants were asked to take a picture of their wrist by using the other hand to position the joint first into full flexion and then into full extension. The hand and arm regions were automatically extracted in the program, and the ROM was estimated after the area of the hand and forearm was cropped. To verify the accuracy of ROM measurements in this system, the proposed method was tested on 66 images of hands from 33 participants; measurements were compared with those taken by hand surgeons. A limit of agreement and an intraclass correlation coefficient (ICC) were used for evaluation. The smallest averages (95% limits of agreement) of flexion and extension were 11.32° (95% confidence interval [CI], 8.88° to 13.76°) and 11.01° (95% CI, 8.64° to 13.39°), respectively. The ICC (1,1) for 3 measurements taken by one assessor was 0.99 (95% CI, 0.986-0.992), and the ICC (2,1) for 2 measurements taken by both assessors was 0.97 (95% CI, 0.947-0.977). In this study, we developed a system to measure the semiautomatic ROM of the wrist joint using a smartphone image. Its accuracy was within a clinically usable error range that was comparable with that of a hand surgeon. This system can reduce the burden of ROM measurement for both patients and doctors.


Effects of the Ultra-High-Frequency Electrical Field Radiofrequency Device on Mouse Skin: A Histologic and Molecular Study.
Radiofrequency technology is one of the most recently developed methods for noninvasive skin tightening and facial contouring, and works by generating thermal energy in the deep dermis. Although clinical improvements have been reported using radiofrequency devices, there are few histologic and molecular studies about the mechanisms of dermal collagen remodeling. The authors investigated the histologic effects of an ultra-high-frequency electrical field (40.68 MHz) radiofrequency device (Polargen) on collagen remodeling in hairless mouse skin and evaluated its relative molecular mechanism. The radiofrequency was applied to the dorsal skin of hairless mice three times per week for 2 weeks. At 21 days after initial treatment, treated skin and nontreated control skin samples were excised for semiquantitative analysis of histologic features, including collagen. The authors also checked the mRNA expression levels of collagen type 1, transforming growth factor (TGF)-β, matrix metalloproteinase-1, vascular endothelial growth factor, tumor necrosis factor-α, and interleukin-1. Histologic examination revealed epidermal hyperplasia, increased collagen staining, and fat atrophy in treated skin area compared with the nontreated skin area. In addition, mRNA expression of collagen type І, TGF-β, and vascular endothelial growth factor in radiofrequency-treated areas was significantly increased compared with that in untreated control areas (p < 0.05, p < 0.05, and p < 0.01, respectively). These results suggest that the device may facilitate replacement of subcutaneous fat tissue with new collagen in association with the increased mRNA levels in TGF-β and vascular endothelial growth factor. Therefore, this device may effectively reduce adipose tissue and achieve facial contouring in addition to skin tightening.


The Oct DNA motif participates in the alcohol inhibition of the inducible nitric oxide synthase gene promoter in rat C6 glioma cells.
Induction of nitric oxide synthase-2 (iNOS) by cytokines and bacterial products is associated with protein binding at the proximal promoter and in an upstream enhancer region of the Nos2 gene. To clarify how ethanol suppresses rat iNOS activity, we constructed several deletion mutants of the Nos2 promoter fused to the luciferase gene and transfected the constructs into C6 glial cells. Acute ethanol exposure of stably transfected cells for 24 h inhibits induced activity of Nos2 promoter constructs containing deletions in the 5' flanking region, including a 94 bp promoter that lacks any known NF-kappaB site but which carries a C/EBPbeta and overlapping gamma-IRE, GAS and Oct motifs. Ethanol failed to inhibit the endogenous activity of a smaller, 78 bp promoter that lacks the C/EBPbeta and overlapping, gamma-IRE and GAS motifs and showed no inducible activity. As another approach, in vivo DNA footprinting was used and identified protein protections at five regions of the proximal Nos2 promoter in induced cells. Exposure to acute ethanol diminished protein occupation in the five promoter regions including the gamma-IRE/NF-kappaB and the overlapping gamma-IRE/GAS/Oct sites. Site-directed mutagenesis in the octamer domain of the gamma-IRE/GAS/Oct motifs was studied in a 1002 bp promoter to examine its role in ethanol inhibition of cytokine and lipopolysaccharide induced activity. The data indicate that ethanol failed to inhibit promoter activity when the Oct motif is missing. Electrophoretic mobility shift assays performed using a 22-mer probe containing the overlapping gamma-IRE/GAS/Oct sites showed three complexes with one of the complexes being competed by an octamer-1 antibody. These observations demonstrate the role of protein-DNA binding at the core promoter, and the likely involvement of the octamer motif, in ethanol modulation of cytokine and lipopolysaccharide induced iNOS expression.


Genome-wide RNA polymerase II: not genes only!
RNA polymerase (Pol) II transcriptional regulation is an essential process for guiding eukaryotic gene expression. Early in vitro studies deciphered the essential steps for transcription, including recruitment, initiation, elongation and termination. Based on these findings, the idea emerged that Pol II should essentially be located on promoters or genic regions of transcribed genes. The development of in vivo localization protocols has enabled the investigation of genome-wide Pol II occupancy. Recent studies from yeast to human show that Pol II can be poised at the transcription start site or can be located outside of gene-coding regions, sometimes dependent on the growth or differentiation stage. These recent results regarding Pol II genomic location and transcription challenge our classical views of transcriptional regulation.


Recent progress and challenges in population genetics of polyploid organisms: an overview of current state-of-the-art molecular and statistical tools.
Despite the importance of polyploidy and the increasing availability of new genomic data, there remain important gaps in our knowledge of polyploid population genetics. These gaps arise from the complex nature of polyploid data (e.g. multiple alleles and loci, mixed inheritance patterns, association between ploidy and mating system variation). Furthermore, many of the standard tools for population genetics that have been developed for diploids are often not feasible for polyploids. This review aims to provide an overview of the state-of-the-art in polyploid population genetics and to identify the main areas where further development of molecular techniques and statistical theory is required. We review commonly used molecular tools (amplified fragment length polymorphism, microsatellites, Sanger sequencing, next-generation sequencing and derived technologies) and their challenges associated with their use in polyploid populations: that is, allele dosage determination, null alleles, difficulty of distinguishing orthologues from paralogues and copy number variation. In addition, we review the approaches that have been used for population genetic analysis in polyploids and their specific problems. These problems are in most cases directly associated with dosage uncertainty and the problem of inferring allele frequencies and assumptions regarding inheritance. This leads us to conclude that for advancing the field of polyploid population genetics, most priority should be given to development of new molecular approaches that allow efficient dosage determination, and to further development of analytical approaches to circumvent dosage uncertainty and to accommodate 'flexible' modes of inheritance. In addition, there is a need for more simulation-based studies that test what kinds of biases could result from both existing and novel approaches.


Magnetically guided capsule versus conventional gastroscopy for upper abdominal complaints: a prospective blinded study.
Upper gastrointestinal endoscopy is mostly performed under sedation and has a low yield of relevant gastric lesions in patients without alarm symptoms. Simpler screening tests such as capsule endoscopy could be helpful, but gastric visualization is insufficient with the current passive capsules. A magnetically guided gastric capsule was prospectively evaluated in patients with routine indications for gastroscopy. A total of 189 symptomatic patients (105 male; mean age 53 y) from 2 French centers subsequently and blindly underwent capsule and conventional gastroscopy by 9 and 6 examiners, respectively. The final gold standard was unblinded conventional gastroscopy with biopsy under propofol sedation. Main outcome was accuracy (sensitivity/specificity) of capsule gastroscopy for diagnosis of major gastric lesions, defined as those lesions requiring conventional gastroscopy for biopsy or removal. Twenty-three major lesions were found in 21 patients. Capsule accuracy was 90.5% [95% confidence interval (CI), 85.4%-94.3%] with a specificity of 94.1% (95% CI, 89.3%-97.1%) and a sensitivity of 61.9% (95% CI, 38%-82%). Accuracy did not correlate with lesion location, gastric luminal visibility, examiner case volume, or examination time. Of the remaining 168 patients, 94% had minor and mostly multiple lesions; the capsule made a correct diagnosis in 88.1% (95% CI, 82.2%-92.6%), with gastric visibility and lesion location in the proximal stomach having significant influence. All patients preferred capsule gastroscopy. In a prospective and strictly blinded study, magnetically guided capsule gastroscopy was shown to be feasible in clinical practice and was clearly preferred by patients. Improvements in capsule technology may render this technique a future alternative to gastroscopy.


Providing a primary care medical home for children and youth with cerebral palsy.
Children and youth with cerebral palsy present pediatricians with complex diagnostic and therapeutic challenges. In most instances, care also requires communication and comanagement with pediatric subspecialists and pediatric surgical specialists, therapists, and community developmental and educational teams. The importance of family resilience to the patient's well-being broadens the ecologic scope of care, which highlights the value of a primary care medical home from which care is initiated, coordinated, and monitored and with which families can form a reliable alliance for information, support, and advocacy from the time of diagnosis through the transition to adulthood. This report reviews the aspects of care specific to cerebral palsy that a medical home should provide beyond the routine health maintenance, preventive care, and anticipatory guidance needed by all children.


Autologous bone marrow transplantation for pediatric Hodgkin's disease: a case-matched comparison with adult patients by the European Bone Marrow Transplant Group Lymphoma Registry.
We analyzed the outcome of autologous bone marrow transplantation (ABMT) in pediatric and adult patients with Hodgkin's disease (HD) by means of a case-controlled study. Eighty-one pediatric HD patients who had undergone ABMT and who had been reported to the European Bone Marrow Transplant Group (EBMTG) Lymphoma Registry were compared with a case-matched group of 81 adult patients who had undergone the same procedure. The case-matching was performed following selection of the main prognostic factors for progression-free survival (PFS) by multivariate analysis. The PFS rate was not significantly different between the groups (39% for the pediatric group v 48% for the adult group). The overall relapse/progression rates for the groups were 52% and 40%, respectively. This was not a statistically significant difference and the sites of relapse were similar. There was no significant difference in the incidence or causes of procedure-related morbidity or mortality of the two groups. This study suggests that patients with pediatric HD have the same outcome at ABMT as their adult counterparts; however, long-term complications will need to be carefully monitored.


Expression of insulin-like growth factor II in spontaneously immortalized rat mesothelial and spontaneous mesothelioma cells: a potential autocrine role of insulin-like growth factor II.
Insulin-like growth factors (IGFs) are polypeptides that play an important role in cellular proliferation and differentiation. The present study examines the role of IGFs in the growth of mesothelial cells. Cell lines derived from normal rat mesothelium as well as lines derived from spontaneous rat mesotheliomas were found to express RNA transcripts for IGF-II. In contrast, cell lines derived from asbestos-induced rat mesotheliomas did not express this growth factor. All cell lines expressed receptors for IGF-I and IGF-II, as well as insulin receptors. Coexpression of IGF-II and its cognate receptor suggested that IGF-II was acting as an autocrine growth factor in the spontaneously immortalized cells and the cells derived from the spontaneous tumors. The biological activity of IGF-II secreted by the cell lines into conditioned medium could be neutralized using an IGF-II-specific antibody. Growth was inhibited in a dose-dependent manner; at the highest antibody concentration used (100 micrograms anti-IGF-II/ml), cell growth was decreased to 47% of control values. This inhibition was partially reversible by treatment of the cultures with IGF-II (91% of the control). These data suggest that IGF-II expression may be involved in the spontaneous alteration of rat mesothelial cells and may function as an autocrine or paracrine growth factor to modulate the growth of these cells in vitro and in vivo. Ubiquitous expression of IGF-II by cells that have not been exposed to asbestos and the lack of IGF-II expression by asbestos-transformed cells suggest that the mechanisms of changes in growth factor expression differ in mesothelial cells transformed by different pathways.


Identification of thresholds for dichotomizing DNA methylation data.
: DNA methylation plays an important role in many biological processes by regulating gene expression. It is commonly accepted that turning on the DNA methylation leads to silencing of the expression of the corresponding genes. While methylation is often described as a binary on-off signal, it is typically measured using beta values derived from either microarray or sequencing technologies, which takes continuous values between 0 and 1. If we would like to interpret methylation in a binary fashion, appropriate thresholds are needed to dichotomize the continuous measurements. In this paper, we use data from The Cancer Genome Atlas project. For a total of 992 samples across five cancer types, both methylation and gene expression data are available. A bivariate extension of the StepMiner algorithm is used to identify thresholds for dichotomizing both methylation and expression data. Hypergeometric test is applied to identify CpG sites whose methylation status is significantly associated to silencing of the expression of their corresponding genes. The test is performed on either all five cancer types together or individual cancer types separately. We notice that the appropriate thresholds vary across different CpG sites. In addition, the negative association between methylation and expression is highly tissue specific.


Red fluorescence of the triplefin Tripterygion delaisi is increasingly visible against background light with increasing depth.
The light environment in water bodies changes with depth due to the absorption of short and long wavelengths. Below 10 m depth, red wavelengths are almost completely absent rendering any red-reflecting animal dark and achromatic. However, fluorescence may produce red coloration even when red light is not available for reflection. A large number of marine taxa including over 270 fish species are known to produce red fluorescence, yet it is unclear under which natural light environment fluorescence contributes perceptively to their colours. To address this question we: (i) characterized the visual system of Tripterygion delaisi, which possesses fluorescent irides, (ii) separated the colour of the irides into its reflectance and fluorescence components and (iii) combined these data with field measurements of the ambient light environment to calculate depth-dependent perceptual chromatic and achromatic contrasts using visual modelling. We found that triplefins have cones with at least three different spectral sensitivities, including differences between the two members of the double cones, giving them the potential for trichromatic colour vision. We also show that fluorescence contributes increasingly to the radiance of the irides with increasing depth. Our results support the potential functionality of red fluorescence, including communicative roles such as species and sex identity, and non-communicative roles such as camouflage.


Long-Term Effects of Psychological Symptoms after Occupational Injury on Return to Work: A 6-Year Follow-Up.
Psychological factors may compromise return to work among workers with occupational injuries, and little is known about the long-term consequences of psychological symptoms relating to return to work. The study examined the impact of psychological symptoms on return to work as well as exploring factors associated with return to work among injured workers. A total of 572 workers who experienced occupational injuries were recruited in this prospective cohort study. Surveys of the psychological symptoms using the 5-item Brief Symptom Rating Scale (BSRS-5) were conducted at 3 and 12 months after the injury. All of the workers were invited to join the study at year 6 after the injury. Sociodemographic factors, psychological symptoms, injury severity, and return-to-work status were collected. Approximately 10% of injured workers could not return to work even 6 years after the injury. Severe psychological symptoms within 1 year after the injury presented a significant risk factor for not returning to work 6 years after the injury (adjusted OR = 0.7, 95% CI: 0.5⁻0.8). Furthermore, age, education level, length of hospitalization, and injury-induced changes in appearance had significant independent influence on return to work as well. These findings highlight the importance of the effects of mental health within 1 year post injury on return to work, and support the concept of early screening, detection, and intervention in at-risk occupational injured workers with severe psychological symptoms.


Metformin Effect on Nontargeted Metabolite Profiles in Patients With Type 2 Diabetes and in Multiple Murine Tissues.
Metformin is the first-line oral medication to increase insulin sensitivity in patients with type 2 diabetes (T2D). Our aim was to investigate the pleiotropic effect of metformin using a nontargeted metabolomics approach. We analyzed 353 metabolites in fasting serum samples of the population-based human KORA (Cooperative Health Research in the Region of Augsburg) follow-up survey 4 cohort. To compare T2D patients treated with metformin (mt-T2D, n = 74) and those without antidiabetes medication (ndt-T2D, n = 115), we used multivariable linear regression models in a cross-sectional study. We applied a generalized estimating equation to confirm the initial findings in longitudinal samples of 683 KORA participants. In a translational approach, we used murine plasma, liver, skeletal muscle, and epididymal adipose tissue samples from metformin-treated db/db mice to further corroborate our findings from the human study. We identified two metabolites significantly (P < 1.42E-04) associated with metformin treatment. Citrulline showed lower relative concentrations and an unknown metabolite X-21365 showed higher relative concentrations in human serum when comparing mt-T2D with ndt-T2D. Citrulline was confirmed to be significantly (P < 2.96E-04) decreased at 7-year follow-up in patients who started metformin treatment. In mice, we validated significantly (P < 4.52E-07) lower citrulline values in plasma, skeletal muscle, and adipose tissue of metformin-treated animals but not in their liver. The lowered values of citrulline we observed by using a nontargeted approach most likely resulted from the pleiotropic effect of metformin on the interlocked urea and nitric oxide cycle. The translational data derived from multiple murine tissues corroborated and complemented the findings from the human cohort.


Combining test statistics and models in bootstrapped model rejection: it is a balancing act.
Model rejections lie at the heart of systems biology, since they provide conclusive statements: that the corresponding mechanistic assumptions do not serve as valid explanations for the experimental data. Rejections are usually done using e.g. the chi-square test (χ2) or the Durbin-Watson test (DW). Analytical formulas for the corresponding distributions rely on assumptions that typically are not fulfilled. This problem is partly alleviated by the usage of bootstrapping, a computationally heavy approach to calculate an empirical distribution. Bootstrapping also allows for a natural extension to estimation of joint distributions, but this feature has so far been little exploited. We herein show that simplistic combinations of bootstrapped tests, like the max or min of the individual p-values, give inconsistent, i.e. overly conservative or liberal, results. A new two-dimensional (2D) approach based on parametric bootstrapping, on the other hand, is found both consistent and with a higher power than the individual tests, when tested on static and dynamic examples where the truth is known. In the same examples, the most superior test is a 2D χ2vsχ2, where the second χ2-value comes from an additional help model, and its ability to describe bootstraps from the tested model. This superiority is lost if the help model is too simple, or too flexible. If a useful help model is found, the most powerful approach is the bootstrapped log-likelihood ratio (LHR). We show that this is because the LHR is one-dimensional, because the second dimension comes at a cost, and because LHR has retained most of the crucial information in the 2D distribution. These approaches statistically resolve a previously published rejection example for the first time. We have shown how to, and how not to, combine tests in a bootstrap setting, when the combination is advantageous, and when it is advantageous to include a second model. These results also provide a deeper insight into the original motivation for formulating the LHR, for the more general setting of nonlinear and non-nested models. These insights are valuable in cases when accuracy and power, rather than computational speed, are prioritized.


Health Equity and the Tripartite Mission: Moving From Academic Health Centers to Academic-Community Health Systems.
Academic health centers (AHCs) play a significant role in educating the health care workforce, conducting innovative biomedical and clinical research, and delivering high-quality patient care. Much work remains, however, to adequately address the social determinants of health and equity that affect communities where patients live, work, and play. Doing so will help achieve the Quadruple Aim while addressing the unjust social structures that disproportionately impact communities of color and vulnerable populations. AHCs have a timely opportunity to focus their leading roles in education, research, and clinical care on social determinants, moving outside their walls to create academic-community health systems: a collection of academic-community partnerships advancing health equity through collaboration, power sharing, and cocreation.This Perspective proposes four strategies to start developing academic-community health systems. First, embark on all efforts through cocreation with communities. Second, address how future health care professionals are recruited. Third, build the right skills and opportunities for health care professionals to address health inequities. Finally, develop research agendas to evaluate programs addressing inequities. A fully realized vision of an academic-community health system will demonstrate interdependence between AHCs and the community. While considerable AHC resources are invested in building community capacity to improve health and health equity, health systems will also benefit in a multitude of ways, including increasing the diversity of ideas and experiences integrated into health systems. These strategies will support AHCs to embed across each arm of the tripartite mission a focus on partnering with communities to advance health equity together.


Chromosomes with high gene density are preferentially repaired in human cells.
It is known that DNA repair is heterogeneous in human cells since open chromatin, active genes and their transcribed strands are preferentially repaired. It is thus expected that DNA repair is clustered in chromosomes with high gene density. We have employed a DNA repair inhibitor, cytosine arabinoside (Ara-C), to convert ethyl methane sulfonate (EMS)-induced excision repairable lesions to chromosomal breaks, to check for the existence of heterogeneity of repair at the chromosome level. Chromosome staining by fluorescence in situ hybridization (FISH) was used to analyze breakage in chromosomes with diverse gene densities. These chromosomes were identified by means of the CpG island distribution after FISH with a CpG island-rich probe isolated from total human genomic DNA. Thus, three chromosomes with very high gene density (numbers 1, 19 and 20) were compared with two chromosomes with very low gene density (numbers 4 and 18) for clastogenicity and sensitivity to co-treatment with Ara-C and EMS. Our data indicate that those chromosome with higher gene density are more sensitive to a combination treatment with Ara-C and EMS, indicating that the level of excision repair synthesis is higher in those chromosome. It is therefore concluded that DNA excision repair is preferentially directed to chromosomes with high gene density. The implications of this finding in human biomonitoring using FISH techniques are discussed.


Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients.
We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard-of-care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (Ctrough ) versus intravenous DARA, with lower maximum concentrations and smaller peak-to-trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure-response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the ≤65-kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients ≤50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800-mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg.