Energy-efficient WDM-OFDM-PON employing shared OFDM modulation modules in optical line terminal.
We propose and experimentally demonstrate a scheme to improve the energy efficiency of wavelength division multiplexing - orthogonal frequency division multiplexing - passive optical networks (WDM-OFDM-PONs). By using an N × M opto-mechanic switch in optical line terminal (OLT), an OFDM modulation module is shared by several channels to deliver data to multiple users with low traffic demands during non-peak hours of the day, thus greatly reducing the number of operating devices and minimizing the energy consumption of the OLT. An experiment utilizing one OFDM modulation module to serve three optical network units (ONUs) in a WDM-OFDM-PON is performed to verify the feasibility of our proposal. Theoretical analysis and numerical calculation show that the proposed scheme can achieve a saving of 23.6% in the energy consumption of the OFDM modulation modules compared to conventional WDM-OFDM-PON.


Niche segregation and genetic structure of Campylobacter jejuni populations from wild and agricultural host species.
Bacterial populations can display high levels of genetic structuring but the forces that influence this are incompletely understood. Here, by combining modelling approaches with multilocus sequence data for the zoonotic pathogen Campylobacter, we investigated how ecological factors such as niche (host) separation relate to population structure. We analysed seven housekeeping genes from published C. jejuni and C. coli isolate collections from a range of food and wild animal sources as well as abiotic environments. By reconstructing genetic structure and the patterns of ancestry, we quantified C. jejuni host association, inferred ancestral populations, investigated genetic admixture in different hosts and determined the host origin of recombinant C. jejuni alleles found in hybrid C. coli lineages. Phylogenetically distinct C. jejuni lineages were associated with phylogenetically distinct wild birds. However, in the farm environment, phylogenetically distant host animals shared several C. jejuni lineages that could not be segregated according to host origin using these analyses. Furthermore, of the introgressed C. jejuni alleles found in C. coli lineages, 73% were attributed to genotypes associated with food animals. Our results are consistent with an evolutionary scenario where distinct Campylobacter lineages are associated with different host species but the ecological factors that maintain this are different in domestic animals such that phylogenetically distant animals can harbour closely related strains.


Bullying-related behaviour in a mainstream high school versus a high school for autism: Self-report and peer-report.
This study examined the frequency of bullying, victimisation and defending behaviours among children with autism spectrum disorder and normal intelligence, using both self-report and peer-report information. Peer-report and self-report data were collected on a single classroom of 26 early adolescent boys attending a special school for children with autism and compared with 23 typically developing boys attending a single mainstream secondary school. Results showed that self- and peer-reported bully and victimisation rates did not differ between boys with autism spectrum disorder and typically developing boys. However, self-reported defending behaviour was less likely to be reported by boys in the autism spectrum disorder school compared to boys in the mainstream school, although there was no such difference for peer-reported defending.


Rhabdomyolysis caused by an unusual interaction between azithromycin and simvastatin.
Rhabdomyolysis is an uncommon but life-threatening adverse effect of simvastatin therapy. A 73-year-old male on chronic simvastatin therapy received azithromycin for acute bronchitis. He presented with weakness of all extremities with a significant increase in creatinine phosphokinase levels and acute kidney injury. Simvastatin was stopped and supportive therapy with intravenous saline and bicarbonate was initiated. The serum creatinine and creatine phosphokinase returned to baseline in the next 7 days. Two months later, simvastatin was resumed without any recurrence of symptoms. Our case report highlights the rare description of rhabdomyolysis caused by a drug interaction between simvastatin with azithromycin.


Synthesis and structure of duplex DNA containing the genotoxic nucleobase lesion N7-methylguanine.
The predominant product of aberrant DNA methylation is the genotoxic lesion N7-methyl-2'-deoxyguanosine (m7dG). M7dG is recognized and excised by lesion-specific DNA glycosylases, namely AlkA in E. coli and Aag in humans. Structural studies of m7dG recognition and catalysis by these enzymes have been hampered due to a lack of efficient means by which to incorporate the chemically labile m7dG moiety site-specifically into DNA on a preparative scale. Here we report a solution to this problem. We stabilized the lesion toward acid-catalyzed and glycosylase-catalyzed depurination by 2'-fluorination and toward base-catalyzed degradation using mild, nonaqueous conditions in the DNA deprotection reaction. Duplex DNA containing 2'-fluoro-m7dG (Fm7dG) cocrystallized with AlkA as a host-guest complex in which the lesion-containing segment of DNA was nearly devoid of protein contacts, thus enabling the first direct visualization of the N7-methylguanine lesion nucleobase in DNA. The structure reveals that the base-pairing mode of Fm7dG:C is nearly identical to that of G:C, and Fm7dG does not induce any apparent structural disturbance of the duplex structure. These observations suggest that AlkA and Aag must perform a structurally invasive interrogation of DNA in order to detect the presence of intrahelical m7dG lesions.


Functional-anatomical validation and individual variation of diffusion tractography-based segmentation of the human thalamus.
Parcellation of the human thalamus based on cortical connectivity information inferred from non-invasive diffusion-weighted images identifies sub-regions that we have proposed correspond to nuclei. Here we test the functional and anatomical validity of this proposal by comparing data from diffusion tractography, cytoarchitecture and functional imaging. We acquired diffusion imaging data in eleven healthy subjects and performed probabilistic tractography from voxels within the thalamus. Cortical connectivity information was used to divide the thalamus into sub-regions with highest probability of connectivity to distinct cortical areas. The relative volumes of these connectivity-defined sub-regions correlate well with volumetric predictions based on a histological atlas. Previously reported centres of functional activation within the thalamus during motor or executive tasks co-localize within atlas regions showing high probabilities of connection to motor or prefrontal cortices, respectively. This work provides a powerful validation of quantitative grey matter segmentation using diffusion tractography in humans. Co-registering thalamic sub-regions from 11 healthy individuals characterizes inter-individual variation in segmentation and results in a population-based atlas of the human thalamus that can be used to assign likely anatomical labels to thalamic locations in standard brain space. This provides a tool for specific localization of functional activations or lesions to putative thalamic nuclei.


Efficient Noninferiority Testing Procedures for Simultaneously Assessing Sensitivity and Specificity of Two Diagnostic Tests.
Sensitivity and specificity are often used to assess the performance of a diagnostic test with binary outcomes. Wald-type test statistics have been proposed for testing sensitivity and specificity individually. In the presence of a gold standard, simultaneous comparison between two diagnostic tests for noninferiority of sensitivity and specificity based on an asymptotic approach has been studied by Chen et al. (2003). However, the asymptotic approach may suffer from unsatisfactory type I error control as observed from many studies, especially in small to medium sample settings. In this paper, we compare three unconditional approaches for simultaneously testing sensitivity and specificity. They are approaches based on estimation, maximization, and a combination of estimation and maximization. Although the estimation approach does not guarantee type I error, it has satisfactory performance with regard to type I error control. The other two unconditional approaches are exact. The approach based on estimation and maximization is generally more powerful than the approach based on maximization.


In vivo indices of oxidative stress in lead-exposed C57BL/6 mice are reduced by treatment with meso-2,3-dimercaptosuccinic acid or N-acetylcysteine.
Knowledge of lead's capacity to disrupt the prooxidant/antioxidant balance within mammalian tissues suggests that definitive therapy for chronic lead poisoning should encompass both chelating and antioxidant actions. The dithiol meso-2,3-Dimercaptosuccinic Acid (DMSA) is the first orally administered metal chelating agent to receive U.S. Food and Drug Administration (FDA) approval for the treatment of childhood plumbism and possesses the potential to function as an antioxidant by removing lead from the site of deleterious oxidation reactions. Five weeks of lead exposure was found to deplete glutathione (GSH) levels, increase oxidized glutathione (GSSG), and promote malondialdehyde (MDA) production in both liver and brain samples taken from C57BL/6 mice. GSH levels increased and GSSG and MDA levels decreased in groups of lead-exposed mice that received 1 mmol/kg DMSA or 5.5 mmol/kg N-acetylcysteine (NAC) for 7 d prior to sacrifice. Treatment with DMSA caused a reduction in blood, liver, and brain lead levels consistent with its function as a chelating agent, while treatment with NAC did not reduce these lead levels. However, NAC did cause a reduction in indices of oxidative stress in both brain and liver samples, which implies that this synthetic thiol-containing antioxidant is capable of abrogating lead-induced oxidative stress in vivo. Overall, these results suggest that lead-induced oxidative stress in vivo can be mitigated by pharmacologic interventions, which encompass both chelating as well as thiol-mediated antioxidant functions.


The efficacy of N-acetylcysteine to protect the human cochlea from subclinical hearing loss caused by impulse noise: a controlled trial.
In military outdoor shooting training, with safety measures enforced, the risk of a permanent, noise-induced hearing loss is very small. But urban warfare training performed indoors, with reflections from walls, might increase the risk. A question is whether antioxidants can reduce the negative effects of noise on human hearing as it does on research animals. Hearing tests were performed on a control group of 23 military officers before and after a shooting session in a bunker-like room. The experiments were repeated on another group of 11 officers with peroral adminstration of N-acetyl-cysteine (NAC), directly after the shooting. The measurements performed were tone thresholds; transient-evoked otoacoustic emissions, with and without contralateral noise; and psycho-acoustical modulation transfer function (PMTF), thresholds for brief tones in modulated noise. Effects from shooting on hearing thresholds were small, but threshold behavior supports use of NAC treatment. On the PMTF, shooting without NAC gave strong effects. Those effects were like those from continuous noise, which means that strict safety measures should be enforced. The most striking finding was that the non-linearity of the cochlea, that was strongly reduced in the group without NAC, as manifested by the PMTF-results, was practically unchanged in the NAC-group throughout the study. NAC treatment directly after shooting in a bunkerlike room seems to give some protection of the cochlea.


Vitamin D and Cancer: Diversity, Complexity, and Still a Ways to Go.
Vitamin D has taken a center-stage role in our basic and population research quest for the panacea for all human maladies, including cancer, yet sufficient evidence for a beneficial role has existed only for bone health. This Commentary discusses and places into a broader context the report of Chandler and colleagues that found a protective association for higher vitamin D status in colorectal cancer in women, consistent with most other cohort studies but not with limited supplementation trial data. Little human evidence exists for the preventive potential in other malignancies, including breast cancer, with the exception of possible benefit in bladder cancer and an adverse serologic association with prostate cancer (pancreatic cancer risk may be similarly influenced) that is supported by vitamin D genetic data. Current vitamin D trials are examining high-dose supplementation (i.e., 1,600-3,333 IU daily) for effects on multiple outcomes, but they may not have sufficient power to test efficacy in colorectal or other specific malignancies and are unlikely to inform any benefit for higher physiologic levels. A more complete understanding of vitamin D and human carcinogenesis will come from multifaceted lines of research, including elucidation of organ site-specific biologic mechanisms, prospective serologic analyses, testing of vitamin D-related genetic variation, and short-term clinical-metabolic biomarker studies of multidose vitamin D supplementation, including metabolomic profiling of controlled supplementation in these and past or ongoing trials.


Weight Changes After Thyroid Surgery for Patients with Benign Thyroid Nodules and Thyroid Cancer: Population-Based Study and Systematic Review and Meta-Analysis.
A key concern among patients who undergo thyroid surgery is postoperative weight gain. Yet, the impact of thyroid surgery on weight is unclear. The population-based Rochester Epidemiology Project was used to examine weight and body mass index (BMI) changes at one, two, and three years of follow-up in (i) patients with thyroid cancer and benign thyroid nodules after thyroid surgery, and (ii) patients with thyroid nodules who did not have surgery. A comprehensive systematic review of the published literature from inception to February 2016 was also conducted. The results were pooled across studies using a random effects model. A total of 435 patients were identified: 181 patients with thyroid cancer who underwent surgery (group A), 226 patients with benign thyroid nodules without surgery (group B), and 28 patients with benign thyroid nodules undergoing surgery (group C). Small changes in mean weight, BMI, and the number of patients whose weight increased between 5 and 10 kg were similar during each year of follow-up between patients in groups A and B. Furthermore, age >50 years, female sex, baseline BMI >25 kg/m2, and thyrotropin value at one to two years were not predictors of a 5% weight change. In the meta-analysis, 11 studies were included. One to two years after surgery for thyroid cancer or thyroid nodules, patients gained on average 0.94 kg [confidence interval (CI) 0.58-1.33] and 1.07 kg [CI 0.26-1.87], respectively. Patients with benign thyroid nodules who did not have surgery gained 1.50 kg [CI 0.60-2.4] at the longest follow-up. On average, patients receiving care for thyroid nodules or cancer gain weight, but existing evidence suggests that surgery for these conditions does not contribute significantly to further weight gain. Clinicians and patients can use this information to discuss what to expect after thyroid surgery.


Daily life impact of malocclusion in Swedish adolescents: a grounded theory study.
To explore how malocclusions affect daily life in adolescents and how adolescents cope with malocclusion-related distress. Twelve strategically selected teenagers, seven girls and five boys aged 13-14 years, participated in this study. Open, tape-recorded in-depth interviews based on Focus Group Discussions (FGD) were performed using a theme guide and analyzed according to the qualitative method of classic grounded theory (GT). A core category was identified and named 'Repeatedly reminded of the malocclusion'. Associated to the core category, five categories were generated and labeled 'Being directed by the media's ideal image', 'Monitoring others' teeth', 'Struggling with low self-esteem', 'Hiding one's teeth' and 'Striving for cure'. Low self-esteem appeared to be frequently reinforced through the concerns for the malocclusion and handled via different coping strategies, such as hiding the teeth and striving to receive orthodontic treatment. Such processes were further enforced through the influence of media. Low self-esteem could be associated to a visible malposition of teeth, according to the informants. Having to wait for orthodontic treatment was frustrating the adolescents. Adolescents with malocclusion are often reminded of their condition, which can lead to avoiding strategies to minimize the negative feelings associated with the teeth and low self-esteem. Clinicians may therefore need to be aware of potential irrational behaviors when interacting with adolescents with malocclusions. The findings also suggest that there might be a discrepancy of attitudes between professionals focusing on oral health aspects of malocclusions and the adolescents focusing on esthetic aspects.


Printed educational materials: effects on professional practice and healthcare outcomes.
Printed educational materials are widely used passive dissemination strategies to improve the quality of clinical practice and patient outcomes. Traditionally they are presented in paper formats such as monographs, publication in peer-reviewed journals and clinical guidelines. To assess the effect of printed educational materials on the practice of healthcare professionals and patient health outcomes.To explore the influence of some of the characteristics of the printed educational materials (e.g. source, content, format) on their effect on professional practice and patient outcomes. For this update, search strategies were rewritten and substantially changed from those published in the original review in order to refocus the search from published material to printed material and to expand terminology describing printed materials. Given the significant changes, all databases were searched from start date to June 2011. We searched: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), HealthStar, CINAHL, ERIC, CAB Abstracts, Global Health, and the EPOC Register. We included randomised controlled trials (RCTs), quasi-randomised trials, controlled before and after studies (CBAs) and interrupted time series (ITS) analyses that evaluated the impact of printed educational materials (PEMs) on healthcare professionals' practice or patient outcomes, or both. We included three types of comparisons: (1) PEM versus no intervention, (2) PEM versus single intervention, (3) multifaceted intervention where PEM is included versus multifaceted intervention without PEM. There was no language restriction. Any objective measure of professional practice (e.g. number of tests ordered, prescriptions for a particular drug), or patient health outcomes (e.g. blood pressure) were included. Two review authors undertook data extraction independently, and any disagreement was resolved by discussion among the review authors. For analyses, the included studies were grouped according to study design, type of outcome (professional practice or patient outcome, continuous or dichotomous) and type of comparison. For controlled trials, we reported the median effect size for each outcome within each study, the median effect size across outcomes for each study and the median of these effect sizes across studies. Where the data were available, we re-analysed the ITS studies and reported median differences in slope and in level for each outcome, across outcomes for each study, and then across studies. We categorised each PEM according to potential effects modifiers related to the source of the PEMs, the channel used for their delivery, their content, and their format. The review includes 45 studies: 14 RCTs and 31 ITS studies. Almost all the included studies (44/45) compared the effectiveness of PEM to no intervention. One single study compared paper-based PEM to the same document delivered on CD-ROM. Based on seven RCTs and 54 outcomes, the median absolute risk difference in categorical practice outcomes was 0.02 when PEMs were compared to no intervention (range from 0 to +0.11). Based on three RCTs and eight outcomes, the median improvement in standardised mean difference for continuous profession practice outcomes was 0.13 when PEMs were compared to no intervention (range from -0.16 to +0.36). Only two RCTs and two ITS studies reported patient outcomes. In addition, we re-analysed 54 outcomes from 25 ITS studies, using time series regression and observed statistically significant improvement in level or in slope in 27 outcomes. From the ITS studies, we calculated improvements in professional practice outcomes across studies after PEM dissemination (standardised median change in level = 1.69). From the data gathered, we could not comment on which PEM characteristic influenced their effectiveness. The results of this review suggest that when used alone and compared to no intervention, PEMs may have a small beneficial effect on professional practice outcomes. There is insufficient information to reliably estimate the effect of PEMs on patient outcomes, and clinical significance of the observed effect sizes is not known. The effectiveness of PEMs compared to other interventions, or of PEMs as part of a multifaceted intervention, is uncertain.


Antibiotic utilization based on primary treatment of pediatric empyema.
Chemical fibrinolysis has been shown to be as effective as surgical debridement for the treatment of pediatric empyema. However, no studies effectively evaluate antibiotic treatment. We evaluated antibiotic utilization among different treatments of pediatric empyema. This is a retrospective review of 169 empyema patients who underwent chemical and/or mechanical fibrinolysis at a dedicated children's hospital from 2005-2013. Data points included duration of therapy, cultures, presence of necrosis or abscess, and adverse drug reactions. Immunocompromised patients and those with additional foci of infection were excluded. Twenty-seven patients underwent video-assisted thoracoscopic surgery (VATS), 123 had chemical fibrinolysis via tube thoracostomy with tissue plasminogen activator (tPA), and 19 had tPA followed by VATS. The mean (± standard deviation) duration of total antibiotic therapy was 25.7 ± 6.5 d; following a 24 h afebrile period of 19.4 ± 6.3 d. Patients who had tPA had a significantly shorter duration of parenteral antibiotic therapy when compared with primary VATS (9.2 ± 3.6 d versus 11.6 ± 5.5 d, P = 0.04) and VATS following tPA (9.2 ± 3.6 d versus 14.3 ± 8.1 d, P < 0.01). Patients with necrosis or abscess (n = 26) had an increased total duration of antibiotics (29.3 ± 5.7 d versus 25.1 ± 6.4 d, P < 0.01). Seventy patients (41%) had an adverse reaction related to antibiotic use. Patients with empyema currently receive a protracted variable course of antibiotic therapy influenced by primary treatment and the presence of necrosis or abscess. With a high incidence of adverse reactions, a standardized protocol with truncated treatment duration should be considered.


The accidental introduction of invasive animals as hitchhikers through inanimate pathways: a New Zealand perspective.
Hitchhiker organisms have been known since the earliest days of international travel, but changes in global trade mean that there are more now than ever before. They include a number of serious invasive species and are among the most difficult of quarantine problems to manage. Invasive animals transported as hitchhikers, other than plant pests, fall largely outside the international frameworks for biosecurity risk analysis. However, this is not necessarily a barrierto either risk analysis or effective management. While there are a number of challenges in managing hitchhiker organisms, the risk analysis tools that are needed already exist. However, opening up access to appropriate information, increasing international cooperation and developing new biosecurity treatments suitable for large-volume pathways will enable significant improvements.


An 18O double-labelling study of haemoglobin catabolism in the rat.
The degradation of haemoglobin to bilirubin in the rat was investigated by 18O labelling of the molecular oxygen consumed by the animal. The oxygen atoms incorporated into bilirubin were derived from two different oxygen molecules. Implications of this finding for the mechanism of haem catabolism in vivo are discussed; both verdohaem and a dioxygen-bridged compound appear to be excluded at intermediates.


Disgust implicated in obsessive-compulsive disorder.
Psychiatric classificatory systems consider obsessions and compulsions as forms of anxiety disorder. However, the neurology of diseases associated with obsessive-compulsive symptoms suggests the involvement of fronto-striatal regions likely to be involved in the mediation of the emotion of disgust, suggesting that dysfunctions of disgust should be considered alongside anxiety in the pathogenesis of obsessive-compulsive behaviours. We therefore tested recognition of facial expressions of basic emotions (including disgust) by groups of participants with obsessive-compulsive disorder (OCD) and with Gilles de la Tourette's syndrome (GTS) with an without co-present obsessive-compulsive behaviours (GTS with OCB; GTS without OCB). A group of people suffering from panic disorder and generalized anxiety were also included in the study. Both groups with obsessive-compulsive symptoms (OCD; GTS with OCB) showed impaired recognition of facial expressions of disgust. Such problems were not evident in participants with panic disorder and generalized anxiety, or for participants with GTS without obsessions or compulsions, indicating that the deficit is closely related to the presence of obsessive-compulsive symptoms. Participants with OCD were able to assign words to emotion categories without difficulty, showing that their problem with disgust is linked to a failure to recognize this emotion in others and not a comprehension or response criterion effect. Impaired recognition of disgust is consistent with the neurology of OCD and with the idea that abnormal experience of disgust may be involved in the genesis of obsessions and compulsions.


Wearable Movement Sensors for Rehabilitation: A Focused Review of Technological and Clinical Advances.
Recent technologic advancements have enabled the creation of portable, low-cost, and unobtrusive sensors with tremendous potential to alter the clinical practice of rehabilitation. The application of wearable sensors to track movement has emerged as a promising paradigm to enhance the care provided to patients with neurologic or musculoskeletal conditions. These sensors enable quantification of motor behavior across disparate patient populations and emerging research shows their potential for identifying motor biomarkers, differentiating between restitution and compensation motor recovery mechanisms, remote monitoring, telerehabilitation, and robotics. Moreover, the big data recorded across these applications serve as a pathway to personalized and precision medicine. This article presents state-of-the-art and next-generation wearable movement sensors, ranging from inertial measurement units to soft sensors. An overview of clinical applications is presented across a wide spectrum of conditions that have potential to benefit from wearable sensors, including stroke, movement disorders, knee osteoarthritis, and running injuries. Complementary applications enabled by next-generation sensors that will enable point-of-care monitoring of neural activity and muscle dynamics during movement also are discussed.


Pseudo-spectral methods and linear instabilities in reaction-diffusion fronts.
We explore the application of a pseudo-spectral Fourier method to a set of reaction-diffusion equations and compare it with a second-order finite difference method. The prototype cubic autocatalytic reaction-diffusion model as discussed by Gray and Scott [Chem. Eng. Sci. 42, 307 (1987)] with a nonequilibrium constraint is adopted. In a spatial resolution study we find that the phase speeds of one-dimensional finite amplitude waves converge more rapidly for the spectral method than for the finite difference method. Furthermore, in two dimensions the symmetry preserving properties of the spectral method are shown to be superior to those of the finite difference method. In studies of plane/axisymmetric nonlinear waves a symmetry breaking linear instability is shown to occur and is one possible route for the formation of patterns from infinitesimal perturbations to finite amplitude waves in this set of reaction-diffusion equations. (c) 1996 American Institute of Physics.


Impact of dual antiplatelet therapy after coronary artery bypass surgery on 1-year outcomes in the Arterial Revascularization Trial.
There is still little evidence to boldport routine dual antiplatelet therapy (DAPT) with P2Y12 antagonists following coronary artery bypass grafting (CABG). The Arterial Revascularization Trial (ART) was designed to compare 10-year survival after bilateral versus single internal thoracic artery grafting. We aimed to get insights into the effect of DAPT (with clopidogrel) following CABG on 1-year outcomes by performing a post hoc ART analysis. Among patients enrolled in the ART (n = 3102), 609 (21%) and 2308 (79%) were discharged on DAPT or aspirin alone, respectively. The primary end-point was the incidence of major adverse cerebrovascular and cardiac events (MACCE) at 1 year including cardiac death, myocardial infarction, cerebrovascular accident and reintervention; safety end-point was bleeding requiring hospitalization. Propensity score (PS) matching was used to create comparable groups. Among 609 PS-matched pairs, MACCE occurred in 34 (5.6%) and 34 (5.6%) in the DAPT and aspirin alone groups, respectively, with no significant difference between the 2 groups [hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.59-1.59; P = 0.90]. Only 188 (31%) subjects completed 1 year of DAPT, and in this subgroup, MACCE rate was 5.8% (HR 1.11, 95% CI 0.53-2.30; P = 0.78). In the overall sample, bleeding rate was higher in DAPT group (2.3% vs 1.1%; P = 0.02), although this difference was no longer significant after matching (2.3% vs 1.8%; P = 0.54). Based on these findings, when compared with aspirin alone, DAPT with clopidogrel prescribed at discharge was not associated with a significant reduction of adverse cardiac and cerebrovascular events at 1 year following CABG.


Corticosteroid treatment in COVID-19 modulates host inflammatory responses and transcriptional signatures of immune dysregulation.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease-2019 (COVID-19), a respiratory disease that varies in severity from mild to severe/fatal. Several risk factors for severe disease have been identified, notably age, male sex, and pre-existing conditions such as diabetes, obesity, and hypertension. Several advancements in clinical care have been achieved over the past year, including the use of corticosteroids (e.g., corticosteroids) and other immune-modulatory treatments that have now become standard of care for patients with acute severe COVID-19. While the understanding of the mechanisms that underlie increased disease severity with age has improved over the past few months, it remains incomplete. Furthermore, the molecular impact of corticosteroid treatment on host response to acute SARS-CoV-2 infection has not been investigated. In this study, a cross-sectional and longitudinal analysis of Ab, soluble immune mediators, and transcriptional responses in young (65 ≤ years) and aged (≥ 65 years) diabetic males with obesity hospitalized with acute severe COVID-19 was conducted. Additionally, the transcriptional profiles in samples obtained before and after corticosteroids became standard of care were compared. The analysis indicates that severe COVID-19 is characterized by robust Ab responses, heightened systemic inflammation, increased expression of genes related to inflammatory and pro-apoptotic processes, and reduced expression of those important for adaptive immunity regardless of age. In contrast, COVID-19 patients receiving steroids did not show high levels of systemic immune mediators and lacked transcriptional indicators of heightened inflammatory and apoptotic responses. Overall, these data suggest that inflammation and cell death are key drivers of severe COVID-19 pathogenesis in the absence of corticosteroid therapy.


Development and psychometric evaluation of the knowledge scale for adults with congenitally malformed hearts.
Adults with congenitally malformed hearts have knowledge gaps regarding their heart condition, and their level of knowledge is not routinely assessed during follow-up. One reason for this is that there are few validated, user-friendly questionnaires to assess knowledge about congenital heart disease and its effects on daily life. Failure to identify low levels of knowledge could lead to less motivated and insecure individuals not actively involved in treatment and care of their heart condition. Therefore, the objective of this study was to develop and test a knowledge scale for adults with congenitally malformed hearts. The development and psychometric evaluation of the Knowledge Scale for Adults With Congenitally Malformed Hearts (KnoCoMH) followed 2 phases: (1) development and evaluation of the initial version, with face validity and content validity assessed by experts and adults with congenitally malformed hearts, and (2) evaluation and refinement of the KnoCoMH in adults with congenitally malformed hearts, including item difficulty level, internal consistency, and test-retest reliability. The development and evaluation of a knowledge scale for adults with congenitally malformed hearts resulted in the KnoCoMH including 46 items in 4 domains: General Knowledge, with a Kuder-Richardson formula 20 (KR-20) value of 0.68; Medical Treatment, with a KR-20 value of 0.74; Endocarditis Prophylaxis, with a KR-20 value of 0.90; and Contraceptives and Pregnancy, with a KR-20 value of 0.65. Test-retest evaluation showed significant correlations between 0.50 and 0.67 (P < .01) in all 4 domains. There was good variation in item difficulty, with a mean value of 0.56 in General Knowledge, 0.62 in Medical Treatment, 0.33 in Endocarditis Prophylaxis, and 0.48 in Contraceptives and Pregnancy. The KnoCoMH has acceptable psychometric properties for most of the knowledge domains included. It can be used for evaluating knowledge among adults with congenitally malformed hearts and its associations with other outcomes. However, further studies are advisable to test construct validity, predictive validity, and responsiveness.


Intravenous rehydration for gastroenteritis: how long does it really take?
For treatment of mild to moderate dehydration arising from viral gastroenteritis, the American Academy of Pediatrics recommends oral rehydration therapy over a 4-hour period. However, oral rehydration therapy remains largely underused by emergency physicians. Studies suggest that a major barrier is a perception that the time requirement for oral rehydration therapy is too long relative to intravenous (IV) hydration. : To test the hypothesis that children who receive IV hydration for gastroenteritis spend significantly less than 4 hours in the emergency department (ED). A prospective case series involving a consecutive sample of 549 children treated with IV hydration for mild to moderate dehydration at an urban pediatric ED. Treatment time was defined as period elapsed between when a physician placed a patient in an ED room and when he/she discharged the patient. We excluded time spent in the waiting room before seeing a physician. Using a standardized procedure, we collected data in September/October 2000 (fall), November 2000 to January 2001 (winter), and April/May 2001 (spring). To provide a measure of average pass-through time at this ED, we also collected data on all patients treated during consecutive 7-day periods in the fall (n = 502), winter (n = 776), and spring (n = 653). We performed univariate analysis of continuous variables using t tests for independent samples. 549 subjects received IV treatment for dehydration; of whom 55% were female, and mean age was 9.7 years. Treatment time for patients undergoing IV hydration exceeded 4 hours (mean = 5.4 +/- 2.4 hours; median = 5.0 hours). Mean time for IV treatment of dehydration was significantly longer than the mean time for treating other patients (5.4 vs. 1.2 hours, P < 0.001). Mean IV treatment times were: fall (5.1 hours), winter (5.5 hours), and spring (4.7 hours). Mean treatment time exceeded 4 hours regardless of time of day, day of the week, or age of child. Contrary to our hypothesis, mean treatment time for IV therapy for mild to moderate dehydration exceeded the 4-hour period recommended by the American Academy of Pediatrics for oral rehydration. The data did not support the perception by emergency physicians that children treated with IV hydration spend significantly less time than 4 hours in the ED. These findings have implications for addressing one of the major barriers to the use of oral rehydration therapy in the ED setting.


Microfluidic Dynamic Interfacial Tensiometry (μDIT).
We designed, developed and characterized a microfluidic method for the measurement of surfactant adsorption kinetics via interfacial tensiometry on a microfluidic chip. The principle of the measurement is based on the deformability of droplets as a response to hydrodynamic forcing through a series of microfluidic expansions. We focus our analysis on one perfluoro surfactant molecule of practical interest for droplet-based microfluidic applications. We show that although the adsorption kinetics is much faster than the kinetics of the corresponding pendant drop experiment, our droplet-based microfluidic system has a sufficient time resolution to obtain quantitative measurement at the sub-second time-scale on nanoliter droplet volumes, leading to both a gain by a factor of ∼10 in time resolution and a downscaling of the measurement volumes by a factor of ∼1000 compared to standard techniques. Our approach provides new insight into the adsorption of surfactant molecules at liquid-liquid interfaces in a confined environment, relevant to emulsification, encapsulation and foaming, and the ability to measure adsorption and desorption rate constants.


Estimating demographic parameters from large-scale population genomic data using Approximate Bayesian Computation.
The Approximate Bayesian Computation (ABC) approach has been used to infer demographic parameters for numerous species, including humans. However, most applications of ABC still use limited amounts of data, from a small number of loci, compared to the large amount of genome-wide population-genetic data which have become available in the last few years. We evaluated the performance of the ABC approach for three 'population divergence' models - similar to the 'isolation with migration' model - when the data consists of several hundred thousand SNPs typed for multiple individuals by simulating data from known demographic models. The ABC approach was used to infer demographic parameters of interest and we compared the inferred values to the true parameter values that was used to generate hypothetical "observed" data. For all three case models, the ABC approach inferred most demographic parameters quite well with narrow credible intervals, for example, population divergence times and past population sizes, but some parameters were more difficult to infer, such as population sizes at present and migration rates. We compared the ability of different summary statistics to infer demographic parameters, including haplotype and LD based statistics, and found that the accuracy of the parameter estimates can be improved by combining summary statistics that capture different parts of information in the data. Furthermore, our results suggest that poor choices of prior distributions can in some circumstances be detected using ABC. Finally, increasing the amount of data beyond some hundred loci will substantially improve the accuracy of many parameter estimates using ABC. We conclude that the ABC approach can accommodate realistic genome-wide population genetic data, which may be difficult to analyze with full likelihood approaches, and that the ABC can provide accurate and precise inference of demographic parameters from these data, suggesting that the ABC approach will be a useful tool for analyzing large genome-wide datasets.


Weathering, Drugs, and Whack-a-Mole: Fundamental and Proximate Causes of Widening Educational Inequity in U.S. Life Expectancy by Sex and Race, 1990-2015.
Discussion of growing inequity in U.S. life expectancy increasingly focuses on the popularized narrative that it is driven by a surge of "deaths of despair." Does this narrative fit the empirical evidence? Using census and Vital Statistics data, we apply life-table methods to calculate cause-specific years of life lost between ages 25 and 84 by sex and educational rank for non-Hispanic blacks and whites in 1990 and 2015. Drug overdoses do contribute importantly to widening inequity for whites, especially men, but trivially for blacks. The contribution of suicide to growing inequity is unremarkable. Cardiovascular disease, non-lung cancers, and other internal causes are key to explaining growing life expectancy inequity. Results underline the speculative nature of attempts to attribute trends in life-expectancy inequity to an epidemic of despair. They call for continued investigation of the possible weathering effects of tenacious high-effort coping with chronic stressors on the health of marginalized populations.


Reducing the burden of influenza-associated complications with antiviral therapy.
Influenza imposes an annual burden on individuals, society, and healthcare systems. This burden is increased by the development of complications that are often more severe than the primary infection. Here, we examine the main complications associated with influenza and review the effectiveness of antiviral therapy in reducing the incidence of such events. The content of this review is taken from the study of the authors' extensive collection of reference materials, examination of the bibliographical content of relevant papers, and the results of Medline searches. The most commonly encountered complications in adults are sinusitis, pharyngitis, bronchitis, and, particularly in the elderly, bacterial pneumonia. Such complications may exacerbate pulmonary complaints. Children are particularly prone to post-influenza croup and otitis media. Complications involving the central nervous system, heart, or skeletal muscle also occur in influenza patients. Influenza-associated complications impose sizeable healthcare costs in terms of outpatient contacts, hospitalizations, and antibiotic use. Vaccination is the primary prevention strategy for influenza and its complications, but has limitations. Neuraminidase inhibitors have demonstrated efficacy in reducing the incidence of influenza-associated complications in populations with different ages and risks. Influenza complications place a large burden on healthcare providers and society. Neuraminidase inhibitors can reduce the incidence of such complications, particularly in high-risk groups.


Light-switchable hemithioindigo-hemistilbene-containing peptides: ultrafast spectroscopy of the Z → E isomerization of the chromophore and the structural dynamics of the peptide moiety.
Two hemithioindigo-hemistilbene (HTI) derivatives, designed to operate as structural switches in peptides, as well as two HTI peptides are characterized by ultrafast spectroscopy in the visible and the infrared. The two HTI switches follow the reaction scheme published for other HTI compounds with a picosecond excited state reaction (τ(1) ≈ 6 ps) and isomerization from Z to E with τ(2) = 13 and 51 ps. As compared to the isolated chromophores, the isomerization reaction is slowed down in the chromopeptides to τ(2) = 24 and 69 ps. For the smaller peptide containing 6 amino acids, the structural changes of the peptide moiety observed via the IR spectrum in the amide I band follow the isomerization of the molecular switch closely. In the larger cyclic chromopeptide, containing 20 amino acids and mimicking a β-hairpin structure in the Z-form of the chromophore, the peptide moiety also changes its structure during isomerization of the chromophore. However, the IR spectrum at the end of the observation period of 3 ns deviates significantly from the stationary difference spectrum. These signatures indicate that strong additional structural changes, e.g., breaking of interchain hydrogen bonds, also occur on longer time scales.


Challenging a dogma: antimicrobial susceptibility testing breakpoints for Mycobacterium tuberculosis.
The rise in multidrug-resistant tuberculosis makes it increasingly important that antimicrobial susceptibility testing of Mycobacterium tuberculosis produce clinically meaningful and technically reproducible results. Unfortunately, this is not always the case because mycobacteriology specialists have not followed generally accepted modern principles for the establishment of susceptibility breakpoints for bacterial and fungal pathogens. These principles specifically call for a definition of the minimum inhibitory concentrations (MICs) applicable to organisms without resistance mechanisms (also known as wild-type MIC distributions), to be used in combination with data on clinical outcomes, pharmacokinetics and pharmacodynamics. In a series of papers the authors have defined tentative wild-type MIC distributions for M. tuberculosis and hope that other researchers will follow their example and provide confirmatory data. They suggest that some breakpoints are in need of revision because they either (i) bisect the wild-type distribution, which leads to poor reproducibility in antimicrobial susceptibility testing, or (ii) are substantially higher than the MICs of wild-type organisms without supporting clinical evidence, which may result in some strains being falsely reported as susceptible. The authors recommend, in short, that susceptibility breakpoints for antituberculosis agents be systematically reviewed and revised, if necessary, using the same modern tools now accepted for all other bacteria and fungi by the scientific community and by the European Medicines Agency and the European Centre for Disease Prevention and Control. For several agents this would greatly improve the accuracy and reproducibility of antimicrobial susceptibility testing of M. tuberculosis.


Functional outcome measures for NF1-associated optic pathway glioma clinical trials.
The goal of the Response Evaluation in Neurofibromatosis and Schwannomatosis Visual Outcomes Committee is to define the best functional outcome measures for future neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG) clinical trials. The committee considered the components of vision, other ophthalmologic parameters affected by OPG, potential biomarkers of visual function, and quality of life measures to arrive at consensus-based, evidence-driven recommendations for objective and measurable functional endpoints for OPG trials. Visual acuity (VA) assessments using consistent quantitative testing methods are recommended as the main functional outcome measure for NF1-OPG clinical trials. Teller acuity cards are recommended for use as the primary VA endpoint, and HOTV as a secondary endpoint once subjects are old enough to complete it. The optic disc should be assessed for pallor, as this appears to be a contributory variable that may affect the interpretation of VA change over time. Given the importance of capturing patient-reported outcomes in clinical trials, evaluating visual quality of life using the Children's Visual Function Questionnaire as a secondary endpoint is also proposed. The use of these key functional endpoints will be essential for evaluating the efficacy of future OPG clinical trials.


Knowledge of energy balance guidelines and associated clinical care practices: the U.S. National Survey of Energy Balance Related Care among Primary Care Physicians.
To assess primary care physicians' (PCPs) knowledge of energy balance related guidelines and the association with sociodemographic characteristics and clinical care practices. As part of the 2008 U.S. nationally representative National Survey of Energy Balance Related Care among Primary Care Physicians (EB-PCP), 1776 PCPs from four specialties who treated adults (n=1060) or children and adolescents (n=716) completed surveys on sociodemographic information, knowledge of energy balance guidelines, and clinical care practices. EB-PCP response rate was 64.5%. For PCPs treating children, knowledge of guidelines for healthy BMI percentile, physical activity, and fruit and vegetables intake was 36.5%, 27.0%, and 62.9%, respectively. For PCPs treating adults, knowledge of guidelines for overweight, obesity, physical activity, and fruit and vegetables intake was 81.4%, 81.3%, 70.9%, and 63.5%, respectively. Generally, younger, female physicians were more likely to exhibit correct knowledge. Knowledge of weight-related guidelines was associated with assessment of body mass index (BMI) and use of BMI-for-age growth charts. Knowledge of energy balance guidelines among PCPs treating children is low, among PCPs treating adults it appeared high for overweight and obesity-related clinical guidelines and moderate for physical activity and diet, and was mostly unrelated to clinical practices among all PCPs.


Thermal imaging diagnostics of high-current electron beams.
The thermal imaging diagnostics of measuring pulsed electron beam energy density is presented. It provides control of the electron energy spectrum and a measure of the density distribution of the electron beam cross section, the spatial distribution of electrons with energies in the selected range, and the total energy of the electron beam. The diagnostics is based on the thermal imager registration of the imaging electron beam thermal print in a material with low bulk density and low thermal conductivity. Testing of the thermal imaging diagnostics has been conducted on a pulsed electron accelerator TEU-500. The energy of the electrons was 300-500 keV, the density of the electron current was 0.1-0.4 kA/cm(2), the duration of the pulse (at half-height) was 60 ns, and the energy in the pulse was up to 100 J. To register the thermal print, a thermal imager Fluke-Ti10 was used. Testing showed that the sensitivity of a typical thermal imager provides the registration of a pulsed electron beam heat pattern within one pulse with energy density over 0.1 J/cm(2) (or with current density over 10 A/cm(2), pulse duration of 60 ns and electron energy of 400 keV) with the spatial resolution of 0.9-1 mm. In contrast to the method of using radiosensitive (dosimetric) materials, thermal imaging diagnostics does not require either expensive consumables, or plenty of processing time.


Development and validation of multivariable clinical diagnostic models to identify type 1 diabetes requiring rapid insulin therapy in adults aged 18-50 years.
To develop and validate multivariable clinical diagnostic models to assist distinguishing between type 1 and type 2 diabetes in adults aged 18-50. Multivariable logistic regression analysis was used to develop classification models integrating five pre-specified predictor variables, including clinical features (age of diagnosis, body mass index) and clinical biomarkers (GADA and Islet Antigen 2 islet autoantibodies, Type 1 Diabetes Genetic Risk Score), to identify type 1 diabetes with rapid insulin requirement using data from existing cohorts. UK cohorts recruited from primary and secondary care. 1352 (model development) and 582 (external validation) participants diagnosed with diabetes between the age of 18 and 50 years of white European origin. Type 1 diabetes was defined by rapid insulin requirement (within 3 years of diagnosis) and severe endogenous insulin deficiency (C-peptide <200 pmol/L). Type 2 diabetes was defined by either a lack of rapid insulin requirement or, where insulin treated within 3 years, retained endogenous insulin secretion (C-peptide >600 pmol/L at ≥5 years diabetes duration). Model performance was assessed using area under the receiver operating characteristic curve (ROC AUC), and internal and external validation. Type 1 diabetes was present in 13% of participants in the development cohort. All five predictor variables were discriminative and independent predictors of type 1 diabetes (p<0.001 for all) with individual ROC AUC ranging from 0.82 to 0.85. Model performance was high: ROC AUC range 0.90 (95% CI 0.88 to 0.93) (clinical features only) to 0.97 (95% CI 0.96 to 0.98) (all predictors) with low prediction error. Results were consistent in external validation (clinical features and GADA ROC AUC 0.93 (0.90 to 0.96)). Clinical diagnostic models integrating clinical features with biomarkers have high accuracy for identifying type 1 diabetes with rapid insulin requirement, and could assist clinicians and researchers in accurately identifying patients with type 1 diabetes.


Correlation of bottom-to-top surface microhardness and conversion ratios for a variety of resin composite compositions.
Knoop microhardness (KHN) and degree of conversion (DC) values were obtained from the bottom and top surfaces of 1-, 2- and 3-mm thick samples of three types of resin composite: an anterior microfill, an anterior hybrid and a posterior hybrid, all having differing filler size and loading but similar shade (A2) and basic monomeric content. Sample infrared spectra were obtained using attenuated total reflectance (ATR) in a Fourier transform infrared (FTIR) spectrometer. The samples were exposed using a 40-second exposure to a quartz-tungsten-halogen light source with an irradiance of approximately 560 mW/cm2. They were stored for 24 hours in complete darkness at 37 degrees C and 100% humidity prior to obtaining cured spectra and KHN readings. KHN andDC values were obtained from the same sample specimen made at similar surface depths, but separate groups were made for obtaining top and bottom values. Cure and hardness data were analyzed with one- and two-way ANOVAs followed by the Tukey-Kramer post-hoc test. Linear regression was also applied. Statistical testing was per. formed at a pre-set 0.05 level of significance. KHN and DC were significantly different according to composite type and depth (p=0.0001), with an interaction effect (p=0.0022). KHN, DC and corresponding bottom/top surface (B/T) ratios decreased with depth. Regression revealed a linear relationship between DC and KHN for each composite type, with no r2 less than 0.96. When B/T ratios were correlated, a B/T-KHN ratio of 0.80 corresponded to a narrow range of B/T-DC ratios (between 88 to 91%) for the three composites tested. When combining results from composite types, linear regression of B/T-DC and B/T-KHN produced a very predictable relationship (r2=0.959), for which a B/T-KHN ratio of 0.80 corresponded to a B/T-DC ratio of 0.90. As a measure of completeness of conversion, B/T-KHN was approximately 2.5 times more sensitive than the B/T-DC ratio. In summary, while KHN cannot be used to directly compare conversion of the different composites tested, the use of B/T ratios for both hardness and conversion resulted in a linear relationship independent of filler size or loading.


Proactive Sensing of Periodic and Aperiodic Auditory Patterns.
The ability to predict when something will happen facilitates sensory processing and the ensuing computations. Building on the observation that neural activity entrains to periodic stimulation, leading neurophysiological models imply that temporal predictions rely on oscillatory entrainment. Although they provide a sufficient solution to predict periodic regularities, these models are challenged by a series of findings that question their suitability to account for temporal predictions based on aperiodic regularities. Aiming for a more comprehensive model of how the brain anticipates 'when' in auditory contexts, we emphasize the capacity of motor and higher-order top-down systems to prepare sensory processing in a proactive and temporally flexible manner. Focusing on speech processing, we illustrate how this framework leads to new hypotheses.


Multiple recognition assay reveals prostasomes as promising plasma biomarkers for prostate cancer.
Prostasomes are microvesicles (mean diameter, 150 nm) that are produced and secreted by normal and malignant prostate acinar cells. It has been hypothesized that invasive growth of malignant prostate cells may cause these microvesicles, normally released into seminal fluid, to appear in interstitial space and therewith into peripheral circulation. The suitability of prostasomes as blood biomarkers in patients with prostate cancer was tested by using an expanded variant of the proximity ligation assay (PLA). We developed an extremely sensitive and specific assay (4PLA) for detection of complex target structures such as microvesicles in which the target is first captured via an immobilized antibody and subsequently detected by using four other antibodies with attached DNA strands. The requirement for coincident binding by five antibodies to generate an amplifiable reporter results in both increased specificity and sensitivity. The assay successfully detected significantly elevated levels of prostasomes in blood samples from patients with prostate cancer before radical prostatectomy, compared with controls and men with benign biopsy results. The medians for prostasome levels in blood plasma of patients with prostate cancer were 2.5 to sevenfold higher compared with control samples in two independent studies, and the assay also distinguished patients with high and medium prostatectomy Gleason scores (8/9 and 7, respectively) from those with low score (≤ 6), thus reflecting disease aggressiveness. This approach that enables detection of prostasomes in peripheral blood may be useful for early diagnosis and assessment of prognosis in organ-confined prostate cancer.


Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.
In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1-hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link between TLRs and vitamin D-mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection.


Task induced modulation of neural oscillations in electrophysiological brain networks.
In recent years, one of the most important findings in systems neuroscience has been the identification of large scale distributed brain networks. These networks support healthy brain function and are perturbed in a number of neurological disorders (e.g. schizophrenia). Their study is therefore an important and evolving focus for neuroscience research. The majority of network studies are conducted using functional magnetic resonance imaging (fMRI) which relies on changes in blood oxygenation induced by neural activity. However recently, a small number of studies have begun to elucidate the electrical origin of fMRI networks by searching for correlations between neural oscillatory signals from spatially separate brain areas in magnetoencephalography (MEG) data. Here we advance this research area. We introduce two methodological extensions to previous independent component analysis (ICA) approaches to MEG network characterisation: 1) we show how to derive pan-spectral networks that combine independent components computed within individual frequency bands. 2) We show how to measure the temporal evolution of each network with millisecond temporal resolution. We apply our approach to ~10h of MEG data recorded in 28 experimental sessions during 3 separate cognitive tasks showing that a number of networks could be identified and were robust across time, task, subject and recording session. Further, we show that neural oscillations in those networks are modulated by memory load, and task relevance. This study furthers recent findings on electrodynamic brain networks and paves the way for future clinical studies in patients in which abnormal connectivity is thought to underlie core symptoms.


Associated Microscale Spine Density and Macroscale Connectivity Disruptions in Schizophrenia.
Schizophrenia is often described as a disorder of dysconnectivity, with disruptions in neural connectivity reported on the cellular microscale as well as the global macroscale level of brain organization. How these effects on these two scales are related is poorly understood. First (part I of this study), we collated data on layer 3 pyramidal spine density of the healthy brain from the literature and cross-analyzed these data with new data on macroscale connectivity as derived from diffusion imaging. Second (part II of this study), we examined how alterations in regional spine density in schizophrenia are related to changes in white matter connectivity. Data on group differences in spine density were collated from histology reports in the literature and examined in a meta-regression analysis in context of alterations in macroscale white matter connectivity as derived from diffusion imaging data of a (separately acquired) group of 61 patients and 55 matched control subjects. Densely connected areas of the healthy human cortex were shown to overlap with areas that display high pyramidal complexity, with pyramidal neurons that are more spinous (p = .0027) compared with pyramidal neurons in areas of low macroscale connectivity. Cross-scale meta-regression analysis showed a significant association between regional variation in level of disease-related spine density reduction in schizophrenia and regional level of decrease in macroscale connectivity (two data sets examined, p = .0028 and p = .0011). Our study presents evidence that regional disruptions in microscale neuronal connectivity in schizophrenia go hand in hand with changes in macroscale brain connectivity.


Bilateral total knee replacement: staging and pulmonary embolism.
When a bilateral total knee replacement is indicated, it is not clear whether it is preferable to operate on both knees during the same hospitalization (simultaneously) or to stage the procedures in two separate hospital stays. A greater risk of pulmonary embolism after simultaneous total knee replacement has been reported by some authors, but little national data are available. We reviewed the records of 122,385 United States Medicare enrollees who had had a total knee replacement in 2000. We noted whether they had had a unilateral procedure or two procedures and, if they had had two procedures, whether both had been done during the same hospitalization or whether the operations had been performed during two separate hospital stays. Age, sex, race, residence, Medicaid eligibility (a proxy for low income), and the Charlson comorbidity score were documented for each patient as were the total numbers of total knee replacements performed in the year 2000 by the hospital and the surgeon. The probability of a symptomatic pulmonary embolism developing in the first three months after surgery was calculated for the simultaneous, staged, and unilateral procedures. Simultaneous procedures were much more likely to be performed in high-volume hospitals and by high-volume surgeons than were staged procedures. Men had proportionately more simultaneous procedures than did women. Hospitals in the northeastern United States were the most likely to perform simultaneous procedures. A pulmonary embolism developed in the first three months in 0.81% of the patients who had had a single procedure compared with 1.44% of the patients who had undergone a simultaneous procedure (adjusted hazard ratio 1.81; 95% confidence interval, 1.49, 2.20). The systematic differences in patient gender, hospital and surgeon volume, and geographic region between those who undergo simultaneous total knee replacements and those who undergo staged procedures should be borne in mind when outcomes are being compared. The adjusted risk of pulmonary embolism is about 80% higher in the three months after a simultaneous procedure than in the three months after a single procedure, which suggests that the sum of the risks associated with the two operations of a staged procedure may equal or exceed the risk of simultaneous total knee replacement.


Light-regulated translation of chloroplast proteins. I. Transcripts of psaA-psaB, psbA, and rbcL are associated with polysomes in dark-grown and illuminated barley seedlings.
We have previously observed (Klein, R. R., and J. E. Mullet, 1986, J. Biol. Chem. 261:11138-11145) that translation of two 65-70-kD chlorophyll a-apoproteins of Photosystem I (gene products of psaA and psaB) and a 32-kD quinone-binding protein of Photosystem II (gene product of psbA) was not detected in plastids of dark-grown barley seedlings even though transcripts for these proteins were present. In the present study it was found that nearly all of the psaA-psaB transcripts in plastids of dark-grown plants were associated with membrane-bound polysomes. Membrane-associated polysomes from plastids of dark-grown plants synthesized the 65-70-kD chlorophyll a-apoproteins at low levels when added to a homologous in vitro translation extract capable of translation elongation. However, when etioplast membranes were disrupted with detergent, in vitro synthesis of the 65-70-kD chlorophyll a-apoproteins increased to levels observed with polysomes of plastids from illuminated plants. These results suggest that synthesis of the chlorophyll a-apoproteins of Photosystem I is arrested on membrane-bound polysomes at the level of polypeptide chain elongation. In addition to the selective activation of chlorophyll a-apoprotein translation, illumination also caused an increase in chloroplast polysomes (membrane-associated and stromal) and induced a recruitment of psbA and rbcL transcripts into chloroplast polysomes. These results indicate that in conjunction with the selective activation of chlorophyll a-apoprotein elongation, illumination also caused a general stimulation of chloroplast translation initiation.


Differential effect of monensin on enveloped viruses that form at distinct plasma membrane domains.
We have observed a striking differential effect of the ionophore, monensin, on replication of influenza virus and vesicular stomatitis virus (VSV) in Madin-Darby canine kidney (MDCK) and baby hamster kidney (BHK21) cells. In MDCK cells, influenza virus is assembled at the apical surfaces, whereas VSV particles bud from the basolateral membranes; no such polarity of maturation is exhibited in BHK21 cells. A 10(-6) M concentration of monensin reduces VSV yields in MDCK cells by greater than 90% as compared with controls, whereas influenza virus yields are unaffected. In BHK21 cells, monensin also inhibits VSV production, but influenza virus is also sensitive to the ionophore. Immunofluorescent staining of fixed and unfixed MDCK monolayers indicates that VSV glycoproteins are synthesized in the presence of monensin, but their appearance on the plasma membrane is blocked. Electron micrographs of VSV-infected MDCK cells treated with monensin show VSV particles aggregated within dilated cytoplasmic vesicles. Monensin-treated influenza virus-infected MDCK cells also contain dilated cytoplasmic vesicles, but virus particles were not found in these structures, and numerous influenza virions were observed budding at the cell surface. These results indicate that influenza virus glycoprotein transport is not blocked by monensin treatment, whereas there is a block in transport of VSV G protein. Thus it appears that at least two distinct pathways of transport of glycoproteins to the plasma membrane exist in MDCK cells, and only one of them is blocked by monensin.


DNA condensation by protamine and arginine-rich peptides: analysis of toroid stability using single DNA molecules.
Both somatic cells and sperm have been shown to take up exogenous DNA, but the frequency of its integration is usually low. Scanning probe microscopy studies of sperm chromatin and synthetic DNA-protamine complexes indicate that the coiling of DNA into toroidal subunits, a process initiated in the maturing spermatid to prepare its genome for delivery into the egg, can be mimicked by simply adding protamine to DNA in vitro. The increased resistance of DNA-protamine complexes to nuclease digestion and their structural similarity to native sperm chromatin suggest that the packaging of DNA by protamine might offer a new approach for improving the efficiency of DNA uptake by sperm. Decondensation experiments performed with individual DNA molecules have provided a direct measure of the stability of toroids produced using salmon protamine and smaller arginine-rich peptides. These experiments show that the arginine content of protamine-related sequences can have a dramatic effect on their rate of dissociation from DNA. This technique and the information it provides can be used to identify protamine analogs that can be bound to DNA to increase the efficiency of its uptake by sperm and other cells.


Fast and Accurate Image Super-Resolution with Deep Laplacian Pyramid Networks.
Convolutional neural networks have recently demonstrated high-quality reconstruction for single image super-resolution. However, existing methods often require a large number of network parameters and entail heavy computational loads at runtime for generating high-accuracy super-resolution results. In this paper, we propose the deep Laplacian Pyramid Super-Resolution Network for fast and accurate image super-resolution. The proposed network progressively reconstructs the sub-band residuals of high-resolution images at multiple pyramid levels. In contrast to existing methods that involve the bicubic interpolation for pre-processing (which results in large feature maps), the proposed method directly extracts features from the low-resolution input space and thereby entails low computational loads. We train the proposed network with deep supervision using the robust Charbonnier loss functions and achieve high-quality image reconstruction. Furthermore, we utilize the recursive layers to share parameters across as well as within pyramid levels, and thus drastically reduce the number of parameters. Extensive quantitative and qualitative evaluations on benchmark datasets show that the proposed algorithm performs favorably against the state-of-the-art methods in terms of run-time and image quality.


Norepinephrine activates dopamine D4 receptors in the rat lateral habenula.
The lateral habenula (LHb) is involved in reward and aversion and is reciprocally connected with dopamine (DA)-containing brain regions, including the ventral tegmental area (VTA). We used a multidisciplinary approach to examine the properties of DA afferents to the LHb in the rat. We find that >90% of VTA tyrosine hydroxylase (TH) neurons projecting to the LHb lack vesicular monoamine transporter 2 (VMAT2) mRNA, and there is little coexpression of TH and VMAT2 protein in this mesohabenular pathway. Consistent with this, electrical stimulation of LHb did not evoke DA-like signals, assessed with fast-scan cyclic voltammetry. However, electrophysiological currents that were inhibited by L741,742, a DA-D4-receptor antagonist, were observed in LHb neurons when DA uptake or degradation was blocked. To prevent DA activation of D4 receptors, we repeated this experiment in LHb slices from DA-depleted rats. However, this did not disrupt D4 receptor activation initiated by the dopamine transporter inhibitor, GBR12935. As the LHb is also targeted by noradrenergic afferents, we examined whether GBR12935 activation of DA-D4 receptors occurred in slices depleted of norepinephrine (NE). Unlike DA, NE depletion prevented the activation of DA-D4 receptors. Moreover, direct application of NE elicited currents in LHb neurons that were blocked by L741,742, and GBR12935 was found to be a more effective blocker of NE uptake than the NE-selective transport inhibitor nisoxetine. These findings demonstrate that NE is released in the rat LHb under basal conditions and that it activates DA-D4 receptors. Therefore, NE may be an important regulator of LHb function.


GPI anchoring facilitates propagation and spread of misfolded Sup35 aggregates in mammalian cells.
Prion diseases differ from other amyloid-associated protein misfolding diseases (e.g. Alzheimer's) because they are naturally transmitted between individuals and involve spread of protein aggregation between tissues. Factors underlying these features of prion diseases are poorly understood. Of all protein misfolding disorders, only prion diseases involve the misfolding of a glycosylphosphatidylinositol (GPI)-anchored protein. To test whether GPI anchoring can modulate the propagation and spread of protein aggregates, a GPI-anchored version of the amyloidogenic yeast protein Sup35NM (Sup35GPI) was expressed in neuronal cells. Treatment of cells with Sup35NM fibrils induced the GPI anchor-dependent formation of self-propagating, detergent-insoluble, protease-resistant, prion-like aggregates of Sup35GPI. Live-cell imaging showed intercellular spread of Sup35GPI aggregation to involve contact between aggregate-positive and aggregate-negative cells and transfer of Sup35GPI from aggregate-positive cells. These data demonstrate GPI anchoring facilitates the propagation and spread of protein aggregation and thus may enhance the transmissibility and pathogenesis of prion diseases relative to other protein misfolding diseases.


Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer.
Nuclear Factor kappa B (NF-κB) is a key mediator of normal immune response but contributes to aggressive cancer cell phenotypes when aberrantly activated. Here we present evidence that the Inhibitor of Growth 4 (ING4) tumor suppressor negatively regulates NF-κB in breast cancer. We surveyed primary breast tumor samples for ING4 protein expression using tissue microarrays and a newly generated antibody. We found that 34% of tumors expressed undetectable to low levels of the ING4 protein (n = 227). Tumors with low ING4 expression were frequently large in size, high grade, and lymph node positive, suggesting that down-regulation of ING4 may contribute to breast cancer progression. In the same tumor set, we found that low ING4 expression correlated with high levels of nuclear phosphorylated p65/RelA (p-p65), an activated form of NF-κB (p = 0.018). Fifty seven percent of ING4-low/p-p65-high tumors were lymph node-positive, indicating a high metastatic tendency of these tumors. Conversely, ectopic expression of ING4 inhibited p65/RelA phosphorylation in T47D and MCF7 breast cancer cells. In addition, ING4 suppressed PMA-induced cell invasion and NF-κB-target gene expression in T47D cells, indicating that ING4 inhibited NF-κB activity in breast cancer cells. Supportive of the ING4 function in the regulation of NF-κB-target gene expression, we found that ING4 expression levels inversely correlated with the expression of NF-κB-target genes in primary breast tumors by analyzing public gene expression datasets. Moreover, low ING4 expression or high expression of the gene signature composed of a subset of ING4-repressed NF-κB-target genes was associated with reduced disease-free survival in breast cancer patients. Taken together, we conclude that ING4 negatively regulates NF-κB in breast cancer. Consequently, down-regulation of ING4 leads to activation of NF-κB, contributing to tumor progression and reduced disease-free patient survival in breast cancer.


The AUA/SUFU Guideline on Adult Neurogenic Lower Urinary Tract Dysfunction: Treatment and Follow-up.
The clinician treating patients with neurogenic lower urinary tract dysfunction (NLUTD) needs to balance a variety of factors when making treatment decisions. In addition to the patient's urologic symptoms and urodynamic findings, other issues that may influence management options of the lower urinary tract include cognition, hand function, type of neurologic disease, mobility, bowel function/management, and social and caregiver support. This Guideline allows the clinician to understand the options available to treat patients, understand the findings that can be seen in NLUTD, and appreciate which options are best for each individual patient. This allows for decisions to be made with the patient, in a shared decision-making manner, such that the patient's quality of life can be optimized with respect to their bladder management. A comprehensive search for studies assessing patients undergoing evaluation, surveillance, management, or follow-up for NLUTD was conducted from January 2001 through October 2017 and was rerun in February 2021 to capture newer literature. The primary search returned 20,496 unique citations. Following a title and abstract screen, full texts were obtained for 3,036 studies. During full-text review, studies were primarily excluded for not meeting the PICO criteria. One hundred eight-four primary literature studies met the inclusion criteria and were included in the evidence base. This guideline was developed to inform clinicians on the proper evaluation, diagnosis, and risk stratification of adult patients with NLUTD and the non-surgical and surgical treatment options available. Additional statements on urinary tract infection and autonomic dysreflexia were developed to guide the clinician. NLUTD patients may undergo non-surgical and surgical treatment options depending on their level of risk, symptoms, and urodynamic findings. Appropriate follow-up, primarily based on their risk stratification, must be maintained after treatment.


The Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES) project--design, population and data harmonization of a large-scale, international study.
There is a public health demand to prevent health conditions which lead to increased morbidity and mortality among the rapidly-increasing elderly population. Data for the incidence of such conditions exist in cohort studies worldwide, which, however, differ in various aspects. The Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES) project aims at harmonizing data from existing major longitudinal studies for the elderly whilst focussing on cardiovascular diseases, diabetes mellitus, cancer, fractures and cognitive impairment in order to estimate their prevalence, incidence and cause-specific mortality, and identify lifestyle, socioeconomic, and genetic determinants and biomarkers for the incidence of and mortality from these conditions. A survey instrument assessing ageing-related conditions of the elderly will be also developed. Fourteen cohort studies participate in CHANCES with 683,228 elderly (and 150,210 deaths), from 23 European and three non-European countries. So far, 287 variables on health conditions and a variety of exposures, including biomarkers and genetic data have been harmonized. Different research hypotheses are investigated with meta-analyses. The results which will be produced can help international organizations, governments and policy-makers to better understand the broader implications and consequences of ageing and thus make informed decisions.


Experimental study on modified linear quadratic Gaussian control for adaptive optics.
To achieve high-resolution imaging the standard control algorithm used for classical adaptive optics (AO) is the simple but efficient proportional-integral (PI) controller. The goal is to minimize the rms error of the residual wave front. However, using the PI controller, it is not possible to do this. One possible way to minimize the rms error is to use linear quadratic Gaussian (LQG) control. In practice, however, this control algorithm still encounters an unexpected problem that leads to the divergence of control in AO. This paper proposes a modified LQG (MLQG) to solve this issue. The controller is analyzed explicitly. Laboratory tests shows strong stability and high precision compared to the classical control.


Long-term test-retest reliability of baseline cognitive assessments using ImPACT.
Computer-based assessment programs are commonly used to document baseline cognitive performance for comparison with postconcussion testing. There are currently no guidelines for how often baseline assessments should be updated, and no data documenting the test-retest stability of baseline measures over relevant time periods. To establish long-term test-retest reliability of baseline assessments using ImPACT, and to compare various statistical methods for establishing test-retest reliability. Case series; Level of evidence, 4. Participants were 95 collegiate varsity athletes completing baseline cognitive testing at 2 time periods, approximately 2 years apart. No participant sustained a concussion between assessments. All athletes completed the ImPACT test battery; dependent measures were the composite scores and total symptom scale score. Intraclass correlation coefficient estimates for visual memory (.65), processing speed (.74), and reaction time (.68) composite scores reflected stability over the 2-year period, with greater variability in verbal memory (.46) and symptom scale (.43) scores. Using reliable change indices and regression-based methods, only a small percentage of participants' scores showed "reliable" or "significant" change on the composite scores (0%-6%), or symptom scale scores (5%-10%). The current results suggest that college athletes' cognitive performance at baseline remains considerably stable over a 2-year period. These data help establish the effects of longer, clinically pragmatic testing intervals on test-retest reliability. The current results suggest that stretching the time between baseline assessments from 1 to 2 years may have little effect on the clinical management of concussions in collegiate athletes. These results should not be generalized to collegiate football players, who were not included in this sample. Youth athletes (high school and younger) should continue to receive annually updated baseline assessments until prospective study of the stability of baseline assessments for this younger age group can be completed.


Botulinum toxin type A for facial wrinkles.
Botulinum toxin type A (BontA) is the most frequent treatment for facial wrinkles, but its effectiveness and safety have not previously been assessed in a Cochrane Review. To assess the effects of all commercially available botulinum toxin type A products for the treatment of any type of facial wrinkles. We searched the following databases up to May 2020: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers, and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). We included RCTs with over 50 participants, comparing BontA versus placebo, other types of BontA, or fillers (hyaluronic acid), for treating facial wrinkles in adults. We used standard methodological procedures expected by Cochrane. Primary outcomes were participant assessment of success and major adverse events (AEs) (eyelid ptosis, eyelid sensory disorder, strabismus). Secondary outcomes included physician assessment of success; proportion of participants with at least one AE and duration of treatment effect. We used GRADE to assess the certainty of the evidence for each outcome. We included 65 RCTs, involving 14,919 randomised participants. Most participants were female, aged 18 to 65 years. All participants were outpatients (private office or day clinic). Study duration was between one week and one year. No studies were assessed as low risk of bias in all domains; the overall risk of bias was unclear for most studies. The most common comparator was placebo (36 studies). An active control was used in 19 studies. There were eight dose-ranging studies of onabotulinumtoxinA, and a small number of studies compared against fillers. Treatment was given in one cycle (54 studies), two cycles (three studies), or three or more cycles (eight studies). The treated regions were glabella (43 studies), crow's feet (seven studies), forehead (two studies), perioral (two studies), full face (one study), or more than two regions (nine studies). Most studies analysed moderate to severe wrinkles; mean duration of treatment was 20 weeks. The following results summarise the main comparisons, based on studies of one treatment cycle for the glabella. AEs were collected over the duration of these studies (over four to 24 weeks). Compared to placebo, onabotulinumtoxinA-20 U probably has a higher success rate when assessed by participants (risk ratio (RR) 19.45, 95% confidence interval (CI) 8.60 to 43.99; 575 participants; 4 studies; moderate-certainty evidence) or physicians (RR 17.10, 95% CI 10.07 to 29.05; 1339 participants; 7 studies; moderate-certainty evidence) at week four. Major AEs are probably higher with onabotulinumtoxinA-20 U (Peto OR 3.62, 95% CI 1.50 to 8.74; 1390 participants; 8 studies; moderate-certainty evidence), but there may be no difference in any AEs (RR 1.14, 95% CI 0.89 to 1.45; 1388 participants; 8 studies; low-certainty evidence). Compared to placebo, abobotulinumtoxinA-50 U has a higher participant-assessed success rate at week four (RR 21.22, 95% CI 7.40 to 60.56; 915 participants; 6 studies; high-certainty evidence); and probably has a higher physician-assessed success rate (RR 14.93, 95% CI 8.09 to 27.55; 1059 participants; 7 studies; moderate-certainty evidence). There are probably more major AEs with abobotulinumtoxinA-50 U (Peto OR 3.36, 95% CI 0.88 to 12.87; 1294 participants; 7 studies; moderate-certainty evidence). Any AE may be more common with abobotulinumtoxinA-50 U (RR 1.25, 95% CI 1.05 to 1.49; 1471 participants; 8 studies; low-certainty evidence). Compared to placebo, incobotulinumtoxinA-20 U probably has a higher participant-assessed success rate at week four (RR 66.57, 95% CI 13.50 to 328.28; 547 participants; 2 studies; moderate-certainty evidence), and physician-assessed success rate (RR 134.62, 95% CI 19.05 to 951.45; 547 participants; 2 studies; moderate-certainty evidence). Major AEs were not observed (547 participants; 2 studies; moderate-certainty evidence). There may be no difference between groups in any AEs (RR 1.17, 95% CI 0.90 to 1.53; 547 participants; 2 studies; low-certainty evidence). AbobotulinumtoxinA-50 U is no different to onabotulinumtoxinA-20 U in participant-assessed success rate (RR 1.00, 95% CI 0.92 to 1.08, 388 participants, 1 study, high-certainty evidence) and physician-assessed success rate (RR 1.01, 95% CI 0.95 to 1.06; 388 participants; 1 study; high-certainty evidence) at week four. Major AEs are probably more likely in the abobotulinumtoxinA-50 U group than the onabotulinumtoxinA-20 U group (Peto OR 2.65, 95% CI 0.77 to 9.09; 433 participants; 1 study; moderate-certainty evidence). There is probably no difference in any AE (RR 1.02, 95% CI 0.67 to 1.54; 492 participants; 2 studies; moderate-certainty evidence). IncobotulinumtoxinA-24 U may be no different to onabotulinumtoxinA-24 U in physician-assessed success rate at week four (RR 1.01, 95% CI 0.96 to 1.05; 381 participants; 1 study; low-certainty evidence) (participant assessment was not measured). One participant reported ptosis with onabotulinumtoxinA, but we are uncertain of the risk of AEs (Peto OR 0.02, 95% CI 0.00 to 1.77; 381 participants; 1 study; very low-certainty evidence). Compared to placebo, daxibotulinumtoxinA-40 U probably has a higher participant-assessed success rate (RR 21.10, 95% CI 11.31 to 39.34; 683 participants; 2 studies; moderate-certainty evidence) and physician-assessed success rate (RR 23.40, 95% CI 12.56 to 43.61; 683 participants; 2 studies; moderate-certainty evidence) at week four. Major AEs were not observed (716 participants; 2 studies; moderate-certainty evidence). There may be an increase in any AE with daxibotulinumtoxinA compared to placebo (RR 2.23, 95% CI 1.46 to 3.40; 716 participants; 2 studies; moderate-certainty evidence). Major AEs reported were mainly ptosis; BontA is also known to carry a risk of strabismus or eyelid sensory disorders. BontA treatment reduces wrinkles within four weeks of treatment, but probably increases risk of ptosis. We found several heterogeneous studies (different types or doses of BontA, number of cycles, and different facial regions) hindering meta-analyses. The certainty of the evidence for effectiveness outcomes was high, low or moderate; for AEs, very low to moderate. Future RCTs should compare the most common BontA (onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, daxibotulinumtoxinA, prabotulinumtoxinA) and evaluate long-term outcomes. There is a lack of evidence about the effects of multiple cycles of BontA, frequency of major AEs, duration of effect, efficacy of recently-approved BontA and comparisons with other treatments.


Apolipoprotein E polymorphism is associated with lower extremity deep venous thrombosis: color-flow Doppler ultrasound evaluation.
Apolipoprotein E (apoE) is a member of apolipoprotein family, and its gene polymorphisms seem to have some impact among patients with cardiovascular disease. However, its role in the lower extremity deep venous thrombosis (LEDVT) has not been well studied. The objective of this study was to investigate the potential association between APOE gene polymorphisms and LEDVT. A hospital-based case-control study was conducted in 300 patients with LEDVT by color-flow Doppler ultrasound and 300 age- and gender-matched healthy controls. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay was applied to assess the APOE gene polymorphisms. Patients with LEDVT had a significantly higher frequency of APOE E3/E4 genotype [odds ratio (OR) =1.48, 95% confidence interval (CI) = 1.05, 2.10; P = 0.03] than healthy controls. When stratifying by family history of LEDVT, it was found that patients with positive family history of LEDVT had a significantly higher frequency of APOE E3/E4 genotype (OR =1.68, 95% CI = 1.04, 0.95; P = 2.70). When stratifying by smoking status, presence of varicose veins, type 2 diabetes mellitus and any hormone administration before, no significant differences were found in any groups. Our study suggested that APOE E3/E4 genotype was associated with a higher LEDVT risk. Additional studies are needed to confirm this finding.


Unusual T cell populations in adult murine bone marrow. Prevalence of CD3+CD4-CD8- and alpha beta TCR+NK1.1+ cells.
The T cell populations present in normal murine bone marrow have not been previously analyzed in detail, mainly because of their relative rarity. In order to permit such analyses, bone marrow T cells were enriched by depleting Mac1-positive cells, which constitute 65 to 90% of bone marrow cells (BMC), and then studied by two-color flow cytometry. Analysis of the remaining cells revealed that the T cell profile of adult murine bone marrow is markedly different from that of other lymphoid organs. A very high proportion of bone marrow CD3+ cells (approximately one-third) are CD4-CD8-. CD3+CD4-CD8- cells are much more concentrated among BMC T cells than among thymocytes or splenic T cells, suggesting that bone marrow may be either a site of extrathymic TCR gene rearrangement, or a major site to which such cells home from the thymus. The expression of NK1.1 was also evaluated on Mac1-depleted BMC populations. Surprisingly, up to 39% of alpha beta TCR+ BMC were found to express NK1.1. Most alpha beta TCR+NK1.1+ BMC also expressed CD4 or CD8. NK1.1+ alpha beta TCR+ cells represented a much greater proportion of BMC T cells than of other lymphoid (splenocyte or thymocyte) T cell populations. Mac1-depleted BMC of nude mice contained very few cells with this phenotype. These results are consistent with the hypothesis that NK1.1+ alpha beta TCR+ cells are generated primarily in the thymus of normal animals and migrate preferentially to bone marrow, where they may function as regulatory elements in hematopoiesis.


Sequence analysis of a 13.4 kbp fragment from the left arm of chromosome XV reveals a malate dehydrogenase gene, a putative Ser/Thr protein kinase, the ribosomal L25 gene and four new open reading frames.
A 13421 bp fragment located near the left telomere of chromosome XV (cosmid pEOA461) has been sequenced. Seven non-overlapping open reading frames (ORFs) encoding polypeptides longer than 100 residues have been found (AOB859, AOC184, AOE375, AOX142i, AOE423, AOA476 and AOE433). An additional ORF (AOE131) is found within AOA476. Three of them (AOC184, AOA476 and AOE433) show no remarkable identity with proteins deposited in the data banks. ORF AOB859 is quite similar to a hypothetical yeast protein of similar size located in chromosome VI, particularly within the C-terminal half. AOE375 encodes a new member of the glycogen synthase kinase-3 subfamily of Ser/Thr protein kinases. AOX142i is the gene encoding the previously described ribosomal protein L25. AOE423 codes for a protein virtually identical to the MDH2 malate dehydrogenase isozyme. However, our DNA sequence shows a single one-base insertion upstream of the reported initiating codon. This would produce a larger ORF by extending 46 residues the N-terminus of the protein. The existence of this insertion has been confirmed in three different yeast strains, including FY1679.


Mutations in the Sec61p channel affecting signal sequence recognition and membrane protein topology.
The orientation of most single-spanning membrane proteins obeys the "positive-inside rule", i.e. the flanking region of the transmembrane segment that is more positively charged remains in the cytosol. These membrane proteins are integrated by the Sec61/SecY translocon, but how their orientation is achieved is unknown. We have screened for mutations in yeast Sec61p that alter the orientation of single-spanning membrane proteins. We identified a class of mutants that are less efficient in retaining the positively charged flanking region in the cytosol. Surprisingly, these mutations are located at many different sites in the Sec61/SecY molecule, and they do not only involve charged amino acid residues. All these mutants have a prl phenotype that so far have only been seen in bacteria; they allow proteins with defective signal sequences to be translocated, likely because the Sec61p channel opens more easily. A similar correlation between topology defects and prl phenotype was also seen with previously identified yeast Sec61 mutants. Our results suggest a model in which the regulated opening of the translocon is required for the faithful orientation of membrane proteins.


Destabilization of the gut microbiome marks the end-stage of simian immunodeficiency virus infection in wild chimpanzees.
Enteric dysbiosis is a characteristic feature of progressive human immunodeficiency virus type 1 (HIV-1) infection but has not been observed in simian immunodeficiency virus (SIVmac)-infected macaques, including in animals with end-stage disease. This has raised questions concerning the mechanisms underlying the HIV-1 associated enteropathy, with factors other than virus infection, such as lifestyle and antibiotic use, implicated as playing possible causal roles. Simian immunodeficiency virus of chimpanzees (SIVcpz) is also associated with increased mortality in wild-living communities, and like HIV-1 and SIVmac, can cause CD4+ T cell depletion and immunodeficiency in infected individuals. Given the central role of the intestinal microbiome in mammalian health, we asked whether gut microbial constituents could be identified that are indicative of SIVcpz status and/or disease progression. Here, we characterized the gut microbiome of SIVcpz-infected and -uninfected chimpanzees in Gombe National Park, Tanzania. Subjecting a small number of fecal samples (N = 9) to metagenomic (shotgun) sequencing, we found bacteria of the family Prevotellaceae to be enriched in SIVcpz-infected chimpanzees. However, 16S rRNA gene sequencing of a larger number of samples (N = 123) failed to show significant differences in both the composition and diversity (alpha and beta) of gut bacterial communities between infected (N = 24) and uninfected (N = 26) chimpanzees. Similarly, chimpanzee stool-associated circular virus (Chi-SCV) and chimpanzee adenovirus (ChAdV) identified by metagenomic sequencing were neither more prevalent nor more abundant in SIVcpz-infected individuals. However, fecal samples collected from SIVcpz-infected chimpanzees within 5 months before their AIDS-related death exhibited significant compositional changes in their gut bacteriome. These data indicate that SIVcpz-infected chimpanzees retain a stable gut microbiome throughout much of their natural infection course, with a significant destabilization of bacterial (but not viral) communities observed only in individuals with known immunodeficiency within the last several months before their death. Am. J. Primatol. 80:e22515, 2018. © 2015 Wiley Periodicals, Inc.