The relationship between cycle track width and the lateral position of cyclists, and implications for the required cycle track width.
Sufficient cycle track width is important to prevent single-bicycle crashes and collisions between cyclists. The assumptions on which the minimum width is based in guidelines is founded on only a few studies. The aim of the present study is to investigate the relationship between cycle track width and lateral position of cyclists. We conducted an experiment to evaluate the lateral position of cyclists along cycle tracks with different widths (Study 1). Participants cycled on an instrumented bicycle with a LIDAR to measure their lateral position. Five conditions were defined: cycle track width of 100 cm, 150 cm and 200 cm without interaction, and cycle track width of 150 cm and 200 cm with an oncoming cyclist simulated by a parked bicycle. The cross-sectional Study 2 is based on the collected lateral position measurements at cycle tracks with varying width reported in Dutch studies since 2010. The experimental Study 1 with 24 participants shows that an increase in cycle track width causes cyclists to ride further away from the verge and keep more distance from an oncoming cyclist. The cross-sectional Study 2 was based on lateral position measured at 33 real-life Dutch cycle tracks. Study 2 yielded similar results, indicating that doubling pavement width increases lateral position by some 50%. Study 2 shows that, compared with a solo cyclist without interaction, a right-hand cyclist of a duo and a cyclist meeting an oncoming cyclist ride around 30% closer to the verge. The wider the cycle track, the more distance cyclists maintain from the verge. Cyclists ride closer to the verge due to oncoming cyclists. Given a cyclists' lateral position while meeting, common variations between cyclists' steering behavior, and vehicle width and circumstances, a cycle track width of 250 cm is needed for safe meeting maneuvers.


Inhibition of the de novo pyrimidine biosynthesis pathway limits ribosomal RNA transcription causing nucleolar stress in glioblastoma cells.
Glioblastoma is the most common and aggressive type of cancer in the brain; its poor prognosis is often marked by reoccurrence due to resistance to the chemotherapeutic agent temozolomide, which is triggered by an increase in the expression of DNA repair enzymes such as MGMT. The poor prognosis and limited therapeutic options led to studies targeted at understanding specific vulnerabilities of glioblastoma cells. Metabolic adaptations leading to increased synthesis of nucleotides by de novo biosynthesis pathways are emerging as key alterations driving glioblastoma growth. In this study, we show that enzymes necessary for the de novo biosynthesis of pyrimidines, DHODH and UMPS, are elevated in high grade gliomas and in glioblastoma cell lines. We demonstrate that DHODH's activity is necessary to maintain ribosomal DNA transcription (rDNA). Pharmacological inhibition of DHODH with the specific inhibitors brequinar or ML390 effectively depleted the pool of pyrimidines in glioblastoma cells grown in vitro and in vivo and impaired rDNA transcription, leading to nucleolar stress. Nucleolar stress was visualized by the aberrant redistribution of the transcription factor UBF and the nucleolar organizer nucleophosmin 1 (NPM1), as well as the stabilization of the transcription factor p53. Moreover, DHODH inhibition decreased the proliferation of glioblastoma cells, including temozolomide-resistant cells. Importantly, the addition of exogenous uridine, which reconstitutes the cellular pool of pyrimidine by the salvage pathway, to the culture media recovered the impaired rDNA transcription, nucleolar morphology, p53 levels, and proliferation of glioblastoma cells caused by the DHODH inhibitors. Our in vivo data indicate that while inhibition of DHODH caused a dramatic reduction in pyrimidines in tumor cells, it did not affect the overall pyrimidine levels in normal brain and liver tissues, suggesting that pyrimidine production by the salvage pathway may play an important role in maintaining these nucleotides in normal cells. Our study demonstrates that glioblastoma cells heavily rely on the de novo pyrimidine biosynthesis pathway to generate ribosomal RNA (rRNA) and thus, we identified an approach to inhibit ribosome production and consequently the proliferation of glioblastoma cells through the specific inhibition of the de novo pyrimidine biosynthesis pathway.


Gephyrin clusters are absent from small diameter primary afferent terminals despite the presence of GABA(A) receptors.
Whereas both GABA(A) receptors (GABA(A)Rs) and glycine receptors (GlyRs) play a role in control of dorsal horn neuron excitability, their relative contribution to inhibition of small diameter primary afferent terminals remains controversial. To address this, we designed an approach for quantitative analyses of the distribution of GABA(A)R-subunits, GlyR α1-subunit and their anchoring protein, gephyrin, on terminals of rat spinal sensory afferents identified by Calcitonin-Gene-Related-Peptide (CGRP) for peptidergic terminals, and by Isolectin-B4 (IB4) for nonpeptidergic terminals. The approach was designed for light microscopy, which is compatible with the mild fixation conditions necessary for immunodetection of several of these antigens. An algorithm was designed to recognize structures with dimensions similar to those of the microscope resolution. To avoid detecting false colocalization, the latter was considered significant only if the degree of pixel overlap exceeded that expected from randomly overlapping pixels given a hypergeometric distribution. We found that both CGRP(+) and IB4(+) terminals were devoid of GlyR α1-subunit and gephyrin. The α1 GABA(A)R was also absent from these terminals. In contrast, the GABA(A)R α2/α3/α5 and β3 subunits were significantly expressed in both terminal types, as were other GABA(A)R-associated-proteins (α-Dystroglycan/Neuroligin-2/Collybistin-2). Ultrastructural immunocytochemistry confirmed the presence of GABA(A)R β3 subunits in small afferent terminals. Real-time quantitative PCR (qRT-PCR) confirmed the results of light microscopy immunochemical analysis. These results indicate that dorsal horn inhibitory synapses follow different rules of organization at presynaptic versus postsynaptic sites (nociceptive afferent terminals vs inhibitory synapses on dorsal horn neurons). The absence of gephyrin clusters from primary afferent terminals suggests a more diffuse mode of GABA(A)-mediated transmission at presynaptic than at postsynaptic sites.


Recent insights into the genetics of inflammatory bowel disease.
Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders that comprise Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies have identified approximately 100 loci that are significantly associated with IBD. These loci implicate a diverse array of genes and pathophysiologic mechanisms, including microbe recognition, lymphocyte activation, cytokine signaling, and intestinal epithelial defense. Consistent with epidemiologic predictions, many IBD-associated loci demonstrate genome-wide significant associations to both CD and UC, notably, genes whose products function in the interleukin-23 pathway, and transcription factors, including NK2 transcription factor related, locus 3 (NKX2-3), SMAD3, STAT3, ZMIZ1, and c-REL. Although CD and UC are both associated with genomic regions that implicate products of genes involved in leukocyte trafficking, there is evidence for association patterns that are distinct between CD and UC. CD-predominant associations include NOD2 and genes that regulate autophagy. In UC, the predominant association signal is on chromosome 6p21, in the major histocompatibility complex region, near HLA class II genes. UC-predominant loci have also implicated genes mediating epithelial defense function. There is a striking overlap of loci between diseases, which could provide comparative insight into mechanisms of disease pathogenesis. Genes that encode factors that function in the interleukin-23 pathway have been associated with a number of chronic inflammatory diseases, notably psoriasis and ankylosing spondylitis. Distinct genetic associations indicate that the colitis associated with primary sclerosing cholangitis is pathophysiologically distinct from UC that is not associated with primary sclerosing cholangitis. As many as 14 susceptibility loci are shared between IBD and celiac disease, indicating significant overlap in pathophysiology. Future genetic studies will be directed toward identifying uncommon variations with potentially greater statistical effects, defining population differences, and more completely accounting for familial transmission of disease.


Personalized commissioning, public spaces: the limits of the market in English social care services.
The article explores the implications of personal budgets within English social care services, which position the individual as market actor. Rooting the research in the broader personalization agenda, the study looks at the limitations of the market in relation to individual purchase of private goods (e.g. home care), in the pooling of funds to purchase group services and in the provision of public goods such as building-based services. The article takes a multi-method approach, combining an interpretive focus on the framing of the personal budget-holder by advocates of personalization with national evaluation data, and data from a small survey of day centre workers. The article identifies three framings of the individual budget-holder articulated by advocates of personalization. The first is that personal budget-holders will be empowered market actors, commissioning the services they need. The second is that budget-holders will pool resources with others to purchase group services in order to broaden the range of options available to them. The third is that services which cannot be disaggregated into individual or group budgets - such as day centres - are not valued by service users. The article looks at the evaluation data on these three claims in turn. It identifies four limitations to the capacity of people to purchase care goods on an individual basis: lack of transparency in allocating budgets, complexity in managing a budget, excessive auditing of spending and lack of responsiveness from the provider market. Pooling of budgets to purchase collective services is found to be underdeveloped, and hampered by the complexity which is a broader limitation on personal budgets. Day centres are found to be closing not in response to commissioning decisions by individual budget-holders but because of decommissioning by local authorities, minimising the scope for individuals to express a preference for this type of care. The survey highlights patterns of day centre closure, rising fees for attendance and reduced eligibility, and the underdevelopment of mechanisms to facilitate commissioning of new collective spaces. The paper concludes that the transition to personal budgets - in the context of the accompanying financial crisis in local authorities - has led to inadequate attention to the potential for an undersupply of collective and public goods. The loss of day centre provision will be felt by personal budget holders but also by self-funders and people in residential accommodation who may no longer be eligible for, or able to afford, to access shared spaces. Local authorities are actively taking on the role of decommissioners without sufficient responsiveness to how and what individuals want them to commission.


MANAGEMENT OF ENDOCRINE DISEASE: Isolated maternal hypothyroxinemia during pregnancy: knowns and unknowns.
Isolated maternal hypothyroxinemia (IMH) during pregnancy is defined as a low maternal T4 in the absence of TSH elevation. As IMH is common, with a prevalence of 1-2% in iodine-sufficient populations, and early research has suggested adverse effects on fetal neurodevelopment, it has been the focus of many studies in the last decade. In the current review, we first discuss the significance of IMH based on data from animal models and recent discoveries regarding the role of thyroid hormone on neurodevelopment. We address issues surrounding the definition and prevalence of this entity and discuss new insights into the etiologies, clinical consequences and management of IMH. A number of large cohort studies have investigated the effects of IMH on the risk of various pregnancy complications and child neurodevelopment. We review these studies in detail and describe their limitations. We discuss the available research on management of IMH, including two recent randomized controlled trials (RCTs). Finally, we delineate the remaining uncertainties in this field and emphasize the need for a sufficiently powered, placebo-controlled RCT on the treatment of IMH early in the first trimester of pregnancy.


Cysteine metabolism and metal toxicity.
Chronic, low level exposure to toxic metals is an increasing global problem. The symptoms associated with the slow accumulation of toxic metals are multiple and rather nondescript, and overt expression of toxic effects may not appear until later in life. The sulfhydryl-reactive metals (mercury, cadmium, lead, arsenic) are particularly insidious and can affect a vast array of biochemical and nutritional processes. The primary mechanisms by which the sulfhydryl-reactive metals elicit their toxic effects are summarized. The pro-oxidative effects of the metals are compounded by the fact that the metals also inhibit antioxidative enzymes and deplete intracellular glutathione. The metals also have the potential to disrupt the metabolism and biological activities of many proteins due to their high affinity for free sulfhydryl groups. Cysteine has a pivotal role in inducible, endogenous detoxication mechanisms in the body, and metal exposure taxes cysteine status. The protective effects of glutathione and the metallothioneins are discussed in detail. Basic research pertaining to the transport of toxic metals into the brain is summarized, and a case is made for the use of hydrolyzed whey protein to support metal detoxification and neurological function. Metal exposure also affects essential element status, which can further decrease antioxidation and detoxification processes. Early detection and treatment of metal burden is important for successful detoxification, and optimization of nutritional status is paramount to the prevention and treatment of metal toxicity.


Transitions from chimeras to coherence: An analytical approach by means of the coherent stability function.
Chimera states have been a vibrant subject of research in the recent past, but the analytical treatment of transitions from chimeras to coherent states remains a challenge. Here we analytically derive the necessary conditions for this transition by means of the coherent stability function approach, which is akin to the master stability function approach that is traditionally used to study the stability of synchronization in coupled oscillators. In chimera states, there is typically at least one group of oscillators that evolves in a drifting, random manner, while other groups of oscillators follow a smoother, more coherent profile. In the coherent state, there thus exists a smooth functional relationship between the oscillators. This lays the foundation for the coherent stability function approach, where we determine the stability of the coherent state. We subsequently test the analytical prediction numerically by calculating the strength of incoherence during the transition point. We use leech neurons, which exhibit a coexistence of chaotic and periodic tonic spiking depending on initial conditions, coupled via nonlocal electrical synapses, to demonstrate our approach. We systematically explore various dynamical states with the focus on the transitions between chimeras and coherence, fully confirming the validity of the coherent stability function. We also observe complete synchronization for higher values of the coupling strength, which we verify by the master stability function approach.


Management of congenital pseudarthrosis of the tibia in children under 3 years of age: effect of early surgery on union of the pseudarthrosis and growth of the limb.
The study was undertaken to determine whether the results of treatment of pseudarthrosis of the tibia in children under age 3 are so poor as to recommend that surgery be deferred until after 3 years of age. Radiographs and case records of 26 consecutive patients with Crawford type IV congenital pseudarthrosis of the tibia who were treated operatively were reviewed. Growth abnormalities of the tibia, fibula, and femur of the affected limb at presentation were identified. The outcome of treatment, in terms of union of the pseudarthrosis, refracture rate, and limb length, in 13 children treated operatively before age 3 years was compared with those operated on later. Union of the pseudarthrosis occurred in 12 of 13 children (92%) who were treated before 3 years of age by excision of the pseudarthrosis, intramedullary rodding, and dual-onlay cortical bone grafting. Union occurred in only five of seven children who underwent the same procedure between the ages of 3 and 12 years. The extent of shortening of the limb at the time of surgery was least in children younger than 3 years. The limb length discrepancy remained virtually static in 11 children who had transarticular Rush rodding before age 3. Growth abnormalities of the fibula, tibia, and femur were less pronounced in children operated on early. The study suggests that there is no need to defer surgery for pseudarthrosis of the tibia until the child is older than 3 years.


Myxoid variant epithelioid pleural mesothelioma defines a favourable prognosis group: an analysis of 191 patients with pleural malignant mesothelioma.
Malignant pleural mesothelioma shows marked cytoarchitectural diversity. The aim of the study was to evaluate how morphological phenotype impacted upon overall survival. 191 cases of malignant pleural mesothelioma with available follow-up were identified, examined and classified according to histological types. The epithelioid mesotheliomas were further subdivided according to morphological subtypes: myxoid, microcystic, tubulopapillary, solid epithelioid, micropapillary and pleomorphic; biphasic mesotheliomas were divided into epithelioid component dominant and sarcomatoid component dominant; pure sarcomatoid mesotheliomas were divided into not otherwise specified, leiomyoid, desmoplastic and heterologous. All cases were confirmed by two experienced observers. Myxoid variant malignant pleural epithelioid mesothelioma was observed to have a favourable overall survival compared with pleomorphic form (p=0.00008). Pleomorphic phenotype had the worst overall survival. Morphological phenotype is an important histological factor that should be included in pathology reports to convey potential favourable prognostic subgroups of patients with mesothelioma.


Public health principles to inform testing and build trust in automated vehicles.
Highly publicised crashes involving self-driving or autonomous vehicles (AVs) have raised questions about safety and eroded public trust in the technology. In this State of the Art Review, we draw on previous successes in injury prevention and public health to focus attention on three strategies to reduce risk and build public confidence as AVs are being tested on public roads. Data pooling, a graduated approach to risk exposure, and harm reduction principles each offer practical lessons for AV testing. The review points out how the eventual deployment of AV technology could have a substantial impact on public health. In this regard, inclusive testing, public education and smart policy could extend the social value of AVs by improving access to mobility and by directing deployments towards scenarios with the greatest population health impact. The application of these strategies does not imply slowing down progress; rather, their implementation could accelerate adoption and result in realising the benefits of AVs more quickly and comprehensively while minimising risks.


Risk adjustment and primary health care in Chile.
To offer a capitation formula with greater capacity for guiding resource spending on population with poorer health and lower socioeconomic status in the context of financing and equity in primary health care. We collected two years of data on a sample of 10,000 individuals from a region in Chile, Valdivia and Temuco and evaluated three models to estimate utilization and expenditures per capita. The first model included age and sex; the second one included age, sex, and the presence of two key diagnoses; and the third model included age, sex, and the presence of seven key diagnoses. Regression results were evaluated by R2 and predictive ratios to select the best specifications. Per-capita expenditures by age and sex confirmed international trends, where children under five, women, and the elderly were the main users of primary health care services. Women sought health advice twice as much as men. Clear differences by socioeconomic status were observed for the indigent population aged > or =65 years who under-utilized primary health care services. From the three models, major improvement in the predictive power occurred from the demographic (adjusted R2, 9%) to the demographic plus two diagnoses model (adjusted R2, 27%). Improvements were modest when five other diagnoses were added (adjusted R2, 28%). The current formula that uses municipality's financial power and geographic location of health centers to adjust capitation payments provides little incentive to appropriate care for the indigent and people with chronic conditions. A capitation payment that adjusts for age, sex, and the presence of diabetes and hypertension will better guide resource allocation to those with poorer health and lower socioeconomic status.


A prospective study of surgeon-performed ultrasound as the primary adjuvant modality for injured patient assessment.
Ultrasound diagnostic imaging, having been used in Germany in the trauma setting for more than 15 years, has unique qualities that give it distinct advantages over other tests (DPL, CT), and is gradually gaining acceptance by surgeons in the United States. In this prospective study, experienced surgeon sonographers successfully used ultrasound as the primary adjuvant modality to detect hemoperitoneum and pericardial effusion in injured patients. The ultrasound evaluations of 371 patients demonstrated that in 65 patients with significant injuries, ultrasound detected 53, that is, had an 81.5% sensitivity and 99.7% specificity. They conclude that ultrasound should be the primary adjuvant instrument for the evaluation of injured patients because it is rapid, accurate, and is potentially cost-effective.


Experimental reactivity parameters for toxicity modeling: application to the acute aquatic toxicity of SN2 electrophiles to Tetrahymena pyriformis.
A diverse set of 60 haloaliphatic compounds were evaluated for reactivity with cysteine thiol groups in the previously described RC(50) assay using glutathione (GSH) as a model nucleophile. Reactivity was quantified by the RC(50) value, the concentration of test compound that produced 50% reaction of the GSH thiol groups in 120 min. Under standard conditions, RC(50) values are mathematically proportional to reciprocal rate constants. Quantitative structure-activity relationship (QSAR) analysis correlating acute aquatic toxicity (IGC(50)) to Tetrahymena pyriformis with RC(50) values was carried out. It was found that subdivision of the compounds into subdomains according to their reaction mechanism characteristics enabled toxicity-reactivity relationships to be identified. The largest subdomain consisting of 22 compounds in which a primary halogen is alpha to a carbonyl or other electronegative unsaturated group and which can be confidently assigned as S(N)2 electrophiles fits the equation pIGC(50) (mM) = 0.94 (+/-0.07) pRC(50) (mM) + 1.34 (+/-0.07), n = 22, r(2) = 0.889, r(2)(adj) = 0.884, s = 0.27, and F = 161. Compounds in which the halogen is not alpha to an unsaturated group are not reactive in the GSH assay and do not exhibit reactive toxicity to T. pyriformis. Compounds tested in which the halogen is alpha to an unsaturated nonelectronegative group were found to be less toxic in the assay than predicted by the above QSAR equation. Within a subdomain of 21 compounds having a halogen alpha to an electronegative unsaturated group that, in the absence of experimental evidence, could not be confidently assigned as S(N)2 electrophiles, 2-bromoalkanoates of general structure R(1)CHBrCO(2)R(2), 2-bromopropionamide, and 2-haloalkanoic acids of general formula R(1)CHXCO(2)H (nine compounds in total) are all well-predicted by the above equation. Of the other 12 compounds of this subdomain, eight are substantially less toxic than predicted by the above equation and are considered to react differently, whereas the alpha-halonitriles (four compounds) are more toxic than predicted and fit a correlation of their own: pIGC(50) = 1.01 (+/-0.05) pRC(50) + 2.04 (+/-0.05), n = 4, r(2) = 0.995, r(2)(adj) = 0.992, s = 0.08, and F = 381, with a similar slope but larger intercept. An explanation in terms of their physical chemistry and possible involvement of released cyanide ion is suggested.


An endoplasmic reticulum protein, p180, is highly expressed in human cytomegalovirus-permissive cells and interacts with the tegument protein encoded by UL48.
We have used a virus overlay assay to detect cellular proteins associated with human cytomegalovirus (HCMV) particles. The radiolabeled HCMV particles specifically bound to two host proteins with molecular sizes of 150 and 180 kDa. By a micro-amino-acid sequencing technique, the 180-kDa protein was identified as a human homologue of the ES130/p180 ribosome receptor (p180), which is an integral endoplasmic reticulum (ER) membrane protein possessing a very unique tandem repeat domain at its N-terminal region. The virus overlay assay using truncated p180 polypeptides revealed that HCMV binding to human p180 occurred through the N-terminal region. In HCMV-permissive cells the high level of expression of the human p180 protein was clearly observed regardless of cell type. Furthermore, we showed that p180 binds to the UL48 gene product, which is one of the predominant tegument proteins of HCMV and which is considered to be tightly associated with the capsid. The interaction between the two proteins was assumed to be specific and was observed both in vitro and in vivo. During the late phase of infection, the unique relocation of human p180 was observed, that is, to the juxtanuclear region, which appeared to be in the vicinity of the area where naked virions were frequently observed in an electron-microscopic study. Thus our data suggest that p180 interacts with the HCMV tegument, at least through pUL48, during the HCMV replication process. We discuss the possible role of the interaction between p180 and pUL48 in the intracellular transport of HCMV virions.


Current realities of delivering mammography services in the community: do challenges with staffing and scheduling exist?
To evaluate the current (2001-2002) capacity of community-based mammography facilities to deliver screening and diagnostic services in the United States. Institutional review board approvals and patient consent were obtained. A mailed survey was sent to 53 eligible mammography facilities in three states (Washington, New Hampshire, and Colorado). Survey questions assessed equipment and staffing availability, as well as appointment waiting times for screening and diagnostic mammography services. Criterion-related content and construct validity were obtained first by means of a national advisory committee of academic, scientific, and clinical colleagues in mammography that reviewed literature on existing surveys and second by pilot testing a series of draft surveys among community mammography facilities not inclusive of the study facilities. The final survey results were independently double entered into a relational database with programmed data checks. The data were sent encrypted by means of file transfer protocol to a central analytical center at Group Health Cooperative. A two-sided P value with alpha = .05 was considered to show statistical significance in all analyses. Forty-five of 53 eligible mammography facilities (85%) returned the survey. Shortages of radiologists relative to the mammographic volume were found in 44% of mammography facilities overall, with shortages of radiologists higher in not-for-profit versus for-profit facilities (60% vs 28% reported). Shortages of Mammography Quality Standards Act-qualified technologists were reported by 20% of facilities, with 46% reporting some level of difficulty in maintaining qualified technologists. Waiting times for diagnostic mammography ranged from less than 1 week to 4 weeks, with 85% performed within 1 week. Waiting times for screening mammography ranged from less than 1 week to 8 weeks, with 59% performed between 1 week and 4 weeks. Waiting times for both diagnostic and screening services were two to three times higher in high-volume compared with low-volume facilities. Survey results show shortages of radiologists and certified mammography technologists.


A model for binding of an antifreeze polypeptide to ice.
A model is proposed, based on recent peptide analog and ice crystal etching studies, whereby an alanine-rich, alpha-helical antifreeze polypeptide (AFP) from the winter flounder inhibits the growth of ice crystals by hydrogen bonding of Thr, Asn, and Asp side chains in a specific pattern to the [2021] hexagonal bipyramidal planes of ice. It is further suggested that this mode of binding is unidirectional, maximizing opportunities for packing of AFPs on the ice surface, and that ice crystal growth inhibition occurs by a two-step mechanism involving hydrogen bonding and hydrophobic interpeptide interactions.


Towards a molecular systems model of coronary artery disease.
Coronary artery disease (CAD) is a complex disease driven by myriad interactions of genetics and environmental factors. Traditionally, studies have analyzed only 1 disease factor at a time, providing useful but limited understanding of the underlying etiology. Recent advances in cost-effective and high-throughput technologies, such as single nucleotide polymorphism (SNP) genotyping, exome/genome/RNA sequencing, gene expression microarrays, and metabolomics assays have enabled the collection of millions of data points in many thousands of individuals. In order to make sense of such 'omics' data, effective analytical methods are needed. We review and highlight some of the main results in this area, focusing on integrative approaches that consider multiple modalities simultaneously. Such analyses have the potential to uncover the genetic basis of CAD, produce genomic risk scores (GRS) for disease prediction, disentangle the complex interactions underlying disease, and predict response to treatment.


A tailored treatment strategy: a modern approach for stroke prevention in patients with atrial fibrillation.
The main priority in atrial fibrillation (AF) management is stroke prevention, following which decisions about rate or rhythm control are focused on the patient, being primarily for management of symptoms. Given that AF is commonly associated with various comorbidities, risk factors such as hypertension, heart failure, diabetes mellitus and sleep apnoea should be actively looked for and managed in a holistic approach to AF management. The objective of this review is to provide an overview of modern AF stroke prevention with a focus on tailored treatment strategies. Biomarkers and genetic factors have been proposed to help identify 'high-risk' patients to be targeted for oral anticoagulation, but ultimately their use must be balanced against that of more simple and practical considerations for everyday use. Current guidelines have directed focus on initial identification of 'truly low-risk' patients with AF, that is those patients with a CHA2 DS2 -VASc [congestive heart failure, hypertension, age ≥75 years (two points), diabetes mellitus, stroke (two points), vascular disease, age 65-74 years, sex category] score of 0 (male) or 1 (female), who do not need any antithrombotic therapy. Subsequently, patients with ≥1 stroke risk factors can be offered effective stroke prevention, that is oral anticoagulation. The SAMe-TT2 R2 [sex female, age <60 years, medical history (>2 comorbidities), treatment (interacting drugs), tobacco use (two points), race non-Caucasian (two points)] score can help physicians make informed decisions on those patients likely to do well on warfarin (SAMe-TT2 R2 score 0-2) or those who are likely to have a poor time in therapeutic range (SAMe-TT2 R2 score >2). A clinically focused tailored approach to assessment and stroke prevention in AF with the use of the CHA2 DS2 VASc, HAS-BLED [hypertension, abnormal renal/liver function (one or two points), stroke, bleeding history or predisposition, labile international normalized ratio, elderly (>65 years) drugs/alcohol concomitantly (one or two points)] and SAMeTT2 R2 scores to evaluate stroke risk, bleeding risk and likelihood of successful warfarin therapy, respectively, is discussed.


The time course of visual field recovery and changes of retinal ganglion cells after optic chiasmal decompression.
To investigate the time course of visual field recovery and changes of retinal ganglion cells (RGCs) after chiasmal decompression using standard automated perimetry (SAP), optical coherence tomography (OCT), and photopic negative response (PhNR). Nineteen patients undergoing chiasmal decompression surgery were prospectively assessed before and 1 and 3 months after surgery. The same examinations were conducted in nine patients at 6 months after surgery. Mean deviation and temporal visual field sensitivity (1/Lambert) of SAP, retinal nerve fiber layer (RNFL) thickness, and ganglion cell complex (GCC) area measured by OCT and PhNR/b-wave ratio were analyzed. Preoperative measurements were compared with those of 20 eyes of normal controls. Postoperative measurements were compared with preoperative data. The relationships among SAP, OCT, and PhNR measurements throughout the observation periods were evaluated by linear and logarithmic regressions. Before surgery, all parameters in patients were significantly worse than those in normal controls. After surgery, the visual field was significantly improved, but RNFL thickness and GCC area were significantly reduced for 3 months. The PhNR/b-wave ratio was also reduced, but not significantly. Six months after surgery, average RNFL thickness, GCC area, and PhNR/b-wave ratio showed significant improvements by 2.82%, 2.66%, and 8.72%, respectively, than those at 3 months. Visual fields were significantly correlated with RNFL thickness, GCC area, and PhNR/b-wave ratio. Visual field recovery and changes of RGCs after chiasmal decompression have similar aspects and are significantly correlated. However, prolonged retrograde degeneration progressed for some period, even after surgical decompression and visual field recovery preceded demonstrable retinal regeneration.


Leishmaniasis: Who Uses Personal Protection among Military Personnel in Colombia?
Leishmaniasis is common in Colombia, negatively affecting the health of military personnel active in endemic areas. The disease is transmitted by sand fly bites. Therefore, during duty, use of long-sleeved uniforms and other clothes treated with permethrin and application of mosquito repellent are important personal preventive measures. The objective of this study was to assess personal and occupational factors associated with the use of personal protection in male soldiers deployed to Leishmaniasis-endemic areas. Three hundred soldiers participated in a cross-sectional questionnaire study (response 84.3%). The self-administered questionnaire contained questions about sociodemographics, duration of service, compliance with personal mosquito protection, and knowledge about leishmaniasis. Descriptive analyses were followed by multiple logistic regression models adjusted for potential confounders (EpiInfo Version 7.0) FINDINGS: Overall, 23% of the soldiers reported complete use of the recommended personal protection measures. About 83% of the participants had heard about leishmaniasis. In the adjusted regression model, knowledge about leishmaniasis (adjusted odds ratio = 2.9; 95% confidence interval: 1.1-7.2) and being enrolled in the army for more than 5 years (2.2; 1.1-4.1) increased the odds of using personal protection. Improving knowledge about leishmaniasis is one measure to increase use of personal protection, thereby diminishing the risk of infection.


[Evaluation of functional capacity and quality of life of the elderly after ischemic stroke with and without dysphagia].
The objective was to analyze the functional capacity and quality of life of elderly individuals with ischemic stroke comparing these with and without dysphagia. Cross sectional study was realized in 60 elderly individuals after ischemic stroke, 30 with dysphagia and 30 without. Their cognitive state was evaluated with the Mini-Mental test. The scales used were: KATZ, Lawton, Barthel and SF-36. The functional capacity was similar in both groups studied. In the SF-36, the group without dysphagia presented more pain and a better general health. Functional capacity, physical limitations those due to emotional aspects, general state of health , social vitality, mental health limitation were similar in both groups. Among men, for all scales used, functional capacity was similar. Among women, functional capacity was similar in both groups; however, in the quality of life, the domain 'vitality' was higher in the group without dysphagia. The income bracket did not influence the functional capacity or the quality of life. There was no difference between groups whether they had or not a care provider. 1) Functional capacity was similar in both groups studied. 2) The group without dysphagia presented better general health.


The ASAP2 gene is a primary target of 1,25-dihydroxyvitamin D3 in human monocytes and macrophages.
A genome-wide data set on vitamin D receptor (VDR) binding sites in human THP-1 cells (monocytes) led us to the genomic region around the ASAP2 (Arf-GAP with SH3 domain, ankyrin repeat and PH domain 2) gene, whose product is involved in the regulation of vesicular transport, cellular migration and autophagy. Using ENCODE data, we demonstrated that the ASAP2 gene is flanked by conserved binding sites of the insulating transcription factor CTCF. These sites define different chromosomal domains containing the ASAP2 gene, up to six additional genes and three VDR binding sites. In human monocytes (THP-1 cells) the ASAP2 gene is more weakly expressed but more and faster inducible by the biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), than in M2-type macrophages (phorbol ester-differentiated THP-1 cells). Within the investigated genomic region, the basal mRNA expressions of the neighboring genes are comparably high in both monocytes and macrophages, but the ASAP2 gene is the only primary 1,25(OH)2D3 target. The three VDR binding sites located 54, 436 and 574kb downstream of the ASAP2 transcription start site each carry a sequence formed by a direct repeat with three intervening nucleotides (DR3). Ligand-inducible VDR binding was confirmed to all three genomic sites in monocytes and macrophages. Taken together, the region around the ASAP2 gene is genome-wide highlighted as a special attraction point for the VDR, but the presently sole known functional consequence of the binding of VDR to three sites within this chromosomal region is that ASAP2 is a primary 1,25(OH)2D3 target gene in monocytes and macrophages. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.


Replication of dengue virus type 2 in human monocyte-derived macrophages: comparisons of isolates and recombinant viruses with substitutions at amino acid 390 in the envelope glycoprotein.
The severity of dengue virus infection ranges from mild fever to dengue hemorrhagic fever and shock syndrome. The association of disease severity with virus replication in monocyte-derived macrophages (MDMs) was examined for dengue virus type 2 (DEN-2) isolates from Asia or America. Additionally, we constructed DEN-2 recombinant viruses with substitutions at residue 390 in the envelope glycoprotein (E390) because this residue is linked with the region of virus origin. Comparisons of virus yields of 3 isolates failed to show a correlation with clinical disease. However, the American strain did not replicate as well as the 2 Asian strains. For the recombinant viruses, substitution of Asn (Asian) at E390 with Asp (American) resulted in decreased ability to replicate in MDMs. These results are consistent with the proposal that the lack of association of native American DEN-2 strains with severe disease is linked to reduced ability to replicate in MDMs, and that Asp at E390 may contribute to this reduction.


"I really should've gone to the doctor": older adults and family caregivers describe their experiences with community-acquired pneumonia.
Responding to acute illness symptoms can often be challenging for older adults. The primary objective of this study was to describe how community-dwelling older adults and their family members responded to symptoms of community-acquired pneumonia (CAP). A qualitative study that used face-to-face semi-structured interviews to collect data from a purposeful sample of seniors aged 60+ and their family members living in a mid-sized Canadian city. Data analysis began with descriptive and interpretive coding, then advanced as the research team repeatedly compared emerging thematic categories to the raw data. Searches for disconfirming evidence and member checking through focus groups provided additional data and helped ensure rigour. Community-acquired pneumonia symptoms varied greatly among older adults, making decisions to seek care difficult for them and their family members. Both groups took varying amounts of time as they attempted to sort out what was wrong and then determine how best to respond. Even after they concluded something was wrong, older adults with confirmed pneumonia continued to wait for days, to over a week, before seeking medical care. Participants provided diverse reasons for this delay, including fear, social obligations (work, family, leisure), and accessibility barriers (time, place, systemic). Several older adults and family members regretted their delays in seeking help. Treatment-seeking delay is a variable, multi-phased decision-making process that incorporates symptom assessment plus psychosocial and situational factors. Public health and health care professionals need to educate older adults about the potential causes and consequences of unnecessary waits. Such efforts may reduce the severity of community-acquired pneumonia upon presentation at clinics and hospitals, and that, in turn, could potentially improve health outcomes.


Biodegradable Synthetic Polyurethane Foam Nasal Packing After Septoplasty.
To determine the usefulness of biodegradable Synthetic Polyurethane Foam (SPF) nasal packing as an adjunct to day-case septoplasty. Comparative, observational case series. Aberdeen Royal Infirmary, University of Aberdeen, Scotland, UK, in the year 2011. One-hundred consecutive patients who underwent septoplasty and received SPF packing in 2010 were prospectively audited while one-hundred consecutive patients undergoing septoplasty in the year 2000 were studied retrospectively. Data collected include demographics, type of operation and duration of hospital stay. Excel and SPSS were used for data collection and analysis. In the year 2000, the average age of the patients was 40.6 years. There were 37 females and 63 males. One patient returned home the same day, 22 stayed one night, 69 spent two nights and 8 stayed more than two nights in hospital for their operation. The average length of stay was 1.84 nights. In 2010, the average age of patients was 37.86 years, with 31 patients being female and 69 male. All patients in this cohort received SPF packing postoperatively. Seventy-three patients went home the same day, 24 patients stayed one night and 3 patients spent two nights in hospital for their operation. Average length of hospital stay was 0.3 nights. Results were statistically significant (p < 0.001). SPF was a useful nasal packing option after septoplasty and inferior turbinate surgery, which enabled the surgeons to carry out this surgery safely as a day-case procedure.


Liv.52 in alcoholic liver disease: a prospective, controlled trial.
Liv.52, a hepatoprotective agent of herbal origin, is used empirically for the treatment of alcoholic liver disease in Sri Lanka. We conducted a controlled trial to assess the efficacy of Liv.52 in patients with alcoholic liver disease. Patients with evidence of alcoholic liver disease attending outpatient clinics were included in a prospective, double blind, randomized, placebo controlled trial. During the trial period, 80 patients who fulfilled inclusion criteria were randomly assigned Liv.52 (cases; n = 40) or placebo (controls) the recommended dose of three capsules twice daily for 6 months. All patients underwent clinical examination (for which a clinical score was computed), and laboratory investigations for routine blood chemistry and liver function before commencement of therapy (baseline). Thereafter, clinical assessments were done monthly for 6 months, while laboratory investigations were done after 1 and 6 months of therapy. There was no significant difference in the age composition, alcohol intake and baseline liver function between the two groups. The two-sample t-test was used to analyze data obtained after 1 and 6 months of therapy against baseline values. There was no significant difference in clinical outcome and liver chemistry between the two groups at any time point. There were no reports of adverse effects attributable to the drug. Our results suggest that Liv.52 may not be useful in the management of patients with alcohol induced liver disease.


Buprenorphine-naloxone maintenance following release from jail.
Primary care is understudied as a reentry drug and alcohol treatment setting. This study compared treatment retention and opioid misuse among opioid-dependent adults seeking buprenorphine/naloxone maintenance in an urban primary care clinic following release from jail versus community referrals. Postrelease patients were either (a) induced to buprenorphine in-jail as part of a clinical trial, or (b) seeking buprenorphine induction post release. From 2007 to 2008, N = 142 patients were new to primary care buprenorphine: n = 32 postrelease; n = 110 induced after community referral and without recent incarceration. Jail-released patients were more likely African American or Hispanic and uninsured. Treatment retention rates for postrelease (37%) versus community (30%) referrals were similar at 48 weeks. Rates of opioid positive urines and self-reported opioid misuse were also similar between groups. Postrelease patients in primary care buprenorphine treatment had equal treatment retention and rates of opioid abstinence versus community-referred patients.


An econometric analysis of the mental-health effects of major events in the life of older individuals.
Major events in the life of an older individual, such as retirement, a significant decrease in income, death of the spouse, disability, and a move to a nursing home, may affect the mental-health status of the individual. For example, the individual may enter a prolonged depression. We investigate this using unique longitudinal panel data that track labor market behavior, health status, and major life events, over time. To deal with endogenous aspects of these events we apply fixed effects estimation methods. We find some strikingly large effects of certain events on the occurrence of depression. We relate the results to the health care and labor market policy towards older individuals.


Lineage, Temperature, and Host Species have Interacting Effects on Lesion Development in Phytophthora ramorum.
There are four recognized clonal lineages of the pathogen Phytophthora ramorum. The two major lineages present in North America are NA1 and NA2. With a few exceptions, NA1 is found in natural forest ecosystems and nurseries, and NA2 is generally restricted to nurseries. Isolates from the NA1 and NA2 lineages were used to infect rhododendron, camellia, and California bay laurel in detached leaf assays to study the effects of lineage, temperature, and host on pathogenicity and host susceptibility. Isolates within both lineages were highly variable in their ability to form lesions on each host. There was also a tendency toward reduced lesion size in successive trials, suggesting degeneration of isolates over time. Temperature had a significant effect on lesion size, with a response that varied depending on the host and isolate. Phenotypic differences between lineages appear to be heavily influenced by the representation of isolates used, host, and temperature. The importance of temperature, host, and lineage are discussed with respect to disease management, as well as future range expansions and migrations of the pathogen.


The Potential Role of Probiotics in the Management of Osteoarthritis Pain: Current Status and Future Prospects.
This narrative review article comprehensively explains the pathophysiology of osteoarthritis (OA) pain perception, how the gut microbiota is correlated with it, possible molecular pathways involved in probiotics-mediated OA pain reduction, limitations in the current research approaches, and future perspectives. The initiation and progression of OA, including the development of chronic pain, is intricately associated with activation of the innate immune system and subsequent inflammatory responses. Trauma, lifestyle (e.g., obesity and metabolic disease), and chronic antibiotic treatment can disrupt commensal homeostasis of the human microbiome, thereby affecting intestinal integrity and promoting leakage of bacterial endotoxins and metabolites such as lipopolysaccharides (LPS) into circulation. Increased level of LPS is associated with knee osteophyte severity and joint pain. Both preclinical and clinical studies strongly suggest that probiotics may benefit patients with OA pain through positive gut microbiota modulation and attenuating low-grade inflammation via multiple pathways. Patent data also suggests increased interest in the development of new innovations that involve probiotic use for reducing OA and joint pain. Recent data suggest that probiotics are attracting more and more attention for OA pain management. The advancement of knowledge in this area may pave the way for developing different probiotic strains that can be used to support joint health, improve treatment outcomes in OA, and reduce the huge impact of the disease on healthcare systems worldwide.


Reactions to dietary tartrazine.
Double blind challenges with tartrazine and benzoic acid were performed in hospital in 24 children whose parents gave a definite history of a purely behavioural immediate adverse reaction to one of these substances. The patients, whose ages ranged from 1.6 to 12.4 years, were on a diet that avoided these items, and in all there was a clear history that any lapse of the diet caused an obvious adverse behavioural reaction within two hours. In no patient was any change in behaviour noted either by the parents or the nursing staff after the administration of placebo or active substances. Twenty two patients returned to a normal diet without problems, but the parents of two children insisted on continuing the diet. While popular belief has it that additives may have harmful behavioural effects, objective verification is required to prevent overdiagnosis.


A Meta-Analysis of Transcranial Direct Current Stimulation on Substance and Food Craving: What Effect Do Modulators Have?
Substance addiction and food addiction are significant social problems worldwide. In previous studies of substance addiction, transcranial direct current stimulation (tDCS) has been used to influence craving of substance or food. However, the reported effects are not always consistent due to inconsistent experimental settings. The way modulators influence the effect of tDCS on substance addiction is worth exploring. This meta-analysis was conducted to estimate the effect size of tDCS on substance and food craving and to investigate the influence of potential modulators. We systemically identified and reviewed studies on substance/food craving using tDCS that were published between January 2008 to January 2020. A total of 32 eligible studies were identified. Hedges' g was computed as an indicator of the effect of tDCS and some potential moderators (substance type, stimulation sites, current intensities, number of sessions, duration of stimulation, and study design) were examined using subgroup analysis. Random effects analysis revealed a total medium effect size [Hedges' g = 0.536, 95% confidence interval (CI): 0.389-0.683, after adjusting Hedges' g = 0.416, 95% CI: 0.262-0.570] preferring active over sham stimulation to reduce craving. A significant difference was observed between the number of sessions (repeated stimulation was better than single stimulation). The duration of stimulation may have a positive influence on the effects of tDCS. No other significant differences were found in other subgroups analysis. In conclusion, our results provided evidence that tDCS can be an effective way to reduce craving of substance or food, and longer multiple stimulus durations in all can more effectively reduce craving; however, the influences of modulators still need be to be examined in depth in future.


Free-breathing pulmonary 1H and Hyperpolarized 3He MRI: comparison in COPD and bronchiectasis.
In this proof-of-concept demonstration, we aimed to quantitatively and qualitatively compare pulmonary ventilation abnormalities derived from Fourier decomposition of free-breathing (1)H magnetic resonance imaging (FDMRI) to hyperpolarized (3)He MRI in subjects with chronic obstructive pulmonary disease (COPD) and bronchiectasis. All subjects provided written informed consent to a protocol approved by a local research ethics board and Health, Canada, and they underwent MRI, computed tomography (CT), spirometry, and plethysmography during a single 2-hour visit. Semiautomated segmentation was used to generate ventilation defect measurements derived from FDMRI and (3)He MRI, and these were compared using analysis of variance and Pearson correlations. Twenty-six subjects were evaluated including 12 COPD subjects (67 ± 9 years) and 14 bronchiectasis subjects (70 ± 11 years). For COPD subjects, FDMRI and (3)He MRI ventilation defect percent (VDP) was 7 ± 6% and 24 ± 14%, respectively (P < .001; bias = -16 ± 9%). In COPD subjects, FDMRI was significantly correlated with (3)He MRI VDP (r = .88; P = .0001), (3)He MRI apparent diffusion coefficient (r = .71; P < .05), airways resistance (r = .60; P < .05), and RA950 (r = .80; P < .01). In subjects with bronchiectasis, FDMRI VDP (5 ± 3%) and (3)He MRI VDP (18 ± 9%) were significantly different (P < .001) and not correlated (P > .05). The Dice similarity coefficient (DSC) for FDMRI and (3)He MRI ventilation was 86 ± 7% for COPD and 86 ± 4% for bronchiectasis subjects (P > .05); the DSC for FDMRI ventilation defects and CT RA950 was 19 ± 20% in COPD and 2 ± 3% in bronchiectasis subjects (P < .01). FDMRI and (3)He MRI VDP were strongly related in COPD but not in bronchiectasis subjects. In COPD only, FDMRI ventilation defects were spatially related with (3)He ventilation defects and emphysema.


Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein.
Interferon-gamma (IFN-gamma) induces the transcription of the gene encoding a guanylate binding protein by activating a latent cytoplasmic factor, GAF (gamma-activated factor). GAF is translocated to the nucleus and binds a DNA element, the gamma-activated site. Through cross-linking and the use of specific antibodies GAF was found to be a 91-kilodalton DNA binding protein that was previously identified as one of four proteins in interferon-stimulated gene factor-3 (ISGF-3), a transcription complex activated by IFN-alpha. The IFN-gamma-dependent activation of the 91-kilodalton DNA binding protein required cytoplasmic phosphorylation of the protein on tyrosine. The 113-kilodalton ISGF-3 protein that is phosphorylated in response to IFN-alpha was not phosphorylated nor translocated to the nucleus in response to IFN-gamma. Thus the two different ligands result in tyrosine phosphorylation of different combinations of latent cytoplasmic transcription factors that then act at different DNA binding sites.


Viewing angle enhanced integral imaging display using two elemental image masks.
A viewing angle enhanced integral imaging display using two elemental image masks is proposed. In our new method, rays emitted from the elemental images are directed by two masks into corresponding lenses. Due to the elemental image guiding of the masks, the number of elemental images for each integrated image point is increased, enhancing the viewing angle. The experimental result shows that the proposed method exhibits two times larger viewing angle than the conventional method with the same lens array.


Life stress and cortisol reactivity: An exploratory analysis of the effects of stress exposure across life on HPA-axis functioning.
Stressful experiences affect biological stress systems, such as the hypothalamic-pituitary-adrenal (HPA) axis. Life stress can potentially alter regulation of the HPA axis and has been associated with poorer physical and mental health. Little, however, is known about the relative influence of stressors that are encountered at different developmental periods on acute stress reactions in adulthood. In this study, we explored three models of the influence of stress exposure on cortisol reactivity to a modified version of the Trier Social Stress Test (TSST) by leveraging 37 years of longitudinal data in a high-risk birth cohort (N = 112). The cumulative stress model suggests that accumulated stress across the lifespan leads to dysregulated reactivity, whereas the biological embedding model implicates early childhood as a critical period. The sensitization model assumes that dysregulation should only occur when stress is high in both early childhood and concurrently. All of the models predicted altered reactivity, but do not anticipate its exact form. We found support for both cumulative and biological embedding effects. However, when pitted against each other, early life stress predicted more blunted cortisol responses at age 37 over and above cumulative life stress. Additional analyses revealed that stress exposure in middle childhood also predicted more blunted cortisol reactivity.


Expressed protein ligation (EPL) in the study of signal transduction, ion conduction, and chromatin biology.
Expressed protein ligation (EPL) is a semisynthetic technique in which a recombinant protein thioester, generated by thiolysis of an intein fusion protein, is reacted with a synthetic or recombinant peptide with an N-terminal cysteine to produce a native peptide bond. This method has been used extensively for the incorporation of biophysical probes, unnatural amino acids, and post-translational modifications in proteins. In the 10 years since this technique was developed, the applications of EPL to studying protein structure and function have grown ever more sophisticated. In this Account, we review the use of EPL in selected systems in which substantial mechanistic insights have recently been gained through the use of the semisynthetic protein derivatives. EPL has been used in many studies to unravel the complexity of signaling networks and subcellular trafficking. Herein, we highlight this application to two different systems. First, we describe how phosphorylated or otherwise modified proteins in the TGF-beta signaling network were prepared and how they were applied to understanding the complexities of this pathway, from receptor activation to nuclear import. Second, Rab-GTPases are multiply modified with lipid derivatives, and EPL-based techniques were used to incorporate these modifications, allowing for the elucidation of the biophysical basis of membrane association and dissociation. We also review the use of EPL to understand the biology of two other systems, the potassium channel KcsA and histones. EPL was used to incorporate d-alanine and an amide-to-ester backbone modification in the selectivity filter of the KcsA potassium channel, providing insight into the mechanism of selectivity in ion conduction. In the case of histones, which are among the most heavily post-translationally modified proteins, the modifications play a key role in the regulation of gene transcription and chromatin structure. We describe how native chemical ligation and EPL were used to generate acetylated, phosphorylated, methylated, and ubiquitylated histones and how these modified histones were used to interrogate chromatin biology. Collectively, these studies demonstrate the utility of EPL in protein science. These techniques and concepts are applicable to many other systems, and ongoing advances promise to extend this semisynthetic technique to increasingly complex biological problems.


Learning Low-Dimensional Representations of Medical Concepts.
We show how to learn low-dimensional representations (embeddings) of a wide range of concepts in medicine, including diseases (e.g., ICD9 codes), medications, procedures, and laboratory tests. We expect that these embeddings will be useful across medical informatics for tasks such as cohort selection and patient summarization. These embeddings are learned using a technique called neural language modeling from the natural language processing community. However, rather than learning the embeddings solely from text, we show how to learn the embeddings from claims data, which is widely available both to providers and to payers. We also show that with a simple algorithmic adjustment, it is possible to learn medical concept embeddings in a privacy preserving manner from co-occurrence counts derived from clinical narratives. Finally, we establish a methodological framework, arising from standard medical ontologies such as UMLS, NDF-RT, and CCS, to further investigate the embeddings and precisely characterize their quantitative properties.


The ATPase activity of Asna1/TRC40 is required for pancreatic progenitor cell survival.
Asna1, also known as TRC40, is implicated in the delivery of tail-anchored (TA) proteins into the endoplasmic reticulum (ER), in vesicle-mediated transport, and in chaperoning unfolded proteins during oxidative stress/ATP depletion. Here, we show that Asna1 inactivation in pancreatic progenitor cells leads to redistribution of the Golgi TA SNARE proteins syntaxin 5 and syntaxin 6, Golgi fragmentation, and accumulation of cytosolic p62+ puncta. Asna1-/- multipotent progenitor cells (MPCs) selectively activate integrated stress response signaling and undergo apoptosis, thereby disrupting endocrine and acinar cell differentiation, resulting in pancreatic agenesis. Rescue experiments implicate the Asna1 ATPase activity and a CXXC di-cysteine motif in ensuring Golgi integrity, syntaxin 5 localization and MPC survival. Ex vivo inhibition of retrograde transport reproduces the perturbed Golgi morphology, and syntaxin 5 and syntaxin 6 expression, whereas modulation of p53 activity, using PFT-α and Nutlin-3, prevents or reproduces apoptosis in Asna1-deficient and wild-type MPCs, respectively. These findings support a role for the Asna1 ATPase activity in ensuring the survival of pancreatic MPCs, possibly by counteracting p53-mediated apoptosis.


Within-person structures of daily cognitive performance differ from between-person structures of cognitive abilities.
Over a century of research on between-person differences has resulted in the consensus that human cognitive abilities are hierarchically organized, with a general factor, termed general intelligence or "g," uppermost. Surprisingly, it is unknown whether this body of evidence is informative about how cognition is structured within individuals. Using data from 101 young adults performing nine cognitive tasks on 100 occasions distributed over six months, we find that the structures of individuals' cognitive abilities vary among each other, and deviate greatly from the modal between-person structure. Working memory contributes the largest share of common variance to both between- and within-person structures, but the g factor is much less prominent within than between persons. We conclude that between-person structures of cognitive abilities cannot serve as a surrogate for within-person structures. To reveal the development and organization of human intelligence, individuals need to be studied over time.


[Outbreak of Salmonella enteriditis food poisoning at a dining hall facility].
An outbreak of Salmonella enteriditis food poisoning having occurred at two banquet halls, affecting eight groups of guests, is described. This research was aimed at determining the food by means of which this illness was transmitted. An analysis was conducted of the food processing procedures subject to having caused the outbreak. The association of the foods with the illness was analyzed by means of a case and control design. The adjusted Odds Ratio (aOR) and the 95% confidence intervals (C195%) were calculated by logic regression. The guests totalled 1771 in number, being divided up into 13 groups for three days running. A total of 629 individuals (36%) were surveyed The probable cases totalled 250 in number, 61 confirmed by Salmonella enterica. The glazed biscuit (dessert with raw egg having undergone no heat processing) showed the highest adjusted Odds Ratio (aOR = 20.40; CI95%:7.52-55.30) and tested positive for Salmonella enterica of the enteritidis serotype. Epidemiological and laboratory evidence supports the glazed biscuit having been the contaminated food having caused the outbreak. The research stressed as contributing factors: the use of raw egg, the production of large quantities ahead of time, prior to the time at which the food item in question was to be eaten.


Stroking modulates noxious-evoked brain activity in human infants.
A subclass of C fibre sensory neurons found in hairy skin are activated by gentle touch [1] and respond optimally to stroking at ∼1-10 cm/s, serving a protective function by promoting affiliative behaviours. In adult humans, stimulation of these C-tactile (CT) afferents is pleasant, and can reduce pain perception [2]. Touch-based techniques, such as infant massage and kangaroo care, are designed to comfort infants during procedures, and a modest reduction in pain-related behavioural and physiological responses has been observed in some studies [3]. Here, we investigated whether touch can reduce noxious-evoked brain activity. We demonstrate that stroking (at 3 cm/s) prior to an experimental noxious stimulus or clinical heel lance can attenuate noxious-evoked brain activity in infants. CT fibres may represent a biological target for non-pharmacological interventions that modulate pain in early life.


Genetic diversity and population structure in a legacy collection of spring barley landraces adapted to a wide range of climates.
Global environmental change and increasing human population emphasize the urgent need for higher yielding and better adapted crop plants. One strategy to achieve this aim is to exploit the wealth of so called landraces of crop species, representing diverse traditional domesticated populations of locally adapted genotypes. In this study, we investigated a comprehensive set of 1485 spring barley landraces (Lrc1485) adapted to a wide range of climates, which were selected from one of the largest genebanks worldwide. The landraces originated from 5° to 62.5° N and 16° to 71° E. The whole collection was genotyped using 42 SSR markers to assess the genetic diversity and population structure. With an average allelic richness of 5.74 and 372 alleles, Lrc1485 harbours considerably more genetic diversity than the most polymorphic current GWAS panel for barley. Ten major clusters defined most of the population structure based on geographical origin, row type of the ear and caryopsis type - and were assigned to specific climate zones. The legacy core reference set Lrc648 established in this study will provide a long-lasting resource and a very valuable tool for the scientific community. Lrc648 is best suited for multi-environmental field testing to identify candidate genes underlying quantitative traits but also for allele mining approaches.


Differential roles of phosphoinositide-dependent protein kinase-1 and akt1 expression and phosphorylation in breast cancer cell resistance to Paclitaxel, Doxorubicin, and gemcitabine.
3-Phosphoinositide-dependent protein kinase-1 (PDK1) and Akt1 are two closely related components of the phosphatidylinositol-3 kinase (PI3K) pathway, which is aberrantly regulated in breast cancer. Despite the importance of PDK1, few studies have evaluated it as a potential target for cancer therapy compared with studies of Akt1. We hypothesized that PDK1 is a superior target in the PI3K pathway. To test this, we first used a mouse mammary cell line retrovirally infected to express human PDK1 or Akt1 for comparative studies of treatment with paclitaxel, doxorubicin, and gemcitabine. Overexpression of PDK1 or Akt1 conferred similar resistance to treatment with paclitaxel or doxorubicin compared with control cells. However, the PDK1-overexpressing cells were more resistant to gemcitabine than were the Akt1-overexpressing cells. We next correlated the expression and activation-specific phosphorylation of PDK1 and Akt1 with the cytotoxic effects of the same agents in several human breast cancer cell lines. Cells with high levels of phosphorylated PDK1 were more resistant to gemcitabine-induced apoptosis than cells expressing high levels of phosphorylated Akt1. To further validate this observation, we used small interfering RNA oligonucleotides to selectively knock down PDK1 or Akt1 expression in MCF7 human breast cancer cells. We found that knockdown of PDK1 expression sensitized MCF7 cells to gemcitabine-induced apoptosis more effectively than did knockdown of Akt1 expression in the same cells. Our findings show that PDK1 may be a superior alternative to Akt1 as a target for sensitizing breast cancer cells to chemotherapeutic agents, particularly gemcitabine.


Early wound irrigation improves the ability to remove bacteria.
Although most surgeons prefer to treat contaminated wounds as soon as possible, the effect of timing on the ability of irrigation to reduce the amount of bacteria in a wound is not fully known. We evaluated the effect of different delays in irrigation on bacterial removal in an animal model. A complex musculoskeletal wound was created in the proximal part of the leg of goats. The wound was contaminated with Pseudomonas aeruginosa (lux) bacteria, genetically modified to emit photons, in order to allow for quantitative analysis of bacterial concentration with a photon-counting camera system. The contaminated wounds were closed, and wound irrigation was performed with 6 L of normal saline solution by means of pulsatile lavage after the assigned time-intervals of three, six, and twelve hours. Images were made before and after treatment. Relative luminescent units and clearance ratios were obtained and calculated for each wound. Earlier wound irrigation resulted in superior bacterial removal in our model. Irrigation resulted in a 70% +/- 2%, 52% +/- 3%, and 37% +/- 4% reduction in bacterial counts from the pre-irrigation level at three, six, and twelve hours, respectively. The clearance ratios were significantly different at all time-points (p < 0.004). Earlier irrigation in our contaminated wound model resulted in superior bacterial removal.


Generalized phase evaluation for stereophotogrammetric correspondence assignment.
Phase-shifting fringe projection is the primary structured illumination method for high-accuracy, three-dimensional (3D) shape measurements in the fields of profilometry and stereophotogrammetry. Many different schemes for the phase evaluation and the phase-shifted fringe pattern design exist. Here we focus on the role of the phase evaluation in the context of stereophotogrammetry, where the nominal phase value itself is merely used as an image feature that can be exploited to establish a correspondence between the two camera views. Starting from the classical phase evaluation function, we will discuss its essential properties for a highly accurate correspondence mapping. Based on the findings, we generalize the classical function to derive a generalized phase value for a sequence of stereo images. An experimental comparison between a correspondence assignment using the classical phase evaluation function and a specifically chosen general phase evaluation function is given.


Perinatal transmission of Ureaplasma urealyticum: current concepts based on review of the literature.
Ureaplasma urealyticum is a common inhabitant of the urogenital tract of pregnant women. This mycoplasma is transmitted from a colonized woman to her newborn infant in one of three ways: (1) in utero either transplacentally from the mother's blood or by an ascending route secondary to colonization of the mother's urogenital tract; (2) at delivery by passage through a colonized birth canal; and (3) postnatally by horizontal or nosocomial transmission. The rate of vertical transmission ranges from 18% to 55% among full-term infants and from 29% to 55% among preterm infants. The rate of vertical transmission is not affected by method of delivery but is significantly increased when chorioamnionitis is present. Moreover, colonization of the infant with U. urealyticum occurs despite delivery by cesarean section with intact fetal membranes; ureaplasmal infection of the amniotic sac without rupture of membranes has been well described. Ultimately, the prevalence of infant colonization will depend on the prevalence of maternal colonization in a given population. However, the rate of colonization appears to be higher in very-low-birth-weight (VLBW) infants. Given this finding, as well as the potential for serious disease that could be attributed to U. urealyticum in this population, it seems reasonable to target the VLBW infant for a clinical treatment trial to determine if eradication of this organism will decrease the incidence of chronic lung disease.


The role of acupuncture in in vitro fertilization: a systematic review and meta-analysis.
In recent years, acupuncture has become more and more popular in the management of subfertility. The aim of this study was to evaluate the impact of acupuncture during in vitro fertilization (IVF) treatment on the outcomes of clinical pregnancy in published randomized studies. This is a systematic review and meta-analysis. Data sources used were MEDLINE, Embase, Web of Knowledge and the Chinese Biomedical Database. There was no statistically significant difference between the acupuncture group and no acupuncture (intervention) controls around the time of embryo transfer (ET; risk ratio, RR, 1.24, 95% confidence interval, CI, 1.02-1.50) or in unblinded trials, trials blinded to physicians and double-blind trials (95% CI 1.26-1.88, 0.82-1.33 and 0.89-1.25, respectively). This was also the case when comparing acupuncture with sham acupuncture controls around the time of ET (RR, 1.03, 95% CI 0.87-1.22) or when restricting to unblinded trials, trials blinded to physicians and double-blind trials (95% CI 0.80-2.02, 0.82-1.18 and 0.77-1.17, respectively). There was a statistically significant difference when performed at 30 min after ET and implantation phase (RR 1.76, 95% CI 1.22-2.55). There was also a statistically significant difference when performed at follicle phase and 25 min before and after ET (RR 1.56, 95% CI 1.04-2.33). Our study showed that acupuncture did not significantly improve the IVF clinical pregnancy rate when performed only at the time of ET, while we found pooled benefit of acupuncture for IVF when performed at follicle phase and 25 min before and after ET, as well as 30 min after ET and implantation phase.


HPV clearance and the neglected role of stochasticity.
Clearance of anogenital and oropharyngeal HPV infections is attributed primarily to a successful adaptive immune response. To date, little attention has been paid to the potential role of stochastic cell dynamics in the time it takes to clear an HPV infection. In this study, we combine mechanistic mathematical models at the cellular level with epidemiological data at the population level to disentangle the respective roles of immune capacity and cell dynamics in the clearing mechanism. Our results suggest that chance-in form of the stochastic dynamics of basal stem cells-plays a critical role in the elimination of HPV-infected cell clones. In particular, we find that in immunocompetent adolescents with cervical HPV infections, the immune response may contribute less than 20% to virus clearance-the rest is taken care of by the stochastic proliferation dynamics in the basal layer. In HIV-negative individuals, the contribution of the immune response may be negligible.


Conservative management of anterior cruciate ligament injury in paediatric population: About 53 patients.
The last symposium held by the French Arthroscopy Society was on anterior cruciate ligament (ACL) reconstruction on children. The first aim of this study was to analyse the tolerance of conservative management of ACL rupture in children. We also tried to find predictive factors of ACL reconstruction. We conducted an observational, retrospective study in an academic department of paediatric orthopaedic surgery. All patients under the age of eighteen, who were treated conservatively for an acute intra-ligamentous ACL rupture confirmed by magnetic resonance imaging (MRI) between 2007 and 2017, were included. Two groups were analysed: operated patients and conservative treatment. We also analysed population according Tanner stage. Fifty-three patients were included in this study. The median length of follow-up was 31.5 months [interquartile range (IQR): 22.3-49.3]. The median age at the last follow-up was 14.4 years [IQR: 12.6-15.5]. All patients were allowed to practice activities without restrictions, including pivoting sports. Tegner activity level scale remains identical before injury and at last follow-up (p: n.s.). Nineteen patients (36%) described knee instability at last follow-up. On the last MRI, 9 (17%) patients had meniscal tears but only one patient (2%) needed a menisectomy. Twenty-one patients (40%) underwent ACL reconstruction. The 4-years successful conservative treatment rate was 92% (95% CI: 85-98%). Clinical instability at first examination was the only significant predictive factors of bad tolerance of conservative management (p=0.047). Conservative management of ACL rupture in paediatric population is a valuable treatment which permits return to a normal life with sports activities without major increasing of meniscal tears. The rehabilitation protocol must restore full knee stability to permit a successful conservative treatment. We must study the impact of pubertal status on larger group. IV, retrospective study.


Ehrlichiosis and anaplasmosis subcommittee report to the Tick-borne Disease Working Group.
Ehrlichioses and anaplasmosis have undergone dramatic increases in incidence, and the geographic ranges of their occurrence and vectors have also expanded. There is marked underreporting of these diseases owing to deficient physician awareness and knowledge of the illnesses as well as limited access to appropriate diagnostic tests. Human monocytic ehrlichiosis and anaplasmosis are life threatening diseases with estimated case fatality rates of 2.7 and 0.3%, respectively. However, knowledge of their full range of signs and symptoms is incomplete, and the incidence of subclinical infections is unknown. Currently available laboratory diagnostic methods are poorly utilized, and with the exception of nucleic acid amplification tests are not useful for diagnosis during the acute stage of illness when timely treatment is needed. The Ehrlichiosis and Anaplasmosis Subcommittee of the Tick-Borne Disease Working Group recommended active clinical surveillance to determine the true incidence, full clinical spectrum, and risk factors for severe illness, as well as standardized surveillance of ticks for these pathogens, and enhanced education of primary medical caregivers and the public regarding these diseases. The subcommittee identified the needs to develop sensitive, specific acute stage diagnostic tests for local clinical laboratories and point-of-care testing, to develop approaches for utilizing electronic medical records, data mining, and artificial intelligence for assisting early diagnosis and treatment, and to develop adjunctive therapies for severe disease.


Update on nephropathic cystinosis.
The cystine that accumulates within cystinotic lysosomes comes primarily from proteins which have been degraded within this organelle. The individual amino acids have specific transport mechanisms to exit the lysosome. The lysosomal cystine transporter is defective in all types of cystinosis. When cells from patients with nephropathic and benign cystinosis were fused, the defect was not corrected and the cystine level remained elevated. This strongly indicates that the genetic defects are allelic (i.e., on the same chromosome). Cysteamine is a weak base which enters the cystinotic lysosome and reacts with cysteamine. forming a mixed disulfide of half-cystine and cysteamine. This mixed disulfide rapidly exits the lysosome via the transport system for cationic amino acids which is normal in cystinosis. Because of the success of renal transplantation, many cystinosis patients are alive in their twenties and even early thirties. Unfortunately, these patients have developed damage to other organs including thyroid, eye, central nervous system, pancreas, and muscle. Cysteamine and its analog, phosphocysteamine, are very beneficial to cystinosis patients, especially when started early in life. These drugs may prevent the need for transplantation. It is too early to know if they will prevent damage to other organs.


The mechanism of recognition of templates by DNA polymerases from pro- and eukaryotes as revealed by affinity modification data.
Pt(2+)-containing derivatives of oligodeoxyribonucleotides were used to evaluate the ligand affinity to the template sites of Klenow fragment of DNA polymerase I from E. coli and DNA polymerase alpha from human placenta. The values of Kd and Gibb's energy (delta G degree) for the complexes of oligodeoxyribonucleotides and their derivatives with the template sites of these enzymes were determined from the effects protecting the enzyme from inactivation by Pt(2+)-containing oligonucleotides. Kd and delta G degree values of the complexes made by DNA polymerases and orthophosphate, triethylphosphate, d(pC)n, d(pT)n, d(pG)n, d(pA)n (where n = 1-25), heterooligonucleotides of various length and structure, and oligothymidylates with partially and completely ethylated internucleotide phosphates were evaluated. The obtained data enabled us to suggest 19-20 mononucleotide units of the template to interact with the protein. Only one template internucleotide phosphate forms a Me(2+)-dependent electrostatic contact (delta G = -1.1...-1.7 kcal/mol) and a hydrogen bond (delta G = -4.4...-4.9 kcal/mol) with the enzyme. It is likely that the mononucleoside units of the template form hydrophobic contacts with the enzymes. The efficiency of such interaction changes with the hydrophobicity of the bases: C less than T less than G approximately A. For both homo- and heterooligonucleotides the contributions of nucleoside units to the affinity of the templates to the enzymes is due to the complementary interactions with the primers. A hypothetical model for the template-primer interaction with DNA polymerases is suggested.


Dynamics of optical matter creation and annihilation in colloidal liquids controlled by laser trapping power.
We investigate the dynamics of optical matter creation and annihilation in a colloidal liquid that was employed to construct an all-optical switch. It is revealed that the switching-on process can be characterized by the Fermi-Dirac distribution function, while the switching-off process can be described by a steady state followed by a single exponential decay. The phase transition times exhibit a strong dependence on trapping power. With an increasing trapping power, while the switching-on time decreases rapidly, the switch-off time increases significantly, indicating the effects of optical binding and van der Waals force on the lifetime of the optical matter.


Cannabinoids in dermatology: a scoping review.
The therapeutic applications of cannabis and cannabinoids are an increasingly conspicuous topic as de-criminalization and legalization of these products continues to expand. A limited number of cannabinoid compounds have been approved for a specific set of conditions. However, the current role of cannabinoids for the treatment of dermatologic conditions remains to be defined. We conducted a review of the current literature to determine the applications of cannabinoids for the therapy of various skin diseases. After conducting our analysis, we found that cannabinoid products have the potential to treat a variety of skin conditions, including acne vulgaris, allergic contact dermatitis, asteatotic dermatitis, atopic dermatitis, hidradenitis suppurativa, Kaposi sarcoma, pruritus, psoriasis, skin cancer, and the cutaneous manifestations of systemic sclerosis. However, the majority of available data on these compounds are pre-clinical and there is a corresponding lack of high-quality randomized, controlled trials that evaluate their effects. Cannabinoids have shown some initial promise as therapy for a variety of skin diseases. However, there is a requirement for thorough pre-clinical research and large-scale, randomized, controlled trials before cannabinoids can be considered safe and effective treatments for these conditions.


Habitat availability and heterogeneity and the indo-pacific warm pool as predictors of marine species richness in the tropical Indo-Pacific.
Range overlap patterns were observed in a dataset of 10,446 expert-derived marine species distribution maps, including 8,295 coastal fishes, 1,212 invertebrates (crustaceans and molluscs), 820 reef-building corals, 50 seagrasses, and 69 mangroves. Distributions of tropical Indo-Pacific shore fishes revealed a concentration of species richness in the northern apex and central region of the Coral Triangle epicenter of marine biodiversity. This pattern was supported by distributions of invertebrates and habitat-forming primary producers. Habitat availability, heterogeneity, and sea surface temperatures were highly correlated with species richness across spatial grains ranging from 23,000 to 5,100,000 km(2) with and without correction for autocorrelation. The consistent retention of habitat variables in our predictive models supports the area of refuge hypothesis which posits reduced extinction rates in the Coral Triangle. This does not preclude support for a center of origin hypothesis that suggests increased speciation in the region may contribute to species richness. In addition, consistent retention of sea surface temperatures in models suggests that available kinetic energy may also be an important factor in shaping patterns of marine species richness. Kinetic energy may hasten rates of both extinction and speciation. The position of the Indo-Pacific Warm Pool to the east of the Coral Triangle in central Oceania and a pattern of increasing species richness from this region into the central and northern parts of the Coral Triangle suggests peripheral speciation with enhanced survival in the cooler parts of the Coral Triangle that also have highly concentrated available habitat. These results indicate that conservation of habitat availability and heterogeneity is important to reduce extinction of marine species and that changes in sea surface temperatures may influence the evolutionary potential of the region.


Sterol synthesis and low density lipoprotein clearance in vivo in the pregnant rat, placenta, and fetus. Sources for tissue cholesterol during fetal development.
Whereas the greatest relative increase in body mass occurs during the third trimester of fetal life, the source of the cholesterol that supports this growth is uncertain. These studies used [3H]water and 125I-cellobiose-labeled low density lipoproteins to quantitate absolute rates of cholesterol acquisition in vivo by the fetus of the rat. Preliminary studies demonstrated that [3H]water administered intravenously to the mother rapidly equilibrated with the body pool of water in the fetus and that 22-microgram atoms of H from the water pool were incorporated into each micromole of newly synthesized cholesterol. After administration of [3H]water to pregnant rats, the rates of sterol synthesis per 100 g of whole body weight were severalfold higher in the fetus than in the dams. Individual organs of the dam such as the liver, however, had much higher synthetic rates than those in the fetus. When maternal hepatic cholesterol synthesis was suppressed by cholesterol feeding, newly synthesized cholesterol disappeared from the maternal blood yet there was essentially no change in the rate of appearance of newly synthesized sterol in the fetus, placenta, and fetal membranes. The placenta did take up low density lipoproteins at rates equal to about one-third of that seen in the maternal liver, but none of the apolipoprotein or cholesterol was transferred to the fetus. These studies indicate that the rat fetus receives little or no cholesterol from the mother but, rather, satisfies its need for cholesterol during fetal development through local synthesis. Furthermore, the fetal membranes appear to be an important site for sterol synthesis in the fetal compartment.


Circulating 25-Hydroxyvitamin D Concentration and Risk of Breast, Prostate, and Colorectal Cancers: The Melbourne Collaborative Cohort Study.
The role of vitamin D in cancer risk remains controversial, and limited data exist on associations between vitamin D and subtypes of specific cancers. We investigated associations between circulating 25-hydroxyvitamin D (25(OH)D) and risk of colorectal, breast, and prostate cancers, including subtypes. A case-cohort study within the Melbourne Collaborative Cohort Study included 547 colorectal, 634 breast, and 824 prostate cancers, and a sex-stratified random sample of participants (n = 2,996). Concentration of 25(OH)D in baseline-dried blood spots was measured using LC-MS/MS. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for each cancer in relation to plasma-equivalent 25(OH)D concentration. Associations by stage and BRAF/KRAS status for colorectal cancer, estrogen receptor status for breast cancer, and aggressiveness for prostate cancer were examined in competing risks models. 25(OH)D concentrations were inversely associated with risk of colorectal cancer [highest vs. lowest 25(OH)D quintile: HR, 0.71; 95% confidence interval (CI), 0.51-0.98], which was limited to women (HR, 0.52; 95% CI, 0.33-0.82). Circulating 25(OH)D was also inversely associated with BRAF V600E-positive colorectal cancer (per 25 nmol/L increment: HR, 0.71; 95% CI, 0.50-1.01). There were no inverse associations with breast cancer (HR, 0.98; 95% CI, 0.70-1.36) or prostate cancer (HR, 1.11; 95% CI, 0.82-1.48). Circulating 25(OH)D concentration was inversely associated with colorectal cancer risk for women, but not with risk of breast cancer or prostate cancer. Vitamin D might play a role in preventing colorectal cancer. Further studies are required to confirm whether vitamin D is associated with specific tumor subtypes.


KI polyomavirus detected in respiratory tract specimens from patients in St. Louis, Missouri.
Studies have reported the presence of KI polyomavirus (KIPyV) and WU polyomavirus (WUPyV) in respiratory secretions of young patients. So far, evidence has not supported a link between infections with either virus and respiratory tract disease; however, there has not been a large comparison of KIPyV-infected patients to age-matched patient groups. A retrospective study comparing clinical aspects of KIPyV-positive patients with respiratory syncytial virus (RSV)-positive, WUPyV-positive, and respiratory-virus negative patients. Using real-time polymerase chain reaction, 2599 respiratory samples from patients ranging from 1 day to 88 years of age were tested for KIPyV. Electronic medical records were reviewed for 65 cases, for a comparison group consisting of 195 patients negative for common respiratory viruses, and for 56 WUPyV-positive patients drawn from the same population. Twelve patients testing positive for KIPyV as the sole pathogen were matched to 36 RSV-positive patients and clinical features of both groups were compared. Seventy-two (2.8%) respiratory samples were positive for KIPyV. Another virus was detected in 71% of the KIPyV-positive samples. Analysis showed no statistically significant differences in clinical manifestations between KIPyV-positive patients and patients negative for common respiratory viruses, however, clinical characteristics of KIPyV-positive patients were less severe than those of patients positive for RSV. KIPyVpositive patients >or=3 years of age were usually immunocompromised in contrast to the younger children with KIPyV. This study did not demonstrate a link between KIPyV infection and symptomatic respiratory disease. Patients positive for KIPyV exhibited less severe clinical symptoms than patients positive for RSV.


Associations of Eating Identities With Self-Reported Dietary Behaviors and Body Mass Index.
To inform dietary interventions, it is important to understand antecedents of recommended (henceforth: healthy) dietary behaviors, beyond dietary beliefs and self-efficacy. We used the validated "Eating Identity Type Inventory" to assess the extent to which participants identified as healthy eaters, meat eaters, emotional eaters or picky eaters. We examined correlations between participants' race/ethnicity and other socio-demographic characteristics and affinity with these eating identities, how affinity with these eating identities correlated with self-reports of dietary beliefs, self-efficacy, dietary behaviors and Body Mass Index (BMI), and how well affinity with these eating identities predicted self-reported dietary behaviors and BMI, as compared to self-reported dietary beliefs and self-efficacy. In an online survey, a diverse sample of 340 Los Angeles County adults reported eating identities, dietary beliefs, and self-efficacy, dietary behaviors and BMI. Pearson correlations revealed that identifying more as a healthy eater was positively associated with self-reports of being non-Hispanic White, non-Hispanic mixed race, older, and college-educated, while identifying more as a meat eater was positively associated with self-reports of being non-Hispanic Black, younger, and male (α = 0.05). Pearson correlations also showed that healthy eaters had more accurate dietary beliefs and self-efficacy, and emotional eaters had lower self-efficacy (α = 0.05). In linear regressions, identifying more as a healthy eater was associated with self-reporting healthier dietary behaviors and lower BMI, and identifying more as a meat eater and emotional eater was associated with reporting less healthy dietary behaviors and higher BMI, even after accounting for correlations with socio-demographics, dietary beliefs, and self-efficacy (α = 0.05). Our findings highlight the importance of eating identities in understanding dietary behaviors and outcomes, with implications for dietary interventions.


Genomic Instability Is an Early Event in Aluminium-Induced Tumorigenesis.
Genomic instability is generally considered as a hallmark of tumorigenesis and a prerequisite condition for malignant transformation. Aluminium salts are suspected environmental carcinogens that transform mammary epithelial cells in vitro through unknown mechanisms. We report here that long-term culture in the presence of aluminium chloride (AlCl3) enables HC11 normal mouse mammary epithelial cells to form tumours and metastases when injected into the syngeneic and immunocompetent BALB/cByJ strain. We demonstrate that AlCl3 rapidly increases chromosomal structural abnormalities in mammary epithelial cells, while we failed to detect direct modulation of specific mRNA pathways. Our observations provide evidence that clastogenic activity-a well-recognized inducer of genomic instability-might account in part for the transforming abilities of aluminium in mammary epithelial cells.


Combined molecular modelling and 3D-QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives.
A combination of three-dimensional quantitative structure-activity relationship (3D-QSAR), and molecular modelling methods were used to understand the potent inhibitory NAD(P)H:quinone oxidoreductase 1 (NQO1) activity of a set of 52 heterocyclic quinones. Molecular docking results indicated that some favourable interactions of key amino acid residues at the binding site of NQO1 with these quinones would be responsible for an improvement of the NQO1 activity of these compounds. The main interactions involved are hydrogen bond of the amino group of residue Tyr128, π-stacking interactions with Phe106 and Phe178, and electrostatic interactions with flavin adenine dinucleotide (FADH) cofactor. Three models were prepared by 3D-QSAR analysis. The models derived from Model I and Model III, shown leave-one-out cross-validation correlation coefficients (q2LOO ) of .75 and .73 as well as conventional correlation coefficients (R2 ) of .93 and .95, respectively. In addition, the external predictive abilities of these models were evaluated using a test set, producing the predicted correlation coefficients (r2pred ) of .76 and .74, respectively. The good concordance between the docking results and 3D-QSAR contour maps provides helpful information about a rational modification of new molecules based in quinone scaffold, in order to design more potent NQO1 inhibitors, which would exhibit highly potent antitumor activity.