Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers.
The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be 'gold standard' on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed.


Biochar composition-dependent impacts on soil nutrient release, carbon mineralization, and potential environmental risk: A review.
Biochar application has multiple benefits for soil fertility improvement and climate change mitigation. Biochar can act as a source of nutrients and sequester carbon (C) in the soil. The nutrient release capacity of biochar once applied to the soil varies with the composition of the biochar, which is a function of the feedstock type and pyrolysis condition used for biochar production. Biochar has a crucial influence on soil C mineralization, including its positive or negative priming of microorganisms involved in soil C cycling. However, in various cases, biochar application to the soil may cause negative effects in the soil and the wider environment. For instance, biochar may suppress soil nutrient availability and crop productivity due to the reduction in plant nutrient uptake or reduction in soil C mineralization. Biochar application may also negatively affect environmental quality and human health because of harmful compounds such as polycyclic aromatic hydrocarbons (PAHs), polychlorinated dibenzodioxins, and dibenzofurans (PCDD/DF). In this review, we discuss the linkage between biochar composition and function, evaluate the role biochar plays in soil fertility improvement and C sequestration, and discuss regulations and concerns regarding biochar's negative environmental impact. We also summarize advancements in biochar production technologies and discuss future challenges and priorities in biochar research.


A graphene field-effect transistor as a molecule-specific probe of DNA nucleobases.
Fast and reliable DNA sequencing is a long-standing target in biomedical research. Recent advances in graphene-based electrical sensors have demonstrated their unprecedented sensitivity to adsorbed molecules, which holds great promise for label-free DNA sequencing technology. To date, the proposed sequencing approaches rely on the ability of graphene electric devices to probe molecular-specific interactions with a graphene surface. Here we experimentally demonstrate the use of graphene field-effect transistors (GFETs) as probes of the presence of a layer of individual DNA nucleobases adsorbed on the graphene surface. We show that GFETs are able to measure distinct coverage-dependent conductance signatures upon adsorption of the four different DNA nucleobases; a result that can be attributed to the formation of an interface dipole field. Comparison between experimental GFET results and synchrotron-based material analysis allowed prediction of the ultimate device sensitivity, and assessment of the feasibility of single nucleobase sensing with graphene.


The unfolded protein response and integrated stress response to anoxia.
The lack of oxygen delivery to tumor cells has profound consequences for tumor growth and correlates with poor prognosis. Some tumors contain regions of very severe hypoxia called anoxia, which constitutes a functionally different state to hypoxia. In response to anoxia, mammalian cells induce coordinated cytoprotective programs that are critical for tumor survival: the unfolded protein response and integrated stress response. Therefore, targeting additional components of anoxic pathways, besides the hypoxia-inducible response, may be effective for future anticancer therapies.


Efficacy of transferrin receptor-targeted immunotoxins in brain tumor cell lines and pediatric brain tumors.
The efficacy and cytotoxic properties of immunotoxin conjugates directed against the transferrin receptor were examined in cell lines and operative specimens from pediatric brain tumors. Dose-response relationships were assessed for immunotoxin-mediated inhibition of protein synthesis for two immunotoxins, 454A12-rRA and anti-tfnR-CRM 107. Three target medulloblastoma cell lines (DAOY, D283MED, and D341MED), a glioblastoma (U373), and a neuroblastoma (SH-SY5Y) cell line exhibited similar sensitivity to both immunotoxins with IC50s in the 10(-9)-10(-10) M range. The time course of protein synthesis inhibition by the immunotoxins in DAOY cells showed that inhibition by anti-tfnR-CRM 107 was rapid and apparent by 6 h of incubation. In contrast, a response to 454A12-rRA was not observed until 16 h. Cell viability was decreased 30-40% by 24 h after removing 454A12-rRA (1 x 10(-9) M) and was maximally decreased 70-80% after 3 days. The efficacy of the immunotoxins on a variety of fresh specimens of pediatric brain tumors was also examined. The more aggressive and malignant tumor types such as glioblastoma multiforme and medulloblastoma had low IC50 values (10(-12) M), indicating that these tumors were extremely sensitive to transferrin receptor-targeted immunotoxins. In general, protein synthesis in slow-growing and benign tumors was not as greatly affected by immunotoxins. Immunoblots showed expression of transferrin receptors on the cell lines and tumors which correlated with in vitro sensitivity to immunotoxin. The results demonstrate that two immunotoxins targeted to the transferrin receptor are efficacious in killing brain tumor cell lines and primary tumor cultures at very low concentrations and that highly malignant tumors are especially sensitive to this cytotoxic response.


Patient-Reported Visual Function Outcomes After Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema Due to Central Retinal or Hemiretinal Vein Occlusion: Preplanned Secondary Analysis of a Randomized Clinical Trial.
Anti-vascular endothelial growth factor (anti-VEGF) therapy is the standard-of-care first-line treatment for macular edema associated with central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO), and information is needed to assess the effect of anti-VEGF therapy on patient-reported visual function. To investigate the effect of intravitreal aflibercept or bevacizumab on patient-reported visual function in patients with macular edema secondary to CRVO or HRVO. This preplanned secondary analysis of the Study of Comparative Treatments for Retinal Vein Occlusion 2, a randomized clinical trial, included 346 participants from 66 private practice or academic centers in the United States. Participants had CRVO- or HRVO-associated macular edema and month 6 outcome information. Data were collected from September 17, 2014, through November 18, 2015, and analyzed from February 7, 2018, through February 26, 2019. Eyes were randomly assigned to receive an intravitreal injection of bevacizumab (1.25 mg) or aflibercept (2.0 mg) at baseline and every 4 weeks through month 5. Difference between treatment arms at month 6 in the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite and subscale scores. Among the 346 participants (56.1% men; mean [SD] age, 69 [12] years), significant improvements occurred from baseline to month 6 in the NEI VFQ-25 composite score in the aflibercept (mean [SE] change, 7.5 [0.9]; P < .001) and bevacizumab (mean [SE], 6.1 [0.9]; P < .001) arms and in 10 of 12 subscale scores after multiplicity adjustment. No differences were observed at month 6 in NEI VFQ-25 composite or subscale scores between participants randomized to aflibercept or bevacizumab treatment. Weak positive correlations were seen between the change in the study eyes' visual acuity and the changes in the NEI VFQ-25 composite score (r = 0.22; P < .001) and the Distance Activities (r = 0.24; P < .001) and Driving (r = 0.19; P = .03) subscale scores. Significant improvement occurred from baseline to month 6 in patient-reported visual function as assessed by the NEI VFQ-25. The lack of difference in NEI VFQ-25 scores between study participants treated with monthly intravitreal aflibercept and bevacizumab for macular edema due to CRVO or HRVO at month 6 is consistent with the primary outcome finding that showed bevacizumab was noninferior to aflibercept with respect to visual acuity improvement from baseline to month 6. ClinicalTrials.gov identifier: NCT01969708.


[Quality evaluation of twelve species of Chinese Ephedra (ma huang)].
The contents of six Ephedra alkaloids, namely ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, methylephedrine and methyl-pseudoephedrine, in 12 species of Chinese Ephedra collected in 24 districts were determined by high performance liquid chromatography (HPLC). Zorbax CN column (25 cm x 4.6 mm I.D.) was used and the temperature of column oven was 23-25 degrees C. Dibutylamine phosphate solution 0.0009 mol/L (pH 2.2) was used as the mobile phase at flow rates: 0.8 ml/min for the first 7 minutes, raised to 1.5 ml/min in 30 sec and maintained for 16 minutes. The alkaloids eluted were detected at wave-length 210 nm. The results showed that ephedrine and pseudoephedrine are the main components in these Ephedra herbs, but the contents of the six Ephedra alkaloids vary greatly with the plant species. The contents of total alkaloids are higher and ephedrine is the main component in samples derived from Ephedra sinica, E. equisetina, E. monosperma and E. intermedia var. tibetica; but in E. intermedia and E. lomatolepis, the content of pseudoephedrine is higher than that of ephedrine. Methylephedrine content is higher in E. intermedia var. tibetica produced in Xizang (Tibet) and in E. sinica produced in north-eastern China than that in other species. The results also showed that the samples derived from E. przewalskii and E. lepidosperma contain so little alkaloids (less than 0.1%) that they are considered not suitable to be used as the drug Ma Huang. It is of interest that the cultivated Ephedra sinica showed lower alkaloids content compared with that growing wild.


Asymmetric interactions and their consequences for vital rates and dynamics: the smaller tea tortrix as a model system.
Asymmetric interactions among conspecifics can have diverse effects on population dynamics including stabilization, generation of cycles, and induction of chaotic fluctuations. A difficult challenge, however, is establishing the link between the impact of asymmetric interactions on life history and the consequences for population dynamics. The smaller tea tortrix, Adoxophyes honmai, is a good example. Larval instars differ dramatically in size and have a tendency for cannibalism, which suggests the potential for strong asymmetric interactions among instars. Yet whether these asymmetries have any role in generating the distinct single-generation cycles observed in the field and laboratory is unclear. Here we report on the development of a new experimental approach to characterize the impact of asymmetric interactions on life history that can be directly embedded into stage-structured population models. The experiments use donor-replacement protocols in which focal individuals are challenged to complete their life cycles in competitive environments where the instar and density of the competitors are held constant. The experimentally derived interaction surface contains all the information about stage-specific interactions and provides a straightforward framework for evaluating alternative ways of abstracting the interactions into traditional models of asymmetric competition. Working with the smaller tea tortrix, we found strong evidence of asymmetric interactions and identified critical "tipping points" in the competitive environment that strongly affected survival but not development. We incorporated the experimentally derived interaction surface into a stage-structured population model and found that despite the strong impact that asymmetric interactions have on tea tortrix life history, they do not scale-up to impact the predicted asymptotic population dynamics. Comparing these dynamics with two abstracted models of stage-structured interactions revealed that while the quantitative details of the emergent dynamics depends on the shape of the interaction surface, the qualitative features, such as the emergence of single-generation cycles and rapid synchronization of development among individuals, are pleasingly robust.


Optimally coherent sets in geophysical flows: a transfer-operator approach to delimiting the stratospheric polar vortex.
The "edge" of the Antarctic polar vortex is known to behave as a barrier to the meridional (poleward) transport of ozone during the austral winter. This chemical isolation of the polar vortex from the middle and low latitudes produces an ozone minimum in the vortex region, intensifying the ozone hole relative to that which would be produced by photochemical processes alone. Observational determination of the vortex edge remains an active field of research. In this paper, we obtain objective estimates of the structure of the polar vortex by introducing a technique based on transfer operators that aims to find regions with minimal external transport. Applying this technique to European Centre for Medium-Range Weather Forecasts (ECMWF) ERA-40 three-dimensional velocity data, we produce an improved three-dimensional estimate of the vortex location in the upper stratosphere where the vortex is most pronounced. This computational approach has wide potential application in detecting and analyzing mixing structures in a variety of atmospheric, oceanographic, and general fluid dynamical settings.


High incidence of scrapie induced by repeated injections of subinfectious prion doses.
To clarify the mechanisms leading to the development of Creutzfeldt-Jakob disease in some recipients of pituitary-derived human growth hormone (hGH), we investigated the effects of repeated injections of low prion doses in mice. The injections were performed, as in hGH-treated children, by a peripheral route at short intervals and for an extended period. Twelve groups of 24 mice were intraperitoneally inoculated one, two, or five times per week for 200 days with 2 x 10(-5) to 2 x 10(-8) dilutions of brain homogenate containing the mouse-adapted C506M3 scrapie strain. Sixteen control mice were injected once a week for 200 days with a 2 x 10(-4) dilution of normal brain homogenate. Of mice injected in a single challenge with a scrapie inoculum of a 2 x 10(-4), 2 x 10(-5), or 2 x 10(-6) dilution, 2/10, 1/10, and 0/10 animals developed scrapie, respectively. Control mice remained healthy. One hundred thirty-five of 135 mice injected with repeated prion doses of a 2 x 10(-5) or 2 x 10(-6) dilution succumbed to scrapie. Of mice injected with repeated scrapie doses of a 2 x 10(-7) or 2 x 10(-8) dilution, 52/59 and 38/67 animals died of scrapie, respectively. A high incidence of scrapie was observed in mice receiving repeated doses at low infectivity, whereas there was no disease in mice that were injected once with the same doses. Repeated injections of low prion doses thus constitute a risk for development of prion disease even if the same total dose inoculated in a single challenge does not induce the disease.


Immediately restored dental implants for partial-arch applications. A literature update.
This article carries out a literature update on immediately restored dental implants in partially edentulous patients. A search was made in Medline of all articles published between the year 2000 and February 2007, including all articles published in both English and Spanish, in which immediate restoration of implants was made of partially edentulous areas with a minimum of 12 implants and six months follow-up. Certain decisive factors exist for the success of this technique in partially edentulous patients, such as primary stability, a roughened implant surface, and the absence of parafunctional habits in patients acceptable for this type of treatment. Following the analysis of these studies of immediate restoration of teeth in partially edentulous areas, a weighted mean survival of 95.39% was observed. In spite of the high success rate, major controversy still exists on this subject resulting in few studies and short follow-up periods, making the routine use of this technique questionable.


Participation in peer support groups after a cardiac event: a 12-month follow-up.
All cardiac patients in Sweden are given the opportunity to participate in group activities that are arranged by the Swedish National Association for Heart and Lung Patients through a program called The Heart School. In this study, we compared persons who participated in the Heart School activities (n = 59, intervention group) with persons who declined to participate (n = 125, comparison group) with regard to their: self-rated health, life situation, social support, clinical data, rehospitalization, and mortality. Participants completed a questionnaire at 2 weeks, 3 months, and 12 months after discharge from a hospital. They also visited a healthcare center for physical examinations. The intervention group reported more physical symptoms and a higher degree of social support. No other differences were found between the groups. Differences within groups were that the intervention group had increased their physical activities and had eventually stopped smoking. This study adds to the knowledge about the use of peer support groups as a support strategy and supports their use in long-term rehabilitation after a cardiac event.


The representation of brightness in primary visual cortex.
Although neurons in primary visual cortex are sensitive to the spatial distribution and intensity of light, their responses have not been thought to correlate with the perception of brightness. Indeed, primary visual cortex is often described as an initial processing stage that sends information to higher cortical areas where perception of brightness, color, and form occurs. However, a significant percentage of neurons in primary visual cortex were shown to respond in a manner correlated with perceived brightness, rather than responding strictly to the light level in the receptive fields of the cells. This finding suggests that even at the first stage of visual cortical processing, spatial integration of information yields perceptual qualities that are only indirectly related to the pattern of illumination of the retina.


Optic nerve head microvasculature of the rabbit eye.
Vascular luminal castings of rabbit eyes were microdissected and studied with scanning electron microscopy to elucidate the three-dimensional angioarchitecture of the optic nerve head. Using sequential microdissection, an incomplete arterial circle was identified as terminal branches of two to three short posterior ciliary arteries around the optic nerve head. Several recurrent branches from the arterial circle form a pial arterial network. This pial system supplies the optic nerve head microvasculature and receives numerous venules from them. The only large vessel to enter the optic nerve is a central retinal artery that has few branches within the optic nerve and provides several branches at the surface of the optic disc. Moderately numerous vessels connect the retinal and ciliary vascular layers within the optic nerve head. Few arterioles to the optic nerve head arise from the choroid; however, there are a small number of capillary and numerous venous connections between them. These results indicate that the principal blood supply of the rabbit optic nerve head is derived from the short posterior ciliary arteries by the arterial circle. The retinal arteries contribute to the surface vasculature of the optic nerve head. The pial system also plays a significant role in both supply and drainage of the rabbit optic nerve head.


Impact of a national multimodal intervention to prevent catheter-related bloodstream infection in the ICU: the Spanish experience.
Prevention of catheter-related bloodstream infection is a basic objective to optimize patient safety in the ICU. Building on the early success of a patient safety unit-based comprehensive intervention (the Keystone ICU project in Michigan), the Bacteremia Zero project aimed to assess its effectiveness after contextual adaptation at large-scale implementation in Spanish ICUs. Prospective time series. A total of 192 ICUs throughout Spain. All patients admitted to the participating ICUs during the study period (baseline April 1 to June 30, 2008; intervention period from January 1, 2009, to June 30, 2010). Engagement, education, execution, and evaluation were key program features. Main components of the intervention included a bundle of evidence-based clinical practices during insertion and maintenance of catheters and a unit-based safety program (including patient safety training and identification and analysis of errors through patient safety rounds) to improve the safety culture. The number of catheter-related bloodstream infections was expressed as median and interquartile range. Poisson distribution was used to calculate incidence rates and risk estimates. The participating ICUs accounted for 68% of all ICUs in Spain. Catheter-related bloodstream infection was reduced after 16-18 months of participation (median 3.07 vs 1.12 episodes per 1,000 catheter-days, p<0.001). The adjusted incidence rate of bacteremia showed a 50% risk reduction (95% CI, 0.39-0.63) at the end of the follow-up period compared with baseline. The reduction was independent of hospital size and type. Results of the Bacteremia Zero project confirmed that the intervention significantly reduced catheter-related bloodstream infection after large-scale implementation in Spanish ICUs. This study suggests that the intervention can also be effective in different socioeconomic contexts even with decentralized health systems.


Variation in use of coercive measures in psychiatric hospitals.
The use of coercive measures in psychiatry is still poorly understood. Most empirical research has been limited to compulsory admission and to risk factors on an individual patient level. This study addresses three coercive measures and the role of predictive factors at both patient and institutional levels. Using the central psychiatric register that covers all psychiatric hospitals in Canton Zurich (1.3 million people), Switzerland, we traced all inpatients in 2007 aged 18-70 (n = 9698). We used GEE models to analyse variation in rates between psychiatric hospitals. Overall, we found quotas of 24.8% involuntary admissions, 6.4% seclusion/restraint and 4.2% coerced medication. Results suggest that the kind and severity of mental illness are the most important risk factors for being subjected to any form of coercion. Variation across the six psychiatric hospitals was high, even after accounting for risk factors on the patient level suggesting that centre effects are an important source of variability. However, effects of the hospital characteristics 'size of the hospital', 'length of inpatient stay', and 'work load of the nursing staff' were only weak ('bed occupancy rate' was not statistically significant). The significant variation in use of coercive measures across psychiatric hospitals needs further study.


Adipose tissue expression of the lipid droplet-associating proteins S3-12 and perilipin is controlled by peroxisome proliferator-activated receptor-gamma.
In a systematic search for peroxisome proliferator-activated receptor-gamma (PPAR-gamma) target genes, we identified S3-12 and perilipin as novel direct PPAR-gamma target genes. Together with adipophilin and tail-interacting protein of 47 kDa, these genes are lipid droplet-associating proteins with distinct expression pattern but overlapping expression in adipose tissue. The expression of S3-12 and perilipin is tightly correlated to the expression and activation of PPAR-gamma in adipocytes, and promoter characterization revealed that the S3-12 and the perilipin promoters contain three and one evolutionarily conserved PPAR response elements, respectively. We furthermore demonstrate that the expression of S3-12 and perilipin is reduced in obese compared with lean Zucker rats, whereas the expression of adipophilin is increased. Others have shown that perilipin is an essential factor in the hormonal regulation of lipolysis of stored triglycerides within adipose tissue. The direct regulation of perilipin and S3-12 by PPAR-gamma therefore is likely to be an important mediator of the in vivo effects of prolonged treatment with PPAR-gamma activators: insulin sensitization, fatty acid trapping in adipose tissue, reduced basal adipose lipolysis, and weight gain.


Temperature-Triggered Colloidal Gelation through Well-Defined Grafted Polymeric Surfaces.
Sufficiently strong interparticle attractions can lead to aggregation of a colloidal suspension and, at high enough volume fractions, form a mechanically rigid percolating network known as a colloidal gel. We synthesize a model thermo-responsive colloidal system for systematically studying the effect of surface properties, grafting density and chain length, on the particle dynamics within colloidal gels. After inducing an attraction between particles by heating, aggregates undergo thermal fluctuation which we observe and analyze microscopically; the magnitude of the variance in bond angle is larger for lower grafting densities. Macroscopically, a clear increase of the linear mechanical behavior of the gels on both the grafting density and chain length arises, as measured by rheology, which is inversely proportional to the magnitude of local bond angle fluctuations. This colloidal system will allow for further elucidation of the microscopic origins to the complex macroscopic mechanical behavior of colloidal gels including bending modes within the network.


Modulation of cell death in age-related diseases.
Aging is a stage of life of all living organisms. According to the free-radical theory, aging cells gradually become unable to maintain cellular homeostasis due to the adverse effects of reactive oxygen species (ROS). ROS can cause irreversible DNA mutations, protein and lipid damage which are increasingly accumulated in the course of time if cells could not overcome these effects by the antioxidant defence system. Accrued damaged molecules in cells may either induce cellular death or contribute to develop various pathologies. Hence, programmed cell death mechanisms, apoptosis and autophagy, play a vital role in the aging process. Although they are strictly controlled by various interconnected signalling pathways, alterations in their regulations may contribute to severe pathologies including cancer, Alzheimer's and Parkinson's diseases. In this review, we summarized our current understanding and hypotheses regarding oxidative stress and age-related dysregulation of cell death signalling pathways.


EVALUATION OF MAGNETIC RESONANCE IMAGING GUIDELINES FOR DIFFERENTIATION BETWEEN THORACOLUMBAR INTERVERTEBRAL DISK EXTRUSIONS AND INTERVERTEBRAL DISK PROTRUSIONS IN DOGS.
Four MRI variables have recently been suggested to be independently associated with a diagnosis of thoracolumbar intervertebral disk extrusion or protrusion. Midline intervertebral disk herniation, and partial intervertebral disk degeneration were associated with intervertebral disk protrusion, while presence of a single intervertebral disk herniation and disk material dispersed beyond the boundaries of the intervertebral disk space were associated with intervertebral disk extrusion. The aim of this retrospective, cross-sectional study was to determine whether using these MRI variables improves differentiation between thoracolumbar intervertebral disk extrusions and protrusions. Eighty large breed dogs with surgically confirmed thoracolumbar intervertebral disk extrusions or protrusions were included. Randomized MRI studies were presented on two occasions to six blinded observers, which were divided into three experience categories. During the first assessment, observers made a presumptive diagnosis of thoracolumbar intervertebral disk extrusion or protrusion without guidelines. During the second assessment they were asked to make a presumptive diagnosis with the aid of guidelines. Agreement was evaluated by Kappa-statistics. Diagnostic accuracy significantly improved from 70.8 to 79.6% and interobserver agreement for making a diagnosis of intervertebral disk extrusion or intervertebral disk protrusion improved from fair (κ = 0.27) to moderate (κ = 0.41) after using the proposed guidelines. Diagnostic accuracy was significantly influenced by degree of observer experience. Intraobserver agreement for the assessed variables ranged from fair to excellent and interobserver agreement ranged from fair to moderate. The results of this study suggest that the proposed imaging guidelines can aid in differentiating thoracolumbar intervertebral disk extrusions from protrusions.


Implementing collaborative primary care for depression and posttraumatic stress disorder: design and sample for a randomized trial in the U.S. military health system.
War-related trauma, posttraumatic stress disorder (PTSD), depression and suicide are common in US military members. Often, those affected do not seek treatment due to stigma and barriers to care. When care is sought, it often fails to meet quality standards. A randomized trial is assessing whether collaborative primary care improves quality and outcomes of PTSD and depression care in the US military health system. The aim of this study is to describe the design and sample for a randomized effectiveness trial of collaborative care for PTSD and depression in military members attending primary care. The STEPS-UP Trial (STepped Enhancement of PTSD Services Using Primary Care) is a 6 installation (18 clinic) randomized effectiveness trial in the US military health system. Study rationale, design, enrollment and sample characteristics are summarized. Military members attending primary care with suspected PTSD, depression or both were referred to care management and recruited for the trial (2592), and 1041 gave permission to contact for research participation. Of those, 666 (64%) met eligibility criteria, completed baseline assessments, and were randomized to 12 months of usual collaborative primary care versus STEPS-UP collaborative care. Implementation was locally managed for usual collaborative care and centrally managed for STEPS-UP. Research reassessments occurred at 3-, 6-, and 12-months. Baseline characteristics were similar across the two intervention groups. STEPS-UP will be the first large scale randomized effectiveness trial completed in the US military health system, assessing how an implementation model affects collaborative care impact on mental health outcomes. It promises lessons for health system change.


A 12-week, naturalistic switch study of the efficacy and tolerability of aripiprazole in stable outpatients with schizophrenia or schizoaffective disorder.
The objectives of this 12-week multicenter open-label switching study were to evaluate the overall clinical efficacy, safety, and tolerability of aripiprazole in stable patients with schizophrenia or schizoaffective disorder, and to assess, in a naturalistic setting, whether such patients experience symptom worsening when switched from D2 receptor antagonists to aripiprazole (a D2 receptor partial agonist). Patients with schizophrenia or schizoaffective disorder in a symptomatically stable state were randomized to aripiprazole or standard-of-care antipsychotics. The Clinical Global Impression (CGI), Positive and Negative Syndrome Scale, and Investigator's Assessment Questionnaire were used monthly. The Udvalg for Kliniske Undersogelser side-effect rating scale scores and treatment emergent adverse events were recorded to assess the safety and tolerability of switching to aripiprazole from other antipsychotics. A total of 292 patients were randomly assigned to receive aripiprazole (N = 245) or non-aripiprazole antipsychotics (N = 47). Mean CGI-Improvement score at 12 weeks was 3.56+/-1.29 (95% confidence interval: 3.39-3.73) in the aripiprazole group, indicating that aripiprazole was effective in treating schizophrenic patients. Aripiprazole treatment resulted in improvement from baseline on all efficacy outcome measures, including Positive and Negative Syndrome Scale total, positive, negative, and general subscale, and CGI-Severity scores. In addition, after aripiprazole treatment, the remission rate was increased from 43.9% at baseline to 51.7% at 12 weeks. The proportion of patients with symptom worsening at 12 weeks was low (12.4%). Both Investigator's Assessment Questionnaire and Udvalg for Kliniske Undersogelser scores showed that there were fewer prolactin-related adverse events in the aripiprazole group than in the standard-of-care antipsychotics group (P<0.05). There were no significant between-group differences in time to failure to maintain remission and time to dropout. In the naturalistic setting, symptomatically stable outpatients with schizophrenia who were switched to aripiprazole showed clinically meaningful treatment benefits. The majority of patients was successfully switched from other antipsychotics without serious symptom exacerbation or adverse events over a course of 12 weeks.


DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2.
The hepatitis C virus (HCV) genome codes for highly mannosylated envelope proteins, which are naturally retained in the endoplasmic reticulum. We found that the HCV envelope glycoprotein E2 binds the dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) and the related liver endothelial cell lectin L-SIGN through high-mannose N-glycans. Competing ligands such as mannan and an antibody directed against the carbohydrate recognition domains (CRD) abrogated binding. While no E2 interaction with distant monomeric CRDs on biosensor chips could be detected, binding is observed if CRDs are closely seeded (Kd = 48 nm) and if the CRD is part of the oligomeric-soluble extracellular domain of DC-SIGN (Kd = 30 nm). The highest affinity is seen for plasma membrane-expressed DC-SIGN and L-SIGN (Kd = 3 and 6 nm, respectively). These results indicate that several high-mannose N-glycans in a structurally defined cluster on E2 bind to several subunits of the oligomeric lectin CRD. High affinity interaction of viral glycoproteins with oligomeric lectins might represent a strategy by which HCV targets to and concentrates in the liver and infects dendritic cells.


Real-life experience with pegylated interferon and conventional interferon in adjuvant melanoma therapy.
Interferon (IFN) is the most studied and the only approved adjuvant therapy for melanoma. There are 2 formulations of IFN, conventional IFN and pegylated IFN (peg-IFN), which have been investigated in multiple randomized clinical trials. We have compared the feasibility and tolerability of low-dose conventional IFN and peg-IFN in real life, outside the controlled settings of clinical trials. In this study, we analyzed 99 patients with resected melanoma, who were treated with either conventional IFN (n=48) or with peg-IFN (n=51), retrospectively. The median treatment duration in conventional IFN group was 13.3 versus 16.5 months in peg-IFN (P=0.52). Moreover, patients with peg-IFN tended to have dose reduction or treatment discontinuation due to adverse events (AE) significantly more often. In addition, neutropenia occurred significantly more often in peg-IFN group versus IFN group (n=2; 5% conventional vs. n=16; 36.4% peg-IFN, P=0.00). More than 90% of these patients developed only grade 2 neutropenia and there were no reported infections. We conclude that the 100 µg flat dose peg-IFN, which is commonly referred to as "low-dose," actually represents a higher dose of IFN, which consequently results in more frequent dose reductions and discontinuation of treatment. The use of peg-IFN is certainly more convenient for the patient in terms of application, thus close monitoring, early medical interventions, and dose adjustments to avoid treatment discontinuation are crucial for compliance.


Intrinsic magnetism and biaxial strain tuning in two-dimensional metal halides V3X8 (X = F, Cl, Br, I) from first principles and Monte Carlo simulation.
A novel family of two-dimensional (2D) crystalline metal superhalogens V3X8 (X = F, Cl, Br, I) with intrinsic magnetism was predicted using first-principles calculations in the framework of density functional theory (DFT). The calculation results show that the V3Cl8 monolayer is an intrinsic anti-ferromagnetic semiconductor (AFS) with an indirect bandgap of 0.086 eV at the PBE functional level, while the V3X8 (X = F, Br, I) monolayer exhibits a fascinating ferromagnetic half-metal (FH) property with 100% spin-polarization at the Fermi level. Such 2D materials possess robust dynamical stability as well as thermal stability at room temperature except for V3Br8. In addition, Monte Carlo simulations based on the Ising model with the classical Heisenberg model estimate a Curie temperature of approximately 77 K and 103 K for the V3F8 and V3I8 systems, respectively. Furthermore, we predict an extraordinary phenomenon induced by biaxial compressive strain from the ferromagnetic half-metal (FH) to the ferromagnetic semiconductor (FS) at 2% strain and then to the antiferromagnetic metal (AM) with the biaxial strain increasing up to about 6.3% in the 2D V3I8 monolayer. In the case of 2D V3F8, as the strain varies from -10% to 8%, a series of electronic and magnetic phase transitions of AFS-AM-FH-AFS will occur. These tunable magnetic and electronic properties of 2D halides originate from the competition between AFM direct nearest-neighbor d-d exchange and FM superexchange via halogen p states, which leads to a variety of magnetic states. The explored controllable magnetic properties, electronic properties and the high Curie temperature render the 2D V3I8 monolayer a promising candidate for applications in magnetic logic devices and strain sensor devices.


Identifying schools at high-risk for elevated lead in drinking water using only publicly available data.
Estimating the risk of lead contamination of schools' drinking water at the State level is a complex, important, and unexplored challenge. Variable water quality among water systems and changes in water chemistry during distribution affect lead dissolution rates from pipes and fittings. In addition, the locations of lead-bearing plumbing materials are uncertain. We tested the capability of six machine learning models to predict the likelihood of lead contamination of drinking water at the schools' taps using only publicly available datasets. The predictive features used in the models correspond to those with a proven correlation to the dominant, but commonly unavailable, factors that govern lead leaching: the presence of lead-bearing plumbing materials and water quality conducive to lead corrosion. By combining water chemistry data from public reports, socioeconomic information from the US census, and spatial features using Geographic Information Systems, we trained and tested models to estimate the likelihood of lead contaminated tap water in over 8,000 schools across California and Massachusetts. Our best-performing model was a Random Forest, with a 10-fold cross validation score of 0.88 for Massachusetts and 0.78 for California using the average Area Under the Receiver Operating Characteristic Curve (ROC AUC) metric. The model was then used to assign a lead leaching risk category to half of the schools across California (the other half was used for training). There was good agreement between the modeled risk categories and the actual lead leaching outcomes for every school; however, the model overestimated the lead leaching risk in up to 17% of the schools. This model is the first of its kind to offer a tool to predict the risk of lead leaching in schools at the State level. Further use of this model can help deploy limited resources more effectively to prevent childhood lead exposure from school drinking water.


Handling stress does not reflect personality in female zebra finches (Taeniopygia guttata).
Although increasing attention is given to both the causes and consequences of variation in animal personality, the measurement of personality in captive or free-ranging individuals remains an issue. In particular, one important question concerns whether personality should be established from the existence of complex behavioral syndromes (a suite of correlated behavioral traits) or could be more easily deduced from a single variable. In that context, it has recently been suggested that handling stress, measured through breathing rate during handling, could be a good descriptor of personality, at least in passerine birds. The authors experimentally investigated to what extent handling stress was correlated with personality in female zebra finches (Taeniopygia guttata), as assessed from a suite of repeatable behavioral traits, including activity, exploratory behavior, neophobia, and reaction to startle. Although breathing rate was repeatable across individuals, it was not related to any behavioral trait, suggesting that it cannot be used to quickly predict personality, at least in zebra finches. Breathing rate during handling, in addition, was related to morphology, questioning the fact that breathing rate during handling reflects personality irrespective of individual state. The authors suggest that inference on global personality from a reduced number of traits should be performed with caution.


Water vapor as an active scalar in tropical atmospheric dynamics.
Water vapor is a constituent of the tropical atmosphere which, though to a significant extent locally controlled by vertical advection, precipitation, and surface evaporation, is also affected by horizontal advection. Water vapor affects the flow in turn, because a humid atmosphere supports deep, precipitating convection more readily than a dry atmosphere. Precipitation heats the atmosphere, and this heating drives the flow. Water vapor is thus a dynamically active constituent. Simplifications to the primitive equations of dynamical meteorology, based on the so-called weak temperature gradient approximation, are presented which highlight this behavior. The weak temperature gradient approximation is valid on large scales near the equator. It eliminates gravity waves, leaving only balanced dynamics, though the fundamental balance occurs in the temperature rather than the momentum equation (as is customary in most balance models of geophysical fluid dynamics). The dynamical role of water vapor is examined in a couple of idealized contexts, where either the vertical or horizontal structure of the flow is severely simplified. (c) 2002 American Institute of Physics.


Effects of community-based natural resource management on household welfare in Namibia.
Biodiversity conservation, as an environmental goal, is increasingly recognized to be connected to the socioeconomic well-being of local communities. The development of a widespread community-based natural resource management (CBNRM) program in Namibia makes it an ideal location to analyze the connection between conservation and socioeconomic well-being of local communities. Namibia's CBNRM program involves the formation of communal conservancies within rural communities and previous studies have found it to be successful on both ecological and economic fronts. In order to broaden the understanding of the program's impact to include social factors, we have conducted a comparative analysis to determine the effects of this program on household welfare outcomes. Data from two rounds of the Namibia Demographic and Health Surveys (2000 and 2006/07) and quasi-experimental statistical methods were used to evaluate changes in various health, education and wealth outcomes of those living in conservancies, relative to non-conservancy comparison groups. Regression results indicate mixed effects of the conservancy program at the household level. The program had positive effects on some health outcome variables, including bednet ownership, which was twice as likely to increase over time in conservancy compared to non-conservancy households. Program impacts were negative for education outcomes, with the proportion of school attendance of conservancy children being 45% less likely to increase over time than non-conservancy children. Wealth outcome results were inconclusive. Our findings highlight the importance of analyzing community conservation programs at a variety of scales when evaluating overall impact, as community-level benefits may not necessarily extend down to the household level (and vice versa).


Auditory sequence: confusion of patterns other than speech or music.
Accurate perception of temporal order is essential for many auditory tasks. Yet the temporal pattern of four successive sounds (for example, hisses, buzzes, and tones) could not be recognized even when the duration of each sound was considerably longer than either the average phoneme in normal discourse or the notes of melodies. Although each of the stimuli was perceived, their order remained frustratingly elusive.


Percutaneous therapies of hepatocellular carcinoma-an update.
Percutaneous image-guided tumor therapies have proved important in the treatment of patients with primary liver cancer. The therapeutic spectrum for the management of this patient group includes ablative techniques such as ethanol ablation and radiofrequency ablation for patients with early-stage disease as well as intra-arterial approaches such as radioembolization and transarterial chemoembolization for patients with intermediate and end-stage disease. The tremendous advantage of such therapies is the reduced systemic toxicity combined with efficient local tumor control. However, specific therapeutic algorithms continue to be highly unstandardized and depend on individual experience of the operator. In this review, we will describe the rationale behind several percutaneous techniques, focusing on intra-arterial therapies of hepatocellular carcinoma (HCC) and review the available clinical evidence. We will also discuss new developments such as the combination of intra-arterial therapies with new systemically applicable drugs.


Failure of swimming exercise to improve capillarization in cardiac hypertrophy of renal hypertensive rats.
Female Sprague-Dawley rats were made hypertensive by the two kidney/one clip Goldblatt procedure, while control animals were sham-operated. One week later, half of the animals were subjected to a moderate swimming exercise and the other half remained sedentary. Thus, four experimental groups, each consisting of 14 rats, were formed: control animals that were exercised or kept sedentary and corresponding renal hypertensive animals either exercised or sedentary. In hypertensive rats, a significantly increased left ventricular weight and reduced coronary reserve were found. Cardiac hypertrophy in hypertensive rats was characterized by a lower number of capillaries on a tissue cross-section, larger heterogeneity of the capillary net, and a less uniform orientation of capillaries in space. Total length of capillaries in the hypertrophic hearts increased significantly, but less than the increase in cardiac weight, resulting in reduced capillary length density. Chronic swimming for 2 hr/day for a period of 6 weeks, subsequent to a 4-week acclimation period, did not significantly influence any of the investigated indexes of capillaries from hypertrophic hearts. In the normotensive rats, chronic swimming resulted only in a moderate increase in total capillary length associated with a small increase in the left ventricular weight of similar degree. Thus, chronic exercise in normotensive rats induced a moderate increase in total capillary length per left ventricle, while it did not alleviate impaired capillarization of hypertrophic hearts from hypertensive rats.


Microsurgical resection of giant T11/T12 conus cauda equina schwannoma.
In this video, we highlight the anatomy involved with microsurgical resection of a giant T11/T12 conus cauda equina schwannoma. Spinal schwannoma remains the third most common intradural spinal tumor. Tumors undergoing gross total resection usually do not recur. To our knowledge, this is the first video case report of giant cauda equina schwannoma resection. A 55-year-old female presented with paraparesis and urinary retention. Lumbar spine MRI revealed a contrast-enhancing intradural extramedullary tumor at the T11/T12 level. Surgery was performed in the prone position with intraoperative neurophysiology monitoring (somatosensory and motor evoked potentials-SSEPs and MEPs). T11/T12 laminectomies were performed. After opening the dura and arachnoid, the tumor was found covered with cauda equina nerve roots. We delineated the inferior pole of the tumor, followed by opening of the capsule and debulking the tumor. Subsequently, the cranial pole was dissected from the corresponding cauda equina nerve roots. Finally, the tumor nerve origin was identified and divided after nerve stimulation confirmed the tumor arose from a sensory nerve root. The tumor was removed; histological analysis revealed a schwannoma (WHO Grade I). Postoperative MRI revealed complete resection. The patient fully recovered her neurological function. This case highlights the importance of careful microsurgical technique and gross total resection of the tumor in the view of favorable postoperative neurological recovery of the patient. Intraoperative use of ultrasound is helpful to delineate preoperatively tumor extension and confirm postoperative tumor resection.


Spatial learning in Long-Evans Hooded rats and C57BL/6J mice: different strategies for different performance.
Spatial learning abilities of rodents have been extensively used to explore the management of a wide range of cognitive and emotional processes such as learning, memory, attention and anxiety. Knowledge about the organization and processing of spatial learning has mainly been obtained in rats. Due to increasing generation of genetically modified mice, cognitive abilities of mice are now extensively tested. The present paper aimed at comparing spatial representation, learning and strategies in C57BL/6J mice and Long-Evans Hooded rats when subjected to the same spatial learning paradigm, i.e. learning a food location in a crossmaze. We also analyzed the influence of environmental richness on learning modalities in both species. Our results showed that rats and mice could exhibit similar spatial learning abilities in some circumstances. However, Long-Evans rats and C57BL/6J mice may set up different strategies depending on the availability of visual information within the environment. Rats' learning strategies mainly relied on distant visual cues and seemed more efficient than those used by mice as they needed less time than mice to solve the task. We emphasize that the strategies of mice are less robust and flexible than the ones set up by rats. Finally, the richness of the environment was shown to affect speed and quality of spatial learning in both species.


Responsiveness of Infrapatellar Fat Pad Volume Change to Body Weight Loss or Gain: Data from the Osteoarthritis Initiative.
Obesity is a potent risk factor for knee osteoarthritis (OA) that is driven by mechanical and potentially endocrine mechanisms, and it affects women more frequently than men. The infrapatellar fat pat (IPFP) represents a potential link between obesity, intra-articular inflammation and structural pathology. Here we investigate whether the IPFP is responsive to body weight loss/gain in women and how its responsiveness to weight change compares to that of subcutaneous fat (SCF) of the thigh. All female participants of the Osteoarthritis Initiative (OAI) with ≥10% weight loss/gain between baseline and a 2-year follow-up were included. Within-subject changes in IPFP volume and SCF cross-sectional areas (CSA) were determined from 3-T magnetic resonance imaging. Linear regression was used to assess the association between change in weight, IPFP volume, and SCF CSA. In the 38 participants with ≥10% weight loss over 2 years (age 59.3 ± 9.1 years, mean loss = 15.9%), there was a significant reduction in IPFP volume (-2.2%, p = 0.02) as well as in SCF CSA (-22%, p < 0.001). In the 34 participants with ≥10% gain (age 61.5 ± 8.7 years, mean gain = 15.9%), there was a significant increase in SCF CSA (+26%, p < 0.001) but not in IPFP volume (0.2%, p = 0.87). Weight change was significantly associated with SCF CSA change (r = 0.76, p < 0.001) but not with IPFP volume change (r = 0.11, p = 0.37). In this first longitudinal, observational study investigating the responsiveness of IPFP and SCF to weight change, IPFP morphology was found responsive to weight loss but not to weight gain. Overall, the responsiveness of the IPFP was substantially less than that of the SCF.


Mesopic luminous-efficiency functions.
In order to establish the luminous-efficiency function for mesopic vision of the standard observer, luminous efficiency functions were measured with the direct heterochromatic brightness-matching method at retinal illuminance in the range of -2-2 log photopic trolands in order to cover the scotopic, mesopic, and photopic conditions. A steady visual field of 10 degrees arc was presented foveally. The functions underwent the usual complicated change from a rod type of luminous-efficiency function close to V'(lambda) to a cone function that had a wide and almost double-peaked shape. A simple formula to represent the mesopic luminous-efficiency functions was derived in which log sensitivities of scotopic and photopic vision were linearly added after being multiplied by coefficients that were dependent on the luminance level. Saturation functions were also obtained at the various luminance levels for which luminous efficiency was investigated. In spite of a great variation of luminance level, the saturation function remained more or less the same, which indicates that the chromatic channels retain their contributions to the brightness sensation at low retinal illumination.


A descriptive analysis of the data availability statements accompanying medRxiv preprints and a comparison with their published counterparts.
To determine whether medRxiv data availability statements describe open or closed data-that is, whether the data used in the study is openly available without restriction-and to examine if this changes on publication based on journal data-sharing policy. Additionally, to examine whether data availability statements are sufficient to capture code availability declarations. Observational study, following a pre-registered protocol, of preprints posted on the medRxiv repository between 25th June 2019 and 1st May 2020 and their published counterparts. Distribution of preprinted data availability statements across nine categories, determined by a prespecified classification system. Change in the percentage of data availability statements describing open data between the preprinted and published versions of the same record, stratified by journal sharing policy. Number of code availability declarations reported in the full-text preprint which were not captured in the corresponding data availability statement. 3938 medRxiv preprints with an applicable data availability statement were included in our sample, of which 911 (23.1%) were categorized as describing open data. 379 (9.6%) preprints were subsequently published, and of these published articles, only 155 contained an applicable data availability statement. Similar to the preprint stage, a minority (59 (38.1%)) of these published data availability statements described open data. Of the 151 records eligible for the comparison between preprinted and published stages, 57 (37.7%) were published in journals which mandated open data sharing. Data availability statements more frequently described open data on publication when the journal mandated data sharing (open at preprint: 33.3%, open at publication: 61.4%) compared to when the journal did not mandate data sharing (open at preprint: 20.2%, open at publication: 22.3%). Requiring that authors submit a data availability statement is a good first step, but is insufficient to ensure data availability. Strict editorial policies that mandate data sharing (where appropriate) as a condition of publication appear to be effective in making research data available. We would strongly encourage all journal editors to examine whether their data availability policies are sufficiently stringent and consistently enforced.


Asymmetries in motor attention during a cued bimanual reaching task: left and right handers compared.
Several studies have indicated that right handers have attention biased toward their right hand during bimanual coordination (Buckingham and Carey, 2009; Peters, 1981). To determine if this behavioral asymmetry was linked to cerebral lateralization, we examined this bias in left and right handers by combining a discontinuous double-step reaching task with a Posner-style hand cueing paradigm. Left and right handed participants received a tactile cue (valid on 80% of trials) prior to a bimanual reach to target pairs. Right handers took longer to inhibit their right hand and made more right hand errors, suggesting that their dominant hand was more readily primed to move than their non-dominant hand, likely due to the aforementioned attentional bias. Left handers, however, showed neither of these asymmetries, suggesting that they lack an equivalent dominant hand attentional bias. The findings are discussed in relation to recent unimanual handedness tasks in right and left handers, and the lateralization of systems for speech, language and motor attention.


Workplace irritant exposures: do they produce true occupational asthma?
To describe the features of irritant-induced asthma and discuss the diagnosis in relation to differing workplace irritant exposures and symptomatic responses. A review of MEDLINE articles on this topic from January 1, 1985, through December 31, 2001 was performed. The author selected relevant articles for inclusion in the review. Many reports indicate that unintentional high-level respiratory irritant exposures can induce the new onset of asthma. Cases that meet strict criteria for a syndrome of irritant-induced asthma, termed reactive airways dysfunction syndrome, can be diagnosed with relative certainty. Several reports of irritant-induced asthma, especially prevalence studies, have relied on historical data or have otherwise modified the reactive airways dysfunction syndrome criteria for diagnosis (eg, expanding the definition to include the symptom onset several days after exposure). Such modifications, or inclusion of cases with incomplete documentation, likely increase diagnostic sensitivity but may reduce the certainty of diagnosis for individual cases. Expanding exposure criteria to moderate or long-term low-level irritant exposures causes difficulty in excluding transient irritant exacerbation of underlying asthma or coincidental onset of asthma during working life. Although recent population studies suggest a greater relative risk of asthma in occupations with expected low-to-moderate respiratory irritant exposures, currently no objective laboratory tests exist to exclude coincidental asthma in such patients. Irritant-induced asthma can be produced by high-level unintentional respiratory irritant exposures at work or outside the workplace. Lower levels of exposure to respiratory irritants at work are more common, and additional studies are needed to determine the airway effects of such exposures.


Handwashing and Ebola virus disease outbreaks: A randomized comparison of soap, hand sanitizer, and 0.05% chlorine solutions on the inactivation and removal of model organisms Phi6 and E. coli from hands and persistence in rinse water.
To prevent Ebola transmission, frequent handwashing is recommended in Ebola Treatment Units and communities. However, little is known about which handwashing protocol is most efficacious. We evaluated six handwashing protocols (soap and water, alcohol-based hand sanitizer (ABHS), and 0.05% sodium dichloroisocyanurate, high-test hypochlorite, and stabilized and non-stabilized sodium hypochlorite solutions) for 1) efficacy of handwashing on the removal and inactivation of non-pathogenic model organisms and, 2) persistence of organisms in rinse water. Model organisms E. coli and bacteriophage Phi6 were used to evaluate handwashing with and without organic load added to simulate bodily fluids. Hands were inoculated with test organisms, washed, and rinsed using a glove juice method to retrieve remaining organisms. Impact was estimated by comparing the log reduction in organisms after handwashing to the log reduction without handwashing. Rinse water was collected to test for persistence of organisms. Handwashing resulted in a 1.94-3.01 log reduction in E. coli concentration without, and 2.18-3.34 with, soil load; and a 2.44-3.06 log reduction in Phi6 without, and 2.71-3.69 with, soil load. HTH performed most consistently well, with significantly greater log reductions than other handwashing protocols in three models. However, the magnitude of handwashing efficacy differences was small, suggesting protocols are similarly efficacious. Rinse water demonstrated a 0.28-4.77 log reduction in remaining E. coli without, and 0.21-4.49 with, soil load and a 1.26-2.02 log reduction in Phi6 without, and 1.30-2.20 with, soil load. Chlorine resulted in significantly less persistence of E. coli in both conditions and Phi6 without soil load in rinse water (p<0.001). Thus, chlorine-based methods may offer a benefit of reducing persistence in rinse water. We recommend responders use the most practical handwashing method to ensure hand hygiene in Ebola contexts, considering the potential benefit of chlorine-based methods in rinse water persistence.


Type III secretion contributes to the pathogenesis of the soft-rot pathogen Erwinia carotovora: partial characterization of the hrp gene cluster.
The virulence of soft-rot Erwinia species is dependent mainly upon secreted enzymes such as pectinases, pectin lyases, and proteases that cause maceration of plant tissue. Some soft-rot Erwinia spp. also harbor genes homologous to the hypersensitive reaction and pathogenesis (hrp) gene cluster, encoding components of the type III secretion system. The hrp genes are essential virulence determinants for numerous nonmacerating gram-negative plant pathogens but their role in the virulence of soft-rot Erwinia spp. is not clear. We isolated and characterized 11 hrp genes of Erwinia carotovora subsp. carotovora. Three putative sigmaL-dependent Hrp box promoter sequences were found. The genes were expressed when the bacteria were grown in Hrp-inducing medium. The operon structure of the hrp genes was determined by mRNA hybridization, and the results were in accordance with the location of the Hrp boxes. An E. carotovora strain with mutated hrcC, an essential hrp gene, was constructed. The hrcC- strain was able to multiply and cause disease in Arabidopsis, but the population kinetics were altered so that growth was delayed during the early stages of infection.


Orthomolecular oncology review: ascorbic acid and cancer 25 years later.
The effect of ascorbic acid on cancer has been a subject of great controversy. This is a follow-up review of the 1979 article by Cameron, Pauling, and Leibovitz published in Cancer Research. In this updated version, the authors address general aspects of ascorbic acid and cancer that have been presented before, while reviewing, analyzing, and updating new existing literature on the subject. In addition, they present and discuss their own mechanistic hypothesis on the effect of ascorbic acid on the cancer cell. The objective of this review is to provide an updated scientific basis for the use of ascorbic acid, especially intravenously as adjuvant treatment in pharmacological nutritional oncology.


Atraumatic spontaneous splenic rupture in a female COVID-19 patient.
Coronavirus disease (COVID-19), an infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has severely ravaged the world since the end of 2019. Although most cases range from mild to severe with primarily respiratory symptoms, there have been some unusual clinical presentations, one of which is described in this case report. A 30 year-old woman with no significant medical history presented to the emergency department (ED) in October 2020 with sudden onset of severe left upper and lower abdominal pain. Her initial triaged blood pressure was 70 mmHg systolic, associated with mild tachycardia. Her beta human chorionic gonadotropin (beta-hCG) was negative, and her initial hemoglobin was 9.3 g/dL. A bedside ultrasound (US) was immediately performed, which showed moderate free fluid in the pelvis as well as in the right and left upper quadrants of the abdomen. She was stabilized with a fluid bolus and later underwent a CT scan of the abdomen and pelvis, which showed an apparent grade III splenic laceration without active extravasation. The patient underwent a successful embolization procedure by interventional radiology (IR) and was discharged from the hospital 2 days later. The initial medical workup included a positive polymerase chain reaction (PCR) COVID-19 test but included no other findings that could serve as a cause for her spleen to spontaneously rupture. The purpose of this case report is to illustrate and make other clinicians aware of unusual potential complications and clinical presentations of COVID-19. The condition of spontaneous splenic rupture (SSR) is an uncommon but an emergent differential diagnosis in an otherwise healthy person with potential drastic outcomes. A careful approach in the management and care of these patients is warranted. This is one of a handful of case reports on SSR secondary to COVID-19 to the best of our knowledge.


The 2008 update of the Aspergillus nidulans genome annotation: a community effort.
The identification and annotation of protein-coding genes is one of the primary goals of whole-genome sequencing projects, and the accuracy of predicting the primary protein products of gene expression is vital to the interpretation of the available data and the design of downstream functional applications. Nevertheless, the comprehensive annotation of eukaryotic genomes remains a considerable challenge. Many genomes submitted to public databases, including those of major model organisms, contain significant numbers of wrong and incomplete gene predictions. We present a community-based reannotation of the Aspergillus nidulans genome with the primary goal of increasing the number and quality of protein functional assignments through the careful review of experts in the field of fungal biology.


A Batteryless Sensor ASIC for Implantable Bio-Impedance Applications.
The measurement of the biological tissue's electrical impedance is an active research field that has attracted a lot of attention during the last decades. Bio-impedances are closely related to a large variety of physiological conditions; therefore, they are useful for diagnosis and monitoring in many medical applications. Measuring living tissues, however, is a challenging task that poses countless technical and practical problems, in particular if the tissues need to be measured under the skin. This paper presents a bio-impedance sensor ASIC targeting a battery-free, miniature size, implantable device, which performs accurate 4-point complex impedance extraction in the frequency range from 2 kHz to 2 MHz. The ASIC is fabricated in 150 nm CMOS, has a size of 1.22 mm × 1.22 mm and consumes 165 μA from a 1.8 V power supply. The ASIC is embedded in a prototype which communicates with, and is powered by an external reader device through inductive coupling. The prototype is validated by measuring the impedances of different combinations of discrete components, measuring the electrochemical impedance of physiological solution, and performing ex vivo measurements on animal organs. The proposed ASIC is able to extract complex impedances with around 1 Ω resolution; therefore enabling accurate wireless tissue measurements.


Status of propranolol for treatment of infantile hemangioma and description of a randomized clinical trial.
Our primary objective was to review the current use of propranolol for treatment of infantile hemangioma (IH), specifically regarding 1) the age at initiation of therapy, 2) the method of initiation, 3) the use of other adjuvant therapy, 4) the duration of therapy and relapse rate, 5) the adverse events, and 6) the outcome. Our secondary objective was to describe a randomized, controlled, single-blinded trial comparing propranolol to prednisolone for treatment of IH. Ovid Medline and PubMed searches were completed for the MeSH keywords "propranolol" and "hemangioma." Forty-nine English-language articles were published between June 2008 and September 2010, and 28 of these reported data from a total of 213 patients. Only 6 studies treated more than 10 patients, and these were selected for review in detail (154 patients). The treatment was initiated during infancy in 92.9% of patients (mean, 4.5 months). Sixty-five percent of patients were treated with 2 mg/kg per day, and 25.3% with 3 mg/kg per day. Patients were monitored overnight at initiation of treatment in 3 series (59 patients), for 4 to 6 hours as outpatients in 2 series (62 patients), and initially as inpatients but later as outpatients in 1 series (32 patients). Propranolol was used as sole therapy in about two thirds of patients (103 patients). Treatment was ongoing in 46% of patients at the time of publication. The average treatment duration in the remaining patients was 5.1 months. Rebound growth occurred in 21% of patients after a mean of 4.3 months of therapy. Adverse events occurred in 18.1% of patients and included hypotension in 6, somnolence in 6, wheezing in 4, insomnia, agitation, and/or nightmares in 6, cool hands or night sweats in 2, gastroesophageal reflux in 3, and psoriasis-like rash in 1. All authors reported a favorable outcome with propranolol, but the definition of efficacy was not standardized. Propranolol is an attractive alternative to other treatments for IH. Despite apparent widespread use of this medication, the data are limited, and prospective studies are lacking for this indication. The relatively high rate of adverse effects supports the need for careful monitoring of patients on this therapy. Fastidious reporting of adverse events and objective evaluation of early and late outcomes are necessary to improve our understanding of the use of propranolol for this indication.


Repeated ovarian stimulations induce oxidative damage and mitochondrial DNA mutations in mouse ovaries.
Superovulation by injection of exogenous gonadotropin is the elementary method to produce in vivo-derived embryos for embryo transfer in women. Increased oocyte aneuploidy, embryo mortality, fetal growth retardation, and congenital abnormalities have been studied at higher-dose stimulations. Ovarian and oocyte biological aging possibly may have adverse implications for human oocyte competence with repeated hyperstimulation. In this study, we found that reduced competence for the human oocyte has been associated with degenerative embryo upsurge during embryo culture and failure to develop into the blastocyst stage in the three, four, five, and six stimulation cycles. On the other hand, the numbers of ovulated oocytes were decreased in the groups with more ovarian stimulation. More aggregated mitochondria were found in the cytoplasm of the repetitively stimulated embryos. Higher amounts of oxidative damage including 8-OH-dG, lipoperoxides, and carbonyl proteins were also revealed in the ovaries with more cycle numbers of ovarian stimulation. Higher proportions of mtDNA mutations were also found. The detected molecular size of the mutated band was approximately 675 bp. Increased amounts of carbonyl proteins were also revealed after repeated stimulation. An understanding of the relationship between oocyte competence and ovarian responses to stimulation in the mouse may provide insights into the origin of oocyte defects and the biology of ooplasmic aging that could be of clinical relevance in the diagnosis and treatment of human infertility.


Enabling stem cell therapies through synthetic stem cell-niche engineering.
Enabling stem cell-targeted therapies requires an understanding of how to create local microenvironments (niches) that stimulate endogenous stem cells or serve as a platform to receive and guide the integration of transplanted stem cells and their derivatives. In vivo, the stem cell niche is a complex and dynamic unit. Although components of the in vivo niche continue to be described for many stem cell systems, how these components interact to modulate stem cell fate is only beginning to be understood. Using the HSC niche as a model, we discuss here microscale engineering strategies capable of systematically examining and reconstructing individual niche components. Synthetic stem cell-niche engineering may form a new foundation for regenerative therapies.


An international prospective general population-based study of respiratory work disability.
Previous cross-sectional studies have shown that job change due to breathing problems at the workplace (respiratory work disability) is common among adults of working age. That research indicated that occupational exposure to gases, dust and fumes was associated with job change due to breathing problems, although causal inferences have been tempered by the cross-sectional nature of previously available data. There is a need for general population-based prospective studies to assess the incidence of respiratory work disability and to delineate better the roles of potential predictors of respiratory work disability. A prospective general population cohort study was performed in 25 centres in 11 European countries and one centre in the USA. A longitudinal analysis was undertaken of the European Community Respiratory Health Survey including all participants employed at any point since the baseline survey, 6659 subjects randomly sampled and 779 subjects comprising all subjects reporting physician-diagnosed asthma. The main outcome measure was new-onset respiratory work disability, defined as a reported job change during follow-up attributed to breathing problems. Exposure to dusts (biological or mineral), gases or fumes during follow-up was recorded using a job-exposure matrix. Cox proportional hazard regression modelling was used to analyse such exposure as a predictor of time until job change due to breathing problems. The incidence rate of respiratory work disability was 1.2/1000 person-years of observation in the random sample (95% CI 1.0 to 1.5) and 5.7/1000 person-years in the asthma cohort (95% CI 4.1 to 7.8). In the random population sample, as well as in the asthma cohort, high occupational exposure to biological dust, mineral dust or gases or fumes predicted increased risk of respiratory work disability. In the random sample, sex was not associated with increased risk of work disability while, in the asthma cohort, female sex was associated with an increased disability risk (hazard ratio 2.8, 95% CI 1.3 to 5.9). Respiratory work disability is common overall. It is associated with workplace exposures that could be controlled through preventive measures.


Defining Taiwanese children's health literacy abilities from a health promotion perspective.
Health literacy is related to health inequality, health behaviors, and health status. Globally, health literacy has primarily focused on adults and has been based on the medical model. It is necessary to understand children's life experiences as they relate to health; thus, this study attempted to evaluate and describe the health literacy abilities of sixth-graders in Taiwan. Interviews were conducted with 10 teachers and 11 caregivers, and focus groups were conducted with 32 children. Health literacy abilities corresponding to real-life situations were identified from life skills and the Taiwanese Curriculum Guidelines for health education. Three expert meetings were held to redefine children's health literacy using a health promotion perspective and confirmed indicators. An operational definition of three aspects of children's health literacy and 25 abilities was proposed: 11 functional health literacy abilities (e.g. understands the connection between personal health care behaviors and health); seven interactive health literacy abilities (e.g. obtains and understands information from various channels); and seven critical health literacy abilities (e.g. analyzes the relationship between personal needs and diet choices for a balanced diet). These indicators cover 10 health education categories. These findings highlight the importance of understanding Taiwanese children's health literacy, and the urgency of developing an appropriate measurement tool. The definition and indicators in this study were identified using a child-centered approach focusing on children's real-life experiences. The result serves as a solid basis for the development of the Taiwan Children's Health Literacy Scale, and provides information for the decision-making sector on health education.


Animal Models of Neurodegenerative Disease: Recent Advances in Fly Highlight Innovative Approaches to Drug Discovery.
Neurodegenerative diseases represent a formidable challenge to global health. As advances in other areas of medicine grant healthy living into later decades of life, aging diseases such as Alzheimer's disease (AD) and other neurodegenerative disorders can diminish the quality of these additional years, owed largely to the lack of efficacious treatments and the absence of durable cures. Alzheimer's disease prevalence is predicted to more than double in the next 30 years, affecting nearly 15 million Americans, with AD-associated costs exceeding $1 billion by 2050. Delaying onset of AD and other neurodegenerative diseases is critical to improving the quality of life for patients and reducing the burden of disease on caregivers and healthcare systems. Significant progress has been made to model disease pathogenesis and identify points of therapeutic intervention. While some researchers have contributed to our understanding of the proteins and pathways that drive biological dysfunction in disease using in vitro and in vivo models, others have provided mathematical, biophysical, and computational technologies to identify potential therapeutic compounds using in silico modeling. The most exciting phase of the drug discovery process is now: by applying a target-directed approach that leverages the strengths of multiple techniques and validates lead hits using Drosophila as an animal model of disease, we are on the fast-track to identifying novel therapeutics to restore health to those impacted by neurodegenerative disease.


Correlates of diabetic complications in Mexican-American elders.
This study was designed to examine the association of sociodemographic and health-related factors with the development of diabetic complications in older Mexican Americans. Data came from the baseline interview of the Hispanic Established Population for the Epidemiological Study of the Elderly (EPESE), conducted in 1993-1994, a population-based study of 3,050 Mexican Americans aged 65 and older from 5 southwestern states. A total of 690 subjects (23%) reported having been diagnosed with diabetes. Of these, 412 (60%) reported having one or more diabetic complications. Multiple logistic regression analysis found that respondents with less than 12 years of education were more likely to report diabetic complications than those with higher school education. Having diabetes for over 15 years, and having had a stroke or a heart attack were also associated with elevated rates of complications. Circulation problems were the most common complication reported by 280 (40%) respondents, followed by eye problems (38%), kidney problems (14%) and amputations (8%). Special attention should be given to sociodemographic and health-related factors influencing the health of older Mexican Americans. Identification of these factors will help physicians better control the disease to prevent complications.


Changes in Circulating Monocyte Subsets (CD16 Expression) and Neutrophil-to-Lymphocyte Ratio Observed in Patients Undergoing Cardiac Surgery.
The characteristics of circulating inflammatory cells (leukocytes) in patients undergoing heart surgery remains poorly understood. Recently, neutrophil-to-lymphocyte ratio (NLR) and specific monocyte subsets (based on CD14/CD16 expression) have been suggested as markers of inflammation and predictors of outcomes. The present study aims to characterize the influence cardiac surgery with cardiopulmonary bypass has on specific circulating leukocytes. All enrolled patients had blood samples taken pre- (0 days), early post- (5 days), and late post- (90 days) surgery. Complete blood counts were performed and whole leukocyte isolations were obtained from blood samples and analyzed with flow cytometry. Fluorophore-linked antibodies (CD45, CD11b, CD14, and CD16) were added to the blood cell isolations and later assessed by flow cytometry. Seventeen patients were enrolled and samples obtained at 0, 5, and 90 days. We demonstrated a significant increase in NLR (2.2-fold; p = 0.0028) and CD16 mean fluorescence index (MFI-measure fluorescence intensity shift of CD16 in a gated cell population) early at day 5 (2.0-fold; p = 0.0051). Both NLR and CD16 MFI levels generally returned to normal by day 90. There was a significant positive correlation between NLR and CD16 MFI (r2 = 0.29; p = 0.0064). Adverse cardiovascular event (AE) was defined as prolonged length of hospitalization or readmission to hospital for cardiac reasons after discharge was seen in 59% of patients (no deaths occurred). In an unadjusted analysis of AE, we identified NLR as a likely predictor of AE, which meant that patients developing AE had a significantly higher baseline NLR (p = 0.0065), something that was not observed with CD16 MFI (p = 0.2541). Cardiac surgery is associated with a significant increase in NLR and CD16 MFI (non-classical monocytes) early after surgery corresponding to the early inflammatory phase after surgery. Furthermore, we have, for the first time, identified a significant correlation between NLR and CD16 MFI. While the mechanism for this relationship remains unclear, our findings support the use of a simple test of NLR as a biomarker of inflammation for predicting outcomes in cardiac surgery patients.


Acetaminophen induced gender-dependent liver injury and the involvement of GCL and GPx.
Acetaminophen (AP) is widely used as the antipyretic and analgesic drug in clinic, and it can induce serious liver injury in the case of excessive abuse. The present study showed that AP (400 mg/kg) induced obvious liver injury, while in male mice the hepatotoxicity induced by AP was much more serious than in female mice as indicated by the results of alanine aminotransferase (ALT) activity and reduced glutathione (GSH) amount. Further, the enzymatic activity and protein expression of glutamate-cysteine ligase (GCL) and glutathione peroxidase (GPx) were all higher in female mice liver than in male after the administration of AP (200 mg/kg). Meanwhile, AP (10 mM) decreased GCL and GPx activity in isolated mouse hepatocytes in the time-dependent manner, while the inhibitors of GCL and GPx can augment AP induced-cytotoxicity. Taken together, our results demonstrate the gender-related liver injury induced by AP and the important role of GCL and GPx in regulating such hepatotoxicity.


[Simulation and air-conditioning in the nose].
Heating and humidification of the respiratory air are the main functions of the nasal airways in addition to cleansing and olfaction. Optimal nasal air conditioning is mandatory for an ideal pulmonary gas exchange in order to avoid dessication and adhesion of the alveolar capillary bed. The complex three-dimensional anatomical structure of the nose makes it impossible to perform detailed in vivo studies on intranasal heating and humidification within the entire nasal airways applying various technical set-ups. The main problem of in vivo temperature and humidity measurements is a poor spatial and time resolution. Therefore, in vivo measurements are feasible to a restricted extent, only providing single temperature values as the complete nose is not entirely accessible. Therefore, data on the overall performance of the nose are only based on one single measurement within each nasal segment. In vivo measurements within the entire nose are not feasible. These serious technical issues concerning in vivo measurements led to a large number of numerical simulation projects in the last few years providing novel information about the complex functions of the nasal airways. In general, numerical simulations only calculate predictions in a computational model, e. g. realistic nose model, depending on the setting of the boundary conditions. Therefore, numerical simulations achieve only approximations of a possible real situation. The aim of this report is the synopsis of the technical expertise on the field of in vivo nasal air conditioning, the novel information of numerical simulations and the current state of knowledge on the influence of nasal and sinus surgery on nasal air conditioning.


Replication and transmission of mammalian-adapted H9 subtype influenza virus in pigs and quail.
Influenza A virus is a major pathogen of birds, swine and humans. Strains can jump between species in a process often requiring mutations and reassortment, resulting in outbreaks and, potentially, pandemics. H9N2 avian influenza is predominant in poultry across Asia and occasionally infects humans and swine. Pandemic H1N1 (H1N1pdm) is endemic in humans and swine and has a history of reassortment in pigs. Previous studies have shown the compatibility of H9N2 and H1N1pdm for reassortment in ferrets, a model for human infection and transmission. Here, the effects of ferret adaptation of H9 surface gene segments on the infectivity and transmission in at-risk natural hosts, specifically swine and quail, were analysed. Reassortant H9N1 and H9N2 viruses, carrying seven or six gene segments from H1N1pdm, showed infectivity and transmissibility in swine, unlike the wholly avian H9N2 virus with ferret-adapted surface genes. In quail, only the reassortant H9N2 with the six internal gene segments from the H1N1pdm strain was able to infect and transmit, although less efficiently than the wholly avian H9N2 virus with ferret-adapted surface genes. These results highlight that ferret-adapted mutations on the haemagglutinin of H9 subtype virus do not restrict the ability of the virus to infect swine and quail, and that the ability to transmit in these species depends on the context of the whole virus. As such, this study emphasizes the threat that H9N2 reassortant viruses pose to humans and agricultural species and the importance of the genetic constellation of the virus to its ability to replicate and transmit in natural hosts of influenza.


Transcatheter Aortic Valve Replacement Complication Rates in Teaching Vs Non-Teaching Centers in the United States.
The objective of our study is to compare transcatheter aortic valve replacement (TAVR) complication rates among teaching vs non-teaching centers in the United States. Using National Inpatient Sample (NIS) data, the largest all-payer database of hospital inpatient stay available in the United States, we identified patients (age ≥18 years) who underwent TAVR from January-December 2012. We constructed multivariable models to determine independent predictors (age, sex, race, Charlson's comorbidity index, hospital size, hospital location, and TAVR approach) of TAVR-associated complications. We identified 7405 TAVR procedures performed in the United States in 2012. In all, 88% of TAVRs were performed in teaching centers. There was no difference in mortality following TAVR between teaching and non-teaching centers. In-hospital complication rate was lower in teaching centers vs non-teaching centers (42% vs. 50%, respectively; P<.001). In adjusted analysis, hemorrhage requiring transfusion (13.2% vs. 20.8%; P<.001), renal complications requiring dialysis (1.2% vs. 2.3%; P<.01), respiratory complications (7.5% vs. 11%; P<.001), and complications requiring open-heart surgery (2% vs. 4.6%; P<.001) were lower in teaching centers vs non-teaching centers. Vascular access-site, pacemaker insertion, pericardial, and neurological complications were similar between teaching and non-teaching centers. Institutional design impacts TAVR complications, albeit with no difference in mortality. In general, complication rates are lower in teaching centers compared with non-teaching centers.


Alternative splicing of the APC gene in the neural retina and retinal pigment epithelium.
Hypertrophy and hyperplasia of the retinal pigment epithelium (RPE) is associated with an inherited predisposition to human familial adenomatous polyposis coli, suggesting that expression of the adenomatous polyposis coli (APC) tumor suppressor may regulate RPE proliferation/differentiation. Distinctive APC isoforms exist in different cell types due to alternative splicing of the APC transcripts. We hypothesize that differences in expression patterns of APC protein isoforms are critical to RPE proliferation/differentiation. To investigate these relationships, APC gene expression was characterized in the retinas and RPE from fetal and adult human and mouse, and in the epiretinal membranes (ERM) from 5 patients with proliferative vitreoretinopathy (PVR). Expression patterns of alternative splice-forms of APC transcripts were evaluated by comparative quantitative RT-PCR. Exon 1 of APC encodes a heptad repeat that confers the ability of APC to homodimerize. APC protein isoforms containing or lacking this heptad were characterized by western blot analysis and immunohistochemistry. Comparative quantitative RT-PCR demonstrated a predominant exon 1 containing, conventional APC splice-form in the early developing fetal RPE and retina, and in all the tested ERM samples from patients with PVR. This method also demonstrated an increased level of exon 1 lacking APC splice-form in the mature RPE and retina. Western blot analysis and immunofluorescence microscopy demonstrated the conventional APC only in the RPE, and the APC isoform without the first heptad repeat in both the retina and RPE. Immunofluorescence microscopy also demonstrated only the conventional APC in the ERM samples tested. These results suggest that alternative splicing of APC leads to differential APC expression with potentially unique functions. APC isoform without the first heptad repeat may play a role in cell cycle cessation in the adult retina and RPE, and the down regulation of this APC isoform may contribute to the potential of RPE to migrate and proliferate.


Discovering social groups via latent structure learning.
Humans form social coalitions in every society on earth, yet we know very little about how social group boundaries are learned and represented. We derive predictions from a computational model of latent structure learning to move beyond explicit category labels and mere similarity as the sole inputs to social group representations. Four experiments examine (a) how evidence for group boundaries is accumulated in a consequential social context (i.e., learning about others' political values), (b) to what extent learning about these boundaries drives one's own choices as well as attributions about other agents in the environment, and (c) whether these latent groups affect choice even in the presence of group labels that contradict the latent group structure. Our results suggest that people integrate information about how agents in the environment relate to one another in addition to oneself to infer social group structure. We argue that this mechanism is a plausible explanation of other theories of social relations-for example, balance theory. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Modulation of the prefrontal blood oxygenation response to intermittent theta-burst stimulation in depression: A sham-controlled study with functional near-infrared spectroscopy.
To better understand the neural mechanisms behind the effect of intermittent theta-burst stimulation (iTBS), we investigated how the prefrontal blood oxygenation response measured by changes in oxygenated haemoglobin (oxy-Hb) was modulated during a sham-controlled iTBS treatment course, and whether this was related to depressive symptom change. In this randomised, double-blind study, patients with ongoing treatment-resistant depression received either active (n = 18) or sham (n = 21) iTBS over the dorsomedial prefrontal cortex for ten to fifteen days with two sessions daily. Event-related functional near-infrared spectroscopy (fNIRS) was measured during each iTBS train, and resting-state oxy-Hb was compared before and after each iTBS session at the first, fifth, and last treatment day. Patients receiving active iTBS had an increase of the event-related oxy-Hb response compared to the sham group on the fifth (bilateral prefrontal cortices p < .001) and last (left prefrontal p = .007, right prefrontal p = .025) treatment day. Resting-state analysis showed suppressed oxy-Hb change in active iTBS compared to sham iTBS on the last treatment day (p = .024). Oxy-Hb change was unrelated to depressive symptom change (p = .474). This study describes a modulation of the blood oxygenation response over the prefrontal cortex that was built up during the course of active iTBS treatment in depression.


Propagation of beta/gamma rhythms in the cortico-basal ganglia circuits of the parkinsonian rat.
Much of the motor impairment associated with Parkinson's disease is thought to arise from pathological activity in the networks formed by the basal ganglia (BG) and motor cortex. To evaluate several hypotheses proposed to explain the emergence of pathological oscillations in parkinsonism, we investigated changes to the directed connectivity in BG networks following dopamine depletion. We recorded local field potentials (LFPs) in the cortex and basal ganglia of rats rendered parkinsonian by injection of 6-hydroxydopamine (6-OHDA) and in dopamine-intact controls. We performed systematic analyses of the networks using a novel tool for estimation of directed interactions (nonparametric directionality, NPD). We used a "conditioned" version of the NPD analysis that reveals the dependence of the correlation between two signals on a third reference signal. We find evidence of the dopamine dependency of both low-beta (14-20 Hz) and high-beta/low-gamma (20-40 Hz) directed network interactions. Notably, 6-OHDA lesions were associated with enhancement of the cortical "hyperdirect" connection to the subthalamic nucleus (STN) and its feedback to the cortex and striatum. We find that pathological beta synchronization resulting from 6-OHDA lesioning is widely distributed across the network and cannot be located to any individual structure. Furthermore, we provide evidence that high-beta/gamma oscillations propagate through the striatum in a pathway that is independent of STN. Rhythms at high beta/gamma show susceptibility to conditioning that indicates a hierarchical organization compared with those at low beta. These results further inform our understanding of the substrates for pathological rhythms in salient brain networks in parkinsonism. NEW & NOTEWORTHY We present a novel analysis of electrophysiological recordings in the cortico-basal ganglia network with the aim of evaluating several hypotheses concerning the origins of abnormal brain rhythms associated with Parkinson's disease. We present evidence for changes in the directed connections within the network following chronic dopamine depletion in rodents. These findings speak to the plausibility of a "short-circuiting" of the network that gives rise to the conditions from which pathological synchronization may arise.